A Double-Blinded, Randomized, Controlled Study to Compare the Efficacy, Time to Onset, and Duration of Effect of Botulinum Type A Toxins in the Treatment of Glabellar Frown Lines
Phase: PHASE2
Conditions: Frown Lines
Sponsor: Croma-Pharma GmbH

 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Double-Blinded Randomized Controlled Study to Compare the 
Efficacy, Time to Onset, and Duration of Effect of 
Botulinum Type A Toxins in the Treatment of  
Glabellar Frown Lines 
 
 
Protocol Identifier: Study CPH-201-201461 
 
Other Identifiers 
EudraCT Number: 2019-003481-41 
IND Number: 123178 
 
 
 
Head 2 Head BLESS 
 
 
 
Version Date: 27 August 2019 
Version Status: 1.0 
 
 
 
 
 
 
 
 
Study Sponsor:  
 
 
 
 
Croma-Pharma GmbH 
 
 
Industriezeile 6 
 
 
A-2100 Leobendorf 
 
 
 
 
Austria 
 
CONFIDENTIAL 
The information contained herein is the property of Croma-Pharma GmbH and may not be produced, 
published, or disclosed to others without written authorization of Croma-Pharma GmbH. No information 
contained herein shall be published or disclosed without prior written approval of Croma-Pharma GmbH, 
except that this document may be disclosed to the appropriate Institutional Review Board or  
Independent Ethics Committee under the condition that it is kept confidential. 
 
 

 
 
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A Double-Blinded Randomized Controlled Study to Compare the Efficacy, Time 
to Onset, and Duration of Effect of Botulinum Type A Toxins in the Treatment of 
Glabellar Frown Lines 
1. 
SPONSOR RELATED CONTACT DETAILS 
Sponsor: 
Croma-Pharma GmbH 
 
 
Industriezeile 6 
 
 
AT-2100, Leobendorf, Austria 
 
Sponsor’s Project Manager: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Sponsor’s Medical Experts: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Responsibilities for study organization, study monitoring, statistical analysis and 
photographic procedures are listed in Section 17.7. A list of investigators and 
investigation sites will be kept in the Trial Master File. 

 
 
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3. 
INVESTIGATOR ACKNOWLEDGEMENT 
PRODUCT: BoNT/A-DP 
STUDY TITLE: A Double-Blinded Randomized Controlled Study to Compare the 
Efficacy, Time to Onset, and Duration of Effect of Botulinum Type A Toxins in the 
Treatment of Glabellar Frown Lines 
PROTOCOL IDENTIFIER: CPH-201-201461 
IND NUMBER: 123178; EudraCT Number: 2019-003481-41 
I have read and understand this protocol, and will comply with the requirements for 
obtaining informed consent from all study subjects prior to initiating any 
protocol-specific procedures, understand and abide by the requirements for 
maintenance of source documentation, and provide assurance that this study will be 
conducted according to all requirements as defined in this protocol; clinical study 
agreement; Code of Federal Regulation (Title 21, CFR Part 312); and all applicable 
regulatory requirements. 
I also agree that persons debarred from conducting or working on clinical studies by 
any court or regulatory agency will not be allowed to conduct or work on this study. I 
will immediately disclose it in writing to the Sponsor if any person who is involved in 
the study is debarred, or if any proceeding for debarment is pending, or, to the best of 
my knowledge, threatened. 
This document contains confidential information of the Sponsor, which must not be 
disclosed to anyone other than the recipient study staff and members of the Institutional 
Review Board/Independent Ethics Committee. I agree to ensure that this information 
will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the Sponsor. 
 
Signature of Principal Investigator  
 
 
 
 
Date 
 
Print Name of Principal Investigator 
 
Site name and address 
 
 
 

 
 
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4. 
SYNOPSIS 
INVESTIGATIONAL MEDICINAL PRODUCT 
Name of 
Investigational 
Medicinal Products 
(IMPs)  
BoNT/A-DP  
 
 
Name of Active 
Ingredient 
Botulinum toxin A 
CLINICAL CONDITION/INDICATION 
Treatment of moderate to severe glabellar frown lines  
PROTOCOL 
IDENTIFIER 
Study CPH-201-201461 
PROTOCOL TITLE 
A Double-Blinded Randomized Controlled Study to Compare the Efficacy, 
Time to Onset, and Duration of Effect of Botulinum Type A Toxins in the 
Treatment of Glabellar Frown Lines 
Short title 
Head 2 Head BLESS (H2H) 
STUDY PHASE 
Phase 2 
PLANNED STUDY PERIOD 
Initiation 
First subject is planned for Q4 2019  
Primary Completion 
Anticipated October 2020 
Study Completion 
Final Clinical Study Report anticipated January 2021 
Duration 
Up to 18 weeks per subject. Total study duration (first subject first visit to 
last subject last visit) up to 30 weeks. 
End of Study 
A subject is considered to have completed the study if they have completed 
the End of Study Visit. 
The end of the study is defined as the date of last subject last visit. 
STUDY OBJECTIVES AND PURPOSE 
Study purpose 
To provide preliminary comparative efficacy and safety data of 
BoNT/A-DP versus 
 
Primary Objective 
To assess the efficacy of treatment with BoNT/A-DP as defined by the 
percentage of responders at Week 4 (Facial Wrinkle Scale [FWS] score of 
0 or 1 and a ≥ 1 point reduction in FWS score) in reducing the severity of 
glabellar frown lines at maximum frown (the worst appearance of upper 
facial lines with maximum load on the muscle; eyebrows pushed together 
as far as they can go) compared to treatment with 
 based 
on independent investigator assessment and subject assessment.  

 
 
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Secondary Objectives 
1. To assess the percentage of responders (FWS score of 0 or 1 and a 
≥ 1 point reduction in FWS score at maximum frown) after a single 
treatment with BoNT/A-DP compared to a single treatment of
 
 at Weeks 1, 2, 8, 12 and 16, based on investigator and subject 
assessments.  
2. To assess the percentage of responders (FWS score of 0 or 1 and a 
≥ 2 point reduction in FWS score at maximum frown) after a single 
treatment with BoNT/A-DP compared to a single treatment of 
 
 at Weeks 1, 2, 4, 8, 12 and 16, based on independent 
investigator and subject assessments. 
3. To assess the percentage of responders (FWS score of 0 or 1 and a 
≥ 1 point reduction in FWS score at rest) after a single treatment with 
BoNT/A-DP compared to a single treatment of 
 at 
Weeks 1, 2, 4, 8, 12 and 16, based on independent investigator and 
subject assessments. 
4. To assess time to onset of effect after a single treatment with 
BoNT/-DP compared to a single treatment of 
 as 
measured at Weeks 1, 2, and 4, based on independent investigator and 
subject assessments. 
5. To assess the duration of effect in subjects who respond after a single 
treatment with BoNT/A-DP or a single treatment of 
 
based on independent investigator and subject assessments. 
6. To assess treatment satisfaction at Weeks 4, 12, and 16 using FACE-Q 
Satisfaction with Outcome Scale. 
7. To determine the safety and presence of any adverse effects of a single 
treatment of BoNT/A-DP compared to a single treatment of 
 
 in the treatment of glabellar lines. 
STUDY DESIGN 
Study Type/ 
Classification/ 
Discipline 
Efficacy and safety 
Control Type 
Concurrent  
Study Indication Type 
Treatment 
Intervention model 
Parallel design 
Blinding/Masking 
Double-blind  
Study Design 
The study is a parallel group, randomized, double-blind, active-controlled 
study. The study will comprise 200 subjects randomized 1:1 to one of two 
treatment groups as follows:  
• 
Group A: 100 subjects treated with BoNT/A-DP (20 units [U], 
0.5 mL) 
• 
Group B: 100 subjects treated with 
 (20 U, 
0.5 mL) 
After a Screening period of 0 to 14 calendar days, eligible subjects will be 
randomized 1:1 at Baseline (Day 0) to Group A or Group B. Subjects will 
receive a single treatment comprising 5 injections of BoNT/A-DP or
 
 on Day 0 and will attend follow-up visits for evaluation of 

 
 
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efficacy and safety at one, two, and four weeks post-treatment and once 
every four weeks thereafter until Week 16. 
Investigators and subjects will be blinded to the treatment administered and 
will evaluate the severity of glabellar lines independently. The subjects 
must perform their assessment independently and ideally before the 
investigators, to ensure they are not biased by the investigator. The same 
investigator must complete the Baseline assessments and FWS at Week 4 
(primary endpoint assessments) for a given subject. 
Planned Duration of 
Subject Participation 
18 weeks per subject, to include a maximum of two weeks of Screening, 
one day of treatment and 16 weeks of follow-up.  
Primary Outcome 
Measure 
The study comprises co-primary endpoints defined as: 
• 
An FWS score at the Week 4 Visit of 0 or 1 and a ≥ 1 point reduction 
in FWS score at maximum frown relative to Baseline, based on 
investigator assessment.  
• 
An FWS score at the Week 4 Visit of 0 or 1 and a ≥ 1 point reduction 
in FWS score at maximum frown relative to Baseline, based on subject 
assessment. 
Secondary Outcome 
Measures 
Secondary Efficacy Endpoints  
The following are considered key secondary endpoints: 
1. Percentage of responders with an  FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at maximum frown at Weeks 1, 2, 8, 12 and 
16, based on independent investigator assessment and subject 
assessment. 
2. Percentage of responders with an FWS score of 0 or 1 and a ≥ 2 point 
reduction in FWS score at maximum frown at Weeks 1, 2, 4, 8, 12 and 
16, based on independent investigator and subject assessments. 
3. Percentage of responders with an FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at rest at Weeks 1, 2, 4, 8, 12 and 16, based on 
independent investigator and subject assessments. 
4. Time to onset of effect, as measured at Weeks 1, 2, and 4, based on 
independent investigator and subject assessments. Onset of effect is 
defined as ≥ 1 point improvement in Glabellar Line Scale - Investigator 
(GLS-I) and Glabellar Line Scale – Subject (GLS-S) score relative to 
Baseline at maximum frown in glabellar lines. In addition, onset of 
effect will be assessed by subjects daily during the first 2 weeks after 
treatment, by recordings in the subject diary. 
5. For subjects who respond, duration of effect will be assessed based on 
independent investigator and subject assessments. Effect will be 
deemed to be lost when scores return to Baseline values. 
6. The FACE-Q assessment at Weeks 4, 12 and 16. 
 
Secondary Safety Endpoint 
1. Frequency, seriousness and severity of treatment-emergent adverse 
events (TEAEs), serious AEs (SAEs) and AEs of special interest 
(AESIs), as well as causal relationship to the study medication and the 
study procedure, during the entire study period. 
2. Change in vital signs from Baseline to post-Baseline visits. 

 
 
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INVESTIGATIONAL MEDICINAL PRODUCTS: DOSE AND MODE OF 
ADMINISTRATION 
BoNT/A-DP 
Dosage form: Injection, lyophilizate for solution for injection 
Dosage frequency for glabellar line: one 20 U treatment of BoNT/A-DP 
(administered as 4 U per 0.1 mL, at each of five injection points)  
Mode of administration for glabellar line: Intramuscular injection at two 
sites in each corrugator supercilii muscle and one site in the procerus 
muscle, with an injection volume of 0.1 mL into each site. 
 
 
Dosage form: Injection, lyophilizate for solution for injection 
Dosage frequency for glabellar line: one 20 U treatment of 
 
 (administered as 4 U per 0.1 mL, at each of five injection points) 
Mode of administration for glabellar line: Intramuscular injection at two 
sites in each corrugator supercilii muscle and one site in the procerus 
muscle, with an injection volume of 0.1 mL into each site 
SUBJECT SELECTION 
Targeted Accrual 
Total of 200 subjects. Subject accrual planned as follows: 
• 
100 subjects per treatment group 
• 
Approximately six sites planned in European Union, United States 
and Canada  
Number of Groups 
Two groups are planned: 
• 
Group A, n=100: BoNT/A-DP (20 U, 0.5 mL) 
• 
Group B, n=100: 
 (20 U, 0.5 mL) 
Inclusion Criteria 
Subjects who meet ALL the following criteria are eligible for this study: 
• 
18 - 75 years of age, inclusive, at the time of Screening. 
• 
Has moderate to severe glabellar frown lines at maximum frown 
(severity score of 2 or 3 on GLS-I/GLS-S) as determined by in-clinic 
assessments by both the investigator and the subject (where: 0='none', 
1='mild', 2='moderate', 3='severe'). 
• 
Subject has a stable medical condition with no uncontrolled systemic 
disease. 
• 
Female subjects of childbearing potential must test negative for 
pregnancy and agree to use highly effective birth control during the 
course of the study. 
• 
Subjects who wear glasses must be able to adequately self-assess the 
severity of their glabellar lines (according to the GLS-S), without 
glasses obstructing the forehead area. 

 
 
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Exclusion Criteria 
Subjects who meet ANY of the following criteria are NOT eligible for this 
study: 
• 
Previous treatment with any serotype of botulinum toxin for any 
indication within the 12 months prior to Screening, or any planned 
treatment with botulinum toxin of any serotype for any reason during 
the study (other than the investigational treatment). 
• 
Known hypersensitivity to either study medication or its excipients. 
• 
Any medical condition that may place the subject at increased risk due 
to exposure to botulinum toxin, including diagnosed myasthenia 
gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, 
profound atrophy or weakness in the target muscles, or any other 
condition (at the investigator's discretion) that might interfere with 
neuromuscular function or contraindicate botulinum toxin therapy. 
• 
Facial laser or light treatment, microdermabrasion, superficial peels 
or retinoid therapy within the three months prior to Screening or 
planned during the study. 
o 
Apart from the procedures specified above, previous treatment 
with any facial aesthetic procedure in the glabellar area 
(including chemical peeling, injection with biodegradable 
fillers, photo-rejuvenation) within 12 months prior to Screening 
or planned during the study. 
• 
Previous insertion of permanent material in the glabellar area, or 
planned insertion during the study. 
• 
Any planned or history of surgery in the glabellar area and/or canthal 
line area, or scars in the glabellar and/or canthal line. 
• 
Active skin disease/infection or irritation at the treatment area. 
• 
Inability to substantially lessen glabellar frown lines and or lateral 
canthal lines even by physically spreading them apart. 
• 
Use of a muscle relaxant within 2 weeks prior to Screening, or 
planned use during the study. 
• 
Marked facial asymmetry or ptosis of eyelid and/or eyebrow, or 
current facial palsy or neuromuscular junction disorders as judged by 
the investigator. 
• 
Pregnant, breastfeeding or planning to become pregnant during the 
study. 
• 
Use of prohibited medication including anticholinergic drugs, or 
drugs which could interfere with neuromuscular function, including 
aminoglycoside antibiotics and curare-like compounds within 
2 weeks prior to Screening or planned during the study. 
• 
Planned surgery with general anesthetic (use of local anesthetic 
outside the glabellar area is permitted). 
• 
Participation in another clinical study within one month of Screening 
and throughout the study. 
• 
Previous participation in another botulinum toxin aesthetic study, 
which involved the treatment of glabellar, lines in combination with 
canthal lines and/or forehead lines in the previous 18 months. 
• 
Chronic drug or alcohol abuse (as per investigator discretion). 

 
 
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STATISTICAL ANALYSIS 
Sample Size 
Calculation 
The purpose of the study is to provide preliminary comparative data on 
BoNT/A-DP versus 
 Subsequently the sample size is 
primarily based on clinical judgement and practical considerations, rather 
than formal statistical arguments. However, with a sample size of 
100 subjects per group, a two-sided 95% confidence interval (CI) for the 
difference between BoNT/A-DP and 
 will extend 10.8% 
from expected proportions of 81.5% in both groups based on large sample 
normal approximation. 
Analysis Data Sets 
Safety Analysis Set (SAF): 
All subjects who received at least one injection with study medication 
(independent of whether it is BoNT/A-DP or 
) will be valid for the 
SAF. Within the SAF, a subject will be considered for the treatment 
actually received and not for the treatment assigned by randomization, if 
different. The SAF will be used for the evaluation of the safety assessments. 
Full Analysis Set (FAS): 
The FAS includes all randomized subjects who had a Baseline Visit 1 at 
Day 0 and at least one post-dose in-clinic assessment with the 4-point scale 
by either the investigator or the subject on visits at Weeks 1, 2, or 4. Within 
the FAS a subject will be considered for the treatment assigned by 
randomization and not for the treatment actually received, if different, 
i.e., following the intent-to-treat principle. The FAS population will be the 
primary population for efficacy parameters.  
General Statistical 
Considerations 
The primary objective of the study is to provide preliminary comparative 
data of BoNT/A-DP versus 
 
The study comprises co-primary responder endpoints defined as: 
• 
An FWS score of 0 or 1 and ≥ 1 point reduction in FWS score at 
maximum frown at the Week 4 Visit relative to Baseline based on 
investigator assessment 
• 
An FWS score of 0 or 1 and ≥ 1 point reduction in FWS score at 
maximum frown at the Week 4 Visit relative to Baseline based on 
subject assessment 
That is, responders are defined as having an FWS score of 0 or 1 and an 
improvement ≥ 1 point at maximum frown of the glabellar lines at Week 4 
relative to Baseline in FWS, based on the investigators’ and the subjects’ 
in-clinic assessments. 
The focus of the statistical analysis for the co-primary endpoints will be on 
descriptive statistics (n and %), and 95% CIs for the difference in treatment 
effects between BoNT/A-DP and 
 
95% Clopper-Pearson CIs will be calculated for the difference between 
BoNT/A-DP and 
 for each co-primary endpoint. No formal 
statistical hypothesis testing will be conducted. 
For other endpoints, categorical variables will be summarized by 
presenting absolute and relative frequencies (n and %) of subjects for each 
endpoint. Continuous variables will be summarized using the following 
descriptive statistics: number of subjects (n), mean, standard deviation, 
median, minimum and maximum. Time-to-response and duration of 
response will be analyzed using Kaplan-Meier methodology. 

 
 
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Analyses will be performed by visit. The main analysis will be performed 
based on all available data. That is, no imputation of missing values will be 
conducted (e.g., no last observation carried forward) except for the 
co-primary endpoints where missing data will be assumed to be 
non-responders. 
Treatment-emergent AEs will be summarized by system organ class (SOC) 
and preferred term (PT) (using current version of Medical Dictionary for 
Regulatory Activities [MedDRA]). The number of events, as well as the 
number and percentage of affected subjects, will be reported. 
Treatment-emergent AEs (SOC and PT) will also be summarized by 
seriousness, severity, relationship to study medication, and relationship to 
procedure. 
 
 

 
 
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4.1  Schedule of Study Procedures and Assessments 
Procedures and assessments 
Screening1 
(Day -14 to 0) 
Randomization1  
(Baseline, Day 0) 
Week 1 
(± 2 days) 
Week 2 
(± 5 days)  
Week 4 
(± 2 days)   
Week 8 
(± 5 days)   
Week 12 
(± 5 days)   
 
Week 16   
(± 5 days) 
End of Study2 
Visit No 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
x 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
x3 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
Pregnancy test4 
x 
x 
 
 
x5 
x5 
x5 
x 
Physical examination 
x 
 
 
 
 
 
 
x 
Vital signs6 
x 
x 
x 
 
x 
 
x 
x 
Concomitant medication 
x 
x 
x 
x 
x 
x 
x 
x 
GLS-I7 
x 
x 
x 
x 
x 
x 
x 
x 
GLS-S8 
x 
x 
x 
x 
x 
x 
x 
x 
Photography9 
 
x 
 
x 
x 
 
x 
x 
Treatment satisfaction10 
 
 
 
 
x 
 
x 
x 
IMP administration 
 
x 
 
 
 
 
 
 
Post-treatment obs./AE & AESI 
assessment11 
 
x 
 
 
 
 
 
 
AE and AESI12 assessment 
 
x 
x 
x 
x 
x 
x 
x 
Subject diary 
 
D 
R/D 
R 
 
 
 
 
 
 

 
 
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1. Screening and Baseline, including randomization and treatment, can be done on the same day. If Screening and Baseline are done on the same day, 
assessments only need to be performed once. 
2. For subjects that are prematurely discontinued from the study (at any time), the End of Study visit will take place within one week of discontinuation.  
3. If Screening and Baseline are done on different days, the following inclusion and exclusion criteria are to be re-confirmed at Baseline: investigator and 
subject assessment of glabellar line severity at maximum frown using GLS-I and GLS-S, respectively, as well as documentation of medical history, 
concomitant medications and AEs. 
4. Pregnancy testing for all women of childbearing potential: Screening, Baseline (if Screening and Baseline are done on different days), and End of Study. 
All pregnancy testing will be urine dip stick testing. 
5. Additional pregnancy testing (urine dipstick) for women of childbearing potential in Austrian sites, only. 
6. Vital signs include blood pressure (diastolic /systolic) and pulse. 
7. Investigator's assessment of glabellar line severity at maximum frown and at rest. Assessment will be made using the 4-point GLS-I: (0 =none, 1=mild, 
2=moderate, 3=severe). Results will be recorded in the eCRF. 
8. Subject's assessment of glabellar line severity at maximum frown and at rest. Assessment will be made using the 4-point GLS-S: (0 =none, 1=mild, 
2=moderate, 3=severe). Results will be recorded in the eCRF. 
9. Photographs to be taken of subject's glabellar lines at maximum frown and at rest.  
10. Treatment satisfaction will be determined using the FACE-Q Satisfaction with Outcome Scale. Results will be recorded in the eCRF. 
11. Subjects will be monitored for AEs for 30 minutes after administration of the IMP. 30-minute post IMP administration, general, non-leading AE 
questioning as well as active AESI questioning must be performed.  
12. General, non-leading AE questioning as well as active AESI questioning at each indicated visit. The first AESI questioning will be completed at Baseline 
Visit in order to obtain a full baseline status of any concomitant diseases PRIOR to the first IMP injection. 
AESI Questioning: active questioning by guided review of systems per AESI manual. If an AESI is reported, a targeted physical examination around the 
area of the reported AESI must follow. 
AE=adverse event; AESI=adverse event of special interest; D=distribution of subject diary; eCRF=electronic Case Report Form; GLS-I=Glabellar Line Scale-
Investigator; GLS-S=Glabellar Line Scale-Subject; IMP=investigational medicinal product; obs=observation; R=return of subject diary 
 
 
 
 

 
 
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5. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
BoNT/A 
botulinum neurotoxin A 
BoNT/A-DP 
Croma-Pharma GmbH's BoNT/A drug product registered 
in Korea under the name “Botulax” 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Croma 
Croma-Pharma GmbH 
DRM 
Data Review Meeting 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
(United States) Food and Drug Administration 
FWS 
Facial Wrinkle Scale 
GLS-I 
Glabellar Line Scale - Investigator 
GLS-S 
Glabellar Line Scale - Subject 
IB 
Investigators Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
i.m. 
intramuscular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
kDa 
kilo Dalton 
LD50 
lethal dose, 50% (median lethal dose) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MW 
molecular weight 
PRO 
patient reported outcome 
PT 
preferred term 
SAE 
serious adverse event 

 
 
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Abbreviation 
Definition 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Sprague Dawley 
SIC 
Subject Identification Code 
SIS 
Subject Information Sheet 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SOPs 
Standard Operating Procedures 
TEAE 
treatment-emergent adverse event 
TMF 
Trial Master File 
U 
Unit 
US 
United States 
WHO 
World Health Organization 

 
 
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6. 
TABLE OF CONTENTS 
1. 
SPONSOR RELATED CONTACT DETAILS ....................................... 2 
2. 
SPONSOR SIGNATURE PAGE .............................................................. 3 
3. 
INVESTIGATOR ACKNOWLEDGEMENT......................................... 5 
4. 
SYNOPSIS .................................................................................................. 6 
4.1 
Schedule of Study Procedures and Assessments .................................. 13 
4.2 
Study Scheme ........................................................................................ 15 
5. 
LIST OF ABBREVIATIONS ................................................................. 16 
6. 
TABLE OF CONTENTS ........................................................................ 18 
7. 
BACKGROUND INFORMATION ....................................................... 23 
7.1 
Background to Botulinum Toxin .......................................................... 23 
7.2 
Clinical Condition/Indication ................................................................ 25 
7.3 
Description of Investigational Medicinal Products ............................... 26 
7.3.1 Description of the Investigational Medicinal Product BoNT/A-
DP .................................................................................................. 26 
7.3.2 Description of the Comparator (
 
 ....................... 27 
7.3.3 Handling of the Investigational Medicinal Products ..................... 27 
7.4 
Non-clinical and Clinical Summaries ................................................... 27 
7.4.1 Non-clinical Summary ................................................................... 27 
7.4.2 Clinical Summary .......................................................................... 28 
7.5 
Study Rationale ..................................................................................... 29 
7.5.1.1 Study Design Justification ................................................. 29 
7.5.1.2 Dose Justification .............................................................. 29 
7.6 
Evaluation of Anticipated Risks and Benefits of the Investigational 
Medicinal Product to Human Subjects .................................................. 30 
7.6.1 Possible Benefits for the Subject ................................................... 30 
7.6.2 Possible Risks/Inconveniences for the Subject .............................. 30 
8. 
STUDY PURPOSE AND OBJECTIVES .............................................. 31 
8.1 
Study Purpose ....................................................................................... 31 
8.2 
Primary Objective ................................................................................. 31 
8.3 
Secondary Objectives ............................................................................ 31 
9. 
STUDY DESIGN ...................................................................................... 32 
9.1 
Brief Summary ...................................................................................... 32 

 
 
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9.2 
Overall Study Design ............................................................................ 32 
9.3 
Population to be Studied ....................................................................... 32 
9.3.1 Treatment and Follow-up ............................................................... 32 
9.3.2 End of Study Visit .......................................................................... 33 
9.3.3 Numbering of Visits ....................................................................... 33 
9.3.4 Allowed Time Deviations per Visit ............................................... 33 
9.3.5 Duration of Study Period and Subject Participation ...................... 33 
9.4 
End of Study Definition ........................................................................ 33 
9.5 
Outcome Measures ................................................................................ 34 
9.5.1 Primary Efficacy Endpoints ........................................................... 34 
9.5.2 Secondary Efficacy Endpoints ....................................................... 34 
9.5.3 Secondary Safety Endpoints .......................................................... 34 
9.6 
Randomization and Blinding ................................................................ 35 
9.6.1 Randomization ............................................................................... 35 
9.6.2 Blinding.......................................................................................... 35 
9.6.3 Unblinding ..................................................................................... 35 
9.7 
Study Stopping Rules ............................................................................ 36 
10. 
SUBJECT SELECTION, WITHDRAWAL AND 
DISCONTINUATION ............................................................................. 38 
10.1 
Inclusion Criteria ................................................................................... 38 
10.2 
Exclusion Criteria.................................................................................. 38 
10.3 
Withdrawal and Discontinuation........................................................... 39 
11. 
INVESTIGATIONAL MEDICINAL PRODUCT AND 
COMPARATOR (
 
 ........................................... 40 
11.1 
Packaging .............................................................................................. 40 
11.2 
Labeling................................................................................................. 40 
11.3 
Storage and Handling ............................................................................ 40 
11.3.1 Administration ............................................................................... 41 
11.3.2 Foreign Body Inspection ................................................................ 41 
11.3.3 Dilution .......................................................................................... 41 
11.3.4 Dose for Administration ................................................................ 41 
11.3.5 Method of Administration.............................................................. 42 
11.3.6 Description of Treatment ............................................................... 43 
11.3.7 Investigational Medicinal Product Accountability ........................ 43 
12. 
STUDY PROCEDURES ......................................................................... 44 
12.1 
Informed Consent and Enrollment ........................................................ 44 
12.2 
Subject Identification Codes ................................................................. 44 
12.3 
Screening and Study Visits ................................................................... 44 

 
 
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12.4 
Unscheduled Visit ................................................................................. 47 
12.5 
Subject Diary and Patient Reported Outcomes ..................................... 47 
12.5.1 Subject Diary ................................................................................. 47 
12.5.2 Patient Reported Outcomes............................................................ 48 
12.6 
Subject Completion/Discontinuation .................................................... 48 
12.7 
Procedures for Monitoring Subject Compliance ................................... 49 
13. 
ASSESSMENT OF EFFICACY ............................................................. 50 
13.1 
Assessment of Glabellar Line Severity: Facial Wrinkle Scale ............. 50 
13.1.1 Investigator and Subject In-clinic Assessment .............................. 50 
13.1.2 Photography ................................................................................... 51 
13.2 
Subject Satisfaction with Treatment ..................................................... 51 
14. 
ASSESSMENT OF SAFETY .................................................................. 52 
14.1 
Adverse Events...................................................................................... 52 
14.2 
Adverse Events of Special Interest ....................................................... 52 
14.3 
Serious Adverse Events......................................................................... 53 
14.4 
Treatment-Emergent Adverse Events (TEAEs) .................................... 54 
14.5 
Evaluation of AEs, AESIs, SAEs, TEAEs ............................................ 54 
14.5.1 Assessment of Causality ................................................................ 54 
14.5.2 Assessment of Severity .................................................................. 55 
14.5.3 Outcome ......................................................................................... 55 
14.5.4 Action Taken with Study Drug ...................................................... 55 
14.6 
Adverse Event Monitoring and Assessment ......................................... 56 
14.6.1 Reporting Serious Adverse Events and Adverse Events of Special 
Interest............................................................................................ 57 
14.6.2 Exposure In Utero during Clinical Studies .................................... 57 
14.6.3 Overdose ........................................................................................ 58 
14.7 
Urgent Safety Measures ........................................................................ 58 
14.8 
Pre-existing Diseases ............................................................................ 58 
14.9 
Unexpected Adverse Events ................................................................. 58 
14.10 Medication and Non-Drug Therapy History ......................................... 59 
14.11 Medical History and Physical Examinations ........................................ 59 
14.12 Pregnancy Test ...................................................................................... 60 
14.13 Vital Signs ............................................................................................. 60 
14.14 Demographic Data ................................................................................ 60 
15. 
STATISTICS ............................................................................................ 61 
15.1 
Sample Size and Power Calculations .................................................... 61 
15.2 
Data Sets and Analysis Cohorts ............................................................ 61 
15.3 
Procedure for Accounting for Missing, Unused, and Spurious Data .... 61 

 
 
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15.4 
Methods of Analysis ............................................................................. 62 
15.4.1 Primary Outcome Measure ............................................................ 62 
15.4.2 Secondary Outcome Measures ....................................................... 63 
15.4.3 Further Analyses ............................................................................ 64 
15.5 
General Statistical Considerations ........................................................ 65 
15.5.1 Interim Analysis ............................................................................. 65 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................... 66 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE ..................... 67 
17.1 
Investigator’s Responsibility ................................................................. 67 
17.2 
Study Organization................................................................................ 67 
17.3 
Training ................................................................................................. 67 
17.4 
Monitoring ............................................................................................ 67 
17.5 
Auditing ................................................................................................ 68 
17.6 
Non-compliance with the Protocol........................................................ 68 
17.7 
Facilities ................................................................................................ 68 
18. 
ETHICS .................................................................................................... 70 
18.1 
Basic Principles ..................................................................................... 70 
18.2 
Ethics Committee and Regulatory Authorities ..................................... 70 
18.3 
Informed Consent .................................................................................. 70 
19. 
DATA HANDLING AND RECORD KEEPING .................................. 72 
19.1 
Confidentiality Policy ........................................................................... 72 
19.2 
Source Documentation and Electronic Case Report Forms .................. 72 
19.2.1 Electronic Case Report Forms ....................................................... 73 
19.2.2 Computer Systems ......................................................................... 74 
19.2.3 Data Entry ...................................................................................... 74 
19.2.4 Medical Information Coding.......................................................... 74 
19.3 
Document and Data Retention .............................................................. 74 
19.4 
Data Base Lock ..................................................................................... 74 
20. 
FINANCING AND INSURANCE .......................................................... 74 
21. 
PUBLICATION POLICY ....................................................................... 75 
22. 
REVISION HISTORY ............................................................................ 75 
23. 
SUPPLEMENTS ...................................................................................... 76 
23.1 
Glabellar Line Scale – Investigator (GLS-I) ......................................... 76 
23.2 
Glabellar Line Scale - Subject (GLS-S) ................................................ 81 

 
 
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23.3 
FACE-Q Satisfaction with Outcome Scale ........................................... 86 
24. 
REFERENCES ......................................................................................... 87 
 
LIST OF TABLES 
Table 7-1 
Composition of BoNT/A-DP and Comparator (
 
 ..... 26 
Table 12-1  
BLESS III Study Visit Schedule: List of Activities and Parameters to 
be assessed at Each Study Visit ........................................................... 45 
 
LIST OF FIGURES 
Figure 1 
Illustration of proposed injection sites ................................................. 42 
 

 
 
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7. 
BACKGROUND INFORMATION 
7.1 
Background to Botulinum Toxin 
Botulinum toxin is produced by anaerobic fermentation of the bacterium Clostridium 
botulinum (C. botulinum). A number of different strains of C. botulinum have been 
identified, which produce eight immunologically distinct serotypes (types A - H), all of 
which interfere with neural transmission by blocking the release of acetylcholine, 
causing muscle paralysis, however only serotypes A and B are used clinically1,2. The 
toxins are released from the bacteria as part of a noncovalent multimeric complex, 
associated with up to six auxiliary proteins, including hemagglutinins and a nontoxin, 
nonhematuglitin3. Botulinum neurotoxin A (BoNT/A) is synthesized as a single-chain 
polypeptide with a molecular weight (MW) of approximately 150 kilo Dalton (kDa), 
comprising a 100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain4. 
The heavy chain targets the toxin to specific types of axon terminals, after which the 
toxin can be taken into neurons by endocytosis5,6. The light chain of the toxin, which 
has zinc-dependent endoprotease activity, is then released from the endocytotic vesicles 
and reaches the cytoplasm. The light chain blocks the release of the neurotransmitter 
acetylcholine, causing dose-dependent weakening of the target muscle. The type A 
toxin proteolytically degrades its target SNAP-25 protein, which is essential for 
exocytosis of acetylcholine vesicles located in the peripheral motor neurons7,8. By 
preventing neurosecretory vesicles from docking/fusing with the nerve synapse plasma 
membrane and inhibiting acetylcholine release, the toxin interferes with nerve impulses 
and causes muscle paralysis3,9. 
The ability of botulinum toxin to inhibit acetylcholine release at the neuromuscular 
junction has been exploited for use in medical conditions characterized by muscle 
hyperactivity10. The broad range of medical indications for botulinum toxin includes 
treatment of movement disorders (e.g., spasticity, cervical dystonia), urological 
disorders (e.g., overactive bladder), dermatological conditions (e.g., axillary 
hyperhidrosis), chronic migraine, as well as cosmetic applications (glabellar lines, 
canthal lines).  
Glabellar lines, which appear as vertical lines between the eyebrows, are caused by 
contraction of the corrugator muscles above the eyebrows. These glabellar frown lines 
often become more prominent with age and can project negative emotions 
unintentionally11,12,13. In addition, the persistent presence of glabellar frown lines can 
be suggestive of an older than actual age, affecting an individual’s self-perception, 
emotional well-being, and perception by others, in some cases contributing to 
depression14,15. 
The first authorized botulinum toxin product on the market was
®, which received 
Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus 

 
 
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The Sponsor is currently using the name BoNT/A-DP for clinical development, with 
plans to introduce a new name for the product in the EU and US after approval. 
The indicated clinical condition (glabellar lines) is chronic in nature and the botulinum 
toxin effect typically lasts only a few months (function is typically recovered by the 
sprouting of nerve terminals and formation of new synaptic contacts, which usually 
takes two to three months), hence subjects need to be injected repeatedly to maintain 
the effect21,22. The aim of the current study is to assess the efficacy and safety of 
BoNT/A-DP in the treatment of glabellar lines in comparison with 
 
. 
7.2 
Clinical Condition/Indication 
Hyperfunctional facial lines (mimic wrinkles) are common aesthetic deformities 
involving the glabellar area, forehead and periorbital area. Glabellar lines occur as a 
result of the pull on the skin on the underlying facial musculature, predominantly the 
procerus muscle and the corrugator supercilli23; the latter muscle has no essential 
function other than to express emotion. Although fine wrinkling on the upper lip and 
cheeks, and crow’s feet, as well as the deeper lines in the nasolabial area are a sign of 
aging, wrinkling in the glabellar area is associated with the expression of frowning. 
Excessively prominent lines in this area (which appear as vertical lines between the 
eyebrows) are often misinterpreted as anger, anxiety, fear, fatigue and melancholia, 
causing the subject considerable distress24. As a result, glabellar lines can negatively 
influence self-perception, perception by others and emotional wellbeing25,26. Although 
treatments are available for such lines (including topical preparations or surgical 
procedures), there are several disadvantages to currently available treatments and most 
facial rejuvenation procedures do not address the underlying musculature responsible 
for facial lines.  
Studies with botulinum toxin have shown that the toxin weakens the overactive 
underlying muscle contraction, causing a flattening of the facial skin and improved 
appearance. The effect of the neurotoxin on facial lines was first reported in the early 
90’s. Subsequent widespread use has supported its efficacy and safety for several 
therapeutic indications including facial aesthetics10,27. Lewis and Bowler (2009)14 have 
reported that people who received botulinum toxin treatment for frown lines were 
significantly happier than those who had received other kinds of cosmetic treatment 
and high rates of subject satisfaction with treatment have been reported13,20,28. 

 
 
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7.3 
Description of Investigational Medicinal Products 
An overview of the investigational and comparator products is provided in Table 7-1. 
Table 7-1 Composition of BoNT/A-DP and Comparator (
 
 
Components 
BoNT/A-DP 
 
 
Active ingredient
Clostridium botulinum type A 
(50 U)* 
Clostridium botulinum type A 
neurotoxin complex 
(50 U) 
Excipients 
human serum albumin  
(0.25 mg) 
human albumin 
(0.25 mg) 
preservative-free sodium chloride
(0.9%) 
preservative-free sodium chloride 
(0.45 mg) 
Dose 
20 U total (0.5 mL)  
4 U (0.1 mL) per five injection 
points 
20 U total (0.5 mL)  
4 U (0.1 mL) per five injection 
points 
Appearance 
Lyophilizate for solution for 
injection, which becomes a 
colorless transparent liquid when 
preservative-free sodium chloride 
is added 
Sterile, vacuum-dried powder that 
becomes clear, colorless, and free 
of particulate matter when 
preservative-free sodium chloride 
is added 
*Reconstitute with 1.25 mL sterile saline, yielding 4 U per 0.1 mL dose 
7.3.1 
Description of the Investigational Medicinal Product BoNT/A-DP 
Croma`s botulinum toxin BoNT/A-DP is a 900 kDa multimeric complex, which is 
composed of a 150 kDa neurotoxin, a 130 kDa non-toxic non-hemagglutinating protein 
and various hemagglutinins ranging between 17 and 48 kDa in size. The investigational 
medicinal product (IMP) is the Clostridium botulinum toxin type A purified from 
anaerobic culture of C. botulinum type A CBFC 26 strain. The genomic DNA sequence 
encoding the toxin in strain CBFC26 is identical to that for the Hall strain A ATCC 
3502. Croma´s BoNT/A is supplied as a freeze-dried powder that is reconstituted with 
sterile diluent (preservative-free saline) prior to injection. The excipients of the IMP 
(BoNT/A-DP) are human serum albumin and sodium chloride (Table 7-1). Human 
serum albumin is used as a stabilizing agent and sodium chloride is added to provide 
isotonicity of the formulation. The labeled potency is 50 (U)/vial, where one unit 
corresponds to the median intraperitoneal lethal dose (LD50) when the reconstituted 
product is injected intraperitoneally into female Swiss-Webster mice under defined 
conditions29.  
Reconstitution with 1.25 mL sterile diluent (0.9% saline) is performed prior to i.m. 
injection, to obtain a solution of 4 U/0.1 mL. 

 
 
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7.3.2 
Description of the Comparator (
 
) 
 is a commercially available product, and will be stored, reconstituted 
and administered per product specifications.  
The Summary of Product Characteristics (SmPC) for 
 will be provided. 
7.3.3 
Handling of the Investigational Medicinal Products 
Both BoNT/A-DP and 
 will be reconstituted and drawn into the 
injection syringe by unblinded study personnel prior to provision to the investigator to 
maintain blinding (Section 9.6.2).  
Handling of both products (reconstitution; storage; temperature control checks; product 
accountability) will be done by unblinded members of the study team. 
7.4 
Non-clinical and Clinical Summaries 
7.4.1 
Non-clinical Summary 
The efficacy and safety of Croma´s BoNT/A have been thoroughly assessed in multiple 
non-clinical studies in Sprague Dawley (SD) rats and Beagle dogs treated up to 28 days; 
fertility and reproductive and developmental studies have been carried out in SD rats; 
and selected safety pharmacology (electrocardiogram) and local tolerance examinations 
have performed as part of repeat-dose toxicity studies in both species.  
Across these studies, no significant or unexpected pathology or toxicity findings have 
been observed in single or multiple dose toxicity studies using the i.m. route; no 
histological changes of muscles were observed at the administration site; and no 
compound-related lesions of the muscle groups distant to the injection sites of the 
peripheral or central nervous system were observed. In both SD rats and Beagle dogs, 
significant decreases in body weight, considered an indirect effect related to paralysis, 
have been observed at doses of BoNT/A-DP ranging from 6-30 U/kg of body. Paralytic 
gait has been seen in reproductive toxicity testing, and was considered to be due to 
exaggerated pharmacologic effects of BoNT/A-DP. The no observed adverse effect 
level (NOAEL) in rats ranged from 1-15 U/kg and in Beagle dogs at or above 30 U/kg. 
The LD50 value has been calculated to be 129.5 U/kg in rats; in dogs, no LD50 has been 
calculated. 
In a comparison efficacy study in SD rats, the extent of Croma´s BoNT/A-DP paralysis 
potential was comparable to that of 
 
 at all time points (3, 7, 14, 21, 
28 days post-dose) and concentrations (2, 4, 8 U/animal) tested.  
Because the mechanism behind the recovery of nerve function is well known and well 
described in peer-reviewed scientific literature, and because the FDA noted no evidence 

 
 
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for local or systemic adverse effects after long-term use when evaluating the safety data 
package of Dysport® (six injections, four week intervals)30, Croma has not evaluated 
local and systemic toxicity following long-term treatment with BoNT/A-DP. No 
standard pharmacokinetic or toxicokinetic studies have been performed with Croma´s 
BoNT/A-DP, since the chemical nature of the drug is a protein and the expected 
consequence of metabolism of proteins is the degradation to small peptides and 
individual amino acids. 
All pivotal studies were performed under Good Laboratory Practice conditions and 
according to International Conference on Harmonization (ICH) guidance. For further 
details, please refer to the Investigators Brochure (IB). 
7.4.2 
Clinical Summary 
To date, the clinical development of BoNT/A-DP has included multiple Phase 3 studies 
and one Phase 3 study; one Phase 3 study is ongoing.  
Two multi-center Phase 3 studies (BLESS I and BLESS II) were performed in the US 
and Europe. Both studies were comprised of two parts. The first parts of the studies 
were randomized, double-blind, placebo-controlled, phases which aimed to 
demonstrate efficacy and safety of BoNT/A-DP compared with placebo. The second 
part was an open label extension phase to evaluate efficacy after repeat treatments and 
long-term safety. Each product was administered at a dose of 20 U (0.5 mL). The on-
going BLESS III study continues with this study design. 
In all three studies, the primary efficacy endpoint was the proportion of subjects among 
BoNT/A-DP and placebo groups with a Facial Wrinkle Scale (FWS) score of 0 or 1 and 
an improvement ≥ 2 points in FWS score (at maximum frown) at the Week 4 visit (of 
the first treatment cycle) relative to Baseline (responders), based on both the 
investigator’s and the subject’s in-clinic assessments. Thus, the primary endpoint was 
a composite endpoint comprising investigator and subject assessments of treatment 
effectiveness. 
In addition, Phase 3 and Phase 4 studies have been performed in Korea using the IMP 
name “Botulax”. The Sponsor is currently using the name BoNT/A-DP for clinical 
development. 
In clinical studies to date, more than 1,400 subjects have been exposed to BoNT/A-DP 
for cosmetic and other indications, with doses ranging from 20 U for glabellar lines up 
to 360 U for the treatment of post stroke upper limb spasticity.  

 
 
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There have been no deaths reported during the studies, no serious adverse events 
(SAEs) related to study medication, no treatment-emergent AEs (TEAEs) that led to 
discontinuation and no development of anti-drug antibody during the studies. 
For further details, please refer to the IB. 
7.5 
Study Rationale 
BoNT/A-DP has been shown to be safe and well tolerated when administered at doses 
up to 360 U, which is well above the 20 U dose planned for use in this study. This 
current Phase 2 study is designed as a randomized double-blind study to assess the 
efficacy and safety of BoNT/A-DP in the treatment of glabellar lines in comparison 
with 
 Data obtained from this study (and from BLESS I, BLESS II and 
BLESS III) will provide evidence of efficacy and subject safety in controlled clinical 
study setting. The dose rationale for this study is described in Section 7.5.1.2.  
7.5.1.1 
Study Design Justification 
This will be a multi-center, randomized, double-blind, comparator-controlled study. 
The study will take place in the EU, US and Canada.  
To allow all subjects to profit from treatment and to obtain adequate data for 
BoNT/A-DP treatment, the study will be comprised of a double-blinded treatment 
comparing BoNT/A-DP with 
 (ratio 1:1). Primary and secondary 
endpoints will compare efficacy, safety and subject satisfaction after a single treatment 
of the investigational BoNT/A-DP to an existing commercially available product 
  
Two hundred subjects will be enrolled, which should allow for a precise estimate of 
response rate and for post-hoc sensitivity analyses.  
7.5.1.2 
Dose Justification 
The dose selected is 20 U, where 1 U is defined as "the calculated median 
intraperitoneal LD50 in mice". Study HG-11-01 performed in South Korea 
demonstrated that a dose of 20 U BoNT/A-DP per treatment was safe and highly 
efficacious in the treatment of glabellar lines. The potency units of botulinum toxins for 
injection are specific to the preparation and assay methods utilized and are not 
interchangeable with other preparations31 (historical data with similar products have 
confirmed the efficacy of a 20 U dose and current safety recommendations favor the 
use of such small doses32; FDA Guidance for Upper Facial Lines). 
Both BoNT/A-DP and 
 will be administered at a dose of 20 U, allowing 
a comparison of equivalent doses.  

 
 
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7.6 
Evaluation of Anticipated Risks and Benefits of the Investigational 
Medicinal Product to Human Subjects 
7.6.1 
Possible Benefits for the Subject 
The benefit of participation in this study is the expected reduction in the severity of 
glabellar frown lines. All subjects will benefit from free medical screenings and 
follow-up.  
7.6.2 
Possible Risks/Inconveniences for the Subject 
Botulinum toxin drug products present a unique set of safety concerns related to the 
potential for local and distant spread of toxin effect. Therefore, an active evaluation of 
subjects for signs and symptoms of local and distant spread of toxin effect will be 
performed throughout the study at each study visit. Subjects will be warned about signs 
of the spread of toxin effects including asthenia, generalized muscle weakness, 
diplopia, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence, breathing 
difficulties and possible AEs of special interest (AESIs; Section 14.1). Respiratory, 
speech or swallowing difficulties can also result, which could be life threatening, 
however no definitive SAE reports of distant spread of toxin effect associated with 
cosmetic or dermatologic use of botulinum toxin at the labeled dose of 20 U (for 
glabellar lines) or 100 U (for severe primary axillary hyperhidrosis) have been reported 
to date. BoNT/A-DP will be administered at a dose of 20 U; 
 will be 
administered per product label (20 U). 
Baseline physical examinations will also be conducted to rule out pre-existing 
neurological or muscular deficiencies. In addition, key safety measures such as vital 
signs and pregnancy tests (where appropriate) will be conducted at suitable intervals to 
ensure no participating subjects are pregnant. 
As is the case with all injected products, injection site reactions such as pain, tenderness, 
redness, induration and/or swelling may occur after administration. In addition, a 
number of other symptoms have been experienced by single subjects including pruritus, 
hypertonia, ptosis, headache, diplopia, edema and blurred vision. The most frequently 
observed injection site reactions were injection site pain and swelling. The vast majority 
of AEs were rated as mild. As a side effect of drawing blood, pain, hematoma, and in 
very rare cases an infection at the venipuncture site may occur. 
In addition, as with any IMP, there may be unforeseeable risks associated with the use 
of BoNT/A-DP.  

 
 
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8. 
STUDY PURPOSE AND OBJECTIVES 
8.1 
Study Purpose 
To provide preliminary comparative efficacy and safety data of BoNT/A-DP versus 
 
8.2 
Primary Objective 
To assess the efficacy of treatment with BoNT/A-DP as defined by the percentage of 
responders at Week 4 (Facial Wrinkle Scale [FWS] score of 0 or 1 and a ≥ 1 point 
reduction in FWS score) in reducing the severity of glabellar frown lines at maximum 
frown (the worst appearance of upper facial lines with maximum load on the muscle; 
eyebrows pushed together as far as they can go) compared to treatment with
 
, based on independent investigator assessment and subject assessment. 
8.3 
Secondary Objectives 
1. To assess the percentage of responders (FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at maximum frown) after a single treatment with 
BoNT/A-DP compared to a single treatment of 
 at Weeks 1, 2, 
8, 12 and 16, based on investigator and subject assessments.  
2. To assess the percentage of responders (FWS score of 0 or 1 and a ≥ 2 point 
reduction in FWS score at maximum frown) after a single treatment with 
BoNT/A-DP compared to a single treatment of 
 at Weeks 1, 2, 
4, 8, 12 and 16, based on independent investigator and subject assessments. 
3. To assess the percentage of responders (FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at rest) after a single treatment with BoNT/A-DP 
compared to a single treatment of 
 at Weeks 1, 2, 4, 8, 12 and 
16, based on independent investigator and subject assessments. 
4. To assess time to onset of effect after a single treatment with BoNT/-DP 
compared to a single treatment of 
 as measured at Weeks 1, 2, 
and 4, based on independent investigator and subject assessments. 
5. To assess the duration of effect in subjects who respond after a single treatment 
with BoNT/A-DP or a single treatment of 
 based on 
independent investigator and subject assessments. 
6. To assess treatment satisfaction at Weeks 4, 12, and 16 using FACE-Q 
Satisfaction with Outcome Scale. 
7. To determine the safety and presence of any adverse effects of a single treatment 
of BoNT/A-DP compared to a single treatment of 
 in the 
treatment of glabellar lines. 

 
 
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9. 
STUDY DESIGN 
9.1 
Brief Summary 
This is a multi-center Phase 2 study.  
Subjects will be randomized 1:1 to receive a single treatment of BoNT/A-DP or 
 
 on Day 0. Subjects will attend six follow-up visits for evaluation of efficacy 
and safety at one, two, and four weeks post-treatment and once every four weeks 
thereafter until Week 16.  
9.2 
Overall Study Design 
The study is a parallel group, randomized, double-blind, comparator-controlled study. 
9.3 
Population to be Studied 
Approximately 200 subjects of either gender, between 18 and 75 years of age inclusive, 
who meet all the inclusion criteria and do not meet any exclusion criteria and who 
provide written informed consent, will be enrolled in the study. 
9.3.1 
Treatment and Follow-up 
Subjects will be randomized 1:1 to one of two treatment groups:  
• Group A (n=100): BoNT/A-DP (20 U, 0.5 mL) 
• Group B (n=100): 
 (20 U, 0.5 mL) 
Eligible subjects will be randomized at Baseline (Day 0) to Group A or B in a 
1:1 randomization scheme. Investigators and subjects will be blinded to the treatment 
administered and will evaluate the severity of glabellar lines independently. The 
subjects should perform their assessment independently and ideally before the 
investigator, to ensure they are not biased by the investigator. The same investigator 
must complete the Baseline assessments and FWS at Week 4 (primary endpoint 
assessments) for a given subject. 
After a Screening period of up to 14 calendar days, subjects will receive a single 
treatment, comprised of five injections, of BoNT/A-DP or 
 on Day 0, 
and attend follow-up visits at one, two, and four weeks after treatment and once every 
four weeks thereafter through Week 16, for evaluation of efficacy and safety. 
Re-screening will not be permitted. 

 
 
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9.3.2 
End of Study Visit 
The End of Study visit is planned to take place 16 weeks after treatment.  
For subjects who are prematurely discontinued from the study (at any time), the End of 
Study visit will take place within one week of discontinuation. 
9.3.3 
Numbering of Visits 
Visit numbers correspond with specific treatment and assessments as outlined in the 
Schedule of Study Procedures and Assessments, Section 4.1 and in the details of the 
Screening and Study Visits, Table 12-1. 
9.3.4 
Allowed Time Deviations per Visit 
A time deviation of ± 5 days is allowed for each visit, except for the Week 1 and 
Week 4 visits, where a time deviation of ± 2 day is permitted. Sites must adhere to the 
schedule of events and visit windows and subjects must ensure they are available for 
those visits. Any deviation from the visit schedule and its associated time windows will 
be documented as a protocol deviation. 
9.3.5 
Duration of Study Period and Subject Participation 
Subjects will participate in this study for a duration of 18 weeks from signing the 
Informed Consent Form (ICF) to the End of Study visit (i.e., up to 14 calendar days for 
Screening, followed by 16 weeks study participation).  
Subjects will receive a single treatment of BoNT/A-DP or 
 on Day 0.  
9.4 
End of Study Definition 
A subject is considered to have completed the study if they have completed the End of 
Study Visit. 
The end of the study is defined as the date of last subject last visit. 

 
 
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9.5 
Outcome Measures 
9.5.1 
Primary Efficacy Endpoints 
The study comprises co-primary endpoints defined as: 
• An FWS score at the Week 4 Visit of 0 or 1 and a ≥ 1 point reduction in FWS 
score at maximum frown relative to Baseline, based on investigator assessment. 
• An FWS score at the Week 4 Visit of 0 or 1 and a ≥ 1 point reduction in FWS 
score at maximum frown relative to Baseline, based on subject assessment.  
Details on subgroup analyses on the primary endpoint variable are provided in 
Section 15.4.1. 
9.5.2 
Secondary Efficacy Endpoints 
1. Percentage of responders with an  FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at maximum frown at Weeks 1, 2, 8, 12 and 16, based 
on independent investigator assessment and subject assessment. 
2. Percentage of responders with an FWS score of 0 or 1 and a ≥ 2 point 
reduction in FWS score at maximum frown at Weeks 1, 2, 4, 8, 12 and 16, 
based on independent investigator and subject assessments. 
3. Percentage of responders with an FWS score of 0 or 1 and a ≥ 1 point 
reduction in FWS score at rest at Weeks 1, 2, 4, 8, 12 and 16, based on 
independent investigator and subject assessments. 
4. Time to onset of effect, as measured at Weeks 1, 2, and 4, based on 
independent investigator and subject assessments. Onset of effect is defined 
as ≥ 1 point improvement in Glabellar Line Scale - Investigator (GLS-I) and 
Glabellar Line Scale – Subject (GLS-S) score relative to Baseline at maximum 
frown in glabellar lines. In addition, onset of effect will be assessed by 
subjects daily during the first 2 weeks after treatment, by recordings in the 
subject diary. 
5. For subjects who respond, duration of effect will be assessed based on 
independent investigator and subject assessments. Effect will be deemed to be 
lost when scores return to Baseline values. 
6. The FACE-Q assessment at Weeks 4, 12 and 16. 
 
9.5.3 
Secondary Safety Endpoints 
1. 
Frequency, seriousness and severity of TEAEs, SAEs and AESIs, as well as 
causal relationship to the study medication and the study procedure, during 
the entire study period. 
2. 
Change in vital signs from Baseline to post-Baseline visits. 

 
 
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9.6 
Randomization and Blinding 
9.6.1 
Randomization 
This is a randomized, double-blind, comparator-controlled efficacy and safety clinical 
study. Subjects will be randomly assigned at Baseline (Day 0) to receive a single 
treatment of BoNT/A-DP or 
 at a ratio of 1:1 
Randomization will be performed per study site via Interactive Web Response System 
(IWRS). One unique randomization code will be assigned to each subject.  
9.6.2 
Blinding 
BoNT/A-DP will be provided to the sites in glass vials. 
 will be 
provided to the sites as commercially available. 
In order to maintain blinding, both BoNT/A-DP and 
 will be 
reconstituted and drawn into the syringes by an unblinded study team member at the 
site. After the IMPs have been drawn into the syringes, the treatments will look identical 
(clear solution, comparable volume), thus maintaining the blind.  
The unblinded study team member preparing the IMP at the study site must not, by any 
means, be involved in any other study data collection activities including AE 
assessment, electronic Case Report Form (eCRF) completion, diary collection, etc. IMP 
will be assigned to the subjects by IWRS with the lot number and kit number assigned 
corresponding to the group to which the subjects are assigned. The assigned vial will 
be reconstituted and the filled syringes for injection will be forwarded to the 
investigator for injection. Specific Blinding Plans will be created at each study site 
during the Study Initiation visits. The blind will be maintained.  
9.6.3 
Unblinding 
The decision to unblind lies fully with the investigator. The randomization assignment 
should not be revealed before the study has been completed and the database has been 
cleaned and closed. The study will be unblinded using the Study Specific Unblinding 
Procedure (an unblinding module is standard on all blinded studies; also it is possible 
to grant access to regulatory unblinding users so that they can monitor the safety of the 
study, if required). 
In case of emergency, the IMP administered to the subjects can be revealed using 
the unblinding function of the IWRS. 
In rare emergencies, unblinding may be necessary for the clinical management of an 
AE. Investigators should consider unblinding only if knowledge of the administered 
product will have an influence on the further treatment of the AE. In such events, the 

 
 
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investigator should make every attempt to inform the Sponsor before breaking the blind 
or as soon as possible after unblinding has been performed. The 
or Croma 
medical team is available to discuss any unblinding need. However, such discussion is 
not mandatory. The investigator can always unblind per his/her discretion if the actual 
treatment information is considered relevant for subsequent event treatment. Once 
unblinding has occurred, the site should immediately contact the 
 or Croma 
medical team. Communication of the unblinding result is considered acceptable. It is at 
the discretion of the investigator to continue an unblinded subject in the study. The date 
and time of breaking the code, the reason for breaking the code, study product 
administered, subject identification number and randomization code will be 
documented within the IWRS. Subjects for whom the blind had been broken may 
continue in the study as per discretion of the Investigator. 
9.7 
Study Stopping Rules 
In a case of critical non-compliance of site to the Code of Federal Regulation (Title 21, 
CFR Part 312); the study protocol; the Declaration of Helsinki; or any applicable 
regulation, the Sponsor may stop the entire study or participation of a study site at any 
time. In addition, the Sponsor may stop the entire study, or terminate participation of a 
study site for any medical reason at any time. 
In the event of individual subject’s premature study termination resulting from an AE, 
refer to Section 12.6. 
Premature termination of a subject 
A subject must be terminated from the study if any of the following occur: 
• Withdrawal of informed consent. 
• Treatment with any other investigational product in another clinical study. 
• Treatment with any BoNT other than study medication. 
• Pregnancy detected at Screening or Baseline. 
• Any significant treatment-related side effects where study continuation would 
constitute an unacceptably high risk for the subject. 
Premature termination of a site or of the entire study 
A site or the entire study may be terminated if any of the following occur: 
• Critical non-compliance to Title 21, CFR Part 312; the study protocol; the 
Declaration of Helsinki; or any applicable regulation. 
• The positive benefit/risk ratio is no longer maintained. 
• The Sponsor may stop the entire study for any medical reason at any time. 

 
 
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• The Sponsor can terminate the study or a study site at any time for any other 
reason. 

 
 
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10. 
SUBJECT SELECTION, WITHDRAWAL AND DISCONTINUATION 
10.1 
Inclusion Criteria 
Subjects who meet ALL of the following criteria are eligible for this study: 
• 18 - 75 years of age, inclusive, at the time of Screening. 
• Has moderate to severe glabellar frown lines at maximum frown (severity score of 
2 or 3 on GLS-I/GLS-S) as determined in-clinic assessments by both the 
investigator and subject (where: 0='none', 1='mild', 2='moderate', 3='severe'). 
• Subject has a stable medical condition with no uncontrolled systemic disease. 
• Female subjects of childbearing potential must test negative for pregnancy and 
agree to use highly effective birth control during the course of the study. 
• Subjects who wear glasses must be able to adequately self-assess the severity of 
their glabellar lines (according to the GLS-S), without glasses obstructing the 
forehead area. 
10.2 
Exclusion Criteria 
Subjects who meet ANY of the following criteria are NOT eligible for this study: 
• Previous treatment with any serotype of botulinum toxin for any indication within 
the 12 months prior to Screening, or any planned treatment with botulinum toxin of 
any serotype for any reason during the study (other than the investigational 
treatment). 
• Known hypersensitivity to either study medication or its excipients. 
• Any medical condition that may place the subject at increased risk due to exposure 
to botulinum toxin, including diagnosed myasthenia gravis, Eaton-Lambert 
syndrome, amyotrophic lateral sclerosis, profound atrophy or weakness in the target 
muscles, or any other condition (at the investigator's discretion) that might interfere 
with neuromuscular function or contraindicate botulinum toxin therapy. 
• Facial laser or light treatment, microdermabrasion, superficial peels or retinoid 
therapy within the three months prior to Screening or planned during the study. 
o Apart from the procedures specified above, previous treatment with any 
facial aesthetic procedure in the glabellar area (including chemical 
peeling, injection with biodegradable fillers, photo-rejuvenation) within 
12 months prior to Screening or planned during the study. 
• Previous insertion of permanent material in the glabellar area, or planned insertion 
during the study. 
• Any planned or history of surgery in the glabellar area and/or canthal line area, or 
scars in the glabellar and/or canthal line. 
• Active skin disease/infection or irritation at the treatment area. 

 
 
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• Inability to substantially lessen glabellar frown lines and or lateral canthal lines 
even by physically spreading them apart. 
• Use of a muscle relaxant within two weeks prior to Screening, or planned use during 
the study. 
• Marked facial asymmetry or ptosis of eyelid and/or eyebrow, or current facial palsy 
or neuromuscular junction disorders as judged by the investigator. 
• Pregnant, breastfeeding or planning to become pregnant during the study. 
• Use of prohibited medication including anticholinergic drugs, or drugs which could 
interfere with neuromuscular function, including aminoglycoside antibiotics and 
curare-like compounds within two weeks prior to Screening or planned during the 
study. 
• Planned surgery with general anesthetic (use of local anesthetic outside the glabellar 
area is permitted). 
• Participation in another clinical study within one month of Screening and 
throughout the study. 
• Previous participation in another botulinum toxin aesthetic study which involved 
the treatment of glabellar lines in combination with canthal lines and/or forehead 
lines in the previous 18 months. 
• Chronic drug or alcohol abuse (as per investigator discretion). 
10.3 
Withdrawal and Discontinuation 
A subject may voluntarily withdraw from study participation and data collection for 
any reason at any time (withdraw consent). A subject will be considered lost to 
follow-up after at least three unsuccessful phone calls have been made and one certified 
letter has been sent, in an attempt to contact the subject. All efforts to contact the subject 
must be documented.  
Every effort will be made to have the withdrawn/discontinued subject complete the End 
of Study visit (Section 9.3.2). The reason for withdrawal/discontinuation will be 
recorded on the eCRF (Section 12.6).  
In the event of an AE/AESI/SAE, clinical and/or laboratory investigations that are 
beyond the scope of the required study procedures may be performed as part of the 
evaluation of the event. Any subject with an AE, AESI, or SAE will be evaluated by 
the investigator and will be treated and/or followed up until the symptoms return to 
normal or acceptable levels, as judged by the investigator. 

 
 
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11. 
INVESTIGATIONAL MEDICINAL PRODUCT AND COMPARATOR 
 
 
Only unblinded personnel will be involved in any handling of the IMP prior to provision 
to the investigator. Unblinded personnel must not disclose unblinding information to 
the investigator or any other blinded member of the study team. 
The SmPC for 
 will be provided.  
11.1 
Packaging 
BoNT/A-DP is provided in single use vials containing 50 U/vial. BoNT/A-DP will be 
reconstituted with a volume of 1.25 mL sterile physiological saline (diluent, as outlined 
in Section 11.3.3). 
 will be provided as commercially available, in single use 50 U vials, 
and will be reconstituted per product instructions.  
11.2 
Labeling 
In accordance with the valid regulatory requirements for blinded clinical studies, 
syringes containing the reconstituted active drug and comparator control will be labeled 
similarly. The content of the labels will be in accordance with the applicable regulatory 
authority requirements. 
11.3 
Storage and Handling 
Unopened BoNT/A-DP must be stored at +2 to +8°C in a refrigerator with a calibrated 
minimum-maximum thermometer. After reconstitution, the product (in the vial) can be 
stored under refrigerated conditions (+2 to +8 °C) for up to 24 hours. Storage at lower 
or higher temperatures should be avoided.  
 will be stored and handled per the product guidelines.  
In order to guarantee proper storage conditions, the current temperature and the 
minimum and maximum temperature since the last reading in the storage refrigerator 
must be monitored and documented five times per week. Monitoring of the storage 
refrigerator and completion of the temperature log are to be done only by unblinded 
study personnel. The temperature log will be included in the Trial Master File (TMF) 
after study completion.  
The investigator should immediately report any temperature deviations. In case of any 
temperature deviation, the IMP must be quarantined and the Sponsor must be contacted 
immediately for resupply.  

 
 
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After administration to subjects, residual drug in the vial or syringe, together with used 
vial and syringes must be inactivated by autoclaving, treatment with hypochlorite or be 
discarded in appropriate containers and disposed of as medical biohazardous waste in 
accordance with local requirements.  
Product accountability is addressed in Section 11.3.7. 
11.3.1 
Administration 
11.3.2 
Foreign Body Inspection 
Prior to use, the vial should be visually inspected by the person responsible for 
reconstitution, to ensure the product is not discolored and that it is free from foreign 
particulate matter. In such a case, the product must be replaced via replacement function 
in IWRS. 
The person responsible for reconstituting the IMP for administration will be unblinded 
and must not disclose unblinding information to the investigator or any other blinded 
member of the study team. 
11.3.3 
Dilution 
Sterile physiological saline (0.9% preservative-free sodium chloride solution for 
injection) will be used as the diluent for reconstitution of BoNT/A-DP and will be added 
at a volume of 1.25 mL for 50 U. Diluent will be injected slowly into the vial, to avoid 
foam/bubble formation or vigorous agitation which may cause denaturation. If a 
vacuum does not pull the diluent into the vial, the vial will be discarded. Reconstituted 
BoNT/A-DP should be colorless and transparent with no visible particulate matter. The 
reconstituted BoNT/A-DP must be administered within 24 hours, during this time the 
product will be stored in a refrigerator (+2 to +8°C). A volume of 0.5 mL will be taken 
from the vial for treatment. 
 will be reconstituted per product instructions.  
The date and time of reconstitution will be recorded in the eCRF.  
The use of product from one vial or syringe is restricted to one single subject 
treatment. 
11.3.4 
Dose for Administration 
The injection sites should be prepared according to standard clinical procedures. 
A volume of 0.5 mL of the properly reconstituted BoNT/A-DP or
 
should be drawn into the sterile syringe and any air bubbles in the syringe barrel 
expelled. The needle used to reconstitute the product should be removed and replaced 

 
 
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with a sterile insulin or tuberculin-type syringe of 1 mL volume with 0.01 mL 
graduation and with the gauge range of 30 to 33 G, which the investigator routinely 
uses for toxin administration.  
Each subject will receive a total of five i.m. injections of 4 U/0.1 mL (total of 20 U) of 
BoNT/A-DP or
: two injections in each corrugator supercilii muscle 
and one injection in the procerus muscle, as shown in Figure 1.  
 
Figure 1 
Illustration of proposed injection sites 
 
11.3.5 
Method of Administration 
The selected injection sites include two sites in each corrugator supercilii muscle and 
one site in the procerus muscle. In order to reduce the complication of blepharoptosis, 
injections near the levatorpalpebrae superioris must be avoided, particularly in subjects 
with large brow depressor complexes. When injecting into two sites of each corrugator 
supercilii muscle, the first injection will be made right above the medial margin of 
eyebrows. The second injection will be made ca. 1 cm above the supraorbital ridge 
(rigid bony boundaries palpable above the upper part of the upper eyelid) where 
midlines of the eyebrows meet. The injection site of the procerus muscle will be just 
above the midline of the nasal bridge where horizontal wrinkles are made between the 
medial ends of eyebrows. When injecting into the medial ends of corrugator supercilii 
muscles and on the midlines of the eyebrows, the injection sites will be at least 1 cm 
away from the supraorbital ridge (rigid bony boundaries palpable above the upper part 
of the upper eyelid). 

 
 
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Injections will be made with caution to avoid intravascular injection. Before injecting 
BoNT/A-DP or
, a thumb or an index finger will be placed firmly below 
the orbital rim to prevent drug effusion to this area. The needle will be oriented 
superiorly and medially and the exact amount of drug will be injected. Additional 
information regarding administration of BoNT/A-DP can be found in the Study 
Reference 
Manual/Operational 
Manual; 
additional 
information 
regarding 
administration of
 can be found in the SmPC. 
11.3.6 
Description of Treatment 
The subject will receive five injections (4 U per 0.1 mL injection) of BoNT/A-DP or 
 on Day 0.  
11.3.7 
Investigational Medicinal Product Accountability 
The investigator will ensure that the required storage conditions as specified in the 
Section 11.3 are guaranteed at the investigational site, as described in the Site Specific 
Blinding Plan. Authorized unblinded study personnel will maintain accurate records of 
the receipt of all blinded IMP shipped by the Sponsor, including date received, drug 
identity code, date of manufacture or expiration date, amount received and disposition. 
IMP must be dispensed only at the study site as specified in the protocol 
(see Section 11.3). Records will be maintained that include the Subject Identification 
Code (SIC), the dispensation date and amount of IMP dispensed. The IMP must be 
dispensed only at the institution specified for each site. After reconciliation by the 
clinical monitor, all remaining unused, unreconstituted IMP will be returned to the 
Sponsor, or destroyed at site with the permission of the Sponsor, in accordance with 
applicable law and study site procedures. Partially used reconstituted IMP will be 
destroyed after use (e.g., autoclaved, treated with hypochlorite or discarded in 
appropriate containers and disposed of as medical biohazardous waste). If unused 
unreconstituted IMP is to be destroyed by the site, the investigator will provide 
documentation in accordance with Sponsor’s specifications. 
 

 
 
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12. 
STUDY PROCEDURES 
12.1 
Informed Consent and Enrollment 
Any subject who provides informed consent (i.e., signs and dates the ICF) and has been 
proven eligible during Screening will be considered enrolled in the study. Study 
procedures cannot commence until the subject has undergone the informed consent 
process and signed the ICF. 
Efforts will be made to include subjects with a diversity of Fitzpatrick skin types. 
12.2 
Subject Identification Codes 
An SIC will automatically be assigned by the IWRS system at Screening, which will 
comprise H2H (denoting “Head 2 Head BLESS”) followed by a single digit country 
identification, a two-digit site identification and a three-digit subject identification 
number. All study documents (e.g., eCRFs, clinical documentation, sample containers, 
drug accountability logs, etc.) will be identified with the SIC. An abbreviated SIC 
containing only the 3-digit subject number is acceptable, when the country identifier 
and site number are clearly assigned to the document. 
12.3 
Screening and Study Visits 
The study site is responsible for maintaining an Enrollment/Screening Log that includes 
all subjects screened. The log will also serve to document the reason for Screening 
failure. All Screening data will be collected and reported in eCRFs, regardless of 
Screening outcome. 
The overall study design is summarized in Section 4.2 and detailed in Section 9. Details 
on the procedures to be performed at each study visit, including Screening, are listed in 
Table 12-1 below and are detailed in Section 4.1 Schedule of Study Procedures and 
Assessments.  
 
 

 
 
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Table 12-1  BLESS III Study Visit Schedule: List of Activities and Parameters 
to be assessed at Each Study Visit 
 
 
VISIT 1 
TIME 2 
ACTION 
Visit 13 
Screening 
0 to 
14 days 
 
 
 
Informed consent (Section 12.1) 
Inclusion and exclusion criteria (Section 10) 
Medical history (Section 14.11) 
Demographic data (Section 14.14) 
Urine dip stick pregnancy test (all applicable subjects, 
Section 14.12) 
Physical examination (Section 14.11) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Visit 23
Treatment 
Baseline 
Day 0 
 
 
Urine dip stick pregnancy test (all applicable subjects, 
Section 14.12) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Photography (Section 13.1.2) 
Inclusion and exclusion criteria4 (Section 10) 
AE assessment (Section 14)  
AESI questioning pre-dose5 (Section 14.2) 
TREATMENT (Section 11.3) 
Post-treatment observation as well as AE and AESI assessment 
after 30 minutes6 
Distribute Subject Diary (Section 12.5) 
Visit 3  
Week 1 
7 days 
± 2 days 
after 
Baseline 
Collect/Review/Distribute Subject Diary (Section 12.5) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10)  
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
AE and AESI assessment (Section 14) 
Visit 4 
Week 2 
14 days 
± 5 days 
after 
Baseline 
(Day 0) 
Collect Subject Diary (Section 12.5) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Photography (Section 13.1.2)  
AE and AESI assessment (Section 14) 

 
 
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1 An unscheduled visit is permitted, if necessary. Assessments performed at an unscheduled visit will be 
at the investigator's discretion, but should include AE assessment, AESI query, concomitant medication 
and possibly GLS-I/GLS-S. 
2 A time deviation of ± 5 days is allowed for each visit, except for the Week 1/Visit 3, and Week 4/Visit 5 
visits, where deviations of ± 2 day are permitted. Sites must adhere to the schedule of events and visit 
windows and subjects must ensure they are available for those visits. Any deviation from the visit 
schedule and its associated time windows will still be documented as a protocol deviation. 
3 Screening and Baseline, including randomization and treatment, can be done on the same day. If 
Screening and Baseline are done on the same day, assessments only need to be performed once. 
Visit 5 
Week 4 
4 weeks 
± 2 days 
after 
Baseline 
(Day 0) 
Urine dip stick pregnancy test ( applicable subjects in Austria 
only , Section 14.12) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Photography (Section 13.1.2) 
FACE-Q Satisfaction with Outcome Scale (Sections 13.2 and 
23.3) 
AE and AESI assessment (Section 14) 
Visit 6 
Week 8 
8 weeks 
± 5 days 
after 
Baseline 
(Day 0) 
 
Urine dip stick pregnancy test (applicable subjects in Austria 
only, Section 14.12) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Concomitant medication (Section 14.10) 
AE and AESI assessment (Section 14) 
Visit 7 
Week 12 
12 weeks 
± 5 days 
after 
Baseline 
(Day 0) 
 Urine dip stick pregnancy test (applicable subjects in Austria 
only, Section 14.12) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Photography (Section 13.1.2)  
FACE-Q Satisfaction with Outcome Scale (Sections 13.2 and 
Section 23.3) 
AE and AESI assessment (Section 14) 
Visit 87 
Week 16 
End of 
Study 
16 weeks 
± 5 days 
after 
Baseline 
(Day 0) 
Urine dip stick pregnancy test (all applicable subjects, 
Section 14.12) 
Physical examination (Section 14.11) 
Vital signs (Section 14.13) 
Concomitant medication (Section 14.10) 
GLS-I (Sections 13.1.1 and 23.1) 
GLS-S (Section 13.1.1 and 23.2) 
Photography (Section 13.1.2)  
FACE-Q Satisfaction with Outcome Scale (Sections 13.2 and 
23.3) 
AE and AESI assessment (Section 14) 

 
 
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Pregnancy testing on all applicable subjects must be repeated at the Baseline Visit if Screening and 
Baseline assessments are not done on the same day. 
4 If Screening and Baseline are done on different days, the following inclusion and exclusion criteria are 
to be re-confirmed at Baseline: GLS-I and GLS-S for investigator and subject, respectively, and 
concomitant medications. 
5 AESI assessment at Visit 2, Day 0 to be done prior to treatment. AESI Questioning: active questioning 
by guided review of systems as per AESI manual. If an AESI is reported, a targeted physical examination 
around the area of the reported AESI must follow. 
6 Subjects will be monitored for AEs 30 minutes after administration of the IMP. 30-minute post IMP 
administration, general, non-leading AE questioning as well as active AESI questioning must be 
performed. 
7 For subjects that are prematurely discontinued from the study (at any time), the End of Study visit will 
take place within one week of discontinuation. For subjects terminating the study early as per decision 
made at a site visit, the study procedures required at the End of Study visit should be performed at the 
visit during which the subject was terminated from the study. 
 
12.4 
Unscheduled Visit 
An unscheduled visit can be held at any time during the study, if deemed necessary by 
the investigator. In addition, an unscheduled visit must be scheduled to occur as soon 
as possible if an AESI is reported during any telephone contact. An unscheduled visit 
will not replace any of the above visits as per schedule of events. Assessments 
performed at an unscheduled visit will be at the investigator’s discretion, but should 
include AE assessment, AESI query, concomitant medication and possibly the GLS-I 
and GLS-S. 
In case of an unscheduled visit, the investigator should complete the “Unscheduled 
Visit Form" in the eCRF. 
12.5 
Subject Diary and Patient Reported Outcomes 
12.5.1 
Subject Diary 
A paper subject diary will be provided to each subject at Visit 2, Baseline (Day 0) and 
at Visit 3 (Week 1) for daily documentation of GLS-S score at maximum frown. 
Subjects will be trained on use of the diary during the Baseline visit and the training 
will be recorded in the source. 
The first subject diary will be collected at Visit 3 (Week 1) one week after treatment; 
the second diary will be collected at Visit 4 (Week 2), two weeks after treatment. The 
diary shall be checked for completeness at both visits to ensure all required data has 
been entered.  
The subject will record the GLS-S score in diaries daily for the first two weeks after 
treatment. 

 
 
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The subject diary will serve as a source record. Entries in the subject diary will be 
transcribed into the electronic data capture (EDC) system by the blinded member of the 
site study team. 
12.5.2 
Patient Reported Outcomes 
A patient reported outcome (PRO) instrument (i.e., a questionnaire plus the information 
and documentation that support its use) is a means to capture subject views of outcomes 
used to measure treatment benefit or risk in IMP clinical studies. Two PRO instruments 
will be used in this study to support claims in the product label, comprising:  
• The GLS-S (Section 13.1.1, Section 23.2). 
• The FACE-Q Satisfaction with Outcome Scale which will be used to measure 
subject satisfaction with treatment (Section 13.2, Section 23.3). 
Entries in the questionnaires will be transcribed into the EDC system by a blinded 
member of the site study team. 
12.6 
Subject Completion/Discontinuation 
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, followed all 
appropriate conditions of a protocol (with or without protocol deviations). Study 
completion will be documented in the eCRF. 
Reasons 
for 
completion 
or 
non-completion 
will 
be 
reported 
on 
the 
Completion/Termination eCRF, including: completed, screen failure, premature 
termination due to AE (including death), discontinuation by subject (e.g., dropout, lost 
to follow-up, withdrawn informed consent), physician decision (e.g., non-compliance 
with protocol, or for safety reasons), study terminated by Sponsor, or other reason to be 
specified by the investigator. Regardless of the reason for subject withdrawal, all data 
available for the subject up to the time of completion/discontinuation should be 
transferred from the subject records on the appropriate eCRF.  
Every effort will be made to have discontinued subjects complete the End of Study 
visit. All procedure and assessment results performed at the End of Study visit will be 
recorded under the Termination visit assessments. If a subject terminates participation 
in the study during or after a visit and does not return for a Completion/Termination 
visit, or is lost to follow up their last recorded assessments shall remain under the last 
visit they attended (i.e., no assessment data shall be recorded under/transferred to the 
Completion/Termination visit assessments). The reason for discontinuation will be 
recorded on the eCRF. 

 
 
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12.7 
Procedures for Monitoring Subject Compliance 
All study procedures are to be performed under supervision at the study site, and thus, 
no separate procedures will be used to monitor subject compliance. 

 
 
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13. 
ASSESSMENT OF EFFICACY 
13.1 
Assessment of Glabellar Line Severity: Facial Wrinkle Scale  
In accordance with FDA Guidelines for Upper Facial Lines, efficacy will be determined 
using well defined, valid and reliable clinician-reported and subject-reported 
assessments, capable of measuring the critical outcomes that contribute to a conclusion 
of overall success or failure. For both investigator and subject assessment, 
measurements will be made at maximum frown (the worst appearance of upper facial 
lines with maximum load on the muscle; eyebrows pushed together as far as they can 
go) and at rest (the best appearance of upper facial lines with the least load on the 
muscle), which allows one to impute benefit when the face is in dynamic motion 
(variable load on the muscle).  
The scale used most frequently in clinical studies is the FWS, which is a four-point 
rating scale as follows: 0=no facial wrinkles; 1=mild facial wrinkles; 2=moderate facial 
wrinkles; and 3=severe facial wrinkles. The scale has been validated and shown to be 
reproducible33. However, this scale includes pictures at rest and at maximum frown 
within the one scale, meaning that the sensitivity of the scale at rest is low. The FWS 
proposed for use in this study is comprised of the GLS-I and GLS-S. The scales and the 
instructions for use for the investigator and subject are provided in Section 23.1 and 
Section 23.2, respectively; additional information for the investigator is provided in the 
completion manuals: ‘Glabellar Line Scale - Subject: Completion Manual for 
Investigator’, and ‘Glabellar Line Scale - Investigator: Completion Manual’. 
13.1.1 
Investigator and Subject In-clinic Assessment 
Investigators and subjects will assess the severity of the subject's glabellar lines at 
maximum frown and at rest using the GLS-I and the GLS-S, respectively.  
Subjects will be trained extensively in accurate self-assessment of their glabellar line 
severity by the investigator at the Screening Visit, as outlined in the completion 
manuals (Glabellar Line Scale - Subject: Completion Manual for Investigator and 
Glabellar Line Scale – Investigator: Completion Manual). Investigators will complete 
training before study initiation. Subject assessment must be performed independently 
of the investigator and ideally before the investigator assessment, to rule out any 
influence or bias from the investigator. The date and time of assessment will be 
recorded for each visit.  
The same investigator must complete Baseline assessments and FWS at Week 4 
(primary endpoint assessments) for a given subject. 
The primary efficacy endpoint will be a composite endpoint of the investigators’ and 
the subjects’ assessments of line severity at maximum frown after treatment with 

 
 
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BoNT/A-DP compared to 
 at Week 4. A subject will be considered a 
responder if they have a FWS score of 0 or 1 and an improvement ≥ 1 point in FWS at 
maximum frown at the Week 4 Visit relative to Baseline, based on both the 
investigator’s and the subject’s in-clinic assessments of the GLS-I and GLS-S, 
respectively.  
13.1.2 
Photography 
Photography will be performed by specifically trained personnel in accordance with the 
relevant imaging manual. Photographs of subjects at maximum frown and at rest will 
be taken at the following visits: Baseline before treatment; at study Visits 4, 5, and 7 
(2, 4, and 12 weeks post-treatment, respectively); and at Visit 8, End of Study (16 weeks 
post-treatment).  
13.2 
Subject Satisfaction with Treatment 
Treatment satisfaction will be measured using the FACE-Q Satisfaction with Outcome 
Scale34 (Section 23.3) at Visits 5 and 7, and at Visit 8, End of Study (4, 12, and 16 weeks 
post-treatment, respectively). 

 
 
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14. 
ASSESSMENT OF SAFETY 
14.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered an IMP 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an IMP, whether 
or not related to the IMP. AEs will be recorded from signing the ICF until the End of 
Study visit. SAEs and AESIs are subgroups of AEs as defined below. Any remark for 
AEs in general also applies to AESIs and SAEs.  
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the 
start of the study (i.e., before informed consent) should be recorded as Medical History; 
however, any increase in severity, frequency or duration of a pre-existing disease during 
the course of the study will be recorded as an AE. Clinically significant test results at 
Screening will be recorded as Medical History. Any untoward medical occurrence in a 
subject between ICF and administration of the study treatment will be recorded as a 
Pre-treatment Event on the Medical History page. Any untoward medical occurrence 
in a subject that occurs after treatment until the End of Study visit will be recorded as 
an AE. All AEs, AESIs, and SAEs must be recorded, irrespective of whether they are 
considered study drug related. 
The investigator may contact the Sponsor’s Medical Expert if additional information is 
needed for the assessment of AEs. 
14.2 
Adverse Events of Special Interest 
A specific concern in treatment with botulinum toxin products is the potential for local 
and distant spread of toxin effect, a unique set of safety concerns related to use of 
botulinum toxin drug products (draft guidance for industry Upper Facial Lines: 
Developing Botulinum Toxin Drug Products). Therefore, subjects will be instructed and 
educated on possible warning signs and precautions and on rare AESIs through the 
Subject Information Sheet (SIS). Safety data related to this specific potential effect 
should be obtained through directed query at each study visit and if an AESI (as listed 
below) is reported, a targeted physical examination should be conducted to evaluate for 
signs and symptoms of local and distant spread of toxin effect. AESI assessment and 
documentation is mandatory based upon the event term. An AESI must also be reported 
even if e.g., the duration of the event is considered unusual for an AESI or if the event 
is considered as being not related to the study drug. AESIs potentially suggestive of 
distant spread of toxin include: 

 
 
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accommodation disorder 
areflexia 
aspiration 
blurred vision 
botulism 
bradycardia  
bulbar palsy 
constipation 
cranial nerve palsies 
cranial nerve paresis 
cranial nerve paralysis 
diaphragmatic paralysis 
diplopia 
dry mouth 
dysarthria  
dysphagia 
dysphonia 
dyspnea 
extraocular muscle paresis 
eyelid function disorder 
eyelid ptosis 
facial palsy 
facial paresis 
fourth cranial nerve 
paresis 
hemiparesis 
hypoglossal nerve paresis 
hyporeflexia 
hypotonia 
monoparesis 
muscular weakness 
paralysis 
paralysis flaccid  
paralytic ileus  
paraparesis 
Paresis 
peripheral nerve palsy 
peripheral paralysis 
pelvic floor muscle 
weakness  
pneumonia aspiration 
pupillary reflex impaired 
quadriparesis 
respiratory arrest 
respiratory depression 
respiratory failure 
speech disorder 
third cranial nerve paresis 
trigeminal nerve paresis  
urinary retention 
vocal cord paralysis  
vocal cord paresis 
The first AESI questioning will be undertaken (in accordance with the AESI Manual) 
prior to treatment, in order to obtain a full Baseline status of any concomitant diseases. 
If an AESI is reported, a targeted physical examination of the relevant area must be 
conducted.  
14.3 
Serious Adverse Events 
An SAE is defined as an untoward medical occurrence that at any dose meets one or 
more of the following criteria: 
• Results in death. 
• Is life threatening – defined as an event in which the subject was, in the 
judgment of the investigator, at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death had it been more 
severe. 
• Requires subject hospitalization or results in prolongation of existing 
hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. 
Note: Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life threatening or result in death or require 
hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the 

 
 
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definitions above. Examples of such events are: invasive or malignant cancers, 
intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse. 
Hospitalization is defined as at least one overnight stay. Pre-planned 
hospitalizations (known already prior to signing the ICF) will not be considered 
an SAE, unless any of above criteria are fulfilled over the course of the 
hospitalization due to unplanned complications. 
14.4 
Treatment-Emergent Adverse Events (TEAEs) 
A TEAE is defined as any event not present prior to the initiation of the treatment, or 
any event already present that worsens in terms of severity, duration, or frequency 
following exposure to the treatment. 
14.5 
Evaluation of AEs, AESIs, SAEs, TEAEs 
14.5.1 
Assessment of Causality 
The investigator is obliged to assess the relationship between the IMP as well as study 
procedure and the occurrence of each AE/AESI/SAE. This relationship will be classed 
as not related, unlikely, possibly, probably or definitely related as follows: 
• Not related (both circumstances must be met): 
 Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs. 
 Is not associated with the IMP or study procedure (i.e., does not follow a 
reasonable temporal relationship to the administration of IMP or has a 
much more likely alternative etiology). 
• Unlikely related (either one or both circumstances are met): 
 Has little or no temporal relationship to the IMP or study procedure. 
 A more likely alternative etiology exists. 
• Possibly related (both circumstances must be met): 
 Follows a reasonable temporal relationship to the administration of IMP. 
 An alternative etiology is equally or less likely compared to the potential 
relationship to the IMP or study procedure. 
• Probably related (both circumstances must be met): 
 Follows a reasonable temporal relationship to the administration of IMP, 
which may include but is not limited to the following: 
o Reappearance of a similar reaction upon re-administration (positive 
re-challenge). 
o Positive results in a drug sensitivity test (skin test, etc.). 
o Toxic level of the IMP as evidenced by measurement of the IMP
 concentrations in the blood or other bodily fluid. 

 
 
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 Another etiology is unlikely or significantly less likely 
• Definitely related: 
 Has clear and undoubted relationship to the administration of IMP. 
 
The investigator will use his/her clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to IMP 
administration will be considered and investigated. The investigator will also consult 
the IB in the determination of his/her assessment. 
For the purpose of expedited regulatory reporting, events assessed as possibly, 
probably, or definitely related to IMP or study procedure will be considered as drug 
related.  
14.5.2 
Assessment of Severity 
The following definitions for rating severity will be used: 
• Mild:  
 The AE is easily tolerated and does not interfere with daily activity. 
• Moderate:  
 The AE interferes with daily activity but the subject is still able to 
function. 
• Severe:  
 The AE is incapacitating and/or requires medical intervention. 
 
14.5.3 
Outcome 
The outcome options that can be utilized include: 
• Ongoing 
• Resolved 
• Resolved with Sequelae 
• Death 
• Unknown 
14.5.4 
Action Taken with Study Drug 
Action taken with study drug includes: 
• None 
• Discontinued 

 
 
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14.6 
Adverse Event Monitoring and Assessment 
Subjects will be monitored for AEs throughout the study from signing the ICF until the 
End of Study visit. Should an SAE occur after the End of Study visit, which is 
considered as at least possibly related to study drug or procedure, such events should 
always be reported to Croma or its representative, even after the end of the study. Such 
events would generally not be entered into the clinical database but will be entered into 
the safety database.  
Subjects will be questioned concerning their well-being at all study visits from 
Screening through to the End of Study visit. Questions for evaluation of AEs will be 
posed in a non-leading manner, so as not to bias the response. In addition to questioning 
at specific time points, subjects will be encouraged to spontaneously report any AEs, 
AESIs, or SAEs. In addition, as per Section 14.2, AESIs will be questioned in an active 
manner. Any subject with an AE, AESI, SAE or clinically significant abnormal test 
result will be evaluated by the investigator and will be treated and/or followed up as per 
local clinical practice. A physician, either at the investigative site or at a nearby hospital 
emergency room, will administer treatment for any SAEs. Where appropriate, medical 
tests and examinations may be performed to ensure that an AE has fully resolved. AEs, 
AESIs, and SAEs ongoing at End of Study will be followed up until the event is 
resolved or stable. Adverse events will be coded using the current version of the 
Medical Dictionary for Regulatory Activities (MedDRA). Whenever possible, a 
specific disease or syndrome, rather than individual associated signs and symptoms, 
should be identified by the investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific 
disease or syndrome by the investigator, it should be recorded as a separate AE on the 
eCRF.  
When documenting AEs, standard medical terminology should be used in order to avoid 
the use of vague, ambiguous, or colloquial expressions (see Section 14.1). Each AE will 
be evaluated by the investigator for: 
• Seriousness, as defined in Section 14.3. 
• Causal relationship to IMP exposure, as defined in Section 14.5.1. 
• Causal relationship to procedure, as defined in Section 14.5.1. 
• Severity, as defined in Section 14.5.2. 
• Outcome, as defined in Section 14.5.3. 
• Action taken with study drug, as defined in Section 14.5.4. 
 

 
 
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If the severity rating for an ongoing AE worsens before the event resolves, the AE will 
be reported in an additional row in the AE log (or additional AE page) with complete 
information (i.e., start and stop date, severity, relationship, outcome, etc.). 
14.6.1 
Reporting Serious Adverse Events and Adverse Events of Special Interest 
All SAEs and AESIs for all subjects occurring from the time of informed consent until 
the End of Study visit must be reported to Croma or their representative within 
24 hours of the knowledge of the occurrence. If considered at least possibly related to 
study treatment, SAEs observed after the End of Study visit must also be reported. 
Paper SAE/AESI forms should be completed at the site and emailed or faxed to the 
 within 24 hours of 
awareness of the event: 
 
 
 
 
The preferred way of submitting safety reports is via email; fax numbers are provided 
for backup. 
If a report is sent via email the completed and signed SAE/AESI or Pregnancy report 
form must be attached to the email; describing an event in the email text is not 
sufficient. 
There may be situations when an SAE/AESI has occurred and the investigator has 
minimal information to include in the initial SAE/AESI report to Croma, or their 
representative. However, it is very important that the investigator always makes an 
assessment of causality for every event prior to transmission of the SAE/AESI report 
form. Minimum criteria are identifiable subject (number), suspect product (i.e., IMP or 
concomitant medication), an identifiable reporting source (investigator/study-site 
identification) and an event or outcome that can be identified as serious or as an AESI. 
The investigator may change his/her opinion of causality in the light of follow-up 
information, amending the SAE/AESI report form accordingly. The causality 
assessment is one of the criteria used when determining regulatory reporting 
requirements for SAEs. 
14.6.2 
Exposure In Utero during Clinical Studies 
The Sponsor or representative must be notified of any subject that becomes pregnant 
while participating in this clinical study. Although pregnancy is not technically an AE, 
all pregnancies must be followed to conclusion to determine their outcome. This 

 
 
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information is important for both drug safety and public health concerns. It is the 
responsibility of the investigator or designee to report any pregnancy in a subject that 
occurs during the study to 
 Clinical Research, as specified above (Section 14.6.1) 
within 24 hours of awareness of the pregnancy, using the pregnancy reporting form. 
Pregnant subjects will be withdrawn from the study if pregnancy is detected at the 
Screening or Baseline Visit. Following detection of pregnancy, no invasive assessments 
may be conducted in pregnant women. The treatment code for pregnant women will be 
unblinded. 
14.6.3 
Overdose 
Overdose is defined as any dose above the total body dose per injection 
(i.e., 20 U/treatment of either BoNT/A-DP or 
). Single treatment doses 
of up to 50 U of 
, a botulinum toxin with similar potency units to the 
study drug, are frequently used for cosmetic/aesthetic indications,35,36,37,38and it is 
generally recognized that doses greater than 20 U may be required for larger muscles39. 
The treatment dose for both products in this study is 20 U and the treatment vials for 
both products contain only 50 U, hence there is virtually no risk of overdose.  
14.7 
Urgent Safety Measures 
The investigator may take appropriate urgent safety measures in order to protect 
subjects against any immediate hazard to their health or safety. The measures should 
be taken immediately and may be taken without prior authorization from Croma. In the 
event of an apparent immediate hazard to the subject, the investigator will notify the 
Sponsor immediately by phone and confirm notification to the Sponsor in writing as 
soon as possible, but within one calendar day after the change is implemented. The 
Sponsor (Croma-Pharma GmbH) will also ensure the responsible Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) is notified of the urgent measures 
taken in such cases, according to local regulations. 
14.8 
Pre-existing Diseases 
Pre-existing diseases that are present before entry into the study and described in the 
medical history and that manifest with the same severity, frequency, or duration 
subsequent to IMP administration, need not be recorded as AEs. However, if there is 
an increase in severity, frequency or duration of a pre-existing disease, the event shall 
be documented as an AE. 
14.9 
Unexpected Adverse Events 
An unexpected AE is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety 
Information of the IB/SmPC. “Unexpected” also refers to the AEs or suspected adverse 

 
 
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reactions that are mentioned in the IB as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Each unexpected AE experienced by a subject will be recorded on the AE eCRF. 
14.10 Medication and Non-Drug Therapy History 
All medication taken for up to eight weeks prior to ICF signature, and all concomitant 
medications taken or administered during the study, will be documented in the subject’s 
clinic/hospital and study records using the guidelines set forth by the Sponsor. The prior 
and concomitant medication information will be documented on the Concomitant 
Medication eCRF.  
In addition to product name (preferably generic name), the dose, indication, route of 
administration and frequency, as well as the start and end date of treatment, will be 
documented. In the context of this study, information on non-drug therapies will only 
be collected in relation to SAEs. 
Prohibited Medication and Excluded Non-drug Therapies  
The medication listed below must not be taken during the conduct of the study: 
• Treatment with botulinum toxin of any serotype for any reason during the study, 
other than BoNT/A-DP or 
 administered as part of this study.  
• Use of a muscle relaxant. 
• Use of anticholinergic drugs, or drugs which could interfere with neuromuscular 
function, including aminoglycoside antibiotics and curare-like compounds. 
• Surgery with general anesthetic. 
The following non-drug therapies are excluded during the study: 
• Facial laser or light treatment, microdermabrasion, superficial peels or retinoid 
therapy. 
• Treatment with any facial aesthetic procedure in the glabellar area (including 
chemical peeling, injection with biodegradable fillers). 
• Insertion of permanent material in the glabellar area. 
• Surgery in the glabellar area including surgical removal of the corrugator, 
procerus or depressor supercilii muscles or a combination of these. 
14.11 Medical History and Physical Examinations 
Medical history will be taken at Screening, including a record of previous treatment 
with botulinum toxin. At Screening and the End of Study visit, a full physical 
examination will be performed by the investigator. A full physical exam will include 

 
 
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neurological assessment (including extraocular movements and cranial nerves) as well 
as assessment for muscle weakness. In addition, if the subject reports an AESI (as 
detailed in the AESI Manual) a focused physical examination by the physician will also 
be undertaken to evaluate these symptoms. Any clinically relevant abnormal finding 
will be documented in the eCRF as AE/medical history. 
14.12 Pregnancy Test 
For all women of childbearing potential (i.e., pre-menopausal with no more than 
12 consecutive months without a menstrual period or not surgically sterilized), a 
pregnancy test will be performed at Screening, Baseline, and at the End of Study visit. 
Additional pregnancy tests will be performed for women of childbearing potential at all 
sites in Austria, at Visits 5, 6 and 7 (4, 8 and 12 weeks post-treatment, respectively).  
All pregnancy tests will be urine dipstick tests. 
14.13 Vital Signs 
Vital signs will include pulse rate (beats/min), and systolic and diastolic blood pressure 
(mmHg). Vital signs will be measured at Screening; Baseline (to be recorded before 
IMP administration); Visits 3, 5, and 7; and at Visit 8, End of Study. Vital sign values 
will be recorded on the eCRF. 
14.14 Demographic Data 
Demographic data will only be collected at Visit 1 (Screening). These data include age 
(at time ICF signed), year of birth, height (cm), weight (kg), gender, race and ethnicity 
(including Fitzpatrick Skin Type). 

 
 
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15. 
STATISTICS 
15.1 
Sample Size and Power Calculations 
The purpose of the study is to provide preliminary comparative data on BoNT/A-DP 
versus 
 Subsequently the sample size is primarily based on clinical 
judgement and practical considerations, rather than formal statistical arguments. 
However, with a sample size of 100 subjects per group, a two-sided 95% confidence 
interval (CI) for the difference between BoNT/A-DP and 
 will extend 
10.8% from expected proportions of 81.5% in both groups based on large sample 
normal approximation.  
15.2 
Data Sets and Analysis Cohorts 
Safety Analysis Set (SAF): 
All subjects who received at least one injection with study medication (independent of 
whether it is BoNT/A-DP or 
) will be valid for the SAF. Within the SAF, a subject 
will be considered for the treatment actually received and not for the treatment assigned 
by randomization, if different. The SAF will be used for the evaluation of the safety 
assessments. 
Full Analysis Set (FAS): 
The FAS includes all randomized subjects who had a Baseline Visit 1 at Day 0 and at 
least one post-dose in-clinic assessment with the 4-point scale by either the investigator 
or the subject on visits at Weeks 1, 2, or 4. Within the FAS a subject will be considered 
for the treatment assigned by randomization and not for the treatment actually received, 
if different, i.e., following the intent-to-treat principle. The FAS will be used for the 
evaluation of the efficacy assessments. The FAS serves as the primary efficacy analysis 
set. 
Data Review Meeting: 
Subjects will be assigned to the SAF and FAS during a Data Review Meeting (DRM). 
Further details on the DRM will be specified within the Statistical Analysis Plan (SAP). 
Details for and decisions on protocol deviations will also be discussed at the DRM, 
taking place between database lock and unblinding. Corresponding documentation 
should be held outside of the SAP. 
15.3 
Procedure for Accounting for Missing, Unused, and Spurious Data 
Analyses will be performed by visit. When estimating the response rate at Week 4 for 
the co-primary endpoints, missing assessments with the FWS at Baseline or Week 4 

 
 
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will be assigned as being non-responders. For all other visits and endpoints, summary 
statistics will be based on observed data. 
15.4 
Methods of Analysis 
15.4.1 
Primary Outcome Measure 
The purpose of the study is to provide preliminary comparative efficacy and safety data 
of BoNT/A-DP versus 
.  
The study comprises co-primary endpoints defined as: 
• An FWS score of 0 or 1 and a ≥ 1 point reduction in FWS score at maximum 
frown at the Week 4 Visit relative to Baseline, based on investigator assessment. 
• An FWS score of 0 or 1 and a ≥ 1 point reduction in FWS score at maximum 
frown at the Week 4 Visit relative to Baseline, based on subject assessment. 
That is, a subject will be considered a responder if they have an FWS score of 0 or 1 
and an improvement ≥ 1 point at maximum frown of the glabellar lines at Week 4 
relative to Baseline in FWS, based on the investigators’ and the subjects’ in-clinic 
assessments. 
The focus of the statistical analysis for the co-primary endpoints will be on descriptive 
statistics (n and %), and 95% CIs for the difference in treatment effects between 
BoNT/A-DP and 
. 95% Clopper-Pearson CIs will be calculated for the 
difference between BoNT/A-DP and 
 for each co-primary endpoint. No 
formal statistical hypothesis testing will be conducted. 
The FAS will serve as the primary analysis set for the descriptive statistics. 
Subjects with missing investigator or subject in-clinic assessments with the FWS at 
Baseline or Week 4 Visit will be assigned as being non-responders. 
Since the focus of the statistical analysis is on descriptive statistics and no formal 
statistical hypothesis testing is planned, no adjustment for controlling the type 1 error 
rate for the co primary endpoints is required. 
Additional Analyses on the Primary Endpoint Variable 
• The primary endpoint measure will also be summarized using the observed 
values only, i.e., missing investigator or subject in-clinic assessments with the 
FWS at Baseline or Week 4 Visits will be excluded from analysis but not 
assigned as being non-responders. 

 
 
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• The following subgroup analysis will be conducted: 
o site  
o previous use of Botulinum  
o race  
o subjects with previous use of botulinum toxin by site 
o naïve subjects by site 
o Fitzpatrick skin type 
o sex 
o ethnicity 
o age groups (below 65 years, 65-74 years and 75-84 years; below 
65 years versus 65 years and older) 
 
15.4.2 
Secondary Outcome Measures 
Key Secondary Analyses: 
Since the focus of the statistical analysis is on descriptive statistics and no formal 
statistical hypothesis testing is planned on secondary endpoints, no adjustment for 
controlling the type 1 error rate is required. 
The following are considered key secondary endpoints: 
1. Percentage of responders with an  FWS score of 0 or 1 and a ≥ 1 point reduction 
in FWS score at maximum frown at Weeks 1, 2, 8, 12 and 16, based on 
independent investigator assessment and subject assessment. 
2. Percentage of responders with an FWS score of 0 or 1 and a ≥ 2 point reduction 
in FWS score at maximum frown at Weeks 1, 2, 4, 8, 12 and 16, based on 
independent investigator and subject assessments. 
3. Percentage of responders with an FWS score of 0 or 1 and a ≥ 1 point reduction 
in FWS score at rest at Weeks 1, 2, 4, 8, 12 and 16, based on independent 
investigator and subject assessments. 
4. Time to onset of effect, as measured at Weeks 1, 2, and 4, based on independent 
investigator and subject assessments. Onset of effect is defined as ≥ 1 point 
improvement in Glabellar Line Scale - Investigator (GLS-I) and Glabellar Line 
Scale – Subject (GLS-S) score relative to Baseline at maximum frown in 
glabellar lines. In addition, onset of effect will be assessed by subjects daily 
during the first 2 weeks after treatment, by recordings in the subject diary. 
5. For subjects who respond, duration of effect will be assessed based on 
independent investigator and subject assessments. Effect will be deemed to be 
lost when scores return to Baseline values. 
6. The FACE-Q assessment at Weeks 4, 12 and 16. 

 
 
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For categorical endpoints, the same analyses will be conducted as described for the 
co-primary endpoints. Continuous variables will be summarized using the following 
descriptive statistics: number of subjects (n), mean, standard deviation, median, 
minimum and maximum. 95% confidence of the difference in treatment effects will be 
calculated. Time-to-response and duration of response will be analyzed using 
Kaplan-Meier methodology. 
The FACE-Q Satisfaction with Outcome Scale will be derived in accordance with the 
developers’ instructions and missing data treated accordingly. 
Secondary Safety Endpoints: 
Safety endpoint variables will be analysed descriptively only. 
Analysis of secondary safety endpoint 1 (AEs): 
Adverse events will be separated to pre-treatment AEs and TEAEs. TEAEs are defined 
as all AEs with onset or worsening (increase in severity) after receiving first dose of 
study medication (independent of whether it is BoNT/A-DP or 
). If it cannot be 
determined whether an AE is treatment-emergent due to a partial onset date, then it will 
be counted as such. 
Treatment-emergent AEs will be summarized by system organ class (SOC) and 
preferred term (PT) (MedDRA). The number of events, as well as the number and rate 
of affected subjects will be reported. Treatment-emergent AEs (SOC and PT) will also 
be summarized by seriousness, severity, relationship to study medication, and 
relationship to procedure. Treatment-emergent AESIs will be tabulated separately. 
Analysis of secondary safety endpoint 2 (vital signs):  
The analyses of variables for vital signs will focus on the evaluation of the change from 
Baseline to the scheduled time points after Baseline. Descriptive analysis with means, 
standard deviations, medians, minima and maxima of the time course and of changes 
from Baseline to each post-Baseline visit will be presented. 
15.4.3 
Further Analyses 
Baseline data, including demographic data, will be analysed descriptively. Subject 
disposition, including discontinuation and reasons for discontinuation, and subject 
exposure will be tabulated in detail. Concomitant medication, including application site 
concomitant medication, will be coded according to the World Health Organization 
(WHO) drug dictionary and tabulated accordingly. 

 
 
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15.5 
General Statistical Considerations 
Further aspects of statistical analyses will be detailed within an SAP. This Plan will be 
finalized prior to the database lock and/or study unblinding.  
For statistical analyses “baseline” refers to the last observation before treatment, i.e., 
pre-treatment values measured on the treatment day (Baseline Visit, Day 0), and if 
missing or not evaluated, values from the Screening Visit will be used. 
Analyses will be performed by visit, irrespective of any time window deviations.  
15.5.1 
Interim Analysis 
No interim analyses are planned. 

 
 
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16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/study site will cooperate and provide direct access to study-related 
records and data, including source documentation for monitoring by the study monitor 
or authorized representatives of the Sponsor, audits by the Sponsor or authorized 
representatives of the Sponsor, IRB/IEC review, and applicable regulatory authority 
inspections. If contacted by applicable regulatory authorities, or during an inspection, 
the investigator will notify the Sponsor of contact, cooperate with the authorities, 
provide the Sponsor with copies of all documents received from the authorities, and 
allow the Sponsor to comment on any responses. In the event of an inspection, the 
investigator agrees to allow the inspector direct access to all relevant documents and to 
allocate his/her time and that of the study site personnel to the inspector to discuss 
findings in any relevant issues. The investigator will allow Croma personnel to be 
present as an observer during a regulatory inspection, if requested. 

 
 
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17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Standard Operating Procedures (SOPs) belonging to
 will be adhered to for all 
activities relevant to the quality of the study, and performed by
 employees, and 
are routinely monitored by the 
 Quality Assurance Division. Vendors 
sub-contracted by 
 or Croma will adhere to their own relevant SOPs. 
A Sponsor-designated monitor (independent to the site) will be responsible for the 
monitoring of the study and its data within the eCRFs. The monitoring of the study will 
be performed according to 
 monitoring SOPs. 
17.1 
Investigator’s Responsibility 
The investigator will comply with the protocol; Title 21, CFR Part 312; applicable 
regulatory requirements; local laws; and regulations. The investigator is ultimately 
responsible for the conduct of all aspects of the study at the study site. The investigator 
verifies by signature the integrity of all data transmitted to the Sponsor. Except where 
the investigator’s signature is specifically required, it is understood that the term 
“investigator”, as used in this protocol, and in study-related documents refers to the 
investigator or authorized study personnel that the investigator has designated to 
perform a certain duty. Sub-investigators or other authorized study personnel are 
eligible to sign for the investigator, except where the investigator’s signature is 
specifically required. 
17.2 
Study Organization 
The name and contact information of all of the individuals involved with the study (e.g., 
investigator(s), medical director, authorized representative(s) of the Sponsor) will be 
maintained by the Sponsor and provided to the investigator. 
17.3 
Training 
The study monitor or authorized representatives of the Sponsor will ensure that the 
investigator and study site personnel understand all requirements of the protocol, the 
study status of the IMP, and his/her regulatory responsibilities as an investigator. 
Training may be provided at an investigator’s meeting, at the study site, and/or by 
instruction manuals. In addition, the study monitor or authorized representatives of the 
Sponsor will be available for consultation with the investigator, and will serve as the 
liaison between the study site and the Sponsor. 
17.4 
Monitoring 
The study monitor and/or other authorized representatives of the Sponsor is/are 
responsible for monitoring that each study site conducts the study according to the 
protocol; SOPs; other written instructions; Title 21, CFR Part 312; and applicable 
regulatory guidelines. The investigator will permit the study monitor or other 

 
 
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authorized representatives to visit the study site at appropriate intervals to observe the 
progress of the study, review study records/documentation, and ensure that informed 
consent has been obtained for each subject prior to performing any study procedure. 
Monitoring processes specific to the study will be described in the Clinical Monitoring 
Plan. 
17.5 
Auditing 
The Sponsor and/or Sponsor’s representatives may conduct audits (quality assurance) 
to evaluate study conduct and compliance with the protocol; SOPs; other written 
instructions/agreements; Title 21, CFR Part 312; and applicable regulatory 
guidelines/requirements. 
The investigator will permit auditors to visit the study site. The quality assurance 
auditor will have access to all medical records, the investigator’s study-related files and 
correspondence, and information in the informed consent documentation of this clinical 
study.  
17.6 
Non-compliance with the Protocol 
The investigator may deviate from the protocol to eliminate an apparent immediate 
hazard to the subject or when the change(s) involves only logistical or administrative 
aspects of the study (e.g., change of phone number). In the event(s) of an apparent 
immediate hazard to the subject, the investigator will notify the Sponsor immediately 
by phone and confirm notification to the Sponsor in writing as soon as possible, but 
within one calendar day after the change is implemented. The Sponsor, or authorized 
designee, will also ensure the responsible IRB/IEC is notified of the urgent measures 
taken in such cases according to local regulations. 
If monitoring and/or auditing identify serious and/or persistent non-compliance with 
the protocol, the Sponsor may terminate the investigator’s participation. The Sponsor 
will notify the IRB/IEC and applicable regulatory authorities of any investigator 
termination. 
17.7 
Facilities 
The study management and monitoring will be performed by: 
 
The statistical analysis will be performed by: 
 
The photographic procedures performed by the clinical study sites will be supported 
by: 
 
 

 
 
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Principal Investigators and Investigation Sites 
A list of investigation sites including names, addresses and professions of the principal 
investigators, names and addresses of investigation sites and names and addresses of 
involved institutions if applicable will be kept in the TMF and will be updated 
accordingly. 
 

 
 
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18. 
ETHICS 
18.1 
Basic Principles 
This research will be carried out in accordance with the current versions of the 
Declaration of Helsinki; Title 21, CFR Part 312; and local regulatory requirements. 
18.2 
Ethics Committee and Regulatory Authorities 
Before enrollment of subjects into this study, the protocol, ICF and any promotional 
material or advertisements will be reviewed and approved by the appropriate IRB/IEC 
and regulatory authorities, where applicable. The IB will be provided for review. The 
study will commence only when the committee has approved the protocol or a 
modification thereof and a copy of the approval letter is received by Croma.  
If the protocol is substantially amended, the protocol amendment, revised ICF (if 
applicable), and any revised promotional material or advertisements will be reviewed 
and approved by the appropriate IRB/IEC and regulatory authorities, where applicable. 
A substantial protocol amendment will only be implemented upon the Sponsor’s receipt 
of approval and, if required, upon the Sponsor’s notification of Regulatory 
Authority(ies) approval. 
It is the investigator’s responsibility to obtain IRB/IEC approval for the protocol and 
all subsequent major changes, in compliance with local law. 
18.3 
Informed Consent 
Investigators will choose subjects in accordance with the eligibility criteria. 
It is the investigator’s or designee’s (where applicable) responsibility to explain the 
study to each potential subject and obtain written informed consent before any study 
procedures are performed. 
The purpose of the study, procedures to be carried out, and potential risks will be 
described to the subjects in non-technical terms in the SIS. Subjects will be required to 
read, sign, and date the ICF, summarizing the discussion prior to Screening, and will 
be assured that they may withdraw from the study at any time without jeopardizing their 
medical care. 
Subjects will sign and date one copy of the ICF, and the investigator/designee providing 
the information and obtaining the consent will also sign. The copy will be retained by 
the subject and the original will be retained on file by the investigator. The copy of the 
SIS will also be given to the subject. 

 
 
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By signing the ICF, subjects agree that they will complete all evaluations required by 
the study, unless they withdraw voluntarily or are terminated from the study for any 
reason. 
The Sponsor will provide to the investigator in written form any new information that 
significantly impacts the subjects’ risks associated with IMP exposure. The SIS and 
ICF will be updated, if necessary. 

 
 
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19. 
DATA HANDLING AND RECORD KEEPING 
All raw data generated in connection with this study (and site files), together with the 
original copy of the final report, will be retained in the archives of 
 until at least 
five years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at 
least five years have elapsed since the formal discontinuation of clinical development 
of BoNT/A-DP. These documents will be retained for a longer period if required by the 
applicable regulatory requirements, or by an agreement with the Sponsor. The TMF 
will be archived by the Sponsor. 
The study site should maintain a study file, which should contain, at minimum, the IB, 
the protocol and any amendments, drug accountability records, correspondence with 
the IRB/IEC and the Sponsor (or designee), and other study-related documents.  
The investigator agrees to keep records and those documents that include (but are not 
limited to) the identification of all participating subjects, medical records, 
study-specific source documents, source worksheets, all original signed and dated ICFs, 
copies of all eCRFs, query responses, and detailed records of drug disposition to enable 
evaluations or audits from regulatory authorities.  
The investigator should retain records required to be maintained for a period of five 
years following the date a marketing application in an ICH region is approved for the 
drug for the indication for which it is being investigated or, if no application is to be 
filed or if the application is not approved for such indication, until at least five years 
after the investigation is discontinued. However, these documents should be retained 
for a longer period if required by the applicable regulatory requirement(s) or if needed 
by the Sponsor. In addition, the investigator must make provision for the subjects’ 
medical records to be kept for the same period of time.  
No data should be destroyed without the agreement of Croma. Should the investigator 
wish to assign the study records to another party or move them to another location, 
Croma must be notified in writing of the new responsible person and/or the new 
location.  
Subjects’ medical records and other original data will be archived in accordance with 
the archiving regulations or facilities of the investigational site. 
19.1 
Confidentiality Policy 
The investigator and all personnel involved in the study will maintain a policy of 
confidentiality.  
19.2 
Source Documentation and Electronic Case Report Forms 
Data will be recorded at sites using eCRFs and reviewed during monitoring visits. The 
recorded data in the EDC system will be verified with source documents. All 

 
 
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corrections or changes made to any study data will be appropriately tracked in an audit 
trail in the EDC system. Electronic CRFs will be considered complete when all missing, 
incorrect, and/or inconsistent data has been accounted for. Data collected at Screening 
will be reported in eCRFs, regardless of Screening outcome. 
Source data (Subject Diary, etc.) should bear the study number, subject number, date 
of data generation, and, if reviewed, dated signature of the investigator or designee. 
Adverse events, concomitant medication data and clinical observations will be in the 
subjects’ hospital notes, or recorded on source data forms, and will be transferred into 
the eCRF after assessment by the investigator or designee. 
Other data of medical measurement without print-outs (date and time of study activities, 
i.e., administration of study medication, completion of PROs) performed during the 
study will be captured on the respective requisition forms or dispensing/administration 
log, which will serve as source documentation for the respective activities. The 
investigator will maintain complete and accurate study documentation in the 
Investigator Site File. 
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to source documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; 2) if not self-evident a reason for the 
change must be given; and 3) each correction must be dated and initialed by the person 
correcting the entry; the use of correction fluid and erasing are prohibited. 
19.2.1 
Electronic Case Report Forms 
The investigator is responsible for the procurement and the quality of source data.  
Authorized study site personnel will transcribe source data and source data changes to 
the eCRF. All data should preferably be entered into the eCRF on the day of the study 
visit, but no later than two working days thereafter. Changes to an eCRF, if not 
self-evident, will require documentation of the reason for each change. After 
completion of the study, an electronic (or if necessary paper) version of the complete 
set of eCRFs for each subject will remain in the investigator file at the study site in 
accordance with the data retention policy (Section 19.3). 
The handling of data by the Sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g., Title 21, CFR Part 312). All data management activities will 
be conducted by the Sponsor’s representative who will follow their SOPs. Data 
management and control processes specific to the study will be described in the Data 
Management Plan. 
Once all the Data Quality Control steps have been performed, the database will be 
locked and the records will be released for reporting and statistical analysis. Data will 

 
 
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be transferred to the study sites via CDs and transferred to the study Sponsor via an 
external hard drive. The media will contain subject PDF files of the eCRFs. 
19.2.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
19.2.3 
Data Entry 
Data must be recorded using the EDC system. All study site personnel must log into 
the system using their secure user name and password in order to enter, review, or 
correct study data. These procedures must comply with the Title 21 CFR Part 11. All 
passwords will be strictly confidential. 
19.2.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Latest version of MedDRA for medical history and AEs. 
• WHO drug information for concomitant medications. 
19.3 
Document and Data Retention 
The investigator will retain study documentation and data (paper and/or electronic 
forms) in accordance with applicable regulatory requirements and the data retention 
policy, as described in the Clinical Study Agreement. 
The medical files of study subjects must be retained in accordance with local legislation 
and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
19.4 
Data Base Lock 
The database will be locked as soon as the database is confirmed as ‘clean’. Before the 
database is locked, a blinded DRM will take place. Further details will be described in 
the Data Management Plan. 
20. 
FINANCING AND INSURANCE 
The investigator will comply with investigator financing, investigator/Sponsor 
insurance, and subject compensation policies, if applicable, as described in the Clinical 
Study Agreement. 

 
 
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21. 
PUBLICATION POLICY 
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 
 
22. 
REVISION HISTORY  
Version
Date 
Reason for Revision
Final 
Version  
 
N/A (original document) 
 

 
 
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23. 
SUPPLEMENTS 
23.1 
Glabellar Line Scale – Investigator (GLS-I) 
• In this questionnaire you will be asked to rate the severity of the subject’s 
glabellar lines when their face is at rest and when they are at maximum frown 
(the worst appearance of upper facial lines with maximum load on the muscle; 
eyebrows pushed together as far as they can go).  
• Please use the accompanying drawings and the photo atlas to help you make 
your ratings.  
• If the subject has any asymmetry in their glabellar lines, please use the most 
severe line to score the questionnaire. 
 
 

 
 
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23.2 
Glabellar Line Scale - Subject (GLS-S) 
• Glabellar lines, also known as frown lines, are the vertical wrinkles between 
your eyebrows that may appear worse when you frown.  
• In this questionnaire you will be asked to rate the severity of your glabellar lines 
(how deep they are) when your face is relaxed (at rest) and then when you are 
frowning (eyebrows pushed together as far as they can go).  
• Please use the accompanying drawings and the photo atlas to help you make 
your ratings.  
• Not everyone’s lines are the same on both sides of their face. Please use your 
most severe line to score the questionnaire. 

 
 
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