Clinical trial NCT03985982
Conditions: Glabellar Frown Lines
Sponsor: Croma-Pharma GmbH
Start date: 2019-04-29; Completion date: 2020-12-22
Enrollment: 410 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to assess the efficacy and safety of BoNT/A-DP in the treatment of glabellar lines in comparison with placebo, including efficacy after repeat treatments and long term safety.

Detailed description:
The study is a parallel-group, randomized, double blind, placebo-controlled study followed by an open label extension.

An interim Analysis will be performed when all subjects finalized the re-evaluation for retreatment visit at week 16 of the first treatment cycle or completed the double blind phase (whichever occurs earlier).

The first treatment cycle of the study will comprise two treatment groups as follows:

* Group A (active): BoNT/A-DP (20 units, 0.5 mL)
* Group B (placebo control): sterile, 0.9% sodium chloride, (0.5 mL). Eligible subjects will be randomized at baseline (day 0) to Group A or B to receive the first treatment in a 3:1 randomization scheme, respectively. Investigators and subjects will be blinded to the treatment administered and will evaluate the severity of glabellar lines independently. The subject should perform their assessment independently and ideally before the investigator, to ensure they are not biased by the investigator. The same investigator should assess the subject at baseline and at the visits at weeks 1, 2 and 4 in the first treatment cycle.

After a screening period of up to14 calendar days, subjects will receive the first treatment (BoNT/A-DP or placebo) and attend for visits at 1, 2 and 4 weeks after treatment and at 4 weekly intervals thereafter for evaluation of efficacy and safety (primary and key secondary efficacy endpoints are evaluated in the first treatment cycle in comparison with placebo).

The first treatment cycle will last at least 12 weeks and will end when the subjects qualify for re-treatment (in accordance with the "eligibility for re-treatment criteria"). After the first treatment cycle is completed, all subjects may enter the open label extension phase and will be dosed with BoNT/A-DP (20 U) for subsequent re-treatments.

Evaluation for re-treatment takes place at the earliest at 12 weeks after the first/previous treatment. Subjects who do not qualify for re-treatment at week 12 will have the option (pending eligibility) of re-treatment at a later visit (at 4 weekly intervals thereafter) until they are eligible for re-treatment or until a total of 48 weeks has elapsed since study start. Subjects will attend for visits at 1 and 4 weeks after any re-treatment and at 4 weekly intervals thereafter. At week 2 and week 8 of each open label cycle a telephone call visit will take place. According to the study schedule (Section 2.1 and Section 2.2), a maximum of 4 treatments per subject (4 treatment cycles) is permitted during the study time frame, with treatments separated by a minimum of 12 weeks.

The number of treatments administered per subject will depend on the subject's qualification for re-treatment; however, the last opportunity for re-treatment is at week 48.

Arms: arm 1: Botulinum Toxin A will be administered in double blind fashion in cycle 1. 20 Units will be administered (divided in five 0.1 mL i.m injections) into glabellar area. arm 2: Placebo will be administered in double blind fashion in cycle 1 divided in five 0.1 mL injections into the glabellar area. arm 3: Open Label Extension Arm where all Subjects from Arm 1 and 2 can receive Experimental Treatment in up to 3 treatment cycles.

20 Units will be administered (divided in five 0.1 mL i.m. injections) into the glabellar area.
Interventions: intervention 1: Botulinum Toxin A intervention 2: Placebo intervention 3: Botulinum Toxin A
Intervention descriptions: intervention 1: Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area intervention 2: injection, sodium chloride 0.9 % divided in five 0.1 mL i.m injections into the glabellar area intervention 3: Injection, 20 Units divided in five 0.1 mL i.m injections into the glabellar area in up to 3 treatment cycles

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: Randomized double blind Phase 3 study to assess the 
efficacy and safety of BoNT/A-DP in the treatment of glabellar lines in 
comparison with placebo followed by an open label extension study 
 
 
Protocol Identifier: CPH-303-201400 
 
Other IDs 
EudraCT Number: 2018-003983-30 
IND Number: 123178 
 
 
 
Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study III (BLESS III) 
 
 
 
Version Date:   15.07.2019 
Version Status:  2.0 
 
 
 
 
 
 
 
 
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/Independent 
Ethics Committee under the condition that it is kept confidential. 
 
 






  
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1.1 
Investigator Acknowledgement 
PRODUCT: BoNT/A-DP 
STUDY TITLE: Randomized double blind Phase 3 study to assess the efficacy and safety of BoNT/A-
DP in the treatment of glabellar lines in comparison with placebo followed by an open label 
extension study. 
PROTOCOL IDENTIFIER: CPH-303-201400 
IND NUMBER: 123178; EudraCT Number: 2018-003983-30 
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 IRB/EC. 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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2. 
SYNOPSIS 
INVESTIGATIONAL MEDICINAL PRODUCT 
Name of Investigational 
Medicinal Product (IMP)  
BoNT/A-DP 
Name(s) 
of 
Active 
Ingredient(s) 
Botulinum toxin A 
CLINICAL CONDITION(S)/INDICATION(S) 
Treatment of moderate to severe glabellar frown lines. 
PROTOCOL IDENTIFIER 
Study CPH-303-201400, IND No: 123178 
PROTOCOL TITLE 
Randomized double blind Phase 3 study to assess the efficacy and safety of 
BoNT/A-DP in the treatment of glabellar lines in comparison with placebo, 
followed by an open label extension study. 
Short title 
Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study III 
(BLESS III) 
STUDY PHASE 
Phase 3 
PLANNED STUDY PERIOD 
Initiation 
Anticipated  April  2019 (FSFV) 
Primary Completion 
Anticipated   January  2021 (LSLV) 
Study Completion 
Final Clinical Study Report anticipated  July  2021 
Duration 
Up to 62 weeks per subject. Total study duration (FSFV to LSLV) up to 23 
months. 
STUDY OBJECTIVES AND PURPOSE 
Study purpose 
To assess the efficacy and safety of BoNT/A-DP in the treatment of glabellar 
lines in comparison with placebo, including efficacy after repeat treatments 
and long term safety. 
Primary Objective 
To assess the efficacy of BoNT/A-DP in reducing the severity of glabellar frown 
lines following treatment (compared with placebo) based on investigator and 
subject assessment at week 4 (of the first treatment cycle). 
Secondary Objective(s) 
1. To assess the proportion of responders at maximum frown and at rest at 
various time points after each treatment, based on investigator and subject 
assessments. 
2. To assess the psychological impact of BoNT/A-DP treatment on subjects (in 
terms of emotional and social functioning and concerns relating to their 
glabellar lines) in comparison with placebo after a single treatment. 


  
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3. To assess onset of effect and the duration of effect (at maximum frown) 
after a single treatment with BoNT/A-DP compared with placebo (first 
treatment cycle), based on investigator and subject assessments. 
4. To provide long term safety data of BoNT/A-DP based on multiple 
treatment cycles and to establish a sufficient safety database to support 
regulatory approval. 
5. To assess subject perceptions of effect of, and satisfaction with, treatment 
in comparison with placebo (first treatment cycle), and during the open-label 
extension phase. 
STUDY DESIGN 
Study Type/ 
Classification/ Discipline 
Efficacy and safety 
Control Type 
Concurrent (placebo) 
Study Indication Type 
Treatment 
Intervention model 
Parallel for first cycle, followed by an open label extension 
Blinding/Masking 
Double blind for first cycle, followed by an open label extension 
Study Design 
The study is a parallel-group, randomized, double blind, placebo-controlled 
study followed by an open label extension.  
An interim Analysis will be performed when all subjects finalized the re-
evaluation for retreatment visit at week 16 of the first treatment cycle or 
completed the double blind phase (whichever occurs earlier).  
The first treatment cycle of the study will comprise two treatment groups as 
follows:  
 
Group A (active): BoNT/A-DP (20 units, 0.5 mL) 
 
Group B (placebo control): sterile, 0.9% sodium chloride, (0.5 mL). 
Eligible subjects will be randomized at baseline (day 0) to Group A or B to 
receive the first treatment in a 3:1 randomization scheme, respectively. 
Investigators and subjects will be blinded to the treatment administered and 
will evaluate the severity of glabellar lines independently. The subject should 
perform their assessment independently and ideally before the investigator, 
to ensure they are not biased by the investigator. The same investigator 
should assess the subject at baseline and at the visits at weeks 1, 2 and 4 in 
the first treatment cycle. 


  
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After a screening period of up to14 calendar days, subjects will receive the 
first treatment (BoNT/A-DP or placebo) and attend for visits at 1, 2 and 4 
weeks after treatment and at 4 weekly intervals thereafter for evaluation of 
efficacy and safety (primary and key secondary efficacy endpoints are 
evaluated in the first treatment cycle in comparison with placebo).   
The first treatment cycle will last at least 12 weeks and will end when the 
subjects qualify for re-treatment (in accordance with the "eligibility for re-
treatment criteria"). After the first treatment cycle is completed, all subjects 
may enter the open label extension phase and will be dosed with BoNT/A-DP 
(20 U) for subsequent re-treatments.   
Evaluation for re-treatment takes place at the earliest at 12 weeks after the 
first/previous treatment. Subjects who do not qualify for re-treatment at 
week 12 will have the option (pending eligibility) of re-treatment at a later 
visit (at 4 weekly intervals thereafter) until they are eligible for re-treatment 
or until a total of 48 weeks has elapsed since study start. Subjects will attend 
for visits at 1 and 4 weeks after any re-treatment and at 4 weekly intervals 
thereafter. At week 2 and week 8 of each open label cycle a telephone call 
visit will take place. According to the study schedule (Section 2.1 and Section 
2.2), a maximum of 4 treatments per subject (4 treatment cycles) is permitted 
during the study time frame, with treatments separated by a minimum of 12 
weeks. 
The number of treatments administered per subject will depend on the 
subject's qualification for re-treatment; however, the last opportunity for re-
treatment is at week 48. 
Planned Duration of 
Subject Participation 
Participation is anticipated to last up to 62 weeks.  
Primary 
Outcome 
Measure 
The primary endpoint is 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 of ≥ 2 points in FWS score (at maximum frown) at week 4 visit 
(of the first treatment cycle) relative to baseline (responders), based on both 
the investigators’ and the subjects’ in-clinic assessments. Thus, the primary 
endpoint is a composite endpoint comprising investigator and subject 
assessments of treatment effectiveness.  


  
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Secondary 
Outcome 
Measure(s) 
Key Secondary Efficacy Endpoints (Applicable for first placebo-controlled 
cycle only) 
1. The extent of change in psychological impact (emotional and social 
functioning and concerns relating to their glabellar lines) at week 4 after 
the first treatment, in the BoNT/A-DP group in comparison with placebo, 
relative to baseline, as assessed by the modified Skindex-16 (Glabellar 
Line Quality of Life Scale, [GL-QoL]) and the FACE-Q (Appraisal of Lines 
Between Eyebrows scale and Age Appraisal visual analog scale [VAS]). 
Additional Secondary Endpoints 
2. The percentage of responders at maximum frown (as defined above) at 
week 12 (after the first treatment with BoNT/A-DP or placebo). 
3. The percentage of responders at week 16 (after the first treatment). 
4. The percentage of responders at week 20 or later (after the first 
treatment). 
5. The proportion of subjects with a ≥ 1 point reduction in FWS score at rest 
at week 4 in the first treatment cycle, based separately on the 
investigators’ and the subjects’ in-clinic assessments (applicable only for 
subjects who have a FWS score at rest ≥ 1 at baseline). 
6. The proportion of responders among BoNT/A-DP and placebo groups 
with a FWS score at maximum frown of 0 or 1 and an improvement ≥ 2 
points in FWS score (at maximum frown) during the first treatment cycle 
visit relative to baseline, based on both the investigators’ and the 
subjects’ in-clinic assessments (composite endpoint, at weeks 1, 2 and 
8). 
7. The proportion of subjects with ≥ 2-point and ≥ 1 reduction in FWS score 
(at maximum frown) in the BoNT/A-DP and placebo groups during the 
first treatment cycle visit relative to baseline, based on the independent 
rater’s assessment of photographs (at baseline and visits 2, 4, 12, 16 and 
20 weeks after treatment, within the first treatment cycle). 
8. Time to onset of effect in the BoNT/A-DP and placebo groups in the first 
treatment cycle, as measured at weeks 1, 2 and 4 based separately on 
subject and investigator assessment. Onset of effect defined as at least a 
1 point improvement in FWS score from baseline (at maximum frown). 


  
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In addition, onset of effect will be assessed by subjects daily in the first 2 
weeks after treatment, by recordings in the subject diary. 
9. The extent of subject perceptions of effect of, and satisfaction with, 
treatment in the BoNT/A-DP and placebo groups, during each treatment 
cycle, as assessed by the FACE-Q Satisfaction with Outcome Scale. 
10. The proportion of subjects with a ≥ 1 point reduction in FWS score at rest 
in the BoNT/A-DP and placebo groups, relative to baseline, during the 
first treatment cycle, based on the independent rater’s assessment of 
photos. 
11. The percentage of subjects with a FWS score of 0 or 1 and an 
improvement ≥ 2 points in FWS score at maximum frown (investigator 
and subject assessment) at 4 weeks after re-treatment relative to the 
rating at the preceding end of cycle visit. 
12. The proportion of subjects with ≥ 1-point reduction in FWS score (at 
maximum frown) in the BoNT/A-DP and placebo groups during the first 
treatment cycle at week 1, 2, 4, 8, 12, 16 and 20  relative to baseline, 
based on both the investigators’ and the subjects’ in-clinic assessments. 
13. The proportion of subjects with ≥ 1-point reduction in FWS score (at 
maximum frown) in the BoNT/A-DP group during each re-treatment 
cycle at week 4 relative to re-treatment-baseline, based on both the 
investigators’ and the subjects’ in-clinic assessments. 
 
Secondary Safety Endpoints 
1. Frequency, severity and causal relationship of adverse events (AEs), 
serious adverse events (SAEs) and adverse events of special interest 
(AESIs) during the entire study period. 
2. Antibody formation, evaluation pre-dose before each treatment, at 4 
weeks after each treatment and at the final study visit. 
3. Safety assessments by evaluating hematology, clinical chemistry, vital 
signs and electrocardiogram (ECG) as per study schedule (Section 2.1). 
INVESTIGATIONAL MEDICINAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION 
Active  
BoNT/A-DP 
Dosage form: Injection, lyophilizate for solution for injection 


  
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Dosage frequency: 20 U/treatment comprising a total of five intramuscular 
(i.m.) injections of BoNT/A-DP (4 U per 0.1 mL injection) administered at a 
minimum interval of 12 weeks. 
Mode of administration: 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. 
Placebo 
Sterile, 0.9% Sodium chloride injection 
Dosage form: Injection  
Dosage frequency: A single treatment comprising five injections of 0.1 mL 
each. 
Mode of administration: Same as for Study IMP. 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 
 353 subjects, with efforts to include a variety of Fitzpatrick skin types. Subject 
accrual planned as follows: 
 
Approximately 7 sites planned, hence for a 3:1 (BoNT/A-DP: Placebo) 
randomization scheme, each site should target between 48 and 52 
subjects.  
Number of 
Groups/Arms/Cohorts 
In the first treatment cycle, two groups.  
 
Group A (active): BoNT/A-DP (20 units, 0.5 mL). 
 
Group B (placebo control): Placebo, 0.5 mL. 
In the open label extension study (cycles 2-4).  
 
BoNT/A-DP (20 units, 0.5 mL). 
Inclusion Criteria 
Subjects who meet ALL the following criteria are eligible for this study: 
 
Aged ≥ 18 years or older at the time of screening (upper limit 75 years, 
inclusive). 
 
Has moderate to severe glabellar frown lines at maximum frown 
(severity score of 2 or 3 on FWS) 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. 


  
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 
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 FWS), without glasses 
obstructing the forehead area. 
 
The moderate to severe glabellar lines have an important psychological 
impact on the subject, as indicated by scores >0 on either the Emotional 
or the Social Functioning subscale of the modified Skindex-16 (GL-QoL). 
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 trial (other than the investigational treatment). 
 
Known hypersensitivity to the 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 3 months prior to screening or planned 
during the study. 
 
Apart from the procedures specified above, previous treatment with any 
facial aesthetic procedure in the glabellar area (including chemical 
peeling, injection with biodegradable fillers,) within 12 months prior to 
screening or planned during the study. 
 
Previous insertion of permanent material in the glabellar area or 
planned during the study. 
 
Any surgery, or history of surgery, in the glabellar area including surgical 
removal of the corrugator, procerus or depressor supercili muscles or a 


  
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combination of these, or scars in the glabellar area, or such surgery 
planned during the study. 
 
Active skin disease/infection or irritation at the treatment area. 
 
Inability to substantially lessen glabellar frown lines even by physically 
spreading them apart. 
 
Use of a muscle relaxant, within 2 weeks prior to screening or planned 
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 
trial. 
 
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 anaesthetic (use of local anaesthetic 
outside the glabellar area is permitted). 
 
Participation in another clinical study within one month of screening and 
throughout the trial. 
 
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). 
 
Eligibility Criteria for re-
treatment 
The following criteria MUST be met for re-treatment: 
 
At time of re-treatment subject does not have relevant changes to their 
health status from enrollment, which would have prevented subject’s 
entry into the study according to the inclusion and exclusion criteria 
 
The subject must have been randomized to receive treatment and must 
have received at least one treatment (BoNT/A-DP or placebo). 
 
A minimum of 12 weeks must have elapsed since the previous study 
treatment. 


  
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 
The subject's glabellar lines at maximum frown must have relapsed to a 
FWS score of 2 or 3 as determined by the investigator and the subject.   
 
No relevant infection or inflammation in the planned injection area. 
 
Negative urine pregnancy test, in women of child-bearing potential. 
 
The subject must have received fewer than four study treatments. 
 
The subject must agree and consent to re-treatment. 
 
Re-treatment will be performed at the latest by week 48. 
 
STATISTICAL ANALYSIS 
Sample Size Calculation 
Primary Analysis: 
The primary endpoint is a composite endpoint comprising investigators and 
subject’s assessments of treatment effectiveness using the FWS.  Composite 
endpoint treatment success (CETS) is defined as a ≥2 point reduction in FWS 
at maximum frown achieving a score of 0 or 1 at the week 4 visit relative to 
baseline based on investigator assessment and subject assessment. Thus, a 
subject is a CETS “Responder” only if both investigator- and subject-rated 
success criteria are satisfied at the week 4 visit after baseline.  
The primary analysis of efficacy is the proportion of responders in the 
BoNT/A-DP treatment group compared with the placebo treatment group. 
For superiority testing of BoNT/A-DP compared with placebo, the following 
assumptions for the sample size calculation will be used: 
 
Item 
Assumption Comments 
Underlying test 
Fisher’s 
Exact Test 
Standard test for a response parameter 
for small numbers 
Randomization 
scheme 
(BoNT-
A/DP:Placebo) 
3:1 
More active treatment subjects to 
enlarge safety data base 
Power 1- 
90% 
Actual power is 92.3%. 
Significance level 
() 
0.025 
one-sided 
 


  
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Response  
Arm BoNT/A-DP 
46% 
Conservative value based on the results 
of previous studies (Bless I and Bless II) 
Response  
Arm Placebo 
2% 
Conservative value based on the results 
of previous studies (Bless I and Bless II) 
Software 
 
The 
sample size 
calculation was 
performed using the software nQuery 
Advisor® 8.2.1.0. 
 
Based on these assumptions, 39 subjects in the BoNT/A-DP arm and 13 
subjects in the placebo arm are required, i.e. 52 subjects in total. This is a very 
small sample size and not sufficient for a detailed evaluation of the data, 
including subgroup analyses. Furthermore, the response rate could not be 
estimated with sufficient precision. Assuming a response rate of 46% in the 
BoNT/A-DG group, a two-sided confidence interval (CI) of 95% with a distance 
from the response rate to the CI limits of about 5.6% could be achieved with 
a sample size of 225 subjects in the BoNT/A-DP group. We propose a 3:1 
randomization of BoNT/A-DP (225 subjects) to placebo (75 subjects), which 
we believe is adequate for a precise estimate of response rate and for post-
hoc sensitivity analyses (i.e. treatment-by-center and other subgroup 
analyses), also taking into account a drop-out rate. 
In addition sample size is justified in order to fulfill FDA request for additional 
subjects treated with BoNT/A-DP to provide an adequate Safety database. 
In total, 353 subjects will be enrolled. Applying a 15% drop out rate would 
result in a total number of completing subjects of about 300. 
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 placebo) 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): 


  
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The FAS includes all randomized subjects. 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 (ITT) 
principle. The FAS will be used for the evaluation of the efficacy assessments. 
The FAS serves as the primary efficacy analysis set.  
Modified Full Analysis Set (MFAS): 
The MFAS includes all randomized subjects who received at least one 
injection with study medication who had a baseline visit 1 at day 0 and at 
least one post-dose in-clinic assessment with the FWS by either the 
investigator or the subject on visits at weeks 1, 2 or 4. Within the MFAS 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 (ITT) principle. The MFAS will be used for the evaluation of the 
efficacy assessments.  
Per-protocol Analysis Set (PP): 
The PP includes all randomized subjects who received at least one injection 
with study medication who had no significant protocol deviations and an in-
clinic assessment with the FWS by the investigator and the subject at baseline 
(day 0) and at the week 4 visit. For the PP, all subjects will be assigned to the 
randomized treatment. 
The PP will only be analyzed for the main efficacy outcome measures. 
General 
Statistical 
Considerations 
Continuous variables will be summarized with means, standard deviations, 
medians, minimums and maximums. Categorical variables will be 
summarized by counts and by percentages of subjects in corresponding 
categories. 
Analyses will be performed by visit.  
For responder analyses on the week 4 and week 12 visits, missing in-clinic 
assessments (by investigator or the subject) with the FWS at baseline or at 
week 4 and week 12 visits will be assigned as being non-responders. 
Additionally, missing values will be analyzed using observed values only, last 
observation carried forward method, and a tipping point analysis approach. 


  
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For patient reported outcome (PRO) instruments, missing data will be 
imputed per developer guidelines, where these are available. 
Treatment emergent adverse events (TEAEs) 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 rate of affected subjects, will be reported. TEAEs (SOC and 
PT) will also be summarized by seriousness, severity, relationship to study 
medication, and relationship to procedure. 
TEAEs will be separately analyzed as events observed on or after first 
treatment up to before the open label extension (first cycle), and events 
starting on or after re-treatment until end of study (open label phase). Events 
in subjects who started the first treatment with placebo but then entered the 
open label extension for re-treatment with BoNT/A-DP, will be considered to 
placebo for the first cycle and to BoNT/A-DP for the open label phase.  
Further aspects of statistical analyses will be detailed within a statistical 
analysis plan (SAP). 
Planned 
Statistical 
Analysis 
Primary Analysis: 
The proportion of subjects (responders) meeting the primary endpoint with 
a FWS score of 0 or 1 and an improvement ≥ 2 points in FWS (at maximum 
frown) at visit week 4 relative to baseline, based on both the investigator and 
the subject in-clinic assessments will be analyzed using Cochran-Mantel-
Haenszel test (with stratification variable site) using a significance level () of  
0.025. The hypothesis to be tested is: 
 
H0: pBoNT/A-DP≤ pPlacebo 
 
H1: pBoNT/A-DP>pPlacebo 
The FAS will serve as the primary analysis set. 
Subjects with missing investigators’ or subjects’ in-clinic assessments with the 
FWS at baseline or week 4 visits will be assigned as being non-responders. 
Additional Analyses on the Primary Endpoint Variable: 
Further analyses on the primary endpoint variable are exploratory. 
A one-sided Pearson 2-test will be applied. 


  
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Two-sided CI of 95% for the responder rates in the BoNT/A-DP and the 
placebo treatment groups will be calculated using Wilson scores. Treatment-
by-center interaction will be tested using the Breslow-Day test for 
homogeneity of the odds ratios. The CIs will also be calculated for the 
additional analyses as listed in the following: 
 
The primary endpoint measure using the observed values only, 
i.e. missing investigator or the subject in-clinic assessments with the 
FWS at baseline or week 4 visit will be excluded from analysis, but 
not assigned as being non-responder. 
 
The primary endpoint measure using the MFAS and PP. 
 
The primary endpoint measure applying the LOCF for week 4 
visit. 
 
Subgroup analysis by site, country and geographic region (US versus 
EU) 
o 
Subgroup analyses will be conducted for sites, country and 
geographic region (US versus EU). Sites with less than 3 
placebo subjects will be combined. The 2-test will be 
applied for each subgroup. In case of a total number of 
observations below 30, or in case of at least one cell 
frequency below 5, Fisher’s exact test will be used instead 
of the 2-test. Stratified analyses applying the Cochran-
Mantel-Haenszel test will also be conducted using factor 
geographic region. 
 
Subgroup analysis by subjects with previous use of botulinum toxin 
versus naïve subjects. 
o 
Subgroup analyses will be conducted for subjects with 
treatment with any serotype of botulinum toxin for any 
indication versus naïve subjects. The 2-test or Fisher’s 
exact test (see above corresponding criteria to use Fisher) 
will be applied for each subgroup. No stratified analysis 
using factor pre-treated/ naïve subjects is currently 
planned. 


  
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 
In addition the following subgroups will be used for the primary 
efficacy endpoint: 
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) 
Key Secondary Analysis: 
The testing of the key secondary endpoint will be performed with appropriate 
multiplicity control based on the FAS population. The results of each test 
result will only be considered confirmative, if the previous test in the order 
showed a confirmatory result at a one-sided significance level of 0.025. If the 
one-sided p-value is larger than 0.025 for any of the tests, the results of the 
subsequent tests will only be considered exploratory, and not confirmatory. 
The application of this hierarchical approach keeps the global significance 
level to 0.025 one-sided and requires no further adjustment of the 
significance level. 
The following order of tests will be defined: 
 
Primary endpoint (composite endpoint) 
 
Key secondary endpoint 1 
1.1 The modified Skindex-16 (GL-QoL) Emotional domain 
1.2 The modified Skindex-16 (GL-QoL) Social Functioning 
domain 
1.3 The modified Skindex-16 (GL-QoL) Overall score 
1.4 The FACE-Q Appraisal of Lines Between Eyebrows scale 
1.5 The FACE-Q Age Appraisal VAS score 
The same analyses, inclusive the additional exploratory analyses, as described 
for the primary endpoint, will be conducted. Subgroup analysis for the key 
secondary endpoint will be conducted by site, country, geographic region (US 


  
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versus EU), and by subjects with previous use of botulinum toxin versus naïve 
subjects. 
Additional Secondary Analyses: 
The additional secondary efficacy endpoints will be analyzed applying the 
appropriate statistical method for the comparison of both treatment arms. 
For proportions, the Cochran-Mantel-Haenszel test (with stratification 
variable site) as well as the 2-test will be applied. In case of a total number 
of observations below 30, or in case of at least one cell frequency below 5, 
Fisher’s exact test will be used instead of the 2-test. The modified Skindex-
16 (GL-QoL) and FACE-Q scales will be analyzed according to the foreseen 
analysis approach of these tools.  
Besides the FAS population for the analysis with multiplicity control, the 
analyses of these endpoints will also be based on the MFAS and the PP 
population. For all analyses, a one-sided significance level of 0.025 will be 
used, if not stated otherwise. 






  
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 7 Laboratory Assessments: Hematology and Serum Chemistry, details in Section 11.15. 
 8 Investigator's assessment of glabellar line severity at maximum frown and at rest. Assessment will be made using the 4-point FWS [GLS-I] (0 =none, 1=mild, 2=moderate, 
3=severe) and will be recorded in the CRF. 
 9 Subject's assessment of glabellar line severity at maximum frown and at rest. Assessment will be made using the 4-point FWS [GLS-S] (0 =none, 1=mild, 2=moderate, 3=severe). 
Subject Assessment will be performed before (ideally) and always independently of investigator assessment and will be recorded in the CRF) 
 10 Photographs of subject's glabellar lines (at maximum frown and at rest) will be taken at C1 Randomization, C1 week 2, C1 week 4 and each C1 Evaluation for Re-Treatment visit 
in Cycle 1 until the subject qualifies for re-treatment in order to provide evidence of effect and confirm that the subject did not qualify for re-treatment on the preceding 
evaluation for re-treatment visit. Although a photograph will be taken at each Evaluation for Re-treatment visit, only the photo of the visit preceding the re-treatment visit will 
be reviewed by the independent reviewers. 
 11 Modified Skindex-16 (GL-QoL) and FACE-Q Appraisal of Lines Between Eyebrows and Age Appraisal VAS scales will be used to measure psychological impact and concerns 
relating to their glabellar lines, respectively (and will be recorded in the CRF). 
 12 Treatment satisfaction will be determined using the FACE-Q Satisfaction with Outcome Scale (and will be recorded in the CRF). 
 13 Subjects will be monitored 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.  
 14 Anti-drug-antibody (ADA) test. If positive, serum samples will be tested for the presence of neutralizing antibodies. 
15   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 (ROS) as 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; C: Cycle; CRF :Case report form; D:Distribution of subject diary; ECG: Electrocardiogram; FWS: Facial Wrinkle Scale; GL-
QoL: Glabellar Line Quality of Life Scale; IMP: Investigational medicinal product; R:Return of subject diary; TC: Telephone call; VAS: Visual Analog Scale 




  
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3. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADA 
Anti Drug Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase (ALAT, GPT) 
AST 
Aspartate aminotransferase (ASAT, GOT) 
BoNT/A 
Botulinum neurotoxin A 
BoNT/A-DP 
CROMA Pharma GmbH's BoNT/A Drug Product registered in 
Korea under the name “Botulax” 
CBC 
Complete blood count 
CETS 
Composite endpoint treatment success 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRF 
Case report form 
CS 
Clinically significant 
DAS 
Disability Assessment Scale 
DF 
Dorsifelxion 
DRM 
Data review meeting 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FAS 
Full Analysis Set 
FDA 
US Food and Drug Administration 
FSFV 
First Subject First Visit 
FWS 
Facial Wrinkle Scale 
GCP 
Good Clinical Practice 
GL-QoL 
Glabellar Line Quality of Life Scale 
GLP 
Good Laboratory Practice 
GLS-I 
Glabellar Line Scale for Investigators 
GLS-S 
Glabellar Line Scale for Subjects 
IB 
Investigators Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
i.m. 
Intramuscular 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention to treat 
IWRS 
Interactive Web Response System 


  
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Abbreviation 
Definition 
kDa 
Kilo Dalton 
LD50 
Lethal dose 50 (Median Lethal Dose) 
LOCF 
Last Observation Carried Forward 
LSLV 
Last Subject Last Visit 
MAA 
Market Access Approval 
MAS 
Modified Ashworth Scale  
MedDRA 
Medical Dictionary for Regulatory Activities 
MW 
Molecular weight 
MFAS 
Modified Full Analysis Set 
NCS 
Not clinically significant 
NOAEL 
No Observed Adverse Effect Level 
PRO 
Patient reported outcome(s) 
PRS 
Physician’s Rating Scale 
PP 
Per protocol 
PT 
Preferred term 
ROS 
Review of systems 
SAE 
Serious adverse event 
SAF 
Safety analysis data set 
SAP 
Statistical analysis plan 
SD 
Sprague Dawley 
SIC 
Subject identification code 
SIS 
Subject Information Sheet 
SOC 
System organ class 
SOPs 
Standard Operating Procedures 
TEAE 
Treatment Emergent Adverse Event 
U 
Unit (s) 
US 
United States 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 


  
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TABLE OF CONTENTS 
1. 
SPONSOR SIGNATURE PAGE ....................................................................................... 3 
1.1 
Investigator Acknowledgement ..................................................................................... 4 
2. 
SYNOPSIS .................................................................................................................. 5 
2.1 
Schedule of Study Procedures and Assessments ......................................................... 20 
2.2 
Study Scheme ............................................................................................................... 23 
3. 
LIST OF ABBREVIATIONS .......................................................................................... 24 
4. 
BACKGROUND INFORMATION ................................................................................. 31 
4.1 
Background to Botulinum Toxin .................................................................................. 31 
4.2 
Clinical Condition/Indication ........................................................................................ 32 
4.3 
Description of Investigational Medicinal Products ...................................................... 33 
4.3.1 
Description of the Investigational Medicinal Product BoNT/A-DP ...................... 33 
4.3.2 
Description of the Placebo Control ...................................................................... 33 
4.4 
Non-clinical and Clinical Summaries ............................................................................ 34 
4.4.1 
Non-clinical Summary .......................................................................................... 34 
4.4.2 
Clinical Summary .................................................................................................. 35 
4.4.2.1 
Phase 3: BLESS I: Indication; Glabellar Lines ........................................... 36 
4.4.2.2 
Phase 3: BLESS II: Indication; Glabellar Lines .......................................... 37 
4.4.2.3 
Phase 3 Study HG-11-01: Indication; Glabellar Lines ............................. 39 
4.4.2.4 
Phase 3 Study HG-06-01: Indication; Blepharospasm ............................ 39 
4.4.2.5 
Phase 3 Study HG-11-02: Indication; Equinus Foot Deformity in 
Children with Cerebral Palsy ................................................................................... 40 
4.4.2.6 
Phase 3 Study HG-13-01: Indication; Post Stroke Upper Limb 
Spasticity 41 
4.4.2.7 
Phase 4 Study HG-BTBPS-12102: Indication; Blepharospasm ................ 42 
4.4.2.8 
Post Marketing Safety Data .................................................................... 60 
4.5 
Study Rationale ............................................................................................................ 61 
4.5.1.1 
Study Design Justification ....................................................................... 61 
4.5.1.2 
Justification for Schedule ........................................................................ 62 
4.5.1.3 
Dose Justification .................................................................................... 62 
4.6 
Evaluation of Anticipated Risks and Benefits of the Investigational Medicinal 
Product to Human Subjects ......................................................................................... 62 
4.6.1 
Possible Benefits for the Subject ......................................................................... 62 
4.6.2 
Possible Risks/Inconveniences for the Subject .................................................... 63 
5. 
STUDY PURPOSE AND OBJECTIVES ........................................................................... 64 
5.1 
Study Purpose .............................................................................................................. 64 
5.2 
Primary Objective ........................................................................................................ 64 
5.3 
Secondary Objectives ................................................................................................... 64 
6. 
STUDY DESIGN ......................................................................................................... 65 
6.1 
Brief Summary ............................................................................................................. 65 


  
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6.2 
Overall Study Design .................................................................................................... 65 
6.3 
Population to be studied.............................................................................................. 65 
6.3.1 
First Treatment Cycle ........................................................................................... 65 
6.3.2 
Open Label Extension ........................................................................................... 66 
6.3.3 
End of Study Visit ................................................................................................. 67 
6.3.4 
Numbering of Visits .............................................................................................. 67 
6.3.5 
Allowed Time Deviations per Visit ....................................................................... 68 
6.3.6 
Duration of Study Period and Subject Participation ............................................ 68 
6.4 
Outcome Measures ...................................................................................................... 68 
6.4.1 
Primary Outcome Measure .................................................................................. 68 
6.4.1.1 
Efficacy .................................................................................................... 68 
6.4.2 
Secondary Outcome Measures ............................................................................ 68 
6.4.2.1 
Key Secondary Efficacy Endpoints .......................................................... 68 
6.4.2.2 
Additional Secondary Endpoints ............................................................. 68 
6.4.2.3 
Safety ...................................................................................................... 69 
6.5 
Randomization and Blinding ........................................................................................ 70 
6.5.1 
Randomization ..................................................................................................... 70 
6.5.2 
Blinding................................................................................................................. 70 
6.5.3 
Unblinding ............................................................................................................ 70 
6.6 
Study Stopping Rules ................................................................................................... 71 
7. 
SUBJECT SELECTION, WITHDRAWAL AND DISCONTINUATION ................................... 72 
7.1 
Inclusion Criteria .......................................................................................................... 72 
7.2 
Exclusion Criteria.......................................................................................................... 72 
7.3 
Eligibility Criteria for Re-treatment .............................................................................. 73 
7.4 
Withdrawal and Discontinuation ................................................................................. 73 
8. 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO ........................................... 75 
8.1 
Packaging ..................................................................................................................... 75 
8.2 
Labeling ........................................................................................................................ 75 
8.3 
Storage and Handling ................................................................................................... 75 
8.3.1 
Administration ..................................................................................................... 75 
8.3.2 
Foreign Body Inspection ....................................................................................... 75 
8.3.3 
Dilution ................................................................................................................. 76 
8.3.4 
Dose for Administration ....................................................................................... 76 
8.3.5 
Method of Administration ................................................................................... 77 
8.3.6 
Description of Treatment ..................................................................................... 78 
8.3.7 
Investigational Medicinal Product Accountability ............................................... 78 
9. 
STUDY PROCEDURES ................................................................................................ 79 
9.1 
Informed Consent and Enrollment .............................................................................. 79 
9.2 
Subject Identification Codes ........................................................................................ 79 
9.3 
Screening and Study Visits ........................................................................................... 79 
9.3.1 
Unscheduled Visit ................................................................................................. 87 
9.4 
Subject Diary and Patient Reported Outcomes ........................................................... 88 
9.4.1 
Subject Diary ........................................................................................................ 88 
9.4.2 
Patient Reported Outcomes ................................................................................ 88 


  
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9.5 
Subject Completion/Discontinuation ........................................................................... 89 
9.6 
Procedures for Monitoring Subject Compliance .......................................................... 89 
10. 
ASSESSMENT OF EFFICACY ....................................................................................... 90 
10.1 
Assessment of Glabellar Line Severity: Facial Wrinkle Scale ....................................... 90 
10.1.1 Subject and Investigator In-clinic Assessment ..................................................... 90 
10.1.2 Photo-evaluator Assessment ............................................................................... 91 
10.2 
Psychological Impact .................................................................................................... 91 
10.3 
Subject Satisfaction with Treatment ............................................................................ 91 
11. 
ASSESSMENT OF SAFETY .......................................................................................... 92 
11.1 
Adverse Events ............................................................................................................. 92 
11.1.1 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs, 
AESIs, and SAEs .................................................................................................... 92 
11.2 
Adverse Events of Special Interest ............................................................................... 92 
11.3 
Serious Adverse Events ................................................................................................ 93 
11.4 
Treatment-Emergent Adverse Events (TEAEs) ............................................................. 94 
11.5 
Evaluation of AEs, AESIs, SAEs, TEAEs .......................................................................... 94 
11.5.1 Assessment of Causality ....................................................................................... 94 
11.5.2 Assessment of Severity ........................................................................................ 95 
11.5.3 Outcome ............................................................................................................... 95 
11.5.4 Action Taken with Study Drug .............................................................................. 96 
11.6 
Adverse Event Monitoring and Assessment ................................................................ 96 
11.6.1 Reporting Serious Adverse Events and Adverse Events of Special Interest ......... 97 
11.6.2 Exposure In Utero During Clinical Trials ............................................................... 98 
11.6.3 Overdose .............................................................................................................. 98 
11.7 
Urgent Safety Measures .............................................................................................. 99 
11.8 
Pre-existing Diseases .................................................................................................... 99 
11.9 
Unexpected Adverse Events ........................................................................................ 99 
11.10 Medical, Medication and Non-Drug Therapy History .................................................. 99 
11.10.1 Medication and Non-Drug Therapies ................................................................... 99 
11.11 Medical History and Physical Examinations ............................................................... 100 
11.12 Pregnancy test ........................................................................................................... 100 
11.13 Vital Signs ................................................................................................................... 100 
11.14 Demographic Data ..................................................................................................... 101 
11.15 Clinical Laboratory Tests (Safety) ............................................................................... 101 
11.15.1 Hematology and Clinical Chemistry ................................................................... 101 
11.15.2 Antibody Test ..................................................................................................... 102 
11.16 Electrocardiograms .................................................................................................... 102 
12. 
STATISTICS ............................................................................................................ 103 
12.1 
Sample Size and Power Calculations .......................................................................... 103 
12.2 
Data Sets and Analysis Cohorts .................................................................................. 104 
12.3 
Procedure for Accounting for Missing, Unused, and Spurious Data ......................... 105 
12.4 
Methods of Analysis ................................................................................................... 105 
12.4.1 Primary Outcome Measure ................................................................................ 105 
12.4.2 Secondary Outcome Measures .......................................................................... 107 


  
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12.4.3 Further Analyses ................................................................................................ 111 
12.5 
General Statistical Considerations ............................................................................. 111 
12.5.1 Demographic and Baseline Characteristics ........................................................ 112 
12.5.2 Interim Analysis .................................................................................................. 112 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................... 113 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................... 114 
14.1 
Investigator’s Responsibility ...................................................................................... 114 
14.2 
Study Organization ..................................................................................................... 114 
14.3 
Training ...................................................................................................................... 114 
14.4 
Monitoring ................................................................................................................. 114 
14.5 
Auditing ...................................................................................................................... 115 
14.6 
Non-compliance with the Protocol ............................................................................ 115 
14.7 
Facilities ..................................................................................................................... 115 
15. 
ETHICS ................................................................................................................... 117 
15.1 
Basic Principles ........................................................................................................... 117 
15.2 
Ethics Committee and Regulatory Authorities .......................................................... 117 
15.3 
Informed Consent ...................................................................................................... 117 
16. 
DATA HANDLING AND RECORD KEEPING ................................................................ 119 
16.1 
Confidentiality Policy ................................................................................................. 119 
16.2 
Source Documentation and Case Report Forms ........................................................ 119 
16.2.1 Case Report Forms ............................................................................................. 120 
16.2.2 Computer Systems ............................................................................................. 121 
16.2.3 Data Entry........................................................................................................... 121 
16.2.4 Medical Information Coding .............................................................................. 121 
16.3 
Document and Data Retention .................................................................................. 121 
16.3.1 Data Base Lock ................................................................................................... 121 
17. 
FINANCING AND INSURANCE ................................................................................. 121 
18. 
PUBLICATION POLICY ............................................................................................. 121 
19. 
REVISION HISTORY ................................................................................................ 122 
20. 
SUPPLEMENTS ....................................................................................................... 124 
20.1 
Glabellar Line Scale - Subject (GLS-S) ......................................................................... 124 
20.2 
Glabellar Line Scale – Investigator (GLS-I) ................................................................. 128 
20.3 
GL-QoL (Modified Skindex-16) ................................................................................... 132 
20.4 
FACE-Q Appraisal of Lines Between Eyebrows Scale ................................................. 134 
20.5 
FACE-Q Age Appraisal VASScale ................................................................................. 135 
20.6 
FACE-Q Satisfaction with Outcome Scale .................................................................. 136 
20.7 
Subject BMI Formula and Calculation ........................................................................ 137 


  
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21. 
REFERENCES .......................................................................................................... 138 
 






  
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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 aesthetics 10,27. 
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. 
4.3 
Description of Investigational Medicinal Products 
4.3.1 
Description of the Investigational Medicinal Product BoNT/A-DP 
CROMA Pharma GmbH'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-haemagglutinating protein and various 
haemagglutinins ranging between 17 and 48 kDa in size. The 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 Pharma GmbH’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 4-1). 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 units (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. 
Table 4-1 Composition of BoNT/A-DP and Placebo 
Name 
Components per vial (50 U) 
Function 
Dose 
Appearance 
BoNT/A-DP  
 
Clostridium botulinum type 
A (50 units)* 
Human serum albumin 
(0.25 mg) 
0.9% Sodium chloride  
Active 
ingredient 
Excipient 
 
Excipient 
20 U total 
(0.5mL) 4U 
(0.1mL) per 
injection point  
Lyophilizate for 
solution for 
injection, which 
becomes a 
colorless 
transparent liquid 
when saline 
diluent is added. 
Placebo 
0.9% sodium chloride 
(diluent) 
Control 
0.1 mL per 
injection point  
Colorless 
transparent liquid 
*Reconstitute with 1.25 mL sterile saline, yielding 4 U per 0.1 mL dose 
4.3.2 
Description of the Placebo Control 
Sterile normal saline (0.9% sodium chloride), which is also used as the diluent for reconstitution, 
will be used as the placebo control in this study. 




  
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Pharma GmbH’s BoNT/A-DP, and thus local and systemic toxicity following long-term treatment has 
not been evaluated for the IMP. 
Reproductive toxicity was investigated in an embryo-foetal development toxicity study in the SD rat 
model, where animals were dosed at 1 to 8 U/kg for 12 days. Clinical signs included paralytic gait in 
all treatment groups, which is considered to be due to exaggerated pharmacologic effects of 
BoNT/A-DP. The NOAEL was less than 1 U/Kg. 
A repeated dose toxicity study in Sprague-Dawley rats was conducted (Study No. 167857). The 
purpose of this study was to obtain information on the toxicity of BoNT-A DP in rats after 
repeated intramuscular administration over a period of six months. Rats initially received doses of 
0, 0.67, 2.0 and 6.0 U/kg (first application). Since animals did not show any signs of paralysis after 
the first administration, dose levels were increased from the second administration onwards to 
3.75, 7.5, and 15 U/kg, respectively. At the end of the study neurotoxic action of BoNT/A-DP 50U 
was demonstrated by clinical symptoms (altered locomotion) occurring at all dose levels and 
atrophy of the injected muscle. This was confirmed histopathologically by diameter and number 
of myofibers in all dose groups. Moreover, fatty infiltration was also seen at all dose groups. 
Often, there was an inflammatory infiltrate at the injection sites and a minor fibrosis. At the end 
of the 6-months treatment-free recovery period in absence of inflammation and fibrosis a partial 
recovery was seen in fiber number and diameter and fatty infiltration at the dose level of 
0.67/3.75 U/kg body weight once monthly. 
At a dose level of 6/15 U/kg body weight BoNT/A-DP 50U showed a clear effect on body weight 
development in both genders. Body weights were significantly lower than controls throughout the 
treatment period and not completely reversible in the recovery period. This coincided with lower 
food consumption during the treatment but not recovery period and was not associated with any 
clinical symptoms or other signs of systemic toxicity. Thus, this effect is considered secondary to 
the local effects described above preventing normal movement of the animal.  
A target organ other than the injected quadriceps muscle was not identified. Based on the results 
of this study that affect the skeletal muscle focally only, and considering the relatively small 
diameter and lengths of the muscle in rats compared to larger species and human, the high 
frequency of injections and the absence of further findings, the systemic NOAEL was established 
at 15 U/kg body weight BoNT/A-DP, when administered once monthly over 6 months. 
No standard pharmacokinetic or toxicokinetic studies were performed with CROMA Pharma 
GmbH’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 (GLP) conditions and according 
to International Conference on Harmonisation (ICH) guidance. 
For further details please refer to the Investigators Brochure (IB). 
4.4.2 
Clinical Summary 
To date, the clinical development of BoNT/A-DP, including clinical two Phase 3 studies (BLESS I and 
BLESS II) have been performed in the US and Europe by the Sponsor.  
The multicenter Phase 3 studies were comprised of two parts. The first part of the studies were a 
randomized, double blind, placebo-controlled, phase which aimed to demonstrate efficacy and 


  
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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 primary efficacy endpoint of these studies was the proportion of subjects among BoNT/A-DP 
and placebo groups with a 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 
is a composite endpoint comprising investigator and subject assessments of treatment 
effectiveness. 
In addition Phase 3 and Phase 4 trials, has been performed in Korea using the IMP name “Botulax”. 
The Sponsor is currently using the name BoNT/A-DP for clinical development. 
In clinical trials 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 (Table 4-2). A brief summary of the results is provided below, 
for further details please refer to the IB. 
4.4.2.1 
Phase 3: BLESS I: Indication; Glabellar Lines 
A total of 708 subjects were randomized; 531 subjects were allocated to BoNT/A-DP and 177 
subjects to placebo. The double-blind phase was completed by 500 (94.2%) and 160 (94.4%) 
subjects in the BoNT/A-DP and placebo groups, respectively; and the study was completed by 456 
(85.9%) and 145 (81.9%) subjects, respectively.  
The composite responder rate (reduction in FWS of ≥ 2 points and FWS score of 0 or 1 at maximum 
frown) at Week 4 from baseline was 46.5% for the BoNT/A-DP group and 0.0% for the placebo 
group; the difference in responder rates between the BoNT/A-DP and placebo groups was 46.50% 
(95% confidence interval [CI]: 41.78, 50.76) (p < 0.001, CMH test) in favor of BoNT/A-DP (FAS); thus 
this study confirmed the superior efficacy of BoNT/A-DP compared to placebo in the treatment of 
glabellar lines. Findings were robust. The results for the Modified Full Analysis Set (MFAS) and Per 
Protocol Set (PPS) are consistent with the FAS results. There was no statistically significant 
treatment-by-center interaction difference in the odds ratios between the centers in the responder 
rates as determined by the investigator (Breslow-Day test p-value = 0.363) (FAS). Sensitivity 
analyses with missing values handled with LOCF and observed values showed results that were 
consistent with the primary results. Results were similar by Fitzpatrick skin type, by demographic 
factors, and by whether the subject had received previous treatment with botulinum toxin. The 
responder rate was 66.5% and 0.6% of subjects for the BoNT/A-DP and placebo group, respectively, 
as assessed by investigators; and 55.6% and 0.0%, respectively, as assessed by subjects (p < 0.001, 
CMH test in both instances) (FAS); thus confirming the conclusions from the composite 
(concordant) primary endpoint. 
The results for the ad hoc analyses for ≥ 1 point improvement in FWS at maximum frown are 
consistent with the primary efficacy endpoint and clearly demonstrate a clinically meaningful effect 
of the BoNT/A-DP on the targeted hyperdynamic lines. During the double-blind phase, the 
composite rate of ≥ 1 point improvement in FWS at maximum frown at Week 4 was 81.5% for the 
BoNT/A-DP group and 1.7% for the placebo group; with rates of 90.9% and 9.7% of subjects for the 


  
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BoNT/A-DP and placebo group, respectively, as assessed by investigators; and 84.5% and 7.4%, 
respectively, as assessed by subjects (p < 0.001, CMH test in all instances) (FAS). 
This benefit was maintained up to Week 16 post-injection for approximately 20% of subjects. 
Composite rates of ≥ 1 point improvement in FWS at maximum frown were 45.1% and 1.2%, 
respectively, in the BoNT/A-DP and placebo groups, at Week 12, 20.8% and 0.6%, respectively, at 
Week 16, and 9.9% and 0.0%, respectively, at Week 20 (p < 0.001 in each instance).  
Consistent with the primary endpoint, efficacy was maintained with up to 3 retreatments, with 
81.5%, 74.4% and 70.3% of subjects in the BoNT/A-DP group at Week 4 after the first, second and 
third retreatment cycles, respectively, having shown composite rates of ≥ 1 point improvement in 
FWS at maximum frown (with rates of 93.1%, 91.1% and 87.4% of subjects as assessed by 
investigators; and 84.4%, 76.7% and 73.4% of subjects, as assessed by subjects after the first, 
second and third retreatment cycles, respectively). 
No deaths and no study drug-related SAEs were reported during the study. One (0.1%) subject 
during the study reported a BoNT/A-DP-related AE that led to discontinuation (headache; during 
the open-label phase). Pregnancy led to discontinuation from the study for 3 subjects. 
During the double-blind phase of the study, 19 (3.6%) subjects experienced TEAEs considered to be 
at least possibly related to BoNT/A-DP and 4 (2.3%) subjects experienced TEAEs considered to be 
at least possibly related to placebo. Study drug-related TEAEs in the BoNT/A-DP and placebo groups, 
respectively included headache: 10 (1.9%) subjects and 1 (0.6%) subject; injection site pain: 2 (0.4%) 
subjects and 1 (0.6%) subject; and head discomfort: 2 (0.4%) subjects in the BoNT/A-DP group and 
none in the placebo group. The rate of headache was higher in the BoNT/A-DP group compared to 
the placebo group. All other events were experienced by no more than 1 (0.1%) subject. 
One AESI was reported for 1 (0.1%) subject each in the BoNT/A DP and placebo groups during the 
double-blind phase and 3 (0.4%) subjects in the open-label phase. A total of 3 (0.4%) subjects had 
AESIs related to BoNT/A-DP and 2 (0.3%) subjects had AESIs related to injection procedure. No 
subjects had AESIs related to placebo or injection procedure. 
A secondary objective of the study was to provide long term safety data of BoNT/A-DP based on 
multiple treatment cycles. This study showed no increases in TEAE rates or TEAE severity with up 
to 4 cycles of treatment, thus confirming safety after repeated treatments and over prolonged 
period of use.  
There was no development of ADA during the study. 
4.4.2.2 
Phase 3: BLESS II: Indication; Glabellar Lines 
The composite responder rate (at maximum frown) at Week 4 was 48.8% for the BoNT/A-DP group 
and 1.9% for the placebo group (FAS); the difference in responder rates between the BoNT/A-DP 
and placebo groups at Week 4 was 46.86% (95% confidence interval [CI]: 35.77, 54.70, p < 0.001, 
CMH test) in favor of BoNT/A-DP (FAS); thus, this study confirmed the superior efficacy of BoNT/A-
DP compared to placebo in the treatment of glabellar lines. Findings were robust. The results for 
the Modified FAS (MFAS) and Per Protocol Set (PPS) were consistent with the FAS results. There 
was no statistically significant treatment-by-center difference in the odds ratios between the 
centers in the composite responder rate (Breslow-Day test p-value = 0.193; FAS). Sensitivity 


  
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analyses with missing values handled with LOCF and observed values showed results that were 
consistent with the primary results. Results were similar according to Fitzpatrick skin type, 
demographic factors (most subjects were white and female), and whether the subject had received 
previous treatment with botulinum toxin. The responder rates were 75.0% for the BoNT/A-DP 
group, and 1.9% for the placebo group as assessed by investigators; and 51.9% and 1.9% for the 
BoNT/A-D and placebo group, respectively as assessed by subjects (p < 0.001, CMH test in both 
instances, FAS), which was consistent with the results obtained from the composite (concordant) 
primary endpoint analyses.  
The results for the ad hoc analyses for rates of ≥ 1 point improvement in FWS at maximum frown 
were consistent with the primary efficacy endpoint and clearly demonstrate a clinically meaningful 
effect of the BoNT/A-DP on the targeted hyperdynamic lines. During the double-blind phase, the 
composite rates of ≥ 1 point improvement in FWS at maximum frown at week 4 were 83.1% for the 
BoNT/A-DP group and 1.9% for the placebo group; with rates of 90.0% and 3.8% of subjects for the 
BoNT/A-DP and placebo group, respectively, as assessed by investigators; and 85.0% and 9.4% 
respectively, as assessed by subjects (p < 0.001, CMH test in all instances) (FAS). 
Composite rates of  ≥ 1 point improvement in FWS at maximum frown were 40.5% and 2.1%, 
respectively in the BoNT/A DP and placebo groups, at Week 12 (p < 0.001), 12.1% and 0.0%, 
respectively at Week 16 (p = 0.006), and 4.7% and 0.0%, respectively at Week 20 (p = 0.068). The 
benefit was maintained up to Week 12 post-injection for approximately 40% of subjects and up to 
Week 16 for approximately 12% of subjects. 
Consistent with the primary endpoint, efficacy was maintained with up to 3 retreatments, with 
82.4%, 78.9% and 71.1% of subjects at Week 4 after the first, second and third retreatment cycles, 
respectively having shown composite rates of improvement of ≥ 1 point in FWS at maximum frown. 
Overall, 213 subjects were randomized and received at least 1 treatment and were included in the 
SAF, 160 subjects in the BoNT/A-DP group, and 53 subjects in the placebo group. No deaths were 
reported during the study. There were no SAEs that were related to study medication, and no TEAEs 
that led to discontinuation. 
TEAEs with an incidence ≥ 1% of subjects in any BoNT/A-DP stratum which were reported more 
frequently in the BoNT/A DP group than in the placebo group and included upper respiratory tract 
infection (6 [3.8%] subjects in the BoNT/A DP group and 1 [1.9%] subject in the placebo group); and 
urinary tract infection (4 [2.5%] subjects), eyelid ptosis (3 [1.9%] subjects), gastroenteritis (2 [1.3%] 
subjects), and concussion (2 [1.3%] subjects), all in the BoNT/A-DP group; no subjects in the placebo 
group experienced these events. TEAEs considered to be at least possibly related to treatment with 
BoNT/A-DP during the double-blind, and open-label parts of the study (N = 208) included 6 (2.9%) 
subjects with headache, 2 (1.0%) subjects with eyelid ptosis, and 1 (0.5%) subject each with 
blepharospasm, injection site nodule, and dry skin. 
A total of 2 (1.0%) subjects who received BoNT/A-DP (N = 208) reported a severe TEAE; these 
included 1 (0.5%) subject each with vitreous detachment and asthma, both unrelated to study drug.  
AESIs during treatment with BoNT/A-DP during the double-blind, included eyelid ptosis, 
constipation and dysarthria reported for 1 (0.6%) subject each. During the open-label phase, AESIs 
included eyelid ptosis reported for 1 (0.5%) subject. All AESIs were of mild severity. None of the 
AESIs was considered to be related to study drug. 


  
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A secondary objective of the study was to provide long term safety data of BoNT/A-DP based on 
multiple treatment cycles. This study showed no increases in TEAE rates or TEAE severity with up 
to 4 cycles of treatment, thus confirming safety after repeated treatments and over prolonged 
period of use.  
There was no development of ADA during the study. 
 
4.4.2.3 
Phase 3 Study HG-11-01: Indication; Glabellar Lines 
Phase 3 study HG-11-01 was a comparative non-inferiority trial to evaluate the safety and efficacy 
for improvement of glabellar lines of BoNT/A-DP compared to
® in subjects with moderate to 
severe glabellar lines. Study HG-11-01 was performed in Korea with 134 subjects receiving BoNT/A-
DP and 137 subjects receiving
20. Each product was administered at a dose of 20 U (0.5 mL). 
The primary endpoint was the response rate of physicians' assessment using the Facial Wrinkle 
Scale (FWS) at week 4. Secondary endpoints included the response rate according to investigator 
at weeks 8, 12 and 16, photographic assessment (3 independent blinded raters) at weeks 4, 8, 12 
and 16, subjects' improvement assessment and subjective self-satisfaction levels. 
Response rates for maximum frown at week 4 were comparable between the groups, at 89.3% in 
the BoNT/A-DP group and 81.9% in the
 group. On the basis of secondary endpoints for 
photographic assessment, the response rates were significantly higher for BoNT/A-DP than
 
at 4weeks (p=0.02) and 8weeks (p< 0.005) after treatment. Thirty eight subjects (28.4%) reported 
63 cases of adverse events (AEs) in the BoNT/A-DP group, and 45 subjects (32.8%) reported 62 cases 
of AEs in the 
 group, thus the incidence of AEs was low and similarly distributed between 
treatment groups. No AE occurred within 30 minutes after administration of the IMP and no 
subjects died during the study. Thirty three treatment-related adverse events (TEAEs) were 
reported in 28 subjects (10.3%) and the incidence rate of TEAEs was lower in the BoNT/A-DP group 
than in the 
 group (9.0% vs. 11.7%). Among TEAEs, injection site reaction was reported in 
four subjects in the BoNT/A-DP group and 11 subjects in the B
 group; eyelid ptosis was 
reported in six subjects in the BoNT/A-DP group and three subjects in the 
 group. No TEAE 
was evaluated to be severe in intensity. Among TEAEs, six cases of moderate severity were reported 
in the BoNT/A-DP group and one in the 
 group. 
One serious adverse event (SAE) was reported in each group (cellulitis in the BoNT/A-DP group and 
sudden hearing loss in the 
® group); however, neither case was treatment-related. Antibody 
formation test results pre- and post-dose were negative for all subjects. 
BoNT/A-DP therefore demonstrated the expected safety and efficacy profile of botulinum toxin A 
products, with no noticeable difference in the assessment of safety and efficacy between the 
groups administered BoNT/A-DP and 
®. 
4.4.2.4 
Phase 3 Study HG-06-01: Indication; Blepharospasm 
Study HG-06-01 was a double blind, randomized, active control comparative, parallel-designed, 
Phase 3 clinical trial to evaluate the safety and efficacy of BoNT/A-DP in essential blepharospasm. 


  
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Study HG-06-01 was performed in Korea with 121subjects receiving BoNT/A-DP and 104subjects 
receiving
®. The total dose administered varied from 12.5 to 60 U.  
The primary endpoint was "efficacy rate after administration of test product" and the efficacy rate 
was defined as an elevation of more than one grade (Scott method) at the fourth week after 
administration. Secondary endpoints included the effectiveness duration period, the degree of 
spasm, eyelid closure force, and vision function at predefined visit points, percentages of 
improvement (to grade 0 or 1) at the fourth week after administration of test product (Scott 
method), and percentages of cases where more than two grades are elevated at the fourth week 
after administration of test product (Scott method). The efficacy rates were comparable (98.91% in 
the BoNT/A-DP group vs. 100% in the
 group) and BoNT/A-DP was not inferior to
 (the 
lower limit of confidence interval [CI] for test group - control group was -2.87%, which exceeded 
the non-inferiority boundary of -10%). With regard to secondary endpoints, there was no statistical 
difference between the test group and control group with respect to the duration of effect.  
A total of 73 AEs was reported in 47 subjects in the BoNT/A-DP group and 77 AEs were reported in 
42 subjects in the 
 group, with no statistically significant difference (p=0.8136). The 
frequency of TEAEs was low and similarly distributed between treatment groups (27.56% in the 
BoNT/A-DP group vs. 39.56% in the
 group).  
Three cases of SAEs requiring hospitalization were reported in two subjects in the BoNT/A-DP 
group. One subject had moderate arrhythmia, and the other two subjects experienced severe 
headache and anxiety. The arrhythmia was considered ‘definitely not related’ to the treatment. The 
cases of headache and anxiety were considered ‘probably not related’ to treatment and the 
subjects completed the study without any further AEs. Other safety endpoints were also 
investigated, including vital signs, laboratory tests, and antibody formation. No clinically significant 
finding was observed, no antibody formation was reported and there was no significant difference 
between treatment groups. 
Long-term safety of BoNT/A-DP was evaluated through the extension study HG-08-01 (up to 48 
weeks) and there was no significant difference in the incidence of AEs between groups (p=0.5293, 
chi-square test). Antibody formation test results pre- and post-dose were negative for all subjects. 
As a result, there was no noticeable difference in the assessment of safety and efficacy between 
the groups administered BoNT/A-DP or
. 
4.4.2.5 
Phase 3 Study HG-11-02: Indication; Equinus Foot Deformity in Children with Cerebral 
Palsy 
Study HG-11-02 was a double blind, randomized, active control comparative, multicenter-designed, 
Phase 3 clinical trial to evaluate the safety and efficacy of BoNT/A-DP versus
 for the 
treatment of dynamic equinus foot deformity in children with cerebral palsy. Study HG-11-02 was 
performed in Korea with 72 subjects receiving BoNT/A-DP and 72 subjects receiving 
 control. 
The total dose administered was 6 U/Kg body weight for bilateral palsy and 4 U/Kg for unilateral 
palsy, with a maximum dose/injection limit not exceeding 200 U. 
The primary endpoint was the responder rate determined by the Physician’s Rating Scale (PRS) 
score at week 12, with a responder defined as an increase in the PRS score by 2 points or more for 
each leg. Secondary endpoints included safety assessment, comparison of the test and control 






  
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unrelated to study drug, was reported in 1 subject, which comprised a case of leukaemia, where 
the subject suffered abdominal pain and was hospitalized due to sepsis. 
The results of this Phase 4 study confirm the efficacy and safety of BoNT/A-DP in treatment of 
subjects with blepharospasm, consistent with the results of the Phase 3 study (HG-06-01) and the 
extension study (HG-01-08). 




  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-13-02 
Botulax Inj. 
Post-
Marketing 
Surveillance in 
patients with 
moderate to 
severe 
Glabellar 
Lines. 
Multi-
center 
Korea 
Status: 
Completed 
Start date:  
26.11.2013 
Completion 
date: 
01 Nov 2016 
 
Post-Marketing 
Surveillance 
BoNT/A-DP 
20U;  
i.m. 
Temporary 
improvement in 
the appearance of 
moderate to 
severe glabellar 
lines associated 
with corrugators 
muscle and/or 
procerus muscle 
activity in adults  
815 subjects  
One admin. 
4 weeks 
follow up  
Male or 
female 
subject 
 
18 to 65 
years 
Male/female 
adults between 
18 and 65. 
Patients with 
moderate to 
severe glabellar 
lines associated 
with corrugator 
muscle and 
procerus 
activity. 
Responder rate at 
Week 4 by 
physician’s rating 
line severity at 
maximum frown  


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
CPH-301-
201030 Phase 
3 study in 
subjects with 
glabellar lines 
Centers in 
Europe and 
US 
Status: 
Completed  
Start Date: 
21.3.2016 
LPO: 
16.11.2017 
1st cycle R, DB, 
PC, 2nd to 4th 
cycle OL, S 
BoNT/A-DP 20U 
or placebo 
i.m. 
To compare the 
safety and 
efficacy of 
BoNT/A-DP with 
placebo in 
reducing the 
severity of 
glabellar lines 
based on 
investigator and 
subject 
assessment. Also 
to assess safety 
and efficacy after 
repeat treatments. 
529 subjects 
active 
treatment, 
175 subjects 
per placebo 
arm 
Administrati
on of first 
dose in 
comparison 
with 
placebo, 
followed by 
an open 
label 
extension 
with 
possibility 
to receive 
three 
additional 
doses over a 
period of up 
to 62 weeks 
per subject 
(FSI - LSLV 
23 months) 
Male or 
female 
subject 
 
18 to 75 
years 
Moderate to 
severe glabellar 
lines as 
assessed by the 
investigator 
and the 
subject. 
Glabellar lines 
have a 
psychological 
impact on the 
subject 
Responder rate by 
investigator- and 
subject assessment 
at maximum frown 
at week 4 after 
treatment by 
injection 
(composite 
endpoint). 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
CPH-302-
201030 Phase 
3 study in 
subjects with 
glabellar lines 
Centers in 
US 
Status: 
Completed 
Start Date: 
12.4.2016 
LPO: 
10.10.2017 
1st cycle R, DB, 
PC, 2nd to 4th 
cycle OL, S 
BoNT/A-DP 20U 
or placebo 
i.m. 
To compare the 
safety and 
efficacy of 
BoNT/A-DP with 
placebo in 
reducing the 
severity of 
glabellar lines 
based on 
investigator and 
subject 
assessment. Also 
to assess safety 
and efficacy after 
repeat treatments. 
160 subjects 
active 
treatment, 
53subjects per 
placebo arm 
Administrati
on of first 
dose in 
comparison 
with 
placebo, 
followed by 
an open 
label 
extension 
with 
possibility 
to receive 
three 
additional 
doses over a 
period of up 
to 62 weeks 
per subject 
(FSI - LSLV 
23 months) 
Male or 
female 
subject 
 
18 to 75 
years 
Moderate to 
severe glabellar 
Lines as 
assessed by the 
investigator 
and the 
subject. 
 
Responder rate by 
investigator- and 
subject assessment 
at maximum frown 
at week 4 after 
treatment by 
injection 
(composite 
endpoint). 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
CPH-303-
201400 Phase 
3 study in 
subjects with 
glabellar lines 
Centers in 
US and EU  
Status: 
to be started  
1st cycle R, DB, 
PC, 2nd to 4th 
cycle OL, S 
BoNT/A-DP 20U 
or placebo 
i.m. 
To compare the 
safety and 
efficacy of 
BoNT/A-DP with 
placebo in 
reducing the 
severity of 
glabellar lines 
based on 
investigator and 
subject 
assessment. Also 
to assess safety 
and efficacy after 
repeat treatments. 
353 planned 
Administrati
on of first 
dose in 
comparison 
with 
placebo, 
followed by 
an open 
label 
extension 
with 
possibility 
to receive 
three 
additional 
doses over a 
period of up 
to 62 weeks 
per subject 
(FSI - LSLV 
23 months) 
Male or 
female 
subject 
 
18 to 75 
years 
Moderate to 
severe glabellar 
Lines as 
assessed by the 
investigator 
and the 
subject. 
 
Responder rate by 
investigator- and 
subject assessment 
at maximum frown 
at week 4 after 
treatment by 
injection 
(composite 
endpoint). 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
Blepharospasm 
HG-06-01 
 
Phase 1 and 3 
 
Blepharospas
m 
Multi-
center 
Korea 
Status: 
Completed 
 
Phase 1 Start 
Date: 
4.12.2007 
Phase 3 start 
date: 
21.04.2008 
 
Completion 
Date: 
Phase1: 
23.12.2009 
LPO: 
14.08.2008 
 
Phase 3: -
23.12.2009 
LPO -
24.07.2008 
R, DB, AC, P 
 
12.5 to 60U per 
subject 
(BoNT/A-DP or 
®) 
i.m. 
To evaluate the 
efficacy of the 
study drug in 
subjects with 
essential 
blepharospasm. 
Verum: 121, 
active 
control:104 
One 
administrati
on 
24 weeks 
follow up 
54 male and 
171 female 
Age 61.4 +/- 
9.03(21 to 
81) 
 
Adults of above 
age 18 and 
below age 75 
Subjects with 
essential 
blepharospasm 
of which degree 
of spasm is 
Grade 2 ~ 4 
(Scott method) 
Safety &Efficacy 
rate after 
administration.The 
drug was consider 
effective when 
symptoms were 
improved by more 
than 1 Grade when 
evaluated at 4 
weeks after drug 
administration 
using Scott’s scale. 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-08-01 
Extension to  
study (HG-06-
01) 
Phase 3 
Blepharospas
m 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
04.08.2008 
 
Completion 
Date: 
-08.03.2011 
LPO 
22.12.2009 
R, DB, AC, P 
 
12.5 to 60U per 
subject(BoNT/A-
DP or
) 
i.m. 
To evaluate the 
duration of the 
effect of the study 
drug after the 
second dose in 
subjects with 
essential 
blepharospasm. 
 
77 verum and 
82 control 
Subjects 
received a 
single dose 
of the study 
(2nd dosing) 
and were 
observed for 
up to 24 
weeks. 
 
41 male 118 
female 
Age 61.8±8.7 
(22 to 75) 
Subjects who 
have entered 
HG-06-01, 
received the 
study drug 
(either the test 
drug or 
comparator), 
and completed 
the study 
according to the 
protocol 
The number of days 
elapsed between 
the 2nd dosing of 
the study drug (test 
drug or 
comparator) and 
the administration 
of
 
or other 
comparable surgical 
intervention due to 
recurrence of 
blepharospasm 
symptoms 
HG-BTBPS-
12102 
Phase 4 
Blepharospas
m 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
07.03. 2013 
 
Completion 
Date: 
28.08.2014 
Phase IV 
OL, S 
12.5-60 U per 
patient 
BoNT/A-DP 
Efficacy and 
safety showing 
that BoNT/A-DP 
is not inferior to 
 
102 
1 admin. 
16 weeks 
follow up 
Both gender 
(24-78) 
Adults of above 
age 18 and 
below age 75 
Patients with 
essential 
blepharospasm, 
degree of 
spasm is Grade 
2 ~ 4 (Scott 
method) 
Response rate of 
subjects with an 
improvement of 
more than one 
grade ar 4 weeks 
post-injection 


  
BoNT/A-DP 
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-10-01 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
05.02.2011 
 
Completion 
date: 
06.03.2017 
 
Post-Marketing 
Surveillance 
12.5-60 U per 
patient 
BoNT/A-DP 
(1)Serious 
adverse 
events/adverse 
drug reactions  
(2)Unexpected 
adverse events/ 
adverse drug 
reactions not 
reflected in the 
precautions for 
use 
(3)Known 
adverse drug 
reactions 
(4)Non-serious 
adverse drug 
reactions 
(5) 
Other 
safety and 
efficacy 
information 
243 
1 admin. 
4 weeks 
follow up  
Both gender 
 
Adults aged 18 
and older with 
benign essential 
belpharospam  
Efficacy will be 
assessed based on 
the symptom 
treatment rate, that 
is, the percentage of 
subjects with 
alleviated 
symptoms at Week 
4 of treatment by at 
least 1 grade of 
Scott`s scale.  


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-13-03 
Phase 4 
Blepharospas
m 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
17.04.2014 
 
Completion 
date: 
03.05.2016 
LPO: 
10.2015 
 
OL, S 
 
12.5-60 U per 
patient 
BoNT/A-DP 
Efficacy and 
safety showing 
that BoNT/A-DP 
is not inferior to 
 
102 
1 admin. 
16 weeks 
follow up  
Both gender 
 
Adults aged 18 
and older with 
benign essential 
belpharospam 
The result was 
determined as 
Effective or 
Ineffective 
(determined as 
Effective in case of 
improvement of ≥1 
grade by Scott’s 
Description at Post-
treatment Week 4) 
and this study was 
declared successful 
if the lower limit of 
the 95% confidence 
interval of the 
difference between 
the reference value 
(92.28%) and the 
study group 
effective rate was 
≥-10%, i.e., a non-
inferiority margin. 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-BOT-IV3 
Phase 4 
Blepharospas
m 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
17.06.2015 
 
Completion 
date: 23.06.-
2016 
LPO: 
01.2016 
 
OL, S 
 
12.5-60 U per 
patient 
BoNT/A-DP 
Efficacy and 
safety showing 
that BoNT/A-DP 
is not inferior to 
 
232 
1 admin. 
16 weeks 
follow up  
Both gender 
 
Adults aged 18 
and older with 
benign essential 
belpharospam 
Change in JRS total 
score at Week 4 
after treatment from 
baseline  
Pediatric cerebral palsy 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-11-02 
 
Phase 3 
 
Pediatric 
cerebral palsy 
Multi-
center 
Korea 
Status: 
Completed 
 
Start Date: 
26.03.2012 
 
Completion 
Date: 
24.11.2014 
LPO 
02.06.2014 
R, DB, AC, P 
 
1. bilateral palsy, 
the 
investigational 
products are 
administered to 
both legs at a 
dose of 6U/kg 
body weight 
(3U/kg for each 
leg). 
 
2. unilateral 
palsy, the 
investigational 
products are 
administered to 
the rigid leg at a 
dose of 4U/kg 
body weight. 
 
3.maximal 
exposure 200 U 
i.m. 
This study aims 
to evaluate the 
safety and 
efficacy of 
“Botulax Inj. 
(study drug)” 
versus 
 Inj. 
(control drug)” 
for improving 
equinus deformity 
in children with 
cerebral palsy. 
144 cases 
(study group: 
72, control 
group: 72) 
One 
administrati
on and 24 
week 
follow-up 
Both 
genders, 
Planned age 
range 2-10 
years 
1.Subject 
diagnosed with 
spastic cerebral 
palsy 
 
2.Subject with 
dynamic 
equinus foot 
deformity 
 
3.Subject with 
GMFCS Level 
I, II or III 
Responder rate of 
subjects whose PRS 
score increased by 
two or more points 
12 weeks after 
administration of 
the Investigational 
Medicinal Products 
compared to that at 
Baseline. 


  
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Page 55 of 141 
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HGPV-16-02 
Botulax Inj. 
Post-
Marketing 
Surveillance 
(pediatric 
cerebral palsy 
patient aged 2 
or above with 
dynamic 
equinus foot 
deformity by 
spasticity) 
Multi-
center 
Korea 
Status: 
Ongoing 
Start date: 
24.06.2016 
 
Post-Marketing 
Surveillance 
Up to 6U per kg 
BoNT/A-
DP,maximal 
exposure 200 U 
i.m. 
1)Serious adverse 
events/adverse 
drug reactions  
(2)Unexpected 
adverse events/ 
adverse drug 
reactions not 
reflected in the 
precautions for 
use 
(3)Known 
adverse drug 
reactions 
(4)Non-serious 
adverse drug 
reactions 
(5) Other safety 
and efficacy 
information(Dista
nce spreading of 
Toxin) 
600 subjects 
planned 
One 
administrati
on and 12 
week 
follow-up 
Both 
genders,  
 
 
≥2 years old 
pediatric 
cerebral palsy 
patient aged 2 
or above with 
dynamic 
equinus foot 
deformity by 
spasticity 
Change in PRS 
score at Week 12 
after treatment from 
baseline 


  
BoNT/A-DP 
Page 56 of 141 
Clinical Trial Protocol CPH-303-201400 
 
 
 
 
STRICTLY CONFIDENTIAL 
 
 
Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
Post stroke upper limb spasticity 


  
BoNT/A-DP 
Page 57 of 141 
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STRICTLY CONFIDENTIAL 
 
 
Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HG-13-01 
 
Phase 3 
 
Post stroke 
upper limb 
spasticity 
Multi-
center 
Korea 
 
 
Prof. Min- 
Ho Jeon 
and others 
 
 
Status: 
Completed 
 
Start Date: 
26.08.2013 
 
Completion 
Date: 
15.11.2014 
LPO 05.2014 
R, DB, AC 
Maximum of 
360 U BoNT/A-
DP or 
®. 
 
i.m 
To evaluate 
efficacy, safety 
and non- 
inferiority of 
BoNT/A-DP 
compared to 
 for 
improvement of 
muscle tone pre- 
dose versus post - 
dose in subjects 
with Post - stroke 
upper limb 
spasticity 
94 verum and 
92 control 
One 
administrati
on and 12 
week 
follow-up 
Male or 
female 
subject (35 - 
75 years) 
 
≥ 6 weeks since 
last stroke, ≥ 2 
points in focal 
spasticity of 
wrist flexor, ≥ 1 
points at least 
1of elbow 
flexor and 
finger flexor as 
measured on 
MAS(0 to 4) 
Targeted 
functional 
disability item 
with a rating of 
2 or greater on 
disability 
assess. scale) (0 
to 3) 
Change from 
Baseline at Week4 
for wrist flexor 
muscle tone as 
measured on the 
MAS (Modified 
Ashworth Scale) 


  
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Protocol No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
Start Date: 
Completed. 
Date: 
Design 
Control Type 
Drugs 
Dose, 
Route 
and Regimen 
Study 
Objective 
No. 
of 
Subjects by 
Arm 
Random/ 
Total 
Treat- 
ment 
Duration 
(Max) 
Gender 
Median 
Age 
(Range) 
Diagnosis 
Main 
Inclusion 
Criteria 
Primary 
Endpoints 
HGPV-16-01 
Botulax Inj. 
Post-
Marketting 
Surveillance 
(Muscle 
spasticity: For 
adult patients 
aged 20 or 
above with 
post stroke 
upper limb 
spasticity) 
Multi-
center 
Korea 
Status: 
Ongoing 
Start date: 
29.04.2016 
 
Post-Marketing 
Surveillance 
Maximum of 
360 U BoNT/A-
DP 
1)Serious adverse 
events/adverse 
drug reactions  
(2)Unexpected 
adverse events/ 
adverse drug 
reactions not 
reflected in the 
precautions for 
use 
(3)Known 
adverse drug 
reactions 
(4)Non-serious 
adverse drug 
reactions 
(5) Other safety 
and efficacy 
information 
600 subjects 
planned 
One 
administrati
on and 12 
week 
follow-up 
Male or 
female 
subject 
 
>20 years old  
Muscle 
spasticity: For 
adult patients 
aged 20 or 
above with 
post stroke 
upper limb 
spasticity 
Change in MAS 
score at Week 4, 12 
after treatment 
from baseline 
Crow`s Feet Lines  




. 
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4.4.2.8 
Post Marketing Safety Data 
BoNT/A-DP (Botulax®) was first authorized to Hugel at a dose of 100 U in the Republic 
of Korea on 13 Mar 2009 and is also authorized at doses of 50 U, 150 U, and 200 U. 
BoNT/A-DP is also authorized in 24 other countries (Azerbaijan, Bolivia, Brazil, Chile, 
Colombia, Costa Rica, Ecuador, El Salvador, Georgia, Guatemala, Honduras, India, 
Kuwait, Mongolia, Panama, Paraguay, Dominican Republic, Peru, Philippines, Russia, 
Thailand, Ukraine, Uruguay and Vietnam). 
According to information by the Korean manufacturer overall 9,054,819  vials (50 U, 100 U, 150U or 200 U) of 
BoNT/A-DP have been distributed during the period between March 13, 2009 to September 2018, (Fehler! 
Verweisquelle konnte nicht gefunden werden.). Approval was obtained in Korea (on April 29, 2016) for 150 U 
Botulax® for the treatment of muscle spasticity in adult patients aged 20 or above with post stroke upper limb 
spasticity and (on June 24, 2016) for the treatment of equinus foot deformity in children with cerebral palsy.   
Table 4 3 Cumulative and Interval Post-Marketing Exposure to BoNT/A DP 
*Export to Japan for use on named patient basis 
*Export to Japan for use on named patient basis 
 Year/ 
U per 
vial 
2009 
2010 
2011 
2012 
2013 
2014 
2015 
2016 
2017 
2018 
(until 
Q3) 
100  
4,515*  
59,091  
139,057  
160,98
9  
286,513  
314,909  
566,655  
1,072,020  
1,939,778 
1,265,831 
50 
  
  
  
33,877  
90,510  
152,789  
115,069 
137,374  
159,686 
139,965 
200 
  
7,325  
4,031  
47,899  
119,114  
284,061  
208,572 
427,536  
631,669 
662,088 
150 
  
 
 
 
 
 
 
43  
10,488 
13,365 
*Export to Japan for use on named patient basis 
 
Table 4-3 Cumulative and Interval Post-Marketing Exposure to BoNT/A-DP 
Hugel, the marketing authorization holder (MAH) in the Republic of Korea for 
BoNT/A-DP (Botulax®), prepared a PSUR for the reporting period 14 Mar 2017 to 
13 Mar 2018. No SAEs were reported in the post-marketing glabellar lines study 
HG-13-02 in the reporting interval or cumulatively.  
The PSUR reported that no new risk minimization activities were considered necessary. 
 


. 
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In conclusion, on the basis of spontaneous reports, post-marketing drug use 
investigations and phase 4 clinical trials, the product's efficacy and safety have been 
confirmed and no particular safety signal was observed. Collection of information on 
adverse events, adverse drug reactions and efficacy will be continued to identify factors 
potentially affecting safety and efficacy and to assure safety of the product. Currently 
further clinical studies are ongoing in Korea for the indications of Crow`s feet (lateral 
canthal lines; Phase I/III), muscle spasticity (post market surveillance) and cerebral 
palsy (post market surveillance), in accordance with Korean regulations. 
Overall drug safety is similar to that reported for other BoNT/A products.  
4.5 
Study Rationale 
As outlined in the Clinical Summary (Section 4.4.2), BoNT/A-DP should be a valuable option 
for the treatment of glabellar lines and other indications. 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. The current Phase 3 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 placebo, followed by an open label extension study to evaluate 
efficacy after repeat treatments and long term safety. Data obtained from this study (and from 
BLESS I and BLESS II) will provide evidence of efficacy and subject safety in controlled clinical 
trial setting and will be used for registration purposes. The dose rationale for this study is 
described in Section 4.5.1.3. 
4.5.1.1 
Study Design Justification 
This will be a multicenter, double blind, placebo-controlled study, followed by an open label 
extension. The study will take place in the US and EU.  
To allow all subjects to profit from treatment and to obtain adequate safety data for BoNT/A-
DP treatment, the study will be comprised of two parts. The first part will comprise a double 
blinded treatment cycle comparing BoNT/A-DP with placebo (ratio 3: 1 respectively) and will 
be used for the determination of primary and key secondary efficacy endpoints. The 3:1 ratio 
was selected to increase the number of subjects on active IMP, thus extending the safety 
database and still providing a sufficient number of placebo subjects for relevant comparisons 
in efficacy and safety. The second part of the study will be an open label safety extension, in 
which all subjects (regardless of initial treatment group assignment) will receive BoNT/A-DP, 
to assess long term safety of the treatment and efficacy after repeat treatments. 
A total of 353 subjects will be enrolled, which should allow for a precise estimate of response 
rate and for post-hoc sensitivity analyses.  


. 
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4.5.1.2 
Justification for Schedule 
The study schedule includes a maximum of four permitted treatments per subject(four 
treatment cycles), separated by a minimum interval of 12 weeks, during the study time frame 
of up to 60 weeks in treatment phase. A minimum interval of 12 weeks between treatments 
was selected, since the median duration of effect has been reported to be 85 days (12.1 
weeks) 31 and this treatment interval has been evaluated in several repeat treatment 
studies32,33.  
However, since treatment duration of 120 days 34 , 17.1± 6.5 weeks 35  or four to six 
months36have been reported and re-treatment intervals have been estimated at a mean of 
3.9 months36, the schedule has been devised flexibly such that subjects can obtain re-
treatment when they qualify (according to the "Eligibility Criteria for Re-treatment" Section 
7.3), which can be at week 12 at the earliest or at four weekly intervals thereafter. Hence, the 
duration of effect of BoNT/-DP will be evaluated in the first treatment cycle compared with 
placebo. The duration of effect of BoNT/-DP after repeat treatment will be assessed in the 
open label extension study. The duration of effect has been reported to increase with repeat 
treatment37. 
4.5.1.3 
Dose Justification 
The dose selected is 20 U, where 1U is defined as "the calculated median intraperitoneal lethal 
dose (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, with reported responder rates similar to those of the
 comparator product 
administered at the same dose (20 U). The potency units of botulinum toxins for injection are 
specific to the preparation and assay methods utilized and are not interchangeable with other 
preparations38(historical data with similar products have confirmed the efficacy of a 20 U dose 
and current safety recommendations favour the use of such small doses39;FDA Guidance for 
Upper Facial Lines). 
4.6 
Evaluation of Anticipated Risks and Benefits of the Investigational Medicinal 
Product to Human Subjects 
4.6.1 
Possible Benefits for the Subject 
The benefit of participation in this study is the expected reduction in the severity of glabellar 
frown lines after treatment with BoNT/A-DP. Since the subjects recruited are also negatively 
impacted psychologically by their glabellar lines, it is anticipated that treated subjects will 
benefit in terms of quality of life (emotional and social functioning; improved self-perception). 
Subjects receiving placebo for the first treatment cycle will benefit from free medical 
screenings and follow-up provided to all study subjects and will benefit from treatment when 
they enter the open label study.  


. 
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4.6.2 
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 adverse events of special 
interest (AESIs, please see Section 11.1). 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. 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. 
In addition, as with any IMP, there may be unforeseeable risks associated with the use of 
BoNT/A-DP or placebo control. As a side effect of drawing blood, pain, hematoma, and in very 
rare cases an infection at the venipuncture site may occur.  


. 
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5. 
STUDY PURPOSE AND OBJECTIVES 
5.1 
Study Purpose 
The purpose of the study is to assess the efficacy and safety of BoNT/A-DP in the treatment 
of glabellar lines in comparison with placebo, including efficacy after repeat treatments and 
long term safety. 
5.2 
Primary Objective 
To assess the efficacy of BoNT/A-DP in reducing the severity of glabellar frown lines following 
treatment (compared with placebo) based on investigator and subject assessment at week 4 
(of the first treatment cycle). 
5.3 
Secondary Objectives 
1. To assess the proportion of responders at maximum frown and at rest at various time 
points after each treatment, based on investigator and subject assessments. 
2. To assess the psychological impact of BoNT/A-DP treatment on subjects (in terms of 
emotional and social functioning and concerns relating to their glabellar lines) in 
comparison with placebo after a single treatment. 
3. To assess onset of effect and the duration of effect (at maximum frown) after a single 
treatment with BoNT/A-DP compared with placebo (first treatment cycle), based on 
investigator and subject assessments. 
4. To provide long term safety data of BoNT/A-DP based on multiple treatment cycles and 
to establish a sufficient safety database to support regulatory approval. 
5. To assess subject perceptions of effect of, and satisfaction with, treatment in comparison 
with placebo (first treatment cycle) and during the open-label extension phase. 


. 
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6. 
STUDY DESIGN 
6.1 
Brief Summary 
This multicenter Phase 3 study is comprised of two parts. The first part of the study is a 
randomized, double blind, placebo-controlled, phase which aims to demonstrate efficacy and 
safety of BoNT/A-DP compared with placebo. The second part is an open label extension 
phase to evaluate efficacy after repeat treatments and long term safety.  
Subjects can receive a maximum of four treatment cycles over the duration of the study, a 
single treatment in the first cycle compared with placebo, and up to three subsequent 
treatments in the open label extension study. 
Based on historical data with similar products, it is anticipated that there will be a significant 
difference in responder rates between BoNT/A-DP and placebo in the first treatment 
cycle11,40,41 and it is anticipated that the duration of effect in subjects administered the active 
treatment will last approximately 12 weeks36. 
6.2 
Overall Study Design 
The study is a parallel-group, randomized, double blind, placebo-controlled study followed by 
an open label extension. 
6.3 
Population to be studied 
A total of approximately 353 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. 
6.3.1 
First Treatment Cycle 
The first treatment cycle of the study will comprise two treatment groups as follows:  
 
Group A (active): BoNT/A-DP (20 units, 0.5 mL). 
 
Group B (placebo control): sterile, 0.9% sodium chloride (0.5 mL). 
An interim Analysis will be performed when all subjects finalized the double blind phase re-
evaluation for retreatment visit at week 16 of the first treatment cycle or completed the 
double blind phase (whichever occurs earlier).  
Eligible subjects will be randomized at baseline (day 0) to Group A or B to receive the first 
treatment in a 3:1 randomization scheme, respectively. 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 should assess the subject at baseline and at the visits at weeks 1, 2 and 4 in the 
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After a screening period of up to 14 calendar days, subjects will receive the first treatment 
(BoNT/A-DP or placebo) and attend for visits at 1, 2 and 4 weeks after treatment and at 4-
weekly intervals thereafter for evaluation of efficacy and safety (primary and key secondary 
efficacy endpoints will only be evaluated in the first treatment cycle in comparison with 
placebo). Re-screening will not be permitted. 
The effect of botulinum toxin typically lasts a few months, hence the first treatment cycle will 
last at least 12 weeks and will end when the subjects qualify for re-treatment (in accordance 
with the "eligibility for re-treatment criteria" as outlined in Section 7.3). Efficacy duration of 
four to six months36 or 17.1 ± 6.5 weeks35 have been reported from other studies, hence the 
study is designed flexibly to adequately assess the duration of effect compared with placebo 
in the first treatment cycle. 
6.3.2 
Open Label Extension 
After the first treatment cycle is completed, all subjects may enter the open label extension 
phase and will be dosed with BoNT/A-DP (20 U) for subsequent re-treatments.   
Subjects will attend for visits at 1 and 4 weeks after re-treatment and at 4-weekly intervals 
thereafter. Additional telephone call follow-ups will take place in the open label extension 
phase two and eight weeks after each re-treatment. Each re-treatment cycle will last at least 
12 weeks and will end when the subject qualifies for re-treatment (in accordance with the 
"eligibility for re-treatment criteria" as outlined in Section 7.3) or with the End of Study visit 
(see below). According to the study schedule (Section 2.2), a maximum of 4 treatments per 
subject (4 treatment cycles) is permitted during the study time frame, with treatments 
separated by a minimum of 12 weeks. 
A subject may move to the next treatment cycle if more than 12 weeks have passed since the 
previous treatment. Starting at week 12 and at 4-weekly intervals thereafter, subjects will 
attend the site for the Evaluation for Re-treatment visit. If the subject has a FWS score (at 
maximum frown) of ≥ 2, as determined by both the subject and the investigator, this visit on 
the same day at the same site visit will then be considered the End of Cycle visit and all other 
criteria required to determine eligibility for re-injection will be assessed e.g. negative urine 
pregnancy test (in women of child-bearing potential), lack of infection or inflammation in the 
planned injection area etc. Furthermore, all additional tests e.g. laboratory tests required for 
final cycle assessment will be performed (as outlined in the Schedule of events, Section 2.1). 
If the subject qualifies for re-treatment, on the same day at the same site visit, the subject will 
then enter the next treatment cycle and will receive the next study drug treatment as part of 
the Re-Treatment visit (i.e. day 0 of the next treatment cycle).  
If the FWS score (at maximum frown) is assessed as ≥2 by both the investigator and the 
subject, but the additional criteria for reinjection are not met, e.g. relevant infection or 
inflammation at the injection site, the subject may attend for a visit 4 weeks thereafter. 
Subjects with a positive pregnancy test, or subjects who do not agree to re-treatment, will be 
withdrawn from the study and the End of Study visit will be conducted at the earliest 
opportunity.  


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If at an Evaluation for Re-treatment visit the subject wants to get re-treated, but the 
investigator does not agree or vice versa (i.e. the FWS score is not ≥ 2 by both assessments), 
the subject will return to the site 4 weeks thereafter for another Evaluation for Re-treatment 
visit. There is no limit to the number of Evaluation for Re-treatment visits. In order to consider 
a visit as the End of Cycle visit, there must always be agreement between investigator and 
subject on a FWS score (at maximum frown) of ≥2.  
6.3.3 
End of Study Visit 
The End of Study visit can take place in four-weekly intervals from study-week 48 until study-
week 60. The last study drug re-treatment will be administered no later than week 48. For 
subjects receiving a re-treatment at week 48, the last cycle will end 12 weeks later at week 60 
(i.e. End of Study visit).  
The End of Study visit will take place at week 48, if the week 48 visit is an Evaluation for Re-
treatment visit and the subject does not meet the criteria for re-treatment i.e. this visit is 12 
or more weeks after the last treatment. As week 48 is the last possible time point for re-
treatment, such subjects will continue with all additional assessments of the End of Study visit 
on the same day. For subjects having received their last injection 8 weeks or less prior to week 
48, the End of Study visit will take place 12 weeks after the last study drug treatment was 
given, e.g. week 52 if the subject was re-treated at week 40.  
For subjects who are prematurely discontinued from the study (at any time), the End of Study 
visit will take place within 1 week of discontinuation. 
The number of treatments administered per subject will depend on the subject's qualification 
for re-treatment. A maximum of four study treatments may be administered per subject, with 
the last opportunity for re-treatment being week 48. A subject will be followed-up until he/she 
would qualify for re-treatment (if below 48 weeks), since there is no maximum time frame for 
re-treatment. 
6.3.4 
Numbering of Visits 
Visit numbers correspond with specific treatment and assessments as outlined in the Schedule 
of Events, Section 2.1. If subjects are not eligible for re-treatment at the "Evaluation for Re-
treatment" visit, they will return at 4-weekly intervals thereafter, until they are eligible for 
treatment. The subsequent visit number for the cycle will remain the same, but will be 
amended with "a, b, c" etc., corresponding to the time extended (at 4-weekly intervals) in that 
treatment cycle. For example, the first evaluation for re-treatment is at visit 7, week 12; 
however for subjects who are not eligible at week 12, but at week 16, this visit will be denoted 
visit "7a", while "visit 7b" will denote week 20 in the first cycle and "visit 7c" will denote week 
24 etc., with each additional letter corresponding to a time point 4 weeks later in that cycle. 
This approach will enable the visit numbers to be standardized, while allowing flexibility to 
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6.3.5 
Allowed Time Deviations per Visit 
A time deviation of ± 5 days is allowed for each visit (including telephone visits), except for 
the week 1 and week 4 visit in each treatment cycle, 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 still be documented as a protocol deviation. 
6.3.6 
Duration of Study Period and Subject Participation 
Subjects will participate in this study for a duration of 50 to 62 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 48 to 60 weeks study participation).  
Subjects will receive a maximum of four permitted rounds of treatment, with a minimum 
interval between treatments of 12 weeks.  
6.4 
Outcome Measures 
6.4.1 
Primary Outcome Measure 
6.4.1.1 
Efficacy 
The primary efficacy endpoint is the proportion of subjects among BoNT/A-DP and placebo 
groups with a 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 
is a composite endpoint comprising investigator and subject assessments of treatment 
effectiveness.  
6.4.2 
Secondary Outcome Measures 
6.4.2.1 
Key Secondary Efficacy Endpoint 
1. The extent of change in psychological impact (emotional and social functioning and 
concerns relating to their glabellar lines) at week 4 after the first treatment, in the 
BoNT/A-DP group in comparison with placebo, relative to baseline, as assessed by the 
modified Skindex-16 (Glabellar Line Quality of Life Scale [GL-QoL]) and the FACE-Q 
(Appraisal of Lines Between Eyebrows scale and Age Appraisal Visual Analog Scale (VAS)), 
respectively. 
6.4.2.2 
Additional Secondary Endpoints 
2. The percentage of responders at maximum frown (as defined in 6.4.1.1) at week 12 (after 
the first treatment with BoNT/A-DP or placebo). 
3. The percentage of responders at week 16 (after the first treatment). 
4. The percentage of responders at week 20 or later (after the first treatment). 


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5. The proportion of subjects with a ≥ 1 point reduction in FWS score at rest at week 4 in the 
first treatment cycle, based separately on the investigators' and the subjects' in-clinic 
assessments (applicable only for subjects who have a FWS score at rest ≥ 1 at baseline). 
6. The proportion of responders among BoNT/A-DP and placebo groups with a FWS score of 
0 or 1 and an improvement ≥ 2 points in FWS score (at maximum frown) during the first 
treatment cycle visit relative to baseline, based on both the investigator’s and the 
subject’s in-clinic assessments (composite endpoint, at weeks 1, 2 and 8). 
7. The proportion of subjects with ≥ 2 point and ≥ 1 point reduction in FWS score (at 
maximum frown) in the BoNT/A-DP and placebo groups during the first treatment cycle 
visit relative to baseline, based on the independent rater’s assessment of photographs (at 
baseline and visits 2, 4, 12, 16 and 20 weeks after treatment, within the first treatment 
cycle). 
8. Time to onset of effect in the BoNT/A-DP and placebo groups in the first treatment cycle, 
as measured at weeks 1, 2 and 4 based separately on subject and investigator 
assessments. Onset of effect defined as at least a 1 point improvement in FWS score from 
baseline (at maximum frown). In addition, onset of effect will be assessed by subjects daily 
in the first 2 weeks after treatment, by recordings in the subject diary. 
9. The extent of subject perceptions of effect of, and satisfaction with, treatment, in the 
BoNT/A-DP and placebo groups, during each treatment cycle, as assessed by the FACE-Q 
Satisfaction with Outcome Scale. 
10. The proportion of subjects with a ≥ 1 point reduction in FWS score at rest in the BoNT/A-
DP and placebo groups, relative to baseline, during the first treatment cycle, based on the 
independent rater’s assessment of photos. 
11. The percentage of subjects with a FWS score of 0 or 1 and an improvement of ≥ 2 points 
in FWS score at maximum frown (investigator and subject assessment) at 4 weeks after 
re-treatment relative to the rating at the preceding end of cycle visit. 
12. The proportion of subjects with ≥ 1-point reduction in FWS score (at maximum frown) in 
the BoNT/A-DP and placebo groups during the first treatment cycle at week 1, 2, 4, 8, 12, 
16 and 20  relative to baseline, based on both the investigators’and the subjects’in-clinic 
assessments. 
13. The proportion of subjects with ≥ 1-point reduction in FWS score (at maximum frown) in 
the BoNT/A-DP group during each re-treatment cycle at week 4 relative to re-treatment-
baseline, based on both the investigators’and the subjects’in-clinic assessments. 
 
6.4.2.3 
Safety 
The secondary safety endpoints include: 
1. Frequency, severity and causal relationship of AEs, SAEs and AESIs during the entire study 
period. 
2. Antibody formation, evaluation pre-dose before each treatment, at 4 weeks after each 
treatment and at the final study visit. 
3. Safety assessments by evaluating hematology, clinical chemistry, vital signs and ECGs as 
per study schedule (Section 2.1). 


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6.5 
Randomization and Blinding 
6.5.1 
Randomization 
This is a randomized, double blind, placebo-controlled efficacy and safety clinical study 
followed by an open label extension. Subjects will be randomly assigned to receive either 
BoNT/A-DP or placebo at a ratio of 3:1 respectively in the first treatment cycle. The 3:1 ratio 
in favor of active treatment versus placebo has been selected to increase the safety data base. 
Randomization will be performed per study site via interactive web response system (IWRS). 
One unique randomization code will be assigned to each subject. 
6.5.2 
Blinding 
For the first placebo controlled treatment cycle (the double-blind cycle of this trial), BoNT/A-
DP and placebo will be provided to the sites in glass vials. Since BoNT/A-DP-vials contain a 
pellet of lyophilized BoNT/A-DP, they can be discerned from placebo-vials (empty vials). 
However, after reconstitution by an unblinded study team member at the site, both 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, case report form (CRF) 
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 (blinded medication number and batch/lot number during the double-blind phase of 
the study at the given site). The assigned vial will be reconstituted and will be forwarded to 
the investigator for injection. Specific Blinding Plans will be created at each study site during 
the Study Initiation visits. .  
6.5.3 
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 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 as per his/her discretion if the actual treatment information is considered relevant for 
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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. 
6.6 
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 9.5. 
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 (with follow-up until the end of the current treatment cycle). 
 
Any significant treatment-related side effects where treatment 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 Code of Federal Regulation (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. 
 
The Sponsor can terminate the study or a study site at any time for any other reason. 


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7. 
SUBJECT SELECTION, WITHDRAWAL AND DISCONTINUATION 
7.1 
Inclusion Criteria 
Subjects who meet ALL of the following criteria are eligible for this study: 
 
Aged ≥ 18 years or older at time of screening (upper limit 75 years, inclusive). 
 
Has moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 
on FWS) as determined by in-clinic assessments by both the investigator and the subject 
(where: 0= 'none', 1= 'mild', 2= 'moderate', 3= 'severe').i 
 
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 FWS), without glasses obstructing the forehead area. 
 
The moderate to severe glabellar lines have an important psychological impact on the 
subject as indicated by scores > 0 on either the Emotional or the Social Functioning 
subscale of the modified Skindex-16 (GL-QoL). 
7.2 
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 trial (other than the investigational treatment). 
 
Known hypersensitivity to the 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 3 months prior to 
screening or planned during the study. 
 
Apart from the procedures specified above, previous treatment with any facial aesthetic 
procedure in the glabellar area (including chemical peeling, injection with biodegradable 
fillers) within 12 months prior to screening or planned during the study. 
 
Previous insertion of permanent material in the glabellar area or planned during the study. 
 
Any surgery, or history of surgery, in the glabellar area including surgical removal of the 
corrugator, procerus or depressor supercilii muscles or a combination of these or scars in 
the glabellar area or such surgery planned during the study. 
 
Active skin disease/infection or irritation at the treatment area. 
 
Inability to substantially lessen glabellar frown lines even by physically spreading them 
apart. 
                                                          
iWill be assessed at screening and at baseline visits. 


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 
Use of a muscle relaxant within 2 weeks prior to screening, or planned during the study.ii 
 
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 trial. 
 
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.iii 
 
Planned surgery with general anaesthetic (use of local anaesthetic outside the glabellar 
area is permitted). 
 
Participation in another clinical study within 1 month of screening and throughout the 
trial. 
 
Previous participation in another botulinum toxin aesthetic study which involved the 
treatment of glabellar lines in combination with canthal lines and/or forehead lines, within 
the previous 18 months. 
 
Chronic drug or alcohol abuse (as per investigator discretion). 
7.3 
Eligibility Criteria for Re-treatment 
The following criteria MUST be met for re-treatment: 
 
At time of re-treatment subject does not have relevant changes to their health status from 
enrollment, which would have prevented subject’s entry into the study according to the 
inclusion and exclusion criteria. 
 
The subject must have been randomized to receive treatment and must have received at 
least one treatment (BoNT/A-DP or placebo). 
 
A minimum of 12 weeks must have elapsed since the previous study treatment. 
 
The subject's glabellar lines at maximum frown must have relapsed to a FWS score of 2 or 
3 as determined by both the investigator and the subject.   
 
No relevant infection or inflammation in the planned injection area. 
 
Negative urine pregnancy test, in women of child-bearing potential. 
 
The subject must have received fewer than four study treatments. 
 
The subject must agree and consent to re-treatment. 
 
Re-treatment will be performed at the latest by week 48. 
7.4 
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 when at least 
three unsuccessful attempts to contact the subject have been documented.  
                                                          
iiWill be assessed at screening and baseline visits. 
iiiWill be assessed at screening and baseline visits. 


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Every effort will be made to have the withdrawn/discontinued subject complete the End of 
Study visit (see Section 6.3.3). The reason for withdrawal/discontinuation will be recorded on 
the CRF (see Section 9.5).  
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, SAE or clinically significant abnormal laboratory, ECG, or 
other clinical test values will be evaluated by the investigator and will be treated and/or 
followed up until the symptoms or values return to normal or acceptable levels, as judged by 
the investigator, or until values are stable, a plausible explanation has been provided, or the 
subject has received another injection with botulinum toxin outside the study. 
 
 


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8. 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO 
8.1 
Packaging 
The dosage form of BoNT/A-DP is lyophilizate for solution for injection. BoNT/A-DP is provided 
in single use vials containing50 U/vial. BoNT/A-DP will be reconstituted with a volume of 
1.25 mL sterile physiological saline (diluent, as outlined in Section 8.3). 
The dosage form of the placebo control is a solution for injection. Empty vials will be provided 
for placebo but identical in appearance to the BoNT/A-DP vials. At the study site, 1.25 mL of 
sterile physiological saline will be added to a vial. 
8.2 
Labeling 
In accordance with the valid regulatory requirements for blinded clinical trials, the active drug 
and placebo control will be labeled similarly for the double blinded part of the study. A 
different label will be used for the open label extension part of the study. The content of the 
labels will be in accordance with the applicable regulatory authority requirements. 
8.3 
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. In order to guarantee proper 
storage conditions, the current temperature and the minimum and maximum temperature 
since the last reading in the storage refrigerator shall be monitored and documented ideally 
five times per week, but no less than three times per week. The temperature log will be 
included in the Trial Master File 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.  
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 8.3.7. 
8.3.1 
Administration 
8.3.2 
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. 
In the double blind phase of the study, 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. 


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8.3.3 
Dilution 
Sterile physiological saline (0.9% 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. 
For the placebo control, 1.25 mL of sterile saline will be added to each vial prior to filling 
syringes. 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. The date and time of reconstitution will be recorded in the 
CRF. Reconstituted IMP should be colorless and transparent with no visible particulate matter. 
The reconstituted drug 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. The use of product from one vial or syringe is restricted to one single subject 
treatment during a single session. 
8.3.4 
Dose for Administration 
The injection sites should be prepared according to standard clinical procedures. 
A volume of 0.5 mL of the properly reconstituted IMP 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 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 31G, which the investigator 
routinely uses for toxin administration. The diluted BoNT/A-DP or placebo will be applied to 
the injection sites using a sterile 30 to 31 G gauge needle. Each subject will receive a total of 
five i.m. injections at each injection visit of 4 U/0.1 mL per injection site (i.e. a total of 20 U, 
0.5mLactive BoNT/-DP or placebo control), that is, two injections in each corrugator supercilii 
muscle and one injection in the procerus muscle with an injection volume of 4U (0.1mL) into 
each site as shown in Figure 1.  


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Figure 1 Illustration of proposed injection sites 
 
8.3.5 
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. 1cm 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 end 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). 
Injections will be made with caution to avoid intravascular injection. Before injecting the test 
drug or placebo control, 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 


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the exact amount of drug will be injected. Additional information regarding administration 
can be found in the Study Reference Manual/Operational Manual. 
8.3.6 
Description of Treatment 
The subject will receive five injections (4U per 0.1 mL injection) per treatment visit (total dose 
of 20 U, 0.5 mL) at a minimum interval of 12 weeks, for a maximum of four treatments during 
the study. Subjects randomized to receive placebo will receive placebo for their first treatment 
and may enter the open label extension after the first treatment cycle and receive BoNT/A-
DP for the subsequent treatments. The treatment schedule is illustrated in Section 2.2. 
8.3.7 
Investigational Medicinal Product Accountability 
The investigator will ensure that the required storage conditions as specified in the Section 
8.3 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 (for the double blind portion of the study), including date 
received, drug identity code, date of manufacture or expiration date, amount received and 
disposition. In the open label extension phase of the study, IMP can be handled by any study 
team member delegated this task. IMP must be dispensed only at the study site as specified 
in the protocol (see Section 8.3). 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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9. 
STUDY PROCEDURES 
9.1 
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. 
9.2 
Subject Identification Codes 
A SIC will automatically be assigned by the IWRS system at screening, which will comprise B3 
(denoting the BLESS III study), followed by a single digit country identification, a two digit site 
identification and a three digit subject identification number. All study documents (e.g. CRFs, 
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. 
9.3 
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 CRFs, regardless of screening outcome. 
The overall study design is illustrated in Section 2.2. Details on the procedures to be 
performed at each study visit, including screening are listed in  
 


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Table 9-1 below and are listed in Section 2.1 Schedule of Study Procedures and Assessments 
and in Section 11.15 Clinical Laboratory Tests. 
 
 


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Table 9-1 BLESS III Study Visit Schedule: List of Activities and Parameters to be 
assessed at Each Study Visit 
VISIT 1 
TIME 2 
ACTION 
COMMENT 
Visit 1 
 
Screening 
Up to 14 
days 
 
 
 
Informed consent (Section 9.1) 
Inclusion and exclusion criteria (Section 7) 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FWS Investigator (GLS-I, Section 10.1.1) 
Demographic data (Section 11.14) 
Medical history (Section 11.11) 
Concomitant medication (Section 11.10.1) 
Vital signs (Section 11.13) 
ECG (Section 11.16) 
Serum pregnancy test (if applicable, Section 11.12) 
Clinical laboratory assessments (Section 11.15) 
Antibody test (Section 11.15.2) 
 
Visit 2 
 
Baseline 
 
First 
treatment 
Baseline 
 
Day 0 
 
 
Inclusion and exclusion criteria3 (Section 7) 
Full physical examination (Section 11.11) 
FWS Subject self-assessment (GLS-S, 
Section  10.1.1) 
FWS Investigator (GLS-I, Section 10.1.1) 
Photography (Section 10.1.2) 
Urine pregnancy test (if applicable) (Section 11.12) 
Concomitant medication (Section 11.10.1) 
AE assessment (Section 11) 
AESI questioning (Section 11.2) 
Vital signs (Section 11.13) 
FIRST TREATMENT (Section 8.3) 
Post-treatment observation and AE assessment 
over 30 minutes.  
AESI questioning after 30 min  
Distribute Subject Diary (Section 9.4) 
 
Visit 3  
 
C1  
 
Week 1 
7 days ± 2 
day after 
Baseline 
(Day 0) 
Collect/ Review/Distribute Subject Diary 
(Section 9.4) 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment (Section 11)13 
Vital signs (Section 11.13) 
Concomitant medication (Section 11.10.1) 
 
Visit 4 
 
C1  
14 days ± 5 
days after 
Collect Subject Diary (Section 9.4) 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
 


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Week 2 
Baseline 
(Day 0) 
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
Photography (Section 10.1.2)12 
Visit 5 
 
C1  
 
Week 4 
4 weeks ± 2 
days after 
Baseline 
(Day 0) 
FWS Subject self-assessment (GLS-S, 
Section  10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6) 
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
Photography (Section 10.1.2) 
Vital signs (Section 11.13) 
ECG (Section 11.16) 
Antibody test (Section 11.15.2) 
Clinical laboratory assessments (Section  11.15) 
 
Visit 6 
 
C1  
 
Week 8 
 
8 weeks ± 5 
days after 
Baseline 
(Day 0) 
 
FWS Subject Self assessment (GLS-S, Section 
10.1.1) 
FWS Investigator (GLS-I, Section 10.1.1) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
 
 
Visit 7 
(or 7a, 7b, 
7c) 
 
Evaluation 
for re-
treatment 
Visit4 
 
End Of 
Cycle5 
 
Second 
treatment - 
entry to 
open label 
extension 
12 weeks ± 5 
days after 
Baseline 
(Day 0), with 
possible 
extension at 
4-weekly (± 
5 days) 
intervals 
until subject 
is eligible for 
re-
treatment 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
FWS Investigator (GLS-I, Section10.1.1) 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
Confirmation of eligibility for re-treatment 
(Section 7.3) 
Photography (Section 10.1.2)  
 
 
 
Urine pregnancy test (if applicable, Section 11.12) 
Vital signs (Section 11.13) 
ECG (Section 11.16) 
Clinical laboratory assessments (Section 11.15) 
Full physical examination (Section 11.11) 
Antibody test (Section 11.15.2) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FACE-Q Satisfaction with Outcome Scale 
(Section20.6) 
 


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Eligibility for re-treatment (Section 7.3) 6  
 
 
Consent for re-treatment 
SECOND TREATMENT - OPEN LABEL (Section 8.3) 
Post-treatment observation and AE assessment 
over 30 minutes 
AESI questioning after 30 min  
 
Visit 8 
 
C2  
 
Week 1 
1 week ± 2 
days after 
second 
treatment 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
Full physical examination (Section 11.11) 
 
 
 
Visit 9 
C2  
Week 2 
14 days ± 5 
days after 
second 
treatment 
AE and AESI assessment(Section11)13 
Concomitant medication (Section11.10.1) 
Telephone call7 
Visit 10 
 
C2  
 
Week 4 
4 weeks ± 2 
days after 
second 
treatment 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section20) 
FACE-Q Satisfaction with Outcome Scale 
(Section20.6) 
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment(Section11)13 
Concomitant medication (Section11.10.1) 
Vital signs (Section11.13) 
Clinical laboratory assessments (Section 11.15) 
Antibody test (Section11.15.2) 
 
Visit 11 
 
C2  
 
Week 8 
8 weeks ± 5 
days after 
second 
treatment 
 
AE and AESI assessment (Section 11)13Concomitant 
medication (Section 11.10.1) 
 
Telephone call7 
Visit 12 (or 
12a, 12b, 
12c) 
 
Evaluation 
for re-
treatment 
Visit 4 
 
End Of 
Cycle5 
12 weeks ± 5 
days after 
second 
treatment, 
with 
possible 
extension at 
4-weekly(± 5 
days)  
intervals 
until subject 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
FWS Investigator (GLS-I, Section 10.1.1) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
Confirmation of eligibility for re-treatment 
(Section 7.3) 
 
 
Urine pregnancy test (if applicable, Section 11.12) 
 


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Third 
treatment 
is eligible for 
re-
treatment 
Vital signs (Section 11.13) 
Clinical laboratory assessments (Section 11.15) 
Full physical examination (Section 11.11) 
Antibody test (Section 11.15.2) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows and Age 
Appraisal VAS scales (Section 20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6) 
Eligibility for re-treatment (Section 7.3)5 
 
Consent for re-treatment 
THIRD TREATMENT (Section 8.3) 
Post-treatment observation and AE assessment 
over 30 min 
AESI questioning after 30 min  
 
Visit 13  
 
C3 
 
Week 1 
1 week ± 2 
days after 
third 
treatment 
Full physical examination (Section 11.11) 
AE and AESI documentation (Section 11)13 
Concomitant medication (Section 11.10.1) 
 
 
Visit  14 
14 days ± 
5days after 
third 
treatment 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
Telephone call7 
Visit 15 
 
C3 
 
Week 4 
4 weeks ± 2 
days after 
third 
treatment 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6) 
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment(Section 11)13 
Concomitant medication (Section11.10.1) 
Vital signs (Section 11.13) 
Antibody test (Section 11.15.2) 
Clinical laboratory assessments (Section 11.15) 
 
Visit 16 
 
C3 
 
Week 8 
8 weeks ± 5 
days after 
third 
treatment 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
 
Telephone call7 
Visit 17 (or 
17a, 17b, 
17c) 
 
12 weeks ± 5 
days after 
third 
treatment, 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
FWS Investigator (GLS-I, Section10.1.1) 
 


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Evaluation 
for re-
treatment 
Visit  
 
End Of Cycle 
 
Fourth 
treatment 
with 
possible 
extension at 
4-weekly (± 
5 days) 
intervals 
until subject 
is eligible for 
re-
treatment 
AE and AESI assessment(Section 11)13 
Concomitant medication (Section11.10.1) 
Confirmation of eligibility for re-treatment 
(Section 7.3) 
 
 
Urine pregnancy test (if applicable, Section 11.12) 
Vital signs (Section 11.13) 
Clinical laboratory assessments (Section 11.15) 
Full physical examination (Section 11.11) 
Antibody test (Section 11.15.2) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6) 
Eligibility for re-treatment (Section7.3)6 
 
Consent for re-treatment 
FOURTH TREATMENT (Section 8.3) 8 
Post-treatment observation and AE  assessment 
over 30 min 
AESI questioning after 30 min  
 
Visit 18 
 
C4 
 
Week 1 
1 week ± 2 
days after 
fourth 
treatment 
Full physical examination (Section 11.11) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
 
 
Visit 19 
C4  
Week 2 
14 days ± 5 
days after 
fourth 
treatment 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
Telephone call7 
Visit 20 
 
C4 
 
Week 4 
4 weeks ± 2 
days after 
fourth 
treatment 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6)  
FWS Investigator (GLS-I, Section 10.1.1) 
Full physical examination (Section 11.11) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
Vital signs (Section 11.13) 
Clinical laboratory assessments (Section 11.15) 
Antibody test (Section 11.15.2) 
 


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1An 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 FWS. 
2   A time deviation of ± 5 days is allowed for each visit, except for the week 1 and week 4 visit in each treatment 
cycle 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 still be documented as a protocol deviation. 
3Inclusion and exclusion criteria to be re-confirmed at baseline include FWS for subject and investigator 
and concomitant medication. 
4 At an Evaluation for Re-treatment visit (visits 7, 12 and 17), if the FWS score (at maximum frown) is 
not ≥ 2, as determined by both the subject and the investigator, the subject will return at 4-weekly 
intervals thereafter until this criteria is met. The subsequent visit number for the cycle will remain the 
same, but will be amended with "a, b, c" etc., corresponding to the time extended (at 4 weekly intervals) 
in that treatment cycle, with each additional letter corresponding to a time point 4 weeks later in that 
cycle. For example, the first evaluation for re-treatment is at visit 7, week 12, however for subjects who 
are not eligible for re-treatment at week 12, but at week 16, this visit will be denoted “visit 7a", while 
"visit 7b" and "visit 7c" will denote visits at week 20 and week 24 in the first treatment cycle, 
respectively. 
If the subject wants to get re-treated, but the investigator does not agree or vice versa (i.e. the FWS 
score is not ≥ 2 by both assessments), the subject will return to the site 4weeks thereafter for another 
Evaluation for Re-treatment visit. 
5 Each treatment/re-treatment cycle will last at least 12 weeks. If more than 12 weeks have passed since 
the previous treatment and the subject has a FWS score (at maximum frown) of ≥ 2, as determined by 
Visit 21 
 
C4 
 
Week 8 
8 weeks ± 5 
days after 
fourth 
treatment 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
 
Telephone call7 
Visit 22 
 
End of Study 
Visit 9 
 
 
12 weeks ± 5 
days after 
fourth 
treatment or 
on the same 
day when no 
further 
treatment 
can be 
given10, 11 
 
 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows scale and 
Age Appraisal VAS (Section 20) 
FACE-Q Satisfaction with Outcome Scale (Section 
20.6) 
FWS Investigator (GLS-I, Section 10.1.1) 
AE and AESI assessment (Section 11)13 
Concomitant medication (Section 11.10.1) 
Serum pregnancy test (if applicable, Section 11.12) 
Vital signs (Section 11.13) 
Full Physical examination (Section 11.11) 
Clinical laboratory assessments (Section 11.15) 
Antibody test (Section 11.15.2) 
 


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both the subject and the investigator, this visit will then be considered the End of Cycle visit and all 
other criteria required to determine eligibility for re-injection will be assessed. 
6 If the subject qualifies for re-treatment (in accordance with the eligibility for re-treatment criteria) at 
the End of Cycle visit, the subject may then enter the next treatment cycle and will receive the next 
study drug treatment. If the FWS score (at maximum frown) is assessed as ≥ 2 by both the investigator 
and the subject, but the additional criteria for reinjection are not met, e.g. presence of relevant 
infection or inflammation at the injection site, the subject will be allowed to return 4 weeks later for 
re-assessment . 
7 Visits 9, 11, 14, 16, 19 and 21 will be telephone calls and will not require the subject to visit the site. 
If an AESI is reported, subjects must come to the site as soon as possible for an unscheduled visit, 
including a targeted physical examination to evaluate the AESI.8 A maximum of four treatments per 
subject (four treatment cycles) is permitted during the study time frame, with treatments separated 
by a minimum of 12 weeks. There is no limit to the number of Evaluation for Re-treatment visits.  
9 The End of Study visit can take place in four-weekly intervals from study-week 48 until study-week 
60. For subjects receiving re-treatment at week 48, the last cycle will end 12 weeks later at week 60 
(=End of Study visit). End of Study visit will take place at week 48 if week 48 visit is an Evaluation for 
Re-treatment visit and the subject is not meeting criteria for re-injection. For subjects having received 
their last injection 8 weeks or less prior to week 48, the End of Study visit will take place 12 weeks 
after the last study drug treatment was given, e.g. week 52 if the subject was retreated at week 40. A 
± 2 day time window is always applied for conducting the End of Study visit.  
10For 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. 
11In subjects who do not receive any additional treatments, assessments already performed that day 
do not need to be repeated if both visits take place on the same day.  
12Photographs of subject's glabellar lines will be taken at C1 Randomization, C1 Week 2, C1 Week 4 
and each C1 Evaluation for Re-Treatment visit in Cycle 1 until the subject qualifies for re-treatment in 
order to provide evidence of effect and confirm that the subject did not qualify for re-treatment on 
the preceding Evaluation for Re-treatment visit. Although a photograph will be taken at each 
Evaluation for Re-treatment visit, only the photo of the visit preceding the re-treatment visit will be 
reviewed by the independent reviewers 
13AESI   Questioning: active questioning by guided review of systems (ROS) as per AESI manual. If an 
AESI is reported, a targeted physical examination around the area of the reported AESI must follow. 
 
9.3.1 
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 
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will be at the investigator’s discretion, but should include AE assessment, AESI query, 
concomitant medication and possibly FWS. 
In case of an unscheduled visit, the investigator should complete the “Unscheduled Visit Form" 
in the CRF. 
9.4 
Subject Diary and Patient Reported Outcomes 
9.4.1 
Subject Diary 
A paper subject diary will be provided to each subject at the baseline visit (day 0) and one 
week after the first treatment visit to record the following information: 
 
Daily documentation of FWS score at maximum frown. 
The subject diary will be collected at the visit one week after the first treatment and the 
subject will be given a second diary to be returned at the visit two weeks after the first 
treatment. Subjects will be trained on use of the diary during the baseline visit (training will 
be recorded in the source). 
Treatment onset will be evaluated by the subject and the investigator (using FWS) at study 
visits one, two and four weeks after the first treatment and documented accordingly. In 
addition, for further determining onset of treatment, the subject will record the FWS score in 
diaries daily for the first two weeks after treatment (in the first treatment cycle). 
The subject diary will serve as a source record and remain at the study site. Entries in the 
subject diary will be transcribed into the electronic data capture (EDC) system by the blinded 
member of the site study team. 
9.4.2 
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 patient, or subject views of 
outcomes used to measure treatment benefit or risk in IMP clinical trials. Three PRO 
instruments will be used in this study to support claims in the product label, comprising:  
 
The FWS, which will be used to evaluate the severity of glabellar lines (Section20.1 
and Section 10.1) which will be completed by the subject (PRO; Glabellar Line Scale 
for Subjects, GLS-S) and the investigator (clinician reported outcome; Glabellar Line 
Scale for Investigators, GLS-I). 
 
The modified Skindex-16 (GL-QoL) and FACE-Q scales (Appraisal of Lines Between 
Eyebrows scale and Age Appraisal VAS), which will be used to measure the 
psychological impact of glabellar lines and concerns relating to their glabellar lines, 
respectively (Section 20.3 and Section20.4, Section 20.5). 


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 
The FACE-Q Satisfaction with Outcome Scale which will be used to measure subject 
satisfaction with treatment (Section 20.6). 
Entries in the questionnaires will be transcribed into the EDC system by a blinded member of 
the site study team. 
9.5 
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). Completion of the first cycle 
and the open label cycles will be documented on two different CRF pages. 
Subjects will be considered to be "per protocol completers" of Cycle 1 if they had no major 
protocol deviations in the first cycle and an in-clinic assessment with the FWS by the 
investigator and the subject at baseline (day 0) and at the week 4 visit were performed. 
Subjects will be considered to be "per protocol completers" of the study if they have 
completed the final cycle within week 48-60, without major protocol deviation. 
Reasons for completion or non-completion will be reported on the Completion/Termination 
CRF, 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 CRF.  
Every effort will be made to have discontinued subjects complete the End of Study visit. All 
procedure and assessment results performed at such visits 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 CRF. 
9.6 
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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10. 
ASSESSMENT OF EFFICACY 
10.1 
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 
(which represents the worst appearance of upper facial lines with maximum load on the 
muscle) and at rest (which represents 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 reproducible 42. 
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 instrument proposed for use in this 
study is the FWS, which is named Glabellar Line Scale for Investigators [GLS-I] and Glabellar 
Line Scale for Subjects [GLS-S], as described in Section 20.1. The scale and the proposed 
instructions for its use by investigators and subjects are described in Section 20.1 and in the 
completion manuals: ‘Glabellar Line Scale– Subject: Completion Manual’, ‘Glabellar Line Scale 
- Subject: Completion Manual for Investigator’, and ‘Glabellar Line Scale – Investigator: 
Completion Manual’. 
10.1.1 
Subject and Investigator In-clinic Assessment 
Subjects will be trained extensively in accurate self-assessment of their glabellar line severity 
by the investigator at the baseline visit, as outlined in FWS completion manuals ‘Glabellar Line 
Scale – Subject: Completion Manual’ and ‘Glabellar Line Scale - Subject: Completion Manual 
for Investigator’. Investigators will complete training before trial initiation and will receive 
training certification. Investigators will also have an FWS completion manual: ‘Glabellar Line 
Scale – Investigator: Completion Manual’. Subject FWS assessment must be performed 
independently of the investigator and ideally before the investigator FWS assessment, to rule 
out any influence or bias from the investigator. The date and time of assessment will be 
recorded for each visit in the double blind cycle and for the week 4 visits during the open label 
cycles.  
Subjects and investigators will assess the severity of the subject's glabellar lines at maximum 
frown and at rest using the FWS instrument (Section20.1), i.e. the GLS-S (for subjects) and the 
GLS-I (for investigators).  
In the first treatment cycle, the severity of the subjects’ glabellar lines will be evaluated by the 
subject and the investigator at baseline and at study visits 1, 2, 4, 8, 12 weeks and at 4 weekly 
intervals thereafter (week 16, week 20, etc.) until the subject qualifies for re-treatment with 
glabellar line severity returning to a score of 2 or 3 on the FWS. The same investigator must 
assess the subjects at baseline and at the visits at weeks 1, 2 and 4 in the first treatment cycle, 


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although every effort shall be made to have the same investigator assess subjects at all time 
points. 
The primary efficacy endpoint will be a composite endpoint of the investigators’ and the 
subjects’ assessments of line severity at maximum frown in comparison with placebo at week 
4. A subject will be considered a responder if they have a 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, based on both the investigator’s and the subject’s in-
clinic assessments. Responder rates at other time points in the first treatment cycle will be 
evaluated as secondary endpoints. 
In the open label extension phase, the percentage of responders (FWS score of 0 or 1 and an 
improvement ≥ 2 points in FWS score at maximum frown) at week 4 after re-treatment 
relative to the rating at the preceding end of cycle visit will be determined as a secondary 
efficacy endpoint. 
10.1.2 
Photo-evaluator Assessment 
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 
in the first treatment cycle at the following visits: baseline before the first treatment, study 
visits 2and 4weeks after the first treatment and at the Evaluation for Re-treatment visits, i.e. 
week 12 after baseline and 4 weekly thereafter until the subject qualifies for re-treatment. 
Selected photographs will subsequently be assessed by independent blinded raters.  Although 
a photograph will be taken at each evaluation for the re-treatment visit, only the photograph 
of the visit preceding the re-treatment visit will be reviewed by the independent raters (in 
addition to the photographs at baseline, week 2 and week 4) and the data will be included in 
the analysis of additional secondary efficacy endpoints. 
10.2 
Psychological Impact 
The psychological impact of glabellar lines and concerns relating to glabellar lines will be 
measured using the modified Skindex-16 (GL-QoL) Scale43 (Section 20.3) and the FACE-Q 
Appraisal of Lines Between Eyebrows scale and Age Appraisal VAS 44  (Section 20.4), 
respectively, at screening, 4weeks after each treatment and the end of each treatment cycle. 
10.3 
Subject Satisfaction with Treatment 
Treatment satisfaction will be measured using the FACE-Q Satisfaction with Outcome Scale45 
(Section20.6) at 4 weeks after each treatment administration and at the end of each 
treatment cycle. 


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11. 
ASSESSMENT OF SAFETY 
11.1 
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 first dose 
will be recorded as a Pre-treatment Event on the Medical History page. Any untoward medical 
occurrence in a subject after first dose until 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. 
11.1.1 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs, AESIs, 
and SAEs 
Newly detected abnormal clinical laboratory findings (e.g. clinical chemistry, hematology) or 
other abnormal assessments (e.g. ECGs, physical examination, vital signs) that are judged by 
the investigator as clinically significant must be recorded as AEs, AESIs, or SAEs. Clinically 
significant abnormal clinical laboratory findings or other abnormal assessments present at the 
Screening visit will be documented as Medical History. If there is worsening during the study 
this will be documented as an AE, AESI, or SAE. 
The investigator will exercise medical and scientific judgment in deciding whether an 
abnormal clinical laboratory finding or other abnormal assessment is clinically significant.  
11.2 
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 below is reported a targeted physical examination should be 


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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. duration of the event is to considered unusual for an AESI or if the 
event is considered as being not related to the study drug. Adverse events of special interest 
potentially suggestive of distant spread of toxin, include: 
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 
the first injection, in order to obtain a full baseline status of any concomitant diseases. If an 
AESI is reported, a targeted physical examination must be conducted. If reported during a 
telephone contact, subjects must come to the site for further assessment as soon as possible.  
11.3 
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. 


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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 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 1 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. 
11.4 
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. 
11.5 
Evaluation of AEs, AESIs, SAEs, TEAEs 
11.5.1 
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): 


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 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. 
 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.  
11.5.2 
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. 
11.5.3 
Outcome 
The outcome options that can be utilized include: 
 
Ongoing 
 
Resolved 
 
Resolved with Sequelae 
 
Death 


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 
Unknown 
11.5.4 
Action Taken with Study Drug 
Action taken with study drug includes: 
 
None 
 
Discontinued 
11.6 
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 
Pharma GmbH 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 11.2, 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 CRF. 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 CRF.  
When documenting AEs, standard medical terminology should be used in order to avoid the 
use of vague, ambiguous, or colloquial expressions (see Section 11.1). Each AE will be 
evaluated by the investigator for: 
 
Seriousness, as defined in Section11.3. 
 
Severity, as defined in Section 11.5.2. 
 
Causal relationship to IMP exposure, as defined in Section 11.5.1. 
 
Causal relationship to procedure. 




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If the report is sent via email then the completed and signed SAE/AESI or Pregnancy report 
form must be attached to the email. A notification email of the event describing it 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 Pharma GmbH, 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), a 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. 
11.6.2 
Exposure In Utero During Clinical Trials 
The Sponsor or representative must be notified of any subject that becomes pregnant while 
participating in this clinical trial. Although pregnancy is not technically an AE, all pregnancies 
must be followed to conclusion to determine their outcome. This 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 trial to
 Clinical 
Research, as specified above (Section 11.6.1) within 24 hours of awareness of the pregnancy, 
using the pregnancy reporting form. 
Once a pregnancy has been detected/reported, no further study drug injections must be 
administered. Pregnant subjects will be followed-up until the end of the current injection cycle 
and will then be withdrawn from the study. At the end of the injection cycle, an End of Study 
visit will be conducted. Following detection of pregnancy, no invasive assessments must be 
conducted in pregnant women including no blood sampling for e.g. safety laboratory 
assessments or antibodies. The treatment code for pregnant women will be unblinded. 
 
 
11.6.3 
Overdose 
Overdose is defined as any dose above the total body dose per injection session (i.e. 20 
U/treatment). 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 
indications31,46,47,48,49and it is generally recognized that doses greater than 20 U may be 
required for larger muscles50. The treatment dose in this study is 20 U and the treatment 
vials contain only 50 U, hence there is virtually no risk of overdose.  


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11.7 
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 Pharma GmbH. 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 1 calendar day after the change is implemented. The Sponsor (CROMA 
Pharma GmbH) will also ensure the responsible ethics committee (EC) is notified of the urgent 
measures taken in such cases, according to local regulations. 
11.8 
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. 
11.9 
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 (IB). 
“Unexpected” also refers to the AEs or suspected adverse 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 CRF. 
11.10 Medical, Medication and Non-Drug Therapy History 
11.10.1 Medication and Non-Drug Therapies 
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 
CRF.  
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: 


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 
Treatment with botulinum toxin of any serotype for any reason during the trial (other 
than the investigational treatment).  
 
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 anaesthetic. 
 
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 supercili muscles or a combination of these, or scars in the glabellar area. 
11.11 Medical History and Physical Examinations 
Medical history will be taken at screening, including a record of previous treatment with 
botulinum toxin. At baseline and subsequent study visits (as listed in Section 2.1 and Section 
9.3), a full physical examination will be performed by the investigator. Full physical exam will 
include neurological assessment (including extraocular movements and cranial nerves) as well 
as assessment for muscle weakness.  In addition, if the subject reports an Adverse Event of 
Special Interest (as detailed in the AESI Manual) a focused physical examination by the 
physician, to evaluate these symptoms will also be undertaken. Any clinically relevant 
abnormal finding will be documented in the CRF as AE/medical history. 
11.12 Pregnancy test 
For women of child-bearing potential (i.e. being pre-menopausal with no 12 consecutive 
months without a menstrual period or not surgically sterilized), a blood serum pregnancy test 
will be performed at screening and at the end of the study and urine dip-stick pregnancy tests 
will be performed before re-treatment. 
Pregnancy tests may be performed at more regular intervals per local regulatory 
requirements. 
11.13 Vital Signs 
Vital signs will include pulse rate (beats/min), and systolic and diastolic blood pressure 
(mmHg). Vital signs will be measured at screening, at each visit involving IMP administration 
(to be recorded before IMP administration, i.e. baseline for the first treatment cycle and end 
of cycle visit before re-treatment), at the visit 4 weeks after treatment and at the end of the 
study. Vital sign values will be recorded on the CRF. 


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11.14 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). Height and weight data will be used for the calculation of body mass 
index. 
11.15 Clinical Laboratory Tests (Safety) 
A full list of the parameters that will be analyzed can be found below. 
Any safety laboratory results outside the normal range will be evaluated by the investigator 
or his designee as “clinically significant” or “not clinically significant”. Any test assessed as 
being clinical significant must be documented as pre-treatment event (if obtained at 
Screening) or as AE. Sites will conduct re-tests for blood samples which could not be analyzed 
at the central lab due to e.g. haemolysis etc. Repeat of lab tests for clinically significant test 
results are at the discretion of the investigator.   
11.15.1 Hematology and Clinical Chemistry 
Blood will be obtained for assessment of complete blood count (CBC) and clinical chemistry 
parameters in accordance with the schedule, i.e. at screening, 4 weeks after each treatment 
and at the end of cycle visit. Please refer to the laboratory manual for collection and 
processing of samples. CBC and clinical chemistry tests will be performed on 
ethylenediaminetetraacetic acid -anticoagulated whole blood and serum, respectively in the 
central laboratory. The CBC will include hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin concentration, red blood cell count, and white blood cell count, 
as well as differential and platelet count.  
The clinical chemistry panel will consist of sodium, potassium, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, 
gamma glutamyltranspeptidase, creatinine, cholesterol and glucose (random). Testing of the 
blood samples will be performed at the central laboratory.  
 
 


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11.15.2 Antibody Test 
Serum samples will be tested for the presence of antibodies to botulinum toxin using an Anti 
Drug Antibody (ADA) ELISA assay; initially only the last sample obtained from each study 
subject will be analyzed together with the pre-dose baseline sample. If a sample tests positive 
for anti-drug antibodies, the other samples from the subject will be analyzed to determine 
when antibodies developed. Serum samples which test positive for binding antibodies will 
subsequently be tested for neutralizing activity. Blood serum for ADA tests will be collected at 
screening, at the visit 4 weeks after treatment and at the end of cycle visit for each treatment 
cycle and will be stored for future analysis should the need arise, based upon the presence of 
ADA at the end of the study. Sample storage at -80°C is preferable, but samples can be stored 
at -20°C at sites if -80°C storage is not available. Samples will be stored (at
.) until 
completion of the trial and will be destroyed thereafter. 
11.16 Electrocardiograms 
A 12-lead ECG will be performed on each subject at screening (which will be taken as baseline), 
at week 4 after the first treatment (presumed steady state) and at the end of cycle for the first 
treatment cycle. Any observation assessed as being clinical significant must be documented 
as pre-treatment event (if obtained at Screening) or as AE. 


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12. 
STATISTICS 
12.1 
Sample Size and Power Calculations 
Primary Analysis: 
The primary endpoint is a composite endpoint comprising investigator and subject 
assessments of treatment effectiveness using the FWS.  Composite endpoint treatment 
success (CETS) is defined as ≥2 point reduction in FWS score at maximum frown achieving a 
score of 0 or 1 at the visit week 4 relative to baseline based on investigator assessment and 
subject assessment. Thus, a subject is a CETS “Responder” only if both investigator- and 
subject-rated success criteria are satisfied at the visit 4 weeks after baseline.  
The primary analysis of efficacy is the proportion of responders in the BoNT/A-DP treatment 
group compared with the placebo treatment group. For superiority testing of BoNT/A-DP 
compared with placebo, the following assumptions for the sample size calculation will be 
used: 
Item 
Assumption 
Comments 
Underlying test 
Fisher’s Exact Test 
Standard test for a response parameter for 
small numbers 
Randomization scheme 
3:1 
More active treatment subjects to enlarge 
safety data base 
Power 1- 
90% 
Actual power is 92.3%. 
Significance level () 
0.025 one-sided 
 
Response  
Arm BoNT/A-DP 
46% 
Conservative value based on the results of 
previous studies (Bless I and Bless II) 
Response  
Arm Placebo 
2% 
Conservative value based on the results of 
previous studies (Bless I and Bless II) 
Software 
 
The sample size calculation was performed 
using the software nQuery Advisor® 8.2.1.0. 
 
Based on these assumptions, 39 subjects in the BoNT/A-DP arm and 13 subjects in the placebo 
arm are required, i.e. 52 subjects in total. This is a very small sample size and not sufficient for 
a detailed evaluation of the data, including subgroup analyses. Furthermore, the response 
rate could not be estimated with sufficient precision. Assuming a response rate of 60% in the 
BoNT/A-DG group, a two-sided CI of 95% with a distance from the response rate to the CI 
limits of about 5.6% could be achieved with a sample size of 225 subjects in the BoNT/A-DP 
group. We propose a 3:1 randomization of BoNT/A-DP (225 subjects) to placebo (75 subjects), 
which we believe is adequate for a precise estimate of response rate and for post-hoc 


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sensitivity analyses (i.e. treatment-by-center and other subgroup analyses), also taking into 
account a drop-out rate. 
In addition sample size is justified in order to fulfill FDA request for additional subjects treated 
with BoNT/A-DP to provide an adequate Safety database. 
In total, 353 evaluable subjects will be enrolled. Applying a 15% drop out rate would result in 
a total number of about 300 subjects.  
 
12.2 
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 placebo) 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, regardless of whether they received study 
medication. 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 (ITT) principle. The FAS will be used for the evaluation of the efficacy 
assessments. The FAS serves as the primary efficacy analysis set. 
Modified Full Analysis Set (MFAS): 
The MFAS includes all randomized subjects who received at least one injection with study 
medication who had a baseline (visit 1 at day 0) and at least one post-dose in-clinic assessment 
with the FWS by either the investigator or the subject on visits at weeks 1, 2 or 4. Within the 
MFAS, 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 (ITT) principle. 
The MFAS will be used for the evaluation of the efficacy assessments.  
Per-protocol Analysis Set (PP): 
The PP includes all randomized subjects who received at least one injection with study 
medication who had no significant protocol deviations and an in-clinic assessment with the 
FWS by the investigator and the subject at baseline (day 0) and at the week 4 visit. For the PP, 
all subjects will be assigned to the randomized treatment. The PP will only be analyzed for 
main efficacy outcome measures. 
Data Review Meeting: 


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Subjects will be assigned to the SAF, FAS, MFAS and PP during a data review meeting (DRM). 
Further details on the analysis sets, criteria for the PP, and the DRM will be specified within 
the statistical analysis plan (SAP). Details for and decisions on protocol deviations will be 
specified in a classification meeting taking place between database lock and unblinding. 
Corresponding documentation should be held outside of the SAP. 
12.3 
Procedure for Accounting for Missing, Unused, and Spurious Data 
Analyses will be performed by visit. For responder analyses on visits at week 4 and week 12, 
missing in-clinic assessments (investigator or the subject) with the FWS at baseline or week 4 
and week 12 visits will be assigned as being non-responders. 
As sensitivity analyses, the following additional approaches for handling of missing values will 
be applied: 
 
Analysis on observed values only, i.e. missing values will be excluded from analysis. 
 
Last observation carried forward (LOCF) 
Tipping point analysis: each missing value will be assigned to either a response or non-
response, so that all possible combinations of replacing 1 or more missing values within each 
treatment group will be analyzed. p-values will be calculated for each combination and 
graphically displayed using a scatter plot. 
 
12.4 
Methods of Analysis 
12.4.1 
Primary Outcome Measure 
Primary Analysis: 
The proportion of subjects (responders) meeting the primary endpoint with a FWS score of 0 
or 1 and an improvement ≥ 2 points in FWS score (at maximum frown) at week 4 visit relative 
to baseline, based on both the investigator and the subject in-clinic assessments will be 
analyzed using the Cochran-Mantel-Haenszel test (with stratification variable site; small sites 
with less than 3 placebo subjects will be combined) using a significance level () of 0.025. The 
hypothesis to be tested is: 
 
H0: pBoNT/A-DP≤ pPlacebo 
 
H1: pBoNT/A-DP>pPlacebo 
The Cochran-Mantel-Haenszel test will be applied using SAS procedure Proc Freq (using the 
General Association Statistic). The one-sided p-value will be derived by halving the two-sided 
p-value delivered by the SAS procedure. Superiority of BoNT/A-DP over placebo will only be 
concluded if, besides statistical significance (one-sided p-value ≤0.025), the proportion of 
responders in the BoNT/A-DP treatment group is higher than for the placebo treatment group. 


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The FAS will serve as the primary analysis set. 
Subjects with missing investigator or subject in-clinic assessments with the FWS at baseline or 
visit week 4 will be assigned as being non-responders. 
Additional Analyses on the Primary Endpoint Variable: 
Further analyses on the primary endpoint variable are exploratory. A one-sided Pearson 2-
test will be applied. Two-sided CI of 95% for the responder rates in the BoNT/A-DP and the 
placebo treatment groups will be calculated using Wilson scores. Treatment-by-center 
interaction will be tested using the Breslow-Day test for homogeneity of the odds ratios. The 
CIs will also be calculated for the additional analyses as listed in the following: 
 
The primary endpoint measure using the observed values only, i.e. missing 
investigator or the subject in-clinic assessments with the FWS at baseline or week 4 
visit will be excluded from analysis but not assigned as being non-responders. 
 
The primary endpoint measure using the MFAS and the PP. 
 
The primary endpoint measure applying the LOCF for week 4 visit. 
 
Subgroup analysis by site, country and geographic region (US versus EU). 
o Subgroup analyses will be conducted for sites, , country and geographic 
region (US versus EU). Sites with less than 3 placebo subjects will be 
combined. The 2-test will be applied for each subgroup. In case of a total 
number of observations below 30, or in case of at least one cell frequency 
below 5, Fisher’s exact test will be used instead of the 2-test.  Stratified 
analyses applying the Cochran-Mantel-Haenszel test will also be conducted 
using factor geographic region. 
 
Subgroup analysis by subjects with previous use of botulinum toxin versus naïve 
subjects. 
o Subgroup analyses will be conducted for subjects with treatment with any 
serotype of botulinum toxin for any indication versus naïve subjects. The 2-
test or Fisher’s exact test (see above corresponding criteria to use Fisher) will 
be applied for each subgroup. No stratified analysis using factor pre-
treated/naïve subjects is currently planned. 
 
In addition, the following subgroups will be used for the primary efficacy endpoint: 
o  Race  
o Subjects with previous use of botulinum toxin by site 
o Naïve subjects by site 
o Fitzpatrick skin type 
o Sex 


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o Ethnicity 
o Age groups (below 65 years, 65-74 years and 75-84 years; below 65 years 
versus 65 years and older) 
12.4.2 
Secondary Outcome Measures 
Key Secondary Analyses: 
The testing of the key secondary endpoint will be performed with appropriate multiplicity 
control based on the FAS population. The results of each test result will only be considered 
confirmative if the previous test in the order showed a confirmatory result at a one-sided 
significance level of 0.025. If the one-sided p-value is larger than 0.025 for any of the tests, 
the results of the subsequent tests will only be considered exploratory, and not confirmatory. 
The application of this hierarchical approach keeps the global significance level to 0.025 one-
sided and requires no further adjustment of the significance level. 
The following order of tests will be defined: 
 
Primary endpoint (composite endpoint) 
 
Key secondary endpoint 1 
 1.1: The modified Skindex-16 (GL-QoL) Emotional domain 
 1.2: The modified Skindex-16 (GL-QoL) Social Functioning domain 
 1.3: The modified Skindex-16 (GL-QoL) Overall score 
 1.4: The FACE-Q Appraisal of Lines Between Eyebrows scale 
 1.5: The FACE-Q Age Appraisal VAS score 
 
Analysis of key secondary endpoint 1: The extent of change in psychological impact (emotional 
and social functioning, and concerns relating to glabellar lines) at week 4 after the first 
treatment, in the BoNT/A-DP group in comparison with placebo, relative to baseline, as 
assessed by the modified Skindex-16 (GL-QoL) and the FACE-Q Appraisal of Lines Between 
Eyebrows and FACE-Q Age Appraisal VAS. 
The modified Skindex-16 (GL-QoL) and FACE-Q Appraisal of Lines Between Eyebrows scale and 
FACE-Q Age Appraisal VAS will be analyzed according to the foreseen analysis approach of 
these tools, as described below. 
Emotional and Social Functioning 
The modified Skindex-16 (GL-QoL) Emotional and Social Functioning domains and overall 
scores will be derived in accordance with the Skindex-16 manual, adapted for the GL-QoL. The 
scores will be standardized on a scale from 0 (no impact) to 100 (maximal impact); a scale 
score is the average of responses to items addressing a construct. Domain and overall scores 
will be calculated if at least two of three social and of at least two of four emotional domain 
items are present. The absolute change from baseline (measured on the screening visit) will 
be calculated for the domain and overall scores and statistically compared between the 
treatment groups using the Wilcoxon Rank Sum test (or t-test). Estimates of ‘mild’, 


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‘moderate’, and ‘severe’ psychological impact, and of the minimal clinical important 
difference, will be used to aid interpretation of scores and will be considered exploratory.  
The analysis will be conducted with respect to the hierarchical order of key secondary 
endpoints; the analysis using the Emotional domain first, the Social Functioning domain 
second, and the overall score third. All analyses will be conducted on observed values only, 
i.e. missing domain and overall scores will be excluded from analysis; no imputation of missing 
domain and overall scores will be performed. 
Concerns Relating to Glabellar Lines 
The FACE-Q Appraisal of Lines Between Eyebrows scale and FACE-Q Age Appraisal VAS scores 
will be derived in accordance with the developers’ instructions and missing data treated 
accordingly. The absolute change from baseline (measured on the screening visit) will be 
calculated for each scale and statistically compared between the treatment groups using the 
Wilcoxon Rank Sum test. All analyses will be conducted on observed values only, i.e. missing 
scale scores will be excluded from analysis; no imputation of missing scores will be performed. 
This analysis will be conducted with respect to the hierarchical order of key secondary 
endpoints as well; the analysis of FACE-Q Appraisal of Lines Between Eyebrows scale first, 
followed by the analysis of FACE-Q Age Appraisal VAS scores. 
Exploratory Analyses 
Exploratory analyses of modified Skindex-16 (GL-QoL) domain and overall score and FACE-Q 
Appraisal of Lines Between Eyebrows scale and FACE-Q Age Appraisal VAS will also be 
conducted using the MFAS and the PP population. Subgroup analysis by site, by geographic 
region, by country and by subjects with previous use of botulinum toxin versus naïve subjects 
will be conducted. 
Additional Secondary Analyses: 
Analysis of additional secondary endpoint 1: The percentage of responders at maximum frown 
(as defined above) at week 12 (after the first treatment with BoNT/A-DP or placebo). 
The same analyses, inclusive of the additional exploratory analyses, as described for the 
primary endpoint will be conducted. 
Analysis of additional secondary endpoint 2: The percentage of responders at week 16 (after 
the first treatment). 
The analysis of the week 16 visit will be conducted on observed values only, i.e. missing 
investigator or the subject in-clinic assessments with the FWS at baseline or week 16 visit will 
be excluded from analysis but not assigned as being non-responders. Subjects who were re-
treated before visit week 16 are considered to be non-responders.  
In addition, the same analyses, inclusive of the additional exploratory analyses, as described 
for the primary endpoint will be conducted. 


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Analysis of additional secondary endpoint 3: The percentage of responders at week 20 or later 
(after the first treatment). 
The analysis of percentage of responders at week 20 (after the first treatment) will be 
conducted on observed values only, i.e. missing investigator or the subject in-clinic 
assessments on FWS at baseline or visit week 20 will be excluded from the analysis but not 
assigned as being non-responders. Subjects who were re-treated before visit week 20 are 
considered to be non-responders. 
In addition, the same analyses, inclusive the additional exploratory analyses as described for 
the primary endpoint, will be conducted (for subgroups also).  
Analysis of additional secondary endpoint 4: The proportion of subjects with a ≥ 1 point 
reduction in FWS score at rest at week 4 in the first treatment cycle, based separately on the 
investigator and the subject in-clinic assessments  
In general, the same statistical analyses, inclusive of the additional exploratory analyses as 
described for the primary endpoint, will be conducted. 
The analysis on the investigator’s in-clinic assessment will be conducted only for subjects who 
have an investigator’s in-clinic assessment of a FWS score at rest ≥ 1 at baseline. This will 
similarly be applied for the analysis of the subject’s in-clinic assessment. 
Subjects with missing investigator in-clinic assessments at baseline or week 4 visit will be 
assigned as being non-responders for this endpoint. This will similarly be applied for the 
subject’s in-clinic assessment. 
In general, the additional secondary efficacy endpoints will be analyzed applying the 
appropriate statistical method for the comparison of both treatment arms. For proportions, 
the Cochran-Mantel-Haenszel test (with stratification variable site) and the Pearson 2-test 
will be applied. In case of a total number of observations below 30, or in case of at least one 
cell frequency below 5, Fisher’s exact test will be used instead of the 2-test. Two-sided 95% 
CIs for response rates will be calculated, where appropriate. Additionally the cumulative 
proportions of effects at weeks 1, 2, and 4 will be calculated. Time to onset of effect in the 
first treatment cycle will be analyzed descriptively and by using the Kaplan-Meier method. 
Moreover, the daily assessments of the line severity when frowning will be analyzed 
descriptively. The FACE-Q satisfaction with outcome scale will be analyzed descriptively. 
All endpoints, with exception of “responder” 4 weeks after re-treatment, will be analyzed for 
the first treatment cycle only. The analysis of “responder” 4 weeks after re-treatment will be 
conducted on observed values only, i.e. subjects with missing investigator or the subject in-
clinic assessments on FWS week 4 or at the preceding end of the cycle visit will be excluded 
from analysis. Subjects who were treated with placebo during the first treatment cycle are 
excluded from the analysis of this endpoint, but not assigned as being non-responders. A two-
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proportions between week 4 re-treatment visit and at the preceding end of the cycle visit. 
This endpoint will be separately analyzed for each open label extension cycle. 
Analyses of percentage of responders at other visits after first treatment but before re-
treatment are exploratory only. Additional exploratory analyses, as described for the primary 
endpoint, will not be conducted, with the exception of the calculation of 95% CIs.  
Besides the FAS population for the analysis with multiplicity control, the analyses of these 
endpoints will also be based on the MFAS and the PP population. For all analyses, a one-sided 
significance level of 0.025 will be used, if not stated otherwise. Additional exploratory 
subgroup analyses by site, or by subjects with previous use of botulinum toxin versus naïve 
subjects, will be conducted for additional secondary analyses. For secondary endpoint 4 all 
subgroup analyses as described for the primary endpoint will be conducted. For the 
proportion of subjects with ≥ 1 point reduction in FWS score during the first treatment cycle 
at week 12, 16 and 20 relative to baseline subgroup analyses by site, by country, by geographic 
region and by subjects with previous use of botulinum toxin versus naïve subjects will be 
conducted. 
Secondary Safety Endpoints: 
No statistical testing methods will be applied to statistically evaluate the differences on safety 
variables between treatment groups. Safety endpoint variables will be analyzed descriptively 
only. 
Analysis of secondary safety endpoint 1 (adverse events): 
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 placebo). If it cannot be determined 
whether an AE is treatment-emergent due to a partial onset date, then it will be counted as 
such. 
TEAEs will be analyzed overall (for BoNT/A-DP or placebo), and for BoNT/A-DP treatment 
group additionally separately per first treatment cycle or open label extension phase: events 
starting on or after first treatment up to before open label extension (first cycle), and events 
starting on or after re-treatment until end of study (open label phase). If it cannot be 
determined whether an AE started during the first treatment cycle or the open label extension 
phase due to a partial onset date, then it will be counted as having started during first 
treatment cycle. 
Events of subjects who started the first treatment with placebo but then entered the open 
label extension for re-treatment with BoNT/A-DP will be considered to placebo for the first 
cycle and to BoNT/A-DP for the open label phase.  
Treatment-emergent adverse events 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. TEAEs (SOC and PT) will also be summarized by seriousness, 


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severity, relationship to study medication, and relationship to procedure. Treatment-
emergent AESIs will be tabulated separately. 
Analysis of secondary safety endpoint 2 (antibody formation):  
The presence of antibodies will be summarized by counts and percentages of subjects by 
treatment group and time point. For the subgroup of subjects with a sample test positive for 
anti-drug antibodies, all analyzed samples will be analyzed descriptively by counts over time 
as well. 
Analysis of secondary safety endpoint 3 (laboratory data, vital signs, ECG):  
All laboratory values will be classified as normal or abnormal according to the central 
laboratory normal ranges and indicated as clinically significant (CS) or not clinically significant 
(NCS) by the investigator. Quantitative laboratory values will be summarized with means, 
standard deviations, medians, minima and maxima at baseline and over time and of absolute 
changes from baseline. Categorical variables will be summarized by counts and percentages 
of subjects in corresponding categories. Shift tables illustrating changes with respect to the 
central laboratory normal ranges and the investigator assessment between baseline and post-
baseline visits will be created: Number and percentage of subjects with normal, CS and NCS 
laboratory values.  
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. 
Normal/abnormal shift tables will be created for the overall ECG interpretation by treatment 
group for all applicable time points. 
An additional safety evaluation will be performed by defining cycle 2 day 0 as baseline for 
subjects who switched from placebo to BoNT/A-DP. 
12.4.3 
Further Analyses 
Baseline data, including demographic data will be analyzed 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. 
12.5 
General Statistical Considerations 
The statistical analysis of the first treatment cycle and the open label extension phase 
(cycles 2-4) will be performed after database lock of all data up to the end of study (can 
take place in four-weekly intervals from study week 48 until study week 60 [see schedule 
of study procedures and assessments Section 2.1]) and final unblinding.  


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Further aspects of statistical analyses will be detailed within a SAP. This plan will be finalized 
prior to the database lock and/or study unblinding. 
Continuous variables will be summarized with means, standard deviations, medians, minima 
and maxima. Categorical variables will be summarized by counts and by percentages of 
subjects in corresponding categories. 
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 screening visit will be used. 
Analyses will be performed by visit, irrespective of any time window deviations.  
12.5.1 
Demographic and Baseline Characteristics 
Summary statistics will be provided by treatment group for demographics (e.g., age, gender, 
race, ethnicity, Fitzpatrick skin type) and for baseline characteristics. 
For all efficacy endpoints, baseline will be defined as the measurement prior to receipt of the 
first dose of study medication. 
12.5.2 
Interim Analysis 
An interim analysis will be performed after all subjects finalized the re-evaluation for 
retreatment visit at week 16 of the first treatment cycle or completed the double blind phase 
(whichever occurs earlier). A data base closure for all data belonging to the double blind phase 
up to and including the C1 re-evaluation for retreatment visit at week 16 will be performed 
prior to this interim analysis. All data belonging to the double blind phase up to and including 
the C1 re-evaluation for retreatment visit at week 16 will be checked and all queries resolved 
before data base closure.  A blind data review will be conducted prior to unblinding based on 
all data of the double blind phase up to and including the C1 re-evaluation for retreatment 
visit at week 16 to check for protocol deviations and to allocate the subjects to the analysis 
sets. After data base closure, data unblinding and analysis for the double blind phase up to 
and including the C1 re-evaluation for retreatment visit at week 16 will be done. 
Since the primary and the key secondary efficacy endpoints belong to the first 16 weeks of 
the double blind phase, the final analysis of these endpoints will be conducted during this 
interim analysis (which is based on the final data of the double blind phase up to and including 
the C1 re-evaluation for retreatment visit at week 16) and no alpha adjustment needs to be 
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13. 
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, EC 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-Pharma 
GmbH personnel to be present as an observer during a regulatory inspection, if requested.   


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14. 
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
. Vendors sub-contracted by
 or 
Croma-Pharma GmbH 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 CRFs. The monitoring of the study will be 
performed according to
 monitoring SOPs. 
14.1 
Investigator’s Responsibility 
The investigator will comply with the protocol, Code of Federal Regulation (Title 21, CFR Part 
312) and applicable regulatory requirements and 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. 
14.2 
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, laboratories, 
steering committees, and oversight committees, if applicable) will be maintained by the 
Sponsor and provided to the investigator. 
14.3 
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. 
14.4 
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, Code of Federal Regulation (Title 21, CFR Part 312) and applicable 
regulatory guidelines. The investigator will permit the study monitor or other 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 


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obtained for each subject prior to performing any study procedure. Monitoring processes 
specific to the study will be described in the clinical monitoring plan. 
14.5 
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, Code of Federal Regulation (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 trial-related files and correspondence, 
and information in the informed consent documentation of this clinical trial.  
14.6 
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 1 calendar day after the 
change is implemented. The Sponsor, or authorized designee, will also ensure the responsible 
EC 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 EC and applicable regulatory authorities of any investigator termination. 
14.7 
Facilities 
The study management will be performed by: 
 
 
The following certified clinical laboratory will perform clinical laboratory tests required by this 
protocol: 
I
 
 
The statistical analysis will be performed by: 
 
 
The photographic procedures performed by the clinical study sites and the independent 
photo assessment will be provided and 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 (PIs), names and addresses of investigation sites and names and addresses of 
involved institutions if applicable will be kept in the Trial Master File (TMF) and will be updated 
accordingly. 
 


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15. 
ETHICS 
15.1 
Basic Principles 
This research will be carried out in accordance with the current versions of the Declaration of 
Helsinki; the Code of Federal Regulation (Title 21, CFR Part 312), and local regulatory 
requirements. 
15.2 
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 EC 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 Pharma GmbH.  
If a 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 EC 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 EC approval for the protocol and all subsequent 
major changes, in compliance with local law. 
15.3 
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 trial to 
each potential subject and obtain written informed consent (stating clearly that the study 
includes the possibility of up to three repeat treatments depending on a number of 
factors)before any trial 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, 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. 
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. 


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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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16. 
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 trial master file (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 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 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 CRFs, 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-Pharma GmbH. Should the 
investigator wish to assign the study records to another party or move them to another 
location, Croma-Pharma GmbH 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. 
16.1 
Confidentiality Policy 
The investigator and all personnel involved in the trial will maintain a policy of confidentiality.  
16.2 
Source Documentation and Case Report Forms 
Data will be recorded at sites using CRFs and reviewed during monitoring visits. The recorded 
data in the EDC system will be verified with source documents. All corrections or changes 
made to any study data will be appropriately tracked in an audit trail in the EDC system. 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 CRFs, regardless of screening 
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Source data (e.g. clinical laboratory reports, ECG printouts) 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 CRF after assessment by the investigator or designee. 
Other data of medical measurement without print-outs (date and time of study activities, i.e. 
time of blood sampling, administration of study medication) performed during the study will 
be captured on the respective laboratory requisition forms or dispensing/administration log, 
which will serve as source documentation for the respective activities. Data produced by 
automatic devices with original print-outs (e.g. clinical laboratory test results, ECG traces, 
blood pressure measurements) will be included in the source documentation. Clinical 
laboratory parameters will be provided in laboratory print-outs which are to be reviewed, 
signed and dated by the investigator or designee. Any results outside the normal range should 
be assessed for clinical significance. 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. 
16.2.1 
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 
CRF. All data should preferably be entered into the CRF on the day of the study visit, but no 
later than 2 working days thereafter. Changes to a CRF, 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 CRFs for each subject will remain in the 
investigator file at the study site in accordance with the data retention policy (see Section 
16.3). 
The handling of data by the Sponsor, including data quality assurance, will comply with 
regulatory guidelines (e.g.Code of Federal Regulation (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 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 electronic CRFs. 


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16.2.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
16.2.3 
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 Code of Federal Regulations (21 CFR Part 11). 
All passwords will be strictly confidential. 
16.2.4 
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. 
16.3 
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. 
16.3.1 
Data Base Lock 
Two data base locks will be performed, one after all subjects finalized the double blind phase 
(see section 12.5.2) and one after all data of the first treatment cycle and of the open label 
extension phase are entered into the CRF. In both cases the data base will be locked as soon 
as the respective data base is confirmed as ‘clean’. Before the data base lock for the double 
blind phase, a data review meeting will take place. Further details will be described in the Data 
Management Plan. 
 
17. 
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. 
18. 
PUBLICATION POLICY 
The investigator will comply with the publication policy as described in the Clinical Study 
Agreement. 


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19. 
REVISION HISTORY  
Version 
Date 
Reason for Revision 
Final 
Version  
17.12.2018  
N/A (original document) 
Final 
Version 2.0 
15.07.2019 
- Reordering of secondary study objectives  
- Key secondary endpoints “percentage of responders at maximum frown at 
week 12 (after the first treatment)”, “percentage of responders at week 16 
(after the first treatment)”, and “proportion of subjects with a ≥ 1 point 
reduction in FWS score at rest at week 4 in the first treatment cycle” are now 
set as additional secondary endpoints, but not as key secondary. 
- Clarification on Analysis sets: 
-The FAS will contain all randomized patients, no injection with study 
medication needed. 
-The MFAS includes all randomized subjects who received at least one 
injection with study medication who had a baseline visit 1 at day 0 and at 
least one post-dose in-clinic assessment with the FWS by either the 
investigator or the subject on visits at weeks 1, 2 or 4. 
- The PP includes all randomized subjects who received at least one injection 
with study medication who had no significant protocol deviations and an in-
clinic assessment with the FWS by the investigator and the subject at 
baseline (day 0) and at the week 4 visit. For the PP, all subjects will be 
assigned to the randomized treatment actually received. 
-Subgroup analysis by site, country and geographic region (US versus EU) was 
added 
- Addition of Subgroup analysis for the primary efficacy endpoint 
- For secondary endpoint 4 all subgroup analyses as described for the 
primary endpoint will be conducted. For the proportion of subjects with ≥ 1 
point reduction in FWS score during the first treatment cycle at week 12, 16 
and 20 relative to baseline subgroup analyses by site, by country, by 
geographic region and by subjects with previous use of botulinum toxin 
versus naïve subjects will be conducted. 
- Physical examination assessment will also be done on each End of Cycle 
Visit  
- Addition of the following clarification regarding AESI questioning: 
30-minute post IMP administration, general, non-leading AE questioning as 
well as active AESI questioning must be performed 
- Clarification on subject Identification code: 
A SIC will automatically be assigned by the IWRS system at screening, which 
will comprise B3 (denoting the BLESS III study), followed by a single digit 


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Version 
Date 
Reason for Revision 
country identification, a two digit site identification and a three digit subject 
identification number 
-Update of emotional and Social functioning: 
Domain and overall scores will be calculated if at least two of three social 
and of at least two of four emotional domain items are present. 
 
 


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20. 
SUPPLEMENTS 
20.1 
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.  
 
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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1) Line severity at rest 
 Please look directly in a mirror in a well-lit room with nothing obstructing your face (for example, tie back your hair or use a hairband, 
remove any make up and ensure your glasses do not obstruct the area between your eyebrows) and rate the lines between your eyebrows 
as they appear when your face is relaxed (at rest).  
 Check the most appropriate scale score in the table below: 


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2) Line severity  when frowning  
 Now please frown (push your eyebrows together as far as they will go, as if you are feeling angry, using your facial muscles not your 
fingers) and look in the mirror. How would you rate the lines between your eyebrows now?  
 Check the most appropriate scale score in the table below: 


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20.2 
Glabellar Line Scale – Investigator (GLS-I) 
 
In this questionnaire you will be asked to rate the severity of the patient’s glabellar lines when 
their face is at rest and when they are at maximum frown.  
 
Please use the accompanying drawings and the photo atlas to help you make your ratings.  
 
If the patient has any asymmetry in their glabellar lines, please use the most severe line to score 
the questionnaire. 
 
 
 


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1) Line severity at rest 
Ask the patient to remove anything obstructing their forehead area (for example glasses and make-up, and tie back their hair or use a 
headband if necessary). In a well-lit room, and when the patient is looking directly at you, please rate the severity of the patient’s glabellar 
lines at rest: 


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2) Line severity at maximum frown 
Please now rate the severity of the patient’s glabellar lines at maximum frown (asking the patient to push their eyebrows together as far as 
they will go):  


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20.3 
GL-QoL (Modified Skindex-16) 
During the past week how much have your glabellar lines bothered you? Glabellar lines are the vertical lines between your eyebrows that are more 
noticeable when you frown.    
For each question please check the box from 0 (Never bothered) to 4 (Always bothered) that best represents how much the lines between your eyebrows 
have bothered you. If the question is not relevant to you, please check ‘Never bothered’. 


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20.4 
 
FACE-Q Appraisal of Lines Between Eyebrows Scale 
 
FACE-Q APPRAISAL OF LINES-BETWEEN EYEBROWS 
 
 
 
These questions ask about how you look right now.  For each question, circle only one answer. With the area between your eyebrows in 
mind, in the past week, how much have you been bothered by: 
 


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FACE-Q © 2013. All Rights Reserved. 
20.5 
 
FACE-Q Age Appraisal VAS Scale44 
 
FACE-Q AGE APPRAISAL-VAS 
 
We would like to know how old you think you look.  How many years younger or older do you think you look compared with your actual age? 
Please circle one number below: 
 
 
 




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20.7 
 
Subject BMI Formula and Calculation 
 
Table 20-1 BMI Formula and Calculation 
Measurement Units 
BMI Formula and Calculation 
Kilograms and meters 
Formula: weight (kg) / [height (m)]2 
Calculate BMI by dividing weight in kilograms (kg) by height 
in meters (m) squared 
Pounds and inches 
Formula: weight (lb) / [height (in)]2 × 703 
Calculate BMI by dividing weight in pounds (lb) by height in inches 
(in) squared and multiplying by a conversion factor of 703. 
 
 
 


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21. 
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SAP_001.pdf: