Clinical trial NCT02677298
Conditions: Glabellar Frown Lines
Sponsor: Croma-Pharma GmbH
Start date: 2016-03-02; Completion date: 2017-11-16
Enrollment: 784 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:
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.

Arms: arm 1: Botulinum Toxin A (Clostridium botulinum toxin type 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 the glabellar area. arm 2: Placebo will be administered in double blind fashion in cycle 1. divided in five 0.1 mL i.m. 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, 0.9% sodium chloride divided in five 0.1 mL i.m. injections into 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-301-201030 
 
Other IDs 
EudraCT Number: 2015-002164-16 
Pre-IND Number: 123178 
 
 
Botulinum Toxin Treatment of Glabellar Lines: Efficacy and Safety Study I (BLESSI) 
 
 
 
 
Version Date: 11 March 2016 
Version Status:  1.2  
 
 
 
 
 
 
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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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 
SPONSOR RELATED CONTACT DETAILS 
Sponsor:  
 
 
CROMA Pharma GmbH 
 
 
 
 
 
Industriezeile 6 
 
 
 
 
 
AT-2100, Leobendorf, Austria 
 
Sponsor’s Project Manager:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor’s Medical Experts:
 
 
 
 
 
 
Medical Consultant for CROMA Pharma GmbH 
 
 
 
 
CROMA Pharma GmbH 
 
 
 
 
Industriezeile 6 
 
AT-2100, Leobendorf, Austria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Study Organization, Study Monitoring, Coordinating Investigator, Principal Investigators, 
Investigation Sites and other study-related information are listed in Section 14.7. 




 
 
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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-301-201030 
EudraCT Number: 2015-002164-16 
Pre-IND NUMBER: 123178 
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, ICH 
GCP guidelines, 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-301-201030, EudraCT No: 2015-002164-16, Pre-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 I 
(BLESS I) 
STUDY PHASE 
Phase 3 
PLANNED STUDY PERIOD 
Initiation 
Anticipated February 2016 (FSFV) 
Primary Completion 
Anticipated December 2017 (LSLV) 
Study Completion 
Final Clinical Study Report anticipated March 2018 
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 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. 
3. To provide long term safety data of BoNT/A-DP based on multiple treatment 


 
 
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cycles and to establish a sufficient safety database to support regulatory 
approval. 
4. 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. 
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. 
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 must 
perform their assessment independently and ideally before the investigator, to 
ensure they are not biased by the investigator. The same investigator must 
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-


 
 
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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 4weekly 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 0), 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.  
Secondary 
Outcome 
Measure(s) 
Key Secondary Efficacy Endpoints (Applicable for first placebo-controlled 
cycle only) 
1. The percentage of responders at maximum frown (as defined above) at 
week 12 (after the first treatment with BoNT/A-DP or placebo). 
2. The percentage of responders at week 16 (after the first treatment). 
3. 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). 
4. The percentage of responders at week 20 or later (after the first treatment). 
5. The extent of change in psychological impact (emotional and social 
functioning and concerns relating to their glabellar lines) at week 4 after 


 
 
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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 and Age Appraisal visual analog [VAS] scales). 
Additional Secondary Endpoints 
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 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). 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. 
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. 


 
 
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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 
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 
700 subjects. Subject accrual planned as follows: 
 
Approximately 50% of subjects enrolled in EU and 50% in US. 
 
Approximately 
18 
sites 
planned, 
hence 
for 
a 
3:1 
(BoNT/A-DP:Placebo) randomization scheme, each site should target 
randomizing at least 32-40 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 


 
 
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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. Such methods include for example: combined (estrogen and 
progestogen 
containing) 
hormonal 
contraception 
associated 
with 
inhibition of ovulation, progestogen-only hormonal contraception 
associated with inhibition of ovulation, intrauterine device, intrauterine 
hormone-releasing system, bilateral tubal occlusion or vasectomized 
partner. 
 
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 
Functioning subscales 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. 


 
 
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 
Any surgery, or history of 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, 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. 
 
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. 


 
 
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 
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 sassessments 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% 
 
Significance level 
() 
0.025 
one-sided 
 
Response  
Arm BoNT/A-DP 
60% 
From the range of observed response 
rates, a more conservative value of 60% 
has been chosen 
Response  
Arm Placebo 
10% 
Conservative value 
Software 
 
The 
sample 
size 
calculation 
was 
performed using the software nQuery 


 
 
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Advisor® 7.0. 
 
Based on these assumptions, 42 subjects in the BoNT/A-DP arm and 14 
subjects in the placebo arm are required, i.e. 56 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. A two-sided confidence interval (CI) of 
95%, and a distance from the CI limit of about 4.5% could be achieved with a 
sample size of 450 subjects in the BoNT/A-DP group. We propose a 3:1 
randomization of BoNT/A-DP(525 subjects) to placebo (175 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 total, 700 evaluable subjects will be enrolled. Applying a 10% drop out rate 
would result in a total number of completing subjects of about 630. 
Analysis Data Sets 
Safety Analysis Set (SAF): 
All randomized 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 subjects included in the SAF. 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 subjects included in the SAF 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. . 


 
 
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Per-protocol Analysis Set (PP): 
The PP includes all subjects 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 treatment actually received. 
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. 
For patient reported outcome (PRO) instruments, missing data will be imputed 
per developer guidelines, where these are available. 
Evaluations of subjects who started the first injection with placebo but then 
switched for further injections to BoNT/A-DP will be excluded from primary 
efficacy analyses.  
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 
Primary Analysis: 


 
 
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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 the 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 visit 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-responder. 
 
The primary endpoint measure using the MFAS and PP. 
 
The primary endpoint measure applying the LOCF for week 4 visit. 
 
Subgroup analysis by geographic region, country, and site 
o 
Subgroup analyses will be conducted for geographic region 
(US/EU), country, and site. 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 
and country. 


 
 
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 
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. 
Key Secondary Analyses: 
The testing of the 5 key secondary endpoints 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 
 
Key secondary endpoint 2 
 
Key secondary endpoint 3 
 
Key secondary endpoint 4 
 
Key secondary endpoint 5 
The same analyses, inclusive the additional exploratory analyses, as described 
for the primary endpoint, will be conducted. 
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.  


 
 
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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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TC = telephone contact: including assessment of concomitant medication, AEs and AESIs15 (as per AESI manual) on weeks 2 and 8 of each open-label cycle (visits 9, 11, 14, 16, 19 
and 21). If an AESI is reported during a telephone contact, subjects will be asked to come to the site for further assessment including a targeted physical examination as soon as 
possible) *  
Visit numbers correspond with specific treatment and assessments. 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.  
** Time differences are measured from the previous treatment administered. A time deviation of ± 2 days is allowed for each visit, except for the week 1 visit in the first treatment 
cycle where a time deviation of ± 1 day is permitted. Sites must adhere to the schedule of events and visit windows and subjects must ensure they are available for those visits. 
However, if for practical reasons e.g.public holidays, a visit window cannot be met, a visit can be scheduled as close as possible to that visit window. However, any deviation from 
the visit schedule and its associated time windows will still be documented as a protocol deviation. 
*** Full physical examination will include neurological assessment (including extraocular movements and cranial nerves) as well as assessment for muscle weakness.  In addition, if 
the subject reports any symptoms related to Adverse Events of Special Interest (as detailed in the AESI Manual) a focused physical examination, to evaluate these symptoms will 
also be undertaken.  
§     The ECG performed at screening is the baseline ECG.  Laboratory and Anti-drug-antibody (ADA) test samples from screening are considered baseline values.  
 1 Depending on the duration of treatment effect, a maximum of 4 treatments is permitted. 
 2 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) for re-treatment at 4-weekly intervals thereafter, until they are eligible for re-treatment. Once the subject is eligible for re-treatment, the end of cycle 
procedures will take place and the subject can receive re-treatment (i.e. the end of cycle visit and the re-treatment visit will be conducted on the same day as the Evaluation for Re-
treatment visit). 
 3 The latest time for re-treatment is study week 48; if a subject is not eligible for re-treatment at study week48, the End of Study visit will be completed. 
 4 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 
the criteria for re-treatment. 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 subject was retreated at week 40. For subjects that get prematurely discontinued from the study (at any time) the End of Study visit will 
take place within 1 week of discontinuation.  
 5 Only in women of child-bearing potential; blood serum test at screening and End of Study visit; otherwise urine dip stick. 
 6 Vital signs include blood pressure (diastolic /systolic) and pulse. 
 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 


 
 
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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 (will be recorded in the CRF). 
 13 Subjects will be monitored for AEs during 30 minutes after administration of the IMP.  No additional questioning of AESIs directly post-injection.  
 14 Anti-drug-antibody (ADA) test. If positive, serum samples will be tested for the presence of neutralizing antibodies. 
15   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 
EU 
European Union 
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 


 
 
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Abbreviation 
Definition 
ITT 
Intention to treat 
IWRS 
Interactive Web Response System 
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 
MFAS 
Modified Full Analysis Set 
MW 
Molecular weight 
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 ......................................................................... 4 
1.1 
Investigator Acknowledgement .......................................................................... 5 
2. 
SYNOPSIS .............................................................................................................. 6 
2.1 
Schedule of Study Procedures and Assessments .............................................. 19 
2.2 
Study Scheme ................................................................................................... 22 
3. 
LIST OF ABBREVIATIONS ............................................................................. 23 
4. 
BACKGROUND INFORMATION ................................................................... 30 
4.1 
Background to Botulinum Toxin ...................................................................... 30 
4.2 
Clinical Condition/Indication ........................................................................... 32 
4.3 
Description of Investigational Medicinal Products .......................................... 32 
4.3.1 Description of the Investigational Medicinal Product BoNT/A-DP ......... 32 
4.3.2 Description of the Placebo Control ........................................................... 33 
4.4 
Non-clinical and Clinical Summaries ............................................................... 33 
4.4.1 Non-clinical Summary ............................................................................... 33 
4.4.2 Clinical Summary ...................................................................................... 35 
4.4.2.1 Phase 3 Study HG-11-01: Indication; Glabellar Lines .................. 35 
4.4.2.2 Phase 3 Study HG-06-01: Indication; Blepharospasm .................. 36 
4.4.2.3 Phase 3 Study HG-11-02: Indication; Equinus Foot Deformity in 
Children with Cerebral Palsy ....................................................................... 37 
4.4.2.4 Phase 3 Study HG-13-01: Indication; Post Stroke Upper Limb 
Spasticity ...................................................................................................... 38 
4.4.2.5 Phase 4 Study HG-BTBPS-12102: Indication; Blepharospasm ... 39 
4.4.2.6 Post Marketing Safety Data........................................................... 45 
4.5 
Study Rationale ................................................................................................. 47 
4.5.1.1 Study Design Justification ............................................................. 48 
4.5.1.2 Justification for Schedule .............................................................. 48 
4.5.1.3 Dose Justification .......................................................................... 49 
4.6 
Evaluation of Anticipated Risks and Benefits of the Investigational 
Medicinal Product to Human Subjects ............................................................. 49 
4.6.1 Possible Benefits for the Subject ............................................................... 49 
4.6.2 Possible Risks/Inconveniences for the Subject ......................................... 49 
5. 
STUDY PURPOSE AND OBJECTIVES .......................................................... 51 
5.1 
Study Purpose ................................................................................................... 51 


 
 
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5.2 
Primary Objective ............................................................................................. 51 
5.3 
Secondary Objectives ....................................................................................... 51 
6. 
STUDY DESIGN ................................................................................................. 52 
6.1 
Brief Summary .................................................................................................. 52 
6.2 
Overall Study Design ........................................................................................ 52 
6.3 
Population to be Studied ................................................................................... 52 
6.3.1 First Treatment Cycle ................................................................................ 52 
6.3.2 Open Label Extension ............................................................................... 53 
6.3.3 End of Study Visit ..................................................................................... 54 
6.3.4 Numbering of Visits .................................................................................. 55 
6.3.5 Allowed Time Deviations Per Visit .......................................................... 55 
6.3.6 Duration of Study Period and Subject Participation .................................. 55 
6.4 
Outcome Measures ........................................................................................... 56 
6.4.1 Primary Outcome Measure ........................................................................ 56 
6.4.1.1 Efficacy ......................................................................................... 56 
6.4.2 Secondary Outcome Measures .................................................................. 56 
6.4.2.1 Key Secondary Efficacy Endpoints ............................................... 56 
6.4.2.2 Additional Secondary Endpoints ................................................... 56 
6.4.2.3 Safety ............................................................................................. 57 
6.5 
Randomization and Blinding ............................................................................ 57 
6.5.1 Randomization ........................................................................................... 57 
6.5.2 Blinding ..................................................................................................... 58 
6.5.3 Unblinding ................................................................................................. 58 
6.6 
Study Stopping Rules ....................................................................................... 59 
7. 
SUBJECT SELECTION, WITHDRAWAL AND DISCONTINUATION .... 60 
7.1 
Inclusion Criteria .............................................................................................. 60 
7.2 
Exclusion Criteria ............................................................................................. 60 
7.3 
Eligibility Criteria for Re-treatment ................................................................. 62 
7.4 
Withdrawal and Discontinuation ...................................................................... 62 
8. 
INVESTIGATIONAL MEDICINAL PRODUCT AND PLACEBO ............. 63 
8.1 
Packaging .......................................................................................................... 63 
8.2 
Labeling ............................................................................................................ 63 
8.3 
Storage and Handling ....................................................................................... 63 
8.3.1 Administration ........................................................................................... 64 
8.3.2 Foreign Body Inspection ........................................................................... 64 
8.3.3 Dilution ...................................................................................................... 64 
8.3.4 Dose for Administration ............................................................................ 64 


 
 
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8.3.5 Method of Administration ......................................................................... 65 
8.3.6 Description of Treatment ........................................................................... 66 
8.3.7 Investigational Medicinal Product Accountability .................................... 66 
9. 
STUDY PROCEDURES ..................................................................................... 67 
9.1 
Informed Consent and Enrollment .................................................................... 67 
9.2 
Subject Identification Codes ............................................................................. 67 
9.3 
Screening and Study Visits ............................................................................... 67 
9.3.1 Unscheduled Visit ..................................................................................... 74 
9.4 
Subject Diary and Patient Reported Outcomes ................................................ 75 
9.4.1 Subject Diary ............................................................................................. 75 
9.4.2 Patient Reported Outcomes ....................................................................... 75 
9.5 
Subject Completion/Discontinuation ................................................................ 76 
9.6 
Procedures for Monitoring Subject Compliance .............................................. 77 
10. 
ASSESSMENT OF EFFICACY ........................................................................ 78 
10.1 
Assessment of Glabellar Line Severity: Facial Wrinkle Scale ......................... 78 
10.1.1 Subject and Investigator In-clinic Assessment .......................................... 78 
10.1.2 Photo-evaluator Assessment ...................................................................... 79 
10.2 
Psychological Impact ........................................................................................ 79 
10.3 
Subject Satisfaction with Treatment ................................................................. 80 
11. 
ASSESSMENT OF SAFETY ............................................................................. 81 
11.1 
Adverse Events ................................................................................................. 81 
11.1.1 Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
AEs, AESIs, and SAEs .............................................................................. 81 
11.2 
Adverse Events of Special Interest ................................................................... 82 
11.3 
Serious Adverse Events .................................................................................... 82 
11.4 
Treatment-Emergent Adverse Events (TEAEs) ............................................... 83 
11.5 
Evaluation of AEs, AESIs, SAEs, TEAEs ....................................................... 83 
11.5.1 Assessment of Causality ............................................................................ 83 
11.5.2 Assessment of Severity .............................................................................. 85 
11.5.3 Outcome .................................................................................................... 85 
11.5.4 Action Taken with Study Drug .................................................................. 85 
11.6 
Adverse Event Monitoring and Assessment ..................................................... 85 
11.6.1 Reporting Serious Adverse Events and Adverse Events of Special 
Interest ....................................................................................................... 87 
11.6.2 Exposure In Utero During Clinical Trials ................................................. 88 
11.6.3 Overdose .................................................................................................... 88 
11.7 
Urgent Safety Measures .................................................................................... 89 


 
 
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11.8 
Pre-existing Diseases ........................................................................................ 89 
11.9 
Unexpected Adverse Events ............................................................................. 89 
11.10 Medical, Medication and Non-Drug Therapy History ..................................... 90 
11.10.1 
Medication and Non-Drug Therapies ................................................... 90 
11.11 Medical History and Physical Examinations .................................................... 91 
11.12 Pregnancy test ................................................................................................... 91 
11.13 Vital Signs ........................................................................................................ 91 
11.14 Demographic Data ............................................................................................ 91 
11.15 Clinical Laboratory Tests (Safety) .................................................................... 92 
11.15.1 
Hematology and Clinical Chemistry .................................................... 92 
11.15.2 
Antibody Test ....................................................................................... 92 
11.16 Electrocardiograms ........................................................................................... 93 
12. 
STATISTICS ........................................................................................................ 94 
12.1 
Sample Size and Power Calculations ............................................................... 94 
12.2 
Data Sets and Analysis Cohorts ........................................................................ 95 
12.3 
Procedure for Accounting for Missing, Unused, and Spurious Data ............... 96 
12.4 
Methods of Analysis ......................................................................................... 96 
12.4.1 Primary Outcome Measure ........................................................................ 96 
12.4.2 Secondary Outcome Measures .................................................................. 98 
12.4.3 Further Analyses ...................................................................................... 103 
12.5 
General Statistical Considerations .................................................................. 103 
12.5.1 Demographic and Baseline Characteristics ............................................. 104 
12.5.2 Interim Analysis ...................................................................................... 104 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................. 105 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .............................. 106 
14.1 
Investigator’s Responsibility .......................................................................... 106 
14.2 
Study Organization ......................................................................................... 106 
14.3 
Training ........................................................................................................... 106 
14.4 
Monitoring ...................................................................................................... 107 
14.5 
Auditing .......................................................................................................... 107 
14.6 
Non-compliance with the Protocol ................................................................. 107 
14.7 
Facilities .......................................................................................................... 107 
15. 
ETHICS .............................................................................................................. 109 
15.1 
Basic Principles .............................................................................................. 109 
15.2 
Ethics Committee and Regulatory Authorities ............................................... 109 
15.3 
Informed Consent ........................................................................................... 109 


 
 
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16. 
DATA HANDLING AND RECORD KEEPING ........................................... 111 
16.1 
Confidentiality Policy ..................................................................................... 111 
16.2 
Source Documentation and Case Report Forms ............................................. 112 
16.2.1 Case Report Forms .................................................................................. 112 
16.2.2 Computer Systems ................................................................................... 113 
16.2.3 Data Entry ................................................................................................ 113 
16.2.4 Medical Information Coding ................................................................... 113 
16.3 
Document and Data Retention ........................................................................ 113 
16.3.1 Data Base Lock ........................................................................................ 114 
17. 
FINANCING AND INSURANCE .................................................................... 114 
18. 
PUBLICATION POLICY ................................................................................ 114 
19. 
REVISION HISTORY ...................................................................................... 114 
20. 
SUPPLEMENTS ................................................................................................ 115 
20.1 
Glabellar Line Scale - Subject (GLS-S) ......................................................... 115 
20.2 
Glabellar Line Scale – Investigator (GLS-I) .................................................. 119 
20.3 
GL-QoL (Modified Skindex-16) .................................................................... 123 
20.4 
FACE-Q Appraisal of Lines Between Eyebrows Scale ................................. 124 
20.5 
FACE-Q Age Appraisal VASScale ................................................................ 125 
20.6 
FACE-Q Satisfaction with Outcome Scale ..................................................... 126 
20.7 
Subject BMI Formula and Calculation ........................................................... 127 
21. 
REFERENCES .................................................................................................. 127 
 


 
 
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4. 
BACKGROUND INFORMATION 
4.1 
Background to Botulinum Toxin 
Botulinum toxin is produced by anaerobic fermentation of the bacterium Clostridium 
botulinum. A number of different strains of C. botulinum have been identified, which 
produce eight immunologically distinct serotypes (types A - H), all of which interfere with 
neural transmission by blocking the release of acetylcholine, causing muscle paralysis, 
however only serotypes A and B are used clinically1 2. The toxins are released from the 
bacteria as part of a noncovalent multimeric complex, associated with up to six auxiliary 
proteins, including haemagglutinins and a nontoxin, nonhematuglitin 3 .Botulinum 
neurotoxin A is synthesized as a single-chain polypeptide with a molecular weight of 
approximately 150 kDa, comprising a 100-kDa heavy chain joined by a disulfide bond to a 
50-kDa light chain4. The heavy chain targets the toxin to specific types of axon terminals, 
after which the toxin can be taken into neurons by endocytosis5,6. The light chain of the 
toxin, which has zinc-dependent endoprotease activity, is then released from the 
endocytotic vesicles and reaches the cytoplasm. The light chain blocks the release of the 
neurotransmitter acetylcholine, causing dose-dependent weakening of the target muscle. 
The type A toxin proteolytically degrades its target SNAP-25 protein, which is essential for 
exocytosis of acetylcholine vesicles located in the peripheral motor neurons3, 7 , 8. By 
preventing neurosecretory vesicles from docking/fusing with the nerve synapse plasma 
membrane and inhibiting acetylcholine release, the toxin interferes with nerve impulses 
and causes muscle paralysis3,9 . 
The ability of botulinum toxin to inhibit acetylcholine release at the neuromuscular 
junction has been exploited for use in medical conditions characterized by muscle 
hyperactivity 10 .The broad range of medical indications for botulinum toxin includes 
treatment of movement disorders (e.g. spasticity, cervical dystonia), urological disorders 
(e.g. overactive bladder), dermatological conditions (e.g. axillary hyperhidrosis),chronic 
migraine, as well as cosmetic applications (glabellar lines, canthal lines).  
Glabellar lines, which appear as vertical lines between the eyebrows, are caused by 
contraction of the corrugator muscles above the eyebrows. These glabellar frown lines 
often become more prominent with age and can project negative emotions 
unintentionally11,12,13. In addition, the persistent presence of glabellar frown lines can be 
suggestive of an older than actual age, affecting an individual’s self-perception, emotional 
well-being, and perception by others, in some cases contributing to depression14,15. 
The first authorised botulinum toxin product on the market was
, which received 
Food and Drug Administration (FDA) approval for therapeutic treatment of strabismus and 
blepharospasm in 1989 and was first licensed for neuromuscular disorders (via 
intramuscular [i.m.] route) in the European Union (EU) in 1994. The first report in medical 




 
 
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4.2 
Clinical Condition/Indication 
Hyperfunctional facial lines (mimic wrinkles) are common aesthetic deformities involving 
the glabellar area, forehead and perorbital area. Glabellar lines occur as a result of the pull 
on the skin on the underlying facial musculature, predominantly the procerus muscle and 
the corrugator supercilli23, the latter muscle has no essential function other than to express 
emotion. Although fine wrinkling on the upper lip and cheeks, and crow’s feet, as well as 
the deeper lines in the nasolabial area are a sign of aging, wrinkling in the glabellar area is 
associated with the expression of frowning. Excessively prominent lines in this area (which 
appear as vertical lines between the eyebrows) are often misinterpreted as anger, anxiety, 
fear, fatigue and melancholia, causing the subject considerable distress24. As a result, 
glabellar lines can negatively influence self-perception, perception by others and emotional 
wellbeing 25 , 26 . Although treatments are available for such lines (including topical 
preparations or surgical procedures), there are several disadvantages to currently available 
treatments and most facial rejuvenation procedures do not address the underlying 
musculature responsible for facial lines.  
Studies with botulinum toxin have shown that the toxin weakens the overactive underlying 
muscle contraction, causing a flattening of the facial skin and improved appearance. The 
effect of the neurotoxin on facial lines was first reported in the early 90’s. Subsequent 
widespread use has supported its efficacy and safety for several therapeutic indications 
including facial 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 


 
 
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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. 
4.4 
Non-clinical and Clinical Summaries 
4.4.1 
Non-clinical Summary 
The efficacy and safety of CROMA Pharma GmbH’s BoNT/A have been thoroughly 
assessed in non-clinical studies. 
Efficacy studies to evaluate the paralysis induction potential of CROMA Pharma GmbH’s 
BoNT/A-DP compared to
 
 after i.m. injection were performed in 
Sprague Dawley (SD) rats. Both toxins showed a concentration dependent reduction of 
amplitude (dY) and response time delay (tC) following administration, which is 
attributable to the expected pharmacological action of BoNT/A. The extent of CROMA 
Pharma GmbH’s BoNT/A-DP paralysis potential was comparable to that of 
 
at all time points (3, 7, 14, 21, 28 days post dose) and concentrations (2, 4, 
8 U/animal) tested.  




 
 
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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. 
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 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 500 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 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 


 
 
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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
 
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
. 
4.4.2.2 
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. 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 








 
 
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effect, changes of severity of spasms, rate of subjects with grade 0 or 1 severity and the 
rate of subjects with more than 2 grades improvement.  
The primary endpoint, which was the rate of subjects with an improvement of one grade in 
severity of spasm (Scott’s method) at week4 post-treatment was met by 87 of 91 (95.6%) 
subjects in the per protocol data set. Response to BoNT/A-DP treatment was non-inferior 
to results from other botulinum toxin A products, assuming a reference value of 92.28%, a 
non-inferiority margin of -10% and a 95% CI. Of the 91 subjects included in the per 
protocol (PP) analysis, 81 subjects (89.01%) were retreated with the IMP. The mean 
duration of drug effect was 108.53 (±1.65) days. A total of 69 subjects (75.82%) showed 
an improvement to grade 0 or 1 and an improvement in severity of spasm of up to two 
grades.  
Among the full analysis set (FAS), which included 101 subjects, 61 AEs were observed in 
41 subjects (40.59%). Among these,30 AEs in 23 subjects (22.77%) were classified as 
related to the study drug. Only 1 AE (1.64%) was evaluated as grade 2 in severity, while 
the remaining 60 AEs (98.36%) were judged as grade 1. Physical examination showed 3 
single findings at one visit. One SAE, judged 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: 
 
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/ 
Blepharo-
spasm 
Multi-center 
Korea 
Completed 
22.12.2009 
R, 
DB, 
AC, P 
 
12.5 to 60U per 
subject(BoNT/A-
DP 
) 
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 
One 
additional 
dose and 24 week 
follow-up 
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 
Duration 
of 
the 
effect of the study 
drug 
(days), 
was 
compared 
between 
thetwo 
treatment 
groups by survival 
analysis 
HG-BTBPS-
12102/ 
Phase 4/ 
Blepharo-
spasm 
Multi-center 
Korea 
Completed 
03.02.2014 
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 




 
 
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Protocol 
No. 
/ 
Phase 
/ 
Indication 
Number/ 
Location 
of 
Centers 
Study 
Status: 
 
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-
201030Phase 3 
study 
in 
subjects 
with 
glabellar lines 
Centers 
in 
Europe and 
US 
Anticipated 
start  
Q42015 
1st 
cycle 
R, DB, PC, 
2nd to 4th 
cycle OL, 
S 
BoNT/A-
DP20Uor 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. 
525subjects 
active 
treatment, 
175subjects 
per 
placebo 
arm 
Administration 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 
glabellarlines 
as 
assessed 
by 
the 
investigator and the 
subject. 
Glabellar lines have 
a 
psychological 
impact 
on 
the 
subject 
Responder rate by 
investigator- 
and 
subjectassessment at 
maximum frown at 
week 
4 
after 
treatment 
by 
injection (composite 
endpoint). 
CPH-302-
201030 Phase 
3 
study 
in 
subjects 
with 
glabellar lines 
Centers 
in 
US 
Anticipated 
start  
Q1 2016 
1st 
cycle 
R, DB, PC, 
2nd to 4th 
cycle OL, 
S 
BoNT/A-DP 
20Uor 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. 
150 subjects 
active 
treatment, 
50subjects 
per 
placebo 
arm 
Administration 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). 
DB=double blind; PB=Subject blinded; P=parallel group; PC=placebo-controlled; R=randomized; AC=Active control; i.m=intramuscular; OL=open label; LSLV=laslt subject last visit;  S=single arm 


 
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4.4.2.6 
Post Marketing Safety Data 
BoNT/A-DP is available in Korea since 2010 under the name Botulax® and is also 
licensed in other countries (as of September 2015: Azerbaijan, Bolivia , Chile, 
Columbia, Costa Rica, Ecuador, El Salvador, Georgia, Guatemala, Honduras, India, 
Paraguay, Peru, Philippines, Thailand, Ukraine, Uruguay and Vietnam). 
According to information by the Korean manufacturer overall 2,076,273 vials (50 U, 
100 U or 200 U) of BoNT/A-DP have been distributed during the period between 
March 13, 2009 to June 30, 2015, including use in clinical trials (Table 4-3). 
Table 4-3 Overall vials distributed in Korea and export countries 
Year/ 
U per vial 
2009 
2010 
2011 
2012 
2013 
2014 
2015 
100 
4,515* 
59,091 
139,057 160,989 286,513 314,909 238,036 
50 
33,877 
90,510 
152,789 
57,613 
200 
7,325 
4,031 
47,899 
119,114 284,061 
75,944 
*Export to Japan for use on named patient basis 
 
Safety data from Korea for the period March 17th 2010 to June 30th 2015, where 
1,672,067 were distributed, are summarized in Table 4-4. In total 265 AEs were 
reported from spontaneous reporting of adverse drug reactions post-marketing drug 
use investigation and phase 4 clinical trials. All subjects fulfilled the minimum data 
requirements for case safety reporting (identifiable patient and reporter, suspected 
drug product, adverse event suspected to be due to drug product). These safety data 
include eighteen unexpected adverse events (2 cases of back pain, 1 case each of 
mouth corner drooping, surgical site reaction, skin ulceration, blepharospasm, 
conjunctival disorder, purpura, blepharitis, asthenopia, photopsia, sepsis, joint 
crepitation, joint lock, dyspepsia, food poisoning, joint dislocation, and Meig's 
syndrome) were reported. In addition, unexpected adverse drug reactions (3 cases 
each of bruise and visual impairment and 1 case each of skin disease, eyelid skin 
disorder, skin ulceration, and Asthenopia) were observed. For this unexpected adverse 
event mouth corner drooping, causal relationship was not assessed, but it is known 
that careful selection of administration sites can prevent such mouth corner drooping. 
Causal relationship between bruise and administration of this product was assessed as 
"possibly related". In phase 4 clinical trial in the indication treatment of 
blepharospasm, a serious adverse event (sepsis) was reported. It was considered that 


 
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this serious adverse event might have resulted from the underlying disease (leukemia). 
The causal relationship with this product was assessed as "definitely not related". 
Table 4-4 Safety data from Korea covering the period 2010 to June 30, 2015 
Event reported 
2010 
2011 
2012 
2013 
2014 
2015 
Pruritus 
7 
3 
2 
5 
Local pain 
7 
14 
10 
1 
Hypertonia 
2 
Tenderness 
1 
Ptosis 
1 
2 
3 
10 
1 
Headache 
1 
1 
Diplopia 
2 
Swelling 
2 
Mouth corner drooping 
1 
Oedema 
6 
16 
21 
1 
1 
Skin eruption 
10 
11 
15 
2 
10 
Injection site Inflammation 
1 
5 
Dizziness 
1 
1 
Visual distruvance 
2 
Eye pain 
1 
Abnormal lacrimation 
3 
Conjunctivitis 
2 
Conjunctival disorder 
1 
Xerophthalmia 
5 
Periorbital edema 
5 
Dystonia 
1 
Blepharospasm 
1 
Skin ulceration 
2 
Eyelid skin disorder 
1 
Skin disease 
1 
Ectropion 
1 
Purpura 
1 
Surgical site reaction 
1 
Common cold 
1 
Bruise 
3 
Eye pain 
5 
Abnormal sensation in eye 
3 
Eyelid oedema 
3 
Foreign body sensation in 
eyes 
 
 
 
 
3 
 
Lacrimation increased 
3 
Visual impairment 
3 
Asthenopia 
2 


 
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Event reported 
2010 
2011 
2012 
2013 
2014 
2015 
Dry eye 
2 
Ocular hyperaemia 
2 
Blepharitis 
1 
Diplopia 
1 
Eye oedema 
1 
Eye pruritus 
1 
Eye swelling 
1 
Lagophthalmos 
1 
Photopsia 
1 
Vision blurred 
1 
Nasopharyngitis 
8 
Sepsis 
1 
Arthralgia 
2 
Back pain 
2 
Joint crepitation 
1 
Joint lock 
1 
Myalgia 
1 
Dermatitis 
1 
Urticaria 
1 
Dyspepsia 
1 
Food poisoning 
1 
Joint dislocation 
1 
Meige's syndrome 
1 
Total 
31 
51 
57 
5 
90 
31 
 
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 post marketing surveillance studies are ongoing in Korea with 600 
subjects planned for the indications treatment of blepharospasm and glabellar lines 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 


 
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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 will provide evidence of efficacy 
and subject safety in a controlled clinical trial 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 Europe and the US.  
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 700 subjects will be enrolled, which should allow for a precise estimate of 
response rate and for post-hoc sensitivity analyses.  
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)31and this treatment interval has been evaluated in several repeat 
treatment studies32,33.  
However, since treatment duration of 120 days34, 17.1± 6.5 weeks35 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-


 
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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.  
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 


 
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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. 
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 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. 
3. 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. 
4. 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. 
5. To assess subject perceptions of effect of, and satisfaction with, treatment in 
comparison with placebo (first treatment cycle) and during the open-label 
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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 700 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). 
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 must perform their assessment 
independently and ideally before the investigator, to ensure they are not biased by the 
investigator. The same investigator must 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 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 sixmonths36 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 


 
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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.  
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 ≥at least 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 


 
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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 assess the duration of efficacy in the first treatment cycle and in the open label 
extension. 
6.3.5 
Allowed Time Deviations Per Visit 
A time deviation of ± 2 days is allowed for each visit (including telephone visits), 
except for the week 1 visit in the first treatment cycle, where a time deviation of ± 1 
day is permitted. Sites must adhere to the schedule of events and visit windows and 
subjects must ensure they are available for those visits. However, if for practical 
reasons, e.g. bank holidays, a visit window cannot be met, a visit can be scheduled as 
close as possible to that visit window. However, 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 60weeks study participation).  
Subjects will receive a maximum of four permitted rounds of treatment, with a 
minimum interval between treatments of 12 weeks.  


 
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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 Endpoints 
1. 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). 
2. The percentage of responders at week 16 (after the first treatment). 
3. 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). 
4. The percentage of responders at week 20 or later (after the first treatment). 
5. 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 and Age 
Appraisal visual analolg scales (VAS)),respectively. 
6.4.2.2 
Additional Secondary Endpoints 
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 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 


 
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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. 
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). 
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 3:1respectively 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. 


 
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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 
collectionetc.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). Once a subject has entered the open label extension, this 
unblinded study team member can then be involved in data collection activities with 
regard to that particular subject. 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, defining the Unblinded Study Team 
and the process of maintaining the blind by this Unblinded Study Team towards the 
blinded rest of the team. 
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 
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event treatment. Once unblinding has occurred, the site should immediately contact 
the
 or CROMA medical team. Communication of the unblinding result is 
considered acceptable. It is at the discretion of the investigator to continue an 
unblinded subject in the study. The date and time of breaking the code, the reason for 
breaking the code, study product administered, subject identification number and 
randomization code will be documented within the IWRS. 
6.6 
Study Stopping Rules 
In a case of critical non-compliance of site to ICH Good Clinical Practice (GCP), 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 ICH GCP, 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. Such 
methods include for example: combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation, progestogen-only 
hormonal contraception associated with inhibition of ovulation, intrauterine 
device, intrauterine hormone-releasing system, bilateral tubal occlusion, or 
vasectomized partner.ii 
 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 Functioning 
subscales 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 
                                                 
iWill be assessed at screening and at baseline visits. 
ii
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf  
 


 
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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. 
 Use of a muscle relaxant within 2 weeks prior to screening or planned during the 
study.iii 
 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.iv 
 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). 
                                                 
iiiWill be assessed at screening and baseline visits. 
ivWill be assessed at screening and baseline visits. 


 
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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.  
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 discontinuation due to an AE/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 withdrawn due to an AE, 
SAE or clinically significant abnormal laboratory test value 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. 


 
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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. 
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 levatorpalpebraesuperiorismust 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 1cm 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 the exact amount of drug will be injected. Additional 
information regarding administration can be found in the Study Reference 
Manual/Operational Manual. 


 
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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 Section8.3). 
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 B1 (denoting the Bless I 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 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. 
Table 9-1 BLESS I 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 and Age 
Appraisal VAS scales (Section 20) 
 


 
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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 
Distribute Subject Diary (Section 9.4) 
 
Visit 3  
 
C1  
 
Week 1 
7 days ± 1 
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  
 
Week 2 
14 days ± 2 
days after 
Baseline 
(Day 0) 
Collect 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 
Concomitant medication (Section 11.10.1) 
Photography (Section 10.1.2)12 
 
Visit 5 
 
C1  
4 weeks ± 2 
days after 
Baseline 
FWS Subject self-assessment (GLS-S, 
Section  10.1.1) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
 


 
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Week 4 
(Day 0) 
Appraisal of Lines Between Eyebrows and Age 
Appraisal VAS scales (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 ± 2 
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 ± 2 
days after 
Baseline 
(Day 0), 
with 
possible 
extension at 
4-weekly (± 
2 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) 
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 
(Section20.6) 
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 
 
Visit 8 
 
1 week ± 2 
days after 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
 


 
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C2  
 
Week 1 
second 
treatment 
Full physical examination (Section 11.11) 
 
Visit 9 
C2  
Week 2 
14 days ± 2 
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 and Age 
Appraisal VAS scales (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 ± 2 
days after 
second 
treatment 
 
AE and AESI assessment (Section11)13 
Concomitant medication (Section11.10.1) 
 
Telephone call7 
Visit 12 (or 
12a, 12b, 
12c) 
 
Evaluation 
for re-
treatment 
Visit 4 
 
End Of 
Cycle5 
 
Third 
treatment 
12 weeks ± 2 
days after 
second 
treatment, 
with 
possible 
extension at 
4-weekly(± 
2 days)  
intervals 
until subject 
is eligible 
for re-
treatment 
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) 
Vital signs (Section 11.13) 
Clinical laboratory assessments (Section 11.15) 
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 
 


 
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Consent for re-treatment 
THIRD TREATMENT (Section 8.3) 
Post-treatment observation and AE assessment over 
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 
C3 
Week 2 
14 days ± 2 
days 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 and Age 
Appraisal VAS scales (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 ± 2 
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) 
 
Evaluation 
for re-
treatment 
Visit  
 
End Of 
Cycle 
 
Fourth 
12 weeks ± 2 
days after 
third 
treatment, 
with 
possible 
extension at 
4-weekly (± 
2 days) 
intervals 
until subject 
is eligible 
for re-
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
FWS Investigator (GLS-I, Section10.1.1) 
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) 
 


 
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treatment 
treatment 
Antibody test (Section 11.15.2) 
Modified Skindex-16 (GL-QoL) and FACE-Q 
Appraisal of Lines Between Eyebrows and Age 
Appraisal VAS scales (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 
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 ± 2 
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 and Age 
Appraisal VAS scales (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) 
 
Visit 21 
 
C4 
 
Week 8 
8 weeks ± 2 
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 ± 2 
days after 
fourth 
treatment or 
on the same 
day when no 
FWS Subject self-assessment (GLS-S, 
Section 10.1.1) 
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 
 


 
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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 ±2 days is allowed for each visit except for the visit 1 week after the first 
treatment (visit 3), where a time deviation of ±1 day is allowed. Furthermore, no time deviation is 
specified between screening, and randomization; a maximum of 2 weeks is permitted for screening. 
Sites must adhere to the schedule of events and visit windows defined and subjects must ensure they 
are available for those visits. However, if for practical reasons, e.g. public holidays, a visit window 
cannot be met, a visit can be scheduled as close as possible to that visit window. However, 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 
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 
further 
treatment 
can be 
given10, 11 
 
 
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) 
Physical examination (Section 11.11) 
Clinical laboratory assessments (Section 11.15) 
Antibody test (Section 11.15.2) 


 
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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 unschedueld 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. Atlhough 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 of the above visits as per schedule of events. Assessments 
performed at an unscheduled visit will be at the investigator’s discretion, but should 
include AE assessment, AESI query, concomitant medication and possibly FWS. 


 
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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 and the CRF). 
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 
(Section 20.1 and Section 10.1) which will be completed by the subject (PRO) 
and the investigator (clinician reported outcome). 
 The modified Skindex-16 (GL-QoL) and FACE-Q scales (Appraisal of Lines 
Between Eyebrows and Age Appraisal VAS scales), 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 
significant 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 significant 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, 
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. 


 
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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 (Glabellar Line Scale 
for Investigators [GLS-I] and Glabellar Line Scale for Subjects [GLS-S]), as 
described in Section 20.1. The FWS instrument is termed GLS-Sand GLS-I. The scale 
and the proposed instructions for its use by investigators and subjects are described in 
Section 20.1 and in the Instruction Manual for Subject Glabellar Line Severity Self-
Assessment. 
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 the Instruction Manual 
for Subject Glabellar Line Severity Self-Assessment. Investigators will complete 
training before trial initiation and will receive training certification. Subject 
assessment must be performed independently of the investigator and ideally before 
the investigator assessment, to rule out any influence or bias from the investigator. 
The date and time of assessment will be recorded for each visit 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).  


 
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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, 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, however, 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 and Age Appraisal VAS 


 
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questionnaires 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.  


 
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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 conducted to evaluate for 
signs and symptoms of local and distant spread of toxin effect. 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. 


 
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 Is life threatening – defined as an event in which the subject was, in the 
judgment of the investigator, at risk of death at the time of the event; it does 
not refer to an event that hypothetically might have caused death had it been 
more severe. 
 Requires subject hospitalization or results in prolongation of existing 
hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital anomaly/birth defect. 
 Is an important medical event. 
Note: Medical or scientific judgment should be exercised in deciding whether 
reporting is appropriate in other situations, such as important medical events 
that may not be immediately life threatening or result in death or require 
hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the 
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): 


 
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 Is due to underlying or concurrent illness, complications, 
concurrent treatments, or effects of concurrent drugs. 
 Is not associated with the IMP or study procedure (i.e. does not 
follow a reasonable temporal relationship to the administration of 
IMP or has a much more likely alternative etiology). 
 Unlikely related (either one or both circumstances are met): 
 Has little or no temporal relationship to the IMP or study 
procedure. 
 A more likely alternative etiology exists. 
 Possibly related (both circumstances must be met): 
 Follows a reasonable temporal relationship to the administration of 
IMP. 
 An alternative etiology is equally or less likely compared to the 
potential relationship to the IMP or study procedure. 
 Probably related (both circumstances must be met): 
 Follows a reasonable temporal relationship to the administration of 
IMP, which may include but is not limited to the following: 
o Reappearance of a similar reaction upon re-administration 
(positive re-challenge). 
o Positive results in a drug sensitivity test (skin test, etc.). 
o Toxic level of the IMP as evidenced by measurement of the 
IMP 
concentrations in the blood or other bodily fluid. 
 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. 


 
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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 
 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 


 
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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. 
 Outcome. 


 
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 Action taken with study drug. 
If the severity rating for an ongoing AE changes before the event resolves, the AE 
will be reported in an additional row in the AE log (or additional AE page) with 
complete information (i.e. start and stop date, severity, relationship, outcome etc.). 
11.6.1 
Reporting Serious Adverse Events and Adverse Events of Special 
Interest 
All SAEs and AESIs for all subjects occurring from the time of informed consent 
until the End of Study visit must be reported to CROMA Pharma GmbH or their 
representative within 24 hours of the knowledge of the occurrence. If considered at 
least possibly related to study treatment, SAEs observed after the End of Study visit 
must also be reported. 
Paper SAE/AESI forms should be completed at the site and faxed to the relevant 
Medical & Safety Services Department
 within 24 hrs of 
awareness of the event. 
Fax number for SAE/AESI and Pregnancy reporting: 
Email all sites:  
 
 
For European sites 
 
 
For North American sites 


 
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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
, 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 


 
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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.  
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. 


 
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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: 
 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. 


 
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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 Events 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. 
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. 


 
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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”. 
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.  
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. 


 
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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. 


 
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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% 
 
Significance level () 0.025 one-sided 
 
Response  
Arm BoNT/A-DP 
60% 
From the range of observed response 
rates, a more conservative value of 60% 
has been chosen 
Response  
Arm Placebo 
10% 
Conservative value 
Software 
 
The 
sample 
size 
calculation 
was 
performed using the software nQuery 
Advisor® 7.0. 
 
Based on these assumptions, 42 subjects in the BoNT/A-DP arm and 14 subjects in 
the placebo arm are required, i.e. 56 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. A 


 
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two-sided CI of 95%, and a distance from the CI limit of about 4.5% could be 
achieved with a sample size of 450 subjects in the BoNT/A-DP group. We propose a 
3:1 randomization of BoNT/A-DP (525 subjects) to placebo (175 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 total, 700 evaluable subjects will be enrolled. Applying a 10% drop out rate would 
result in a total number of about 630 subjects. 
12.2 
Data Sets and Analysis Cohorts 
Safety Analysis Set (SAF): 
All randomized 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 subjects included in the SAF. 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 FAS includes all subjects included in the SAF 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.  


 
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Per-protocol Analysis Set (PP): 
The PP includes all subjects 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 treatment 
actually received. The PP will only be analyzed for main efficacy outcome measures. 
Data Review Meeting: 
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 


 
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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. 
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 geographic region, country, and site. 
o Subgroup analyses will be conducted for geographic region (US/EU), 
country, and site. 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-


 
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test. Stratified analyses applying the Cochran-Mantel-Haenszel test 
will also be conducted using factor geographic region and country. 
 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. 
12.4.2 
Secondary Outcome Measures 
Key Secondary Analyses: 
The testing of the 5 key secondary endpoints 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 
 Key secondary endpoint 2 
 Key secondary endpoint 3 
 3.1: The investigator’s in-clinic assessments 
 3.2: The subject’s in-clinic assessments 
 Key secondary endpoint 4 
 Key secondary endpoint 5 
 5.1: The modified Skindex-16 (GL-QoL) Emotional domain 
 5.2: The modified Skindex-16 (GL-QoL) Functioning domain 
 
Analysis of key 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). 


 
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The same analyses, inclusive of the additional exploratory analyses, as described for 
the primary endpoint will be conducted. 
Analysis of key 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. 
Analysis of key secondary endpoint 3: 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 using the investigator’s in-clinic assessment will be conducted first with 
respect to the hierarchical order of key secondary endpoints, with the analysis using 
the subjects’s in-clinic assessment second.  
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. 
Analysis of key secondary endpoint 4: The percentage of responders at week 20 or 
later (after the first treatment). 
The analysis of visit week 20 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. 


 
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In addition, the same analyses, inclusive the additional exploratory analyses as 
described for the primary endpoint, will be conducted (for subgroups also).  
Analyses of 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.  
Analysis of key secondary endpoint 5: 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 scales 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 Functioning domain 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 each of three 
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’, ‘moderate’, and ‘severe’ psychological impact, and of the 
minimal clinical important difference, will be used to aid interpretation of scores.  
The analysis will be conducted with respect to the hierarchical order of key secondary 
endpoints; the analysis using the Emotional domain first, the 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 


 
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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 geographic region, country, and site, or by subjects with 
previous use of botulinum toxin versus naïve subjects will not be conducted. 
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) 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. 
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-sided McNemar test (using 
a significance level of 0.05) will be used to compare the response 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. 
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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Additional exploratory subgroup analyses by geographic region, country, and site, or 
by subjects with previous use of botulinum toxin versus naïve subjects, will not be 
conducted for additional secondary analyses. 
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, 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. 


 
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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 categorical variables of the overall 
ECG interpretation. 
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.  
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. 


 
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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 
There will be no formal interim analysis during the study. 


 
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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, ICH GCP, 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. 


 
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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, ICH GCP, 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 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, ICH GCP 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: 
 
 


 
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The following certified clinical laboratory will perform clinical laboratory tests 
required by this protocol: 
 
 
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: 
 
 
 
 
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 ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996), 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. 


 
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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. 
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.  


 
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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 outcome. 
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 


 
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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. ICH GCP). 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. 
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), Directive 95/46/EC of the European Parliament and of 
the Council of 24 October 1995 and Directive 2001/20/EC of the European 
Parliament and of the Council of 4 April 2001. 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. 


 
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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 
The data base will be locked after all data of the first treatment cycle and of the open 
label extension phase are entered into the CRF, the data base is confirmed as ‘clean’, 
and the data review meeting has taken 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. 
19. 
REVISION HISTORY  
 
Version 
Date 
Reason for Revision 
1.2 
11.03.2016 
Clarification on AE follow-up 
1.1 
28.01.2016 
Update in sections 2, 6, 7, 11, 12 and 19, as per 
BfArM request and FDA advice to address safety 
procedures and assessments, statistical analyses 
in the study, minor change in scales, and contact 
details for reporting SAEs and AESIs  
Final 
version 
13.10.2015 
N/A (original document) 
 
 


 
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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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20.5 
 
FACE-Q Age Appraisal VASScale44 
 
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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20.6 
 
FACE-Q Satisfaction with Outcome Scale45 
 
 
FACE-Q SATISFACTION WITH OUTCOME 
 
We would like to know how you feel about your most recent procedure. For each statement, circle only one answer. Please indicate how 
much you agree or disagree with each statement. 
 
 
 
 


 
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20.7 
 
Subject BMI Formula and Calculation 
 
Table 20-1 BMI Formula and Calculation 
Measurement Units 
BMI Formula and Calculation 
Pounds and inches 
Formula: weight (kg) / [height (m)]2  
Calculate BMI by dividing weight in kilograms (kg) by height 
in meters (m) squared.  
 
21. 
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2Carruthers A, Carruthers J. Botulinum toxin products overview. Skin therapy letter 
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3Said S, Meshkinpour A, Carruthers A, Carruthers J. Botulinum toxin A: its 
expanding role in dermatology and esthetics.American journal of clinical dermatology 
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4Brin M. Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. 
Muscle Nerve Suppl1997; 6: S146-68. 
5Bandyopadhyay S CA, DasGupta BR, Sathyamoorthy V. Role of the heavy and light 
chains of botulinum neurotoxin in neuromuscular paralysis. The Journal of biological 
chemistry 1987; 262(6): 2660-3. 
6BR D, H. S. A common subunit structure in Clostridium botulinum type A, B and E 
toxins. BiochemBiophys Res Commun1972; 48(1): 108-12. 
7Coffield JA, Considine RV, Jeyapaul J, Maksymowych AB, Zhang RD, Simpson LL. 
The role of transglutaminase in the mechanism of action of tetanus toxin.The Journal 
of biological chemistry 1994; 269(39): 24454-8. 
8Lebeda FJ, Olson MA. Secondary structural predictions for the clostridial 
neurotoxins.Proteins 1994; 20(4): 293-300. 
9Simpson LL. Identification of the major steps in botulinum toxin action. Annual 
review of pharmacology and toxicology 2004; 44: 167-93. 
10Frevert J. Pharmaceutical, biological, and clinical properties of botulinum 
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11Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical 
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12 Carruthers JA, Lowe NJ, Menter MA, et al. A multicenter, double-blind, 
randomized, placebo-controlled study of the efficacy and safety of botulinum toxin 
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13Cox SE, Finn JC. Social implications of hyperdynamic facial lines and patient 
satisfaction outcomes.International ophthalmology clinics 2005; 45(3): 13-24. 
14Lewis MB, Bowler PJ. Botulinum toxin cosmetic therapy correlates with a more 
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16Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-
A exotoxin. The Journal of dermatologic surgery and oncology 1992; 18(1): 17-21. 
17Carruthers A, Carruthers J. You want to inject what? Dermatologic surgery : official 
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18Wilson SC, Soares MA, Reavey PL, Saadeh PB.Trends and drivers of the aesthetic 
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19Frevert J. Content of botulinum neurotoxin in Botox(R)/Vistabel(R), 
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67-73. 
20Kim BJ, Kwon HH, Park SY, et al. Double-blind, randomized non-inferiority trial of 
a novel botulinum toxin A processed from the strain CBFC26, compared with 
onabotulinumtoxin A in the treatment of glabellar lines. Journal of the European 
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endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic 
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22Lebeda FJ, Cer RZ, Stephens RM, Mudunuri U. Temporal characteristics of 
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1993; 119(9): 1018-22. 
24Carruthers A, Carruthers J. A single-center dose-comparison study of botulinum 
neurotoxin type A in females with upper facial rhytids: assessing patients' perception 
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26Fagien S, Cox SE, Finn JC, Werschler WP, Kowalski JW. Patient-reported 
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28Fagien S, Carruthers JD. A comprehensive review of patient-reported satisfaction 
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2008. 
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surgery 2009; 29(6 Suppl): S57-65. 
32Monheit GD, Cohen JL, Reloxin Investigational G. Long-term safety of repeated 
administrations of a new formulation of botulinum toxin type A in the treatment of 
glabellar lines: interim analysis from an open-label extension study. Journal of the 
American Academy of Dermatology 2009; 61(3): 421-5. 
33Rzany B, Flynn TC, Schlobe A, Heinz M, Harrington L. Long-term results for 
incobotulinumtoxinA in the treatment of glabellar frown lines. Dermatologic surgery 
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35Kawashima M, Harii K. An open-label, randomized, 64-week study repeating 10- 
and 20-U doses of botulinum toxin type A for treatment of glabellar lines in Japanese 
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36Flynn TC. Botulinum toxin: examining duration of effect in facial aesthetic 
applications. American journal of clinical dermatology 2010; 11(3): 183-99. 
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clinical immunotherapeutics, biopharmaceuticals and gene therapy 2012; 26(2): e1-9. 
40Carruthers A, Carruthers J, Coleman WP, 3rd, et al. Multicenter, randomized, phase 
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the treatment of glabellar frown lines. Dermatologic surgery : official publication for 
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41Hanke CW, Narins RS, Brandt F, et al. A randomized, placebo-controlled, double-
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42Honeck P, Weiss C, Sterry W, Rzany B, Gladys study g. Reproducibility of a four-
point clinical severity score for glabellar frown lines. The British journal of 
dermatology 2003; 149(2): 306-10. 
43Chren MM. The Skindex instruments to measure the effects of skin disease on 
quality of life. Dermatologic clinics 2012; 30(2): 231-6, xiii. 
44Panchapakesan V, Klassen AF, Cano SJ, Scott AM, Pusic AL. Development and 
psychometric evaluation of the FACE-Q Aging Appraisal Scale and Patient-Perceived 
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45Klassen AF, Cano SJ, Schwitzer JA, Scott AM, Pusic AL. FACE-Q scales for 
health-related quality of life, early life impact, satisfaction with outcomes, and 
decision to have treatment: development and validation. Plastic and reconstructive 
surgery 2015; 135(2): 375-86. 
46Rubin M, Dover J, Maas C, Nestor M.An analysis of safety data from five phase III 
clinical trials on the use of botulinum neurotoxin type A-ABO for the treatment of 
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surgery 2009; 29(6 Suppl): S50-6. 
47Rzany B, Ascher B, Monheit G. Treatment of glabellar lines with botulinum toxin 
type A (Speywood Unit): a clinical overview. Journal of the European Academy of 
Dermatology and Venereology : JEADV 2010; 24 Suppl 1: 1-14. 
48Kane MA, Brandt F, Rohrich RJ, et al. Evaluation of variable-dose treatment with a 
new U.S. Botulinum Toxin Type A (Dysport) for correction of moderate to severe 
glabellar lines: results from a phase III, randomized, double-blind, placebo-controlled 
study. Plastic and reconstructive surgery 2009; 124(5): 1619-29. 
49Carruthers J, Rivkin A, Donofrio L, et al. A Multicenter, Randomized, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Repeated 
OnabotulinumtoxinA Treatments in Subjects With Crow's Feet Lines and Glabellar 
Lines. Dermatologic surgery: official publication for American Society for 
Dermatologic Surgery [et al] 2015; 41(6): 702-11. 
50Carruthers J, Fagien S, Matarasso SL, Botox Consensus G. Consensus 
recommendations on the use of botulinum toxin type a in facial aesthetics. Plastic and 
reconstructive surgery 2004; 114(6 Suppl): 1S-22S. 

SAP_001.pdf: 
.. 
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Statistical Analysis Plan (SAP) 
CROMA 
Protocol Title: 
Protocol Number: 
Protocol Version, Date 
IIIIIIIIID: 
Document Version, Date: 
Confidentiality statement: 
ttL\ll"H • <!-'/; ~
A!ICN 
: !!!!~ 
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 
CPH-301-201030 
1.2, 11 Mar 2016 
3428/0002 
FINAL 1.0, 23 June 2017 
Prepared by: 
On behalf of: 
CROMA Phaima GmbH 
The infonnation provided in this document is strictly confidential. 
The recipients of the SAP must not disclose the confidential info1mation 
contained within this document or any related info1mation to other persons 
without the pennission of the sponsor. 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 1 of 44 


SIGNATURE PAGE 
Prepared at 
Reviewed at 
Approved at CROMA Pharma GmbH by: 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: .FINAL 1.0, Date: 23 June 201'.7 
Page2of44 


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Statistical Analysis Plan (SAP) 
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REVISION IDSTORY 
Version/Date 
Version Name 
0.l/1 l-Nov-2016 
Initial version 
0.2122-Dec-2016 
Draft 0.2 
0.3116-Feb-2017 
Draft 0.3 
0.4128-Apr-2017 
Draft 0.4 
1.0123-Jun-2017 
Final 1.0 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Section 
NIA 
NIA 
NIA 
NIA 
NIA 
ttL\ll"H • <!-'/; ~
A!ICN 
: !!!!~ 
Changes implemented 
NIA 
Comments on first review cycle 
Comments on second review cycle 
plus decisions during SAP TC 
Comments on third review cycle 
Comments on folllth review cycle 
Version: FINAL 1.0, Date: 23 June 2017 
Page 3 of 44 


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Statistical Analysis Plan (SAP) 
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TABLE OF CONTENTS 
ttL\ll"H • <!-'/; ~
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: !!!!~ 
SIGNATURE PAGE ....................................................................................................................... 2 
REVISION HISTORY .................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
1 INTRODUCTION ..................................................................................................................... 8 
2 STUDY OBJECTIVES ............................................................................................................. 9 
2.1 
Pri1na1y objective .............................................................................................................. 9 
2.2 Secondary objectives ........................................................................................................ 9 
3 STUDY DESIGN .................................................................................................................... 10 
3 .1 
General study design ...................................................................................................... 10 
3.2 Randomization and blinding ........................................................................................... 12 
3.3 
Study treatments and assessments .................................................................................. 13 
4 STUDYENDPOINTS ............................................................................................................. 19 
4.1 
Primary efficacy endpoint(s) .......................................................................................... 19 
4.2 Key Secondary efficacy endpoints ................................................................................. 19 
4.3 
Additional Secondaiy endpoints ..................................................................................... 19 
4.4 Safety endpoint(s) ........................................................................................................... 20 
5 SAMPLE SIZE AND POWER ............................................................................................... 21 
6 ANALYSIS POPULATIONS ................................................................................................. 23 
6.1 
Safety Analysis Set (SAF) .............................................................................................. 23 
6.2 Full Analysis Set (FAS) .................................................................................................. 23 
6.3 Modified Full Analysis Set (MF AS) .............................................................................. 23 
6.4 Per-Protocol Analysis Set (PP) ....................................................................................... 23 
6.5 Protocol deviations and exclusions from analysis sets ................................................... 24 
6.6 DRM ............................................................................................................................... 24 
7 Statistical Considerations and analysis .................................................................................... 25 
7 .1 
Derived Variables ........................................................................................................... 25 
7.2 Handling of missing data ................................................................................................ 25 
7.2.1 Missing data analysis methods ........................................................................... 25 
7.2.2 Handling of missing or incomplete dates ........................................................... 26 
7 .2.2.1 Imputation rnles for missing or partial AE start date: ........................................ 26 
7.2.2.2 Imputation rnles for missing or partial medication start/stop dates .................... 27 
8 STATISTICAL METHODS .................................................................................................... 28 
8.1 
General statistical conventions ....................................................................................... 28 
8.2 Subject disposition .......................................................................................................... 29 
8.3 Protocol deviations ......................................................................................................... 29 
8.4 Demographics and baseline characteristics .................................................................... 30 
8.4.1 Demographics ..................................................................................................... 30 
8.4.2 Baseline characteristics ....................................................................................... 30 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
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8.4.3 Medical history ................................................................................................... 30 
8.4.4 Prior and concomitant medications .................................................................... 30 
8.5 
Extent of exposure .......................................................................................................... 31 
8.5.1 Dmation of studydrng exposme ........................................................................ 31 
8.5.2 Treatment compliance ........................................................................................ 31 
8.6 Efficacy analyses ............................................................................................................ 31 
8.6.1 Analysis methods ................................................................................................ 31 
8.6.1.1 Multiplicity ......................................................................................................... 31 
8.6.1.2 Treatment by center interaction analysis (multi-center study) ........................... 32 
8.6.2 Analysis of primru.y efficacy endpoint(s) ........................................................... 32 
8.6.3 
Analysis of secondary efficacy endpoint(s ) ........................................................ 33 
8.6.4 Additional secondru.y analyses ........................................................................... 37 
8.7 
Safety analyses ............................................................................................................... 37 
8.7.1 Treatment Exposm·e ............................................................................................ 38 
8.7.2 Adverse events (secondru.y safety endpoint 1) ................................................... 38 
8.7.3 Antibody fo1mation (secondru.y safety endpoint 2) ........................................... .40 
8.7.4 Laborato1y data (secondru.y safety endpoint 3) ................................................. .40 
8.7.5 Vital signs (secondru.y safety endpoint 3) ......................................................... .40 
8.7.6 Electrocardiograms (secondary safety endpoint 3) ........................................... .41 
8.7.7 Physical examinations ........................................................................................ 41 
8.8 Other analysis ................................................................................................................. 41 
8.8.1 Subgroups ........................................................................................................... 41 
8.9 Interim analysis .............................................................................................................. 42 
9 CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL. ............................. .43 
10 REFERENCES ........................................................................................................................ 44 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 5 of 44 


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Statistical Analysis Plan (SAP) 
CROMA 
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LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
Abbreviation 
ADA 
AE 
AESI 
ATC 
BoNT/A 
BoNT/A-DP 
CETS 
CFR 
CI 
CRA 
CRF 
cs 
CSR 
DRM 
ECG 
eCRF 
EU 
FAS 
FWS 
GCP 
GL-QoL 
GLS-I 
GLS-S 
ICF 
ICH 
IMP 
ITT 
IWRS 
LOCF 
MedDRA 
MFAS 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Definition 
Anti Drug Antibody 
Adverse event 
Adverse event of special interest 
Anatomical Therapeutic Chemical 
Botulinum nemotoxin A 
CROMA Phrum a GmbH's BoNT/A Drug Product registered in Korea 
under the name "Botulax" 
Composite endpoint treatment success 
Code of Federal Regulations 
Confidence interval 
Clinical Research Associate 
Case rep01t f01m 
Clinically significant 
Clinical Study Repo1t 
Data Review Meeting 
Electrocru·diogram 
Electronic Case Repo1t F 01111 
Emopean Union 
Full Analysis Set 
Facial Wrinkle Scale 
Good Clinical Practice 
Glabellru· Line Quality of Life Scale 
Glabellru· Line Scale for Investigators 
Glabellru· Line Scale for Subjects 
Info1med consent fonn 
International Council for Ha1monization 
Investigational Medicinal Product 
Intent-to-treat 
Interactive Web Response System 
Last Observation CruTied Fo1ward 
Medical Dictionruy for Regulat01y Activities 
Modified Full Analysis Set 
Version: FINAL 1.0, Date: 23 June 2017 
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Statistical Analysis Plan (SAP) 
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NCS 
PRO 
pp 
PT 
ROS 
SAE 
SAF 
SAP 
SD 
soc 
SOPs 
TEAE 
TFL 
us 
VAS 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Not clinically significant 
Patient rep01ted outcome( s) 
Per-protocol analysis set 
PrefetTed te1m 
Review of systems 
Serious adverse event 
Safety analysis set 
Statistical analysis plan 
Standard deviation 
System organ class 
Standard Operating Procedures 
Treatment Emergent Adverse Event 
Tables, figures, and listings 
United States 
Visual Analog Scale 
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: !!!!~ 
Version: FINAL 1.0, Date: 23 June 2017 
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Statistical Analysis Plan (SAP) 
CROMA 
1 
INTRODUCTION 
ttL\ll"H • <!-'/; ~
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The pm-pose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of 
the statistical methods, data derivations and data. displays for study protocol CPH-301-
201030 Version 1.2 "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" dated 11 Mar 2016 for the final analysis. The 
table of contents and templates for the tables, figures, and listings (TFLs) will be produced 
in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Repo1t 
(CSR). 
The preparation of this SAP has been based on International Conference on Hannonization 
(ICH) E9 guideline and the Code of Federal Regulations (CFR) 21, pa1t 11 . 
All data analyses and generation of TFLs will be perfonned using SAS 9.3® or higher. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
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Statistical Analysis Plan (SAP) 
CROMA 
2 
STUDY OBJECTIVES 
2.1 
Primary objective 
ttL\ll"H • <!-'/; ~
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: !!!!~ 
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 four (from the first treatment cycle). 
2.2 
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 onset of effect and the dmation 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. 
3. To provide long te1m safety data of BoNT/A-DP based on multiple treatment cycles 
and to establish a sufficient safety database to suppo1t regulato1y approval. 
4. To assess the psychological impact of BoNT/A-DP treatment on subjects (in te1ms of 
emotional and social functioning and concerns relating to their glabellar lines) m 
comparison with placebo after a single treatment. 
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. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 9 of 44 


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Statistical Analysis Plan (SAP) 
CROMA 
3 
STUDY DESIGN 
3.1 
General study design 
ttL\ll"H • <!-'/; ~
A!ICN 
: !!!!~ 
This multicenter Phase 3 study is comprised of two pa1ts. The first pait of the study is a 
randomized, double blind, placebo-controlled, phase which aims to demonstrate efficacy 
and safety of BoNT/A-DP compai·ed with placebo. The second pait 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 
tTeatments in the open label extension study. 
Adult subjects less or equal 75 years old with moderate to severe glabellar frown lines at 
maximum frown with an impo1tant psychological impact as indicated by scores >0 on 
either the Emotional or F1mctioning subscales of the modified Skindex-16 (GL-QoL) will 
be enrolled in this study. Approximately 18 sites (50% in EU and 50% in US) will enroll in 
total 700 evaluable subjects. Applying a 10% drop out rate will result in a total number of 
completing subjects of about 630. 
The overall study scheme is presented below: 
1st treatment cycle 
re-treatment cycle 
re-treatment cycle 
re-treatment cycle 
48 to 60 study weeks/ up to four cycles 
The duration of study paiticipation for each subject will be up to 14 calendai· days of 
screening followed by 48 to 60 weeks of treatment (re-screening will not be permitted). 
The first treatment cycle will be a double blinded cycle followed by up to three open label 
treatment cycles. Each cycle will be at least 12 weeks and can be prolonged in 4-week 
increments, depending on treatment effect. Re-treatment is possible until study-week 48. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 10 of 44 


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Statistical Analysis Plan (SAP) 
CROMA 
Visit Scheme/Treatment Cycle 1 (double blind) 
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Protocol Number: CPH-301-201030 
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Version: FINAL 1.0, Date: 23 June 2017 
Page 11 of44 


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Statistical Analysis Plan (SAP) 
CROMA 
3.2 
Randomization and blinding 
3.2.1 
Randomization 
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: !!!!~ 
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 
Bo NT I 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 size. 
Randomization will be perfo1med per study site via interactive web response system 
(IWRS). One unique randomization code will be assigned to each subject. 
3.2.2 
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 fuvestigational Medicinal Product 
(IMP) at the study site must not, by any means, be involved in any other study data 
collection activities including Adverse event (AE) assessment, case repo1i fo1m (CRF) 
completion, diaiy collection etc. IMP will be assigned to the subjects by IWRS with the lot 
number and kit number assigned con esponding 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). Once a subject has entered the open label extension, this 
unblinded study team member can then be involved in data collection activities with regard 
to that paiiiculai· subject. The assigned vial will be reconstituted and will be fo1warded to 
the investigator for injection. Specific Blinding Plans will be created at each study site 
during the Study fuitiation visits, defining the Unblinded Study Team and the process of 
maintaining the blind by this Unblinded Study T earn towards the blinded rest of the team. 
3.2.3 
Un blinding 
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 regulato1y unblinding users so that they can monitor the safety of the study, 
if required). 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 12 of 44 


Statistical Analysis Plan (SAP) 
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CROMA 
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: !!!!~ 
In case of emergency, the Ilv1P administered to the subjects can be revealed using the 
unblinding function of the IWRS. 
In rare emergencies, unblinding may be necessa1y 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 eve1y attempt to infonn the Sponsor before breaking the blind or as soon as 
possible after unblinding has been perfo1med. Th~ 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 info1mation 
is considered relevant for subsequent event treatment. Once unblinding has occmTed, the 
site should immediately contact th~ 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. 
3.3 
Study treatments and assessments 
Subjects will participate in this study for a dmation of 50 to 62 weeks from signing the 
infonned consent fo1m (ICF) to the End of Study visit (i.e. up to 14 calendar days for 
screening, followed by 48 to 60 weeks study participation). 
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 subjects must perfo1m their assessment independently and ideally 
before the investigator, to ensme they are not biased by the investigator. The same 
investigator must 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 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 
compai·ison with placebo). Re-screening will not be pe1mitted. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
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Statistical Analysis Plan (SAP) 
CROMA 
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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. 
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 one and fom weeks aBer 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 or with the 
End of Study visit. According to the study schedule, a maximum of four treatments per 
subject (four treatment cycles) is pennitted 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. Sta1iing 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 Facial 
Wrinkle Scale (FWS) score (at maximum frown) of ~ 2, as dete1mined by both the subject 
using the Glabellar Line Scale for Subjects (GLS-S) and the investigator using the 
Glabellar Line Scale for Investigators (GLS-I), 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 
dete1mine 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. Fmthennore, all additional tests e.g. laboratory tests required for final 
cycle assessment will be pe1fonned. 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 drng treatment as pali of the Re-Treatment visit (i.e. day O 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 
opp01tunity. 
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 ~at least 2 by both 
assessments), the subject will retmn to the site four weeks thereafter for another Evaluation 
for Re-treatment visit. There is no limit to the number of Evaluation for Re-treatment 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
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Statistical Analysis Plan (SAP) 
CROMA 
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A!ICN 
: !!!!~ 
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. 
The End of Study visit c.an take place in fom-weekly intervals from study-week 48 until 
study-week 60. The last study drng 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 in case 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 eight weeks or 
less prior to week 48, the End of Study visit will take place 12 weeks after the last study 
drng 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 one week of discontinuation. 
A detailed description of procedmes and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 1 below. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 15 of 44 


Statistical Analysis Plan (SAP) 
Table 1: Schedule of Study Assessments 
I 
Double-blind phase 
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X 
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Photography 10 
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X 
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Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Open label phase 
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Version: FINAL 1.0, Date: 23 Jnne 2017 
Page 16 of 44 


Statistical Analysis Plan (SAP) 
. ;;ee . 
... . . . 
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CROMA 
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TC= telephone contact: including assessment of concomitant medication, AEs and AESls 15 (as per AESI manual) on weeks 2 and 8 of each open-label cycle (visits 9, 
11, 14, 16, 19 and 21). If an AESI is reported during a telephone contact, subjects will be asked to come to the site for further assessment including a targeted 
physical examination as soon as possible) • 
Visit numbers correspond with specific treatment and assessments. 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. 
Time differences are measured from the previous treatment administered. A time deviation of :1: 2 days is allowed for each visit, except for the week 1 visit in the 
first treatment cycle where a time deviation of :1: 1 day is permitted. Sites must adhere to the schedule of events and visit windows and subjects must ensure they 
are available for those visits. However, if for practical reasons e.g. public holidays, a visit window cannot be met, a visit can be scheduled as close as possible to 
that visit window. However, any deviation from the visit schedule and its associated time windows will still be documented as a protocol deviation. 
••· Full physical examination will include neurological assessment (including extraocular movements and cranial nerves) as well as assessment for muscle weakness. 
In addition, if the subject reports any symptoms related to Adverse Events of Special Interest (as detailed in the AESI Manual) a focused physical examination, to 
evaluate these symptoms will also be undertaken. 
§ 
The ECG performed at screening is the baseline ECG. Laboratory and Anti-drug-antibody (ADA) test samples from screening are considered baseline values. 
1 Depending on the duration of treatment effect, a maximum of 4 treatments is permitted. 
2 Evaluation for re-treatment takes place at the earliest at 12 weeks after the first/previous tre.atment. Subjects who do not qualify for re-treatment at week 12 will 
have the option (pending eligibility) for re-treatment at 4-weekly intervals thereafter, until they are eligible for re-treatment. Once the subject is eligible for re-
treatment, the end of cycle procedures will take place and the subject can receive re-treatment (i.e. the end of cycle visit and the re-treatment visit will be 
conducted on the same day as the Evaluation for Re-treatment visit). 
3 The latest time for re-treatment is study week 48; if a subject is not eligible for re-treatment at study week48, the End of Study visit will be completed. 
4 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 the criteria for re-treatment. 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 subject was retreated at week 40. For subjects that get prematurely 
discontinued from the study (at any time) the End of Study visit will take place within 1 week of discontinuation. 
5 Only in women of child-bearing potential; blood serum test at screening and End of Study visit; otherwise urine dip stick. 
6 Vital signs include blood pressure (diastolic /systolic) and pulse. 
7 Laboratory Assessments: Hematology and Serum Chemistry, details in Section 11.15 of the study protocol.. 
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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 (will be recorded in the CRF). 
13 Subjects will be monitored for AEs during 30 minutes after administration of the IMP. No additional questioning of AESls directly post-injection. 
14 Anti-drug-antibody (ADA) test. If positive, serum samples will be tested for the presence of neutralizing antibodies. 
15 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: lnvestigational medicinal product; R:Retum of subject diary; TC: telephone call; VAS: Visual analog 
scale 
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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint(s) 
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The primary efficacy endpoint is the propo1tion of subjects among BoNT/A-DP and 
placebo groups with a FWS score of O 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 primaiy endpoint is a composite endpoint comprising investigator and subject 
assessments of treatment effectiveness. 
4.2 
Key Secondary efficacy endpoints 
The key secondary efficacy endpoints of this study are: 
1. The percentage of responders at maximum frown at week 12 (after the first treatment 
with BoNT/A-DP or placebo). 
2. The percentage ofresponders at week 16 (after the first treatment). 
3. 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). 
4. The percentage ofresponders at week 20 or later (after the first treatment). 
5. The extent of change in psychological impact (emotional and social functioning and 
concerns relating to their glabellar lines) at week 4 aft.er the first treatment, in the 
BoNT/A-DP group in compai·isou with placebo, relative to baseline, as assessed by the 
modified Skindex-16 (Glabellai· Line Quality of Life Scale (GL-QoL]) and the FACE-
Q (Appraisal of Lines Between Eyebrows and Age Appraisal visual analog scales 
(VAS)), respectively. 
4.3 
Additional Secondary endpoints 
The additional secoudaiy endpoints of this study are: 
6. The prop01tion of responders among BoNT/A-DP and placebo groups with a FWS 
score of O 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). 
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7. The prop01tion of subjects with :::: 2 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). fu 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 
F ACE-Q Satisfaction with Outcome Scale. 
10. The propo1tion 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 four 
weeks after re-treatment relative to the rating at the preceding end of cycle visit. 
4.4 
Safety endpoint(s) 
The safety endpoints of this study are: 
1. Frequency, severity and causal relationship of AEs, Serious Adverse Events (SAEs) 
and Adverse Events of Special futerest (AESis) during the entire study period. 
2. Antibody fonnation, evaluation pre-dose before each treatment, at four 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. 
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5 
SAMPLE SIZE AND POWER 
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The primary endpoint is a composite endpoint compnsmg investigator and subject 
assessments of treatment effectiveness using the FWS. The FWS in this study coITesponds 
to the FWS Investigator assessment (GLS-I) and the FWS for Subject self-assessment 
(GLS-S). Composite endpoint treatment success (CETS) is defmed as ~2 point reduction in 
FWS score at maximum frown achieving a score of O 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 aBer baseline. 
The primary analysis of efficacy is the propo1iion 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 are used: 
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Item 
Assumption 
Underlying test 
Fisher's Exact Test 
Randomization 
3:1 
scheme 
Power 1-13 
90% 
Significance level (a) 0.025 one-sided 
Response 
60% 
AimBoNT/A-DP 
Response 
10% 
Alm Placebo 
Software 
Comments 
Standard test for a 
for small numbers 
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response parameter 
More active treatment subjects to enlarge 
safety data base 
From the range of obse1ved response 
rates, a more conse1vative value of 60% 
has been chosen 
Conse1vative value 
The 
sample 
size 
calculation 
was 
perfonned using the software nQuery 
Advisor® 7.0. 
Based on these assumptions, 42 subjects in the BoNT/A-DP aim and 14 subjects in the 
placebo ann are required, i.e. 56 subjects in total. This is a very small sample size and not 
sufficient for a detailed evaluation of the data, including subgroup analyses. Fmthe1more, 
the response rate could not be estimated with sufficient precision. A two-sided confidence 
interval (Cl) of 95%, and a distance from the CI limit of about 4.5% could be achieved 
with a sample size of 450 subjects in the BoNT/A-DP group. Therefore, a 3:1 
randomization of BoNT/A-DP (525 subjects) to placebo (175 subjects) was proposed, 
which should be 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 total, 700 evaluable subjects will be emolled. Applying a 10% drop out rate would result 
in a total number of about 630 subjects. 
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6 
ANALYSIS POPULATIONS 
6.1 
Safety Analysis Set (SAF) 
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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 and for the individual subject data listings. 
6.2 
Full Analysis Set (FAS) 
The FAS includes all randomized subjects who received at least one injection with study 
medication (independent of whether it is BoNT/A-DP or placebo). 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 
primaiy efficacy analysis set. 
6.3 
Modified Full Analysis Set (MF AS) 
The MFAS includes all subjects included in the FAS who had a baseline (visit 1 at dayO) 
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 ITT principle. The MFAS will be used for the evaluation of the 
efficacy assessments. 
6.4 
Per-Protocol Analysis Set (PP) 
The PP includes all subjects 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 treatment actually received. 
The PP will only be analyzed for main efficacy outcome measures. 
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Protocol deviations and exclusions from analysis sets 
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All protocol deviations and exclusions of subjects from analysis sets will be identified at 
the Data Review Meeting (DRM) just prior to study unblinding. 
Deviations from protocol will be classified as major or minor. 
The following protocol deviations are considered to be major and will lead to exclusion 
from the PP: 
• 
Subject or investigator lmblinded to treatment 
• 
Improper storage of IMP and IMP temperature excmsion without proper notice to 
theCRA 
• 
Inconect treatment allocation or dose 
• 
Wrong injection points used. 
• 
Site staff perfom1ing the study assessment not trained 
6.6 
DRM 
For the DRM appropriate listings displaying all relevant data will be provided to the 
sponsor and serve as a somce for the protocol deviations discussion about the classification 
into major and minor. No unblinding will be done for creation of these listings. 
The following protocol deviations will be assessed on a case-by-case basis and a final 
decision on a possible exclusion from the PP will be done dming the DRM: 
• 
Inclusion/exclusion criteria violated 
• 
Use of disallowed medications 
• 
Serious breach of GCP 
• 
Photography not collected or available for all visits 
• 
Site staff perfomoog the study assessment not trained 
• 
Failme to discontinue subjects where appropriate. 
• 
Subject re-treated despite not meeting all re-treatment eligibility criteria 
Patients with minor protocol deviations will not be excluded from the PP. 
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7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived Variables 
The below, table provide the list of derived variables for various duration derivations and 
baseline derivations applicable for this study. 
Variables 
Formula 
Derivation of Duration 
Study day at any visit 
Date of interest - date of first dose of study drug. 
Extent of Exposure (Days) 
Date of last study medication administration - Date of 
first study medication administration + 1 
Extent of Exposure (Weeks) 
Extent of exposure ( days )/7 
Baseline Derivations 
Baseline 
The baseline value is defined as 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, the value from screening visit. 
Change from baseline 
Post baseline value - Baseline value 
Relative change from baseline 
[(Post baseline value 
-
Baseline value )/Baseline 
value]*l00 
7.2 
Handling of missing data 
7.2.1 Missing data analysis methods 
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. rmssmg values will be excluded from 
analysis. 
• 
Last observation cm.Tied fo1ward (LOCF) 
• 
Tipping point analysis: each missing value will be assigned to either a response or 
non-response, so that all possible combinations of replacing one or more missing 
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values within each treatment group will be analyzed. p-values will be calculated for 
each combination and graphically displayed using a scatter plot. 
The analysis of the week 16 visit regarding the endpoint 'percentage of responders at week 
16 (after first treatment)' 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. The same 
approach holds for the endpoint 'percentage of responders at week 20 or later (after first 
treatment)' respectively. 
All analyses of the modified Skindex-16 (GL-QoL) Emotional and Functioning domain 
and overall scores 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. The same approach will be followed for the analyses of the 
F ACE-Q scales. 
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. 
7.2.2 Handling of missing or incomplete dates 
7.2.2.1 Imputation rules for missing or partial AE start date: 
If only Day of AE start date is missing: 
If the AE strut year and month ru·e the same as that for the first dose date, then: 
• 
If the full (or prutial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE strut day as the day of first dose date. 
• 
Othe1wise, impute the AE sta1t day as 1. 
Othe1wise, if the AE strut year and month are not the same as that for the first dose date, 
then impute the AE strut day as 1. 
Compare the imputed AE strut date with treatment period to dete1mine whether the AE is 
pre-treatment AE or treatment emergent adverse event (TEAE). 
If only Day and Month of AE start date are missing: 
If AE stali year = first dose year, then: 
• 
If the full (or prutial) AE end date is NOT before the first dose date or AE end date 
is missing, then impute the AE stait Month and Day as the Month and Day of first 
dose date; 
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• 
Othe1wise, impute the AE sta1t Month as Januaiy and the AE stait Day as 1. 
Othe1wise, if AE stait year not equal first dose year, then impute the AE sta1t Month as 
Januaiy and the AE sta1t Day as 1. 
Compare the imputed AE stait date with treatment period to detennine whether the AE is 
pre-treatment AE or TEAE. 
If Year of AE start date is missing: 
If the year of AE stait is missing or AE stait date is completely missing then que1y site 
with no imputation. Also compare the full ( or pa1tial) AE end date to the first dose date. If 
the AE end date is before the first dose date then the AE should be considered as a pre-
treatment AE. Othe1wise, the AE will be considered as TEAE. 
7.2.2.2 Imputation rules for missing or partial medication start/stop dates 
Missing or partial medication start date: 
• 
If only Day is missing, use the first day of the month. 
• 
If Day and Month are both missing, use the first day of the year. 
• 
If Day, Month and Year are all missing, use a date before the first dose date. 
Missing or partial medication stop date: 
• 
If only Day is missing, use the last day of the month. 
• 
If Day and Month are both missing, use the last day of the year. 
• 
If Day, Month and year ai·e all missing, assign 'continuing' status to stop date 
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STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedmes will be completed using SAS version 9 .3 or higher. 
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The statistical analysis of the first treatment cycle and the open label extension phase 
( cycles 2-4) will be perfo1med after database lock of all data up to the end of the study ( can 
take place in fom-weekly intervals from study week 48 until study week 60) and final 
unblinding. 
The statistical testing of the primary endpoint as well as the key secondruy endpoints will 
be one-sided and will be perfo1med using a significance (alpha) level of 0.025. A two-
sided McNemar test (using a significance level of 0.05) will be used to compare the 
response propo1tions 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. 
Two-sided 95% Cls will be provided when relevant. 
Continuous variables will be summarized using descriptive statistics, including number of 
subjects (n), mean, standard deviation (SD), median, Ininimmn and maximun1. One 
additional decimal point for mean and median and two additional decimal points for SD 
will be used in addition to the number of decimal points used for the measured values. 
For categorical variables, summaries will include counts of subjects and percentages in 
con esponding categories. Percentages will be rounded to one decimal place. 
For statistical analyses "baseline" refers to the last observation before treatment, i.e. pre-
treatment values measmed on the treatment day (baseline visit, day 0), and if Inissing or 
not evaluated, values from screening visit will be used. 
All summaries will be presented by treatment group, unless othe1wise specified. 
Analyses will be perfo1med by visit, iiTespective of any time window deviations. 
All subject data, including those derived, will be presented in individual subject data 
listings. Unless othe1wise stated, unscheduled visit results will be included in date/time 
chronological order, within patient listings only. All listings will be s01ted by 
investigational site, patient number, date/time and visit. The treatment group will be stated 
on each listing. Unless othe1wise stated, data listings will be based on the Safety Analysis 
Set. A listing with demographic data for screening failures will be presented. 
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Subject disposition 
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Subject disposition info1mation will be summarized for the double-blind phase by 
treatment group and overall as well as separately for the open label phase. The nlllllber and 
percent of subjects who are randomized, who obtained a dose of study diug, who were 
randomized and not treated, who were treated and not randomized, who complete the 
double-blind treatment phase, who complete the study and who withdraw early from the 
study will be presented. 
The primary reason for early withdi·awal will also be tabulated. 
Subject disposition will be listed. 
The number and percent of subjects in each analysis set will also be tabulated. 
Treatment Misallocations: 
If a subject was: 
• 
Randomized but not treated, then they will be rep01ied under their randomized 
treatment group for efficacy analyses. However, they are by definition excluded 
from the safety analyses as actual treatment is missing. 
• 
Treated but not randomized, then by definition they will be excluded from the 
efficacy analyses since they are not randomized but will be included in safety 
analyses. 
• 
Randomized but got incon ect treatment, then they will be repo1ied under their 
randomized treatment group for all efficacy analysis, but will be reported under 
the treatment they actually received for all safety analyses. 
• 
Patients who were not treated as randomized will be excluded from the per-
protocol analysis. 
8.3 
Protocol deviations 
The nlllllber of patients excluded from SAF, FAS, MFAS, and PP and reasons for 
exclusion will be sUllllnarized by treatment group and overall. 
Analysis set membership details will be listed, including reason for exclusion from each 
analysis set. 
All major protocol deviations identified will be summarized by treatment group and 
overall. Minor protocol deviations will be listed only. 
A listing will include the inclusion/exclusion criteria violated at Screening and at Re-
treatment on cycles 2, 3 and 4 as well as other protocol deviations identified based on data 
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recorded on the electronic case report form ( eCRF) and/or protocol deviation Logs from 
(based on the Safety Analysis Set). 
8.4 
Demographics and baseline characteristics 
8.4.1 
Demographics 
Age, sex, race, ethnicity, height, weight, body mass index, and Fitzpatrick skin type at 
baseline will be summarized descriptively by treatment group and overall using the FAS 
Population. The FDA guideline regarding "Collection of race and ethnicity data in clinical 
trials" will be followed. 
8.4.2 Baseline characteristics 
The categorical baseline characteristics such as baseline ECG, pregnancy test results and 
antibody test sample collection (yes/no) at screening will be summarized using frequency 
counts for the FAS Population. Continuous baseline variables such as systolic blood 
pressure (mmHg), diastolic blood pressure (mmHg) and pulse rate (beats/min) will be 
summarised by descriptive statistics in the same way as continuous demographic variables 
for the FAS Population. 
8.4.3 Medical history 
A sUIIUnaiy of medical history will be presented by system organ class (SOC) and 
prefe1Ted te1m (PT) using Medical Dictionaiy for Regulatory Activities® (MedDRA) 
Version 19.0 or higher. The previous toxin treatment will be listed only. 
8.4.4 Prior and concomitant medications 
Medications used in this study will be coded by using the latest available version of the 
World Health Organization Dmg Dictionary Standai·d or Enhanced and categorized as 
follows: 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables by anatoinical therapeutic chemical (ATC) class and prefe1Ted naine by 
treatment group on the FAS and presented separately for the following groups: 
• 
Medication (recent) discontinued prior to Baseline (Day 0) 
• 
Concomitant medication staiied at or after Baseline, or sta1ied before Baseline and 
were not discontinued prior to Baseline 
Details for imputing Inissing or paiiial staii and/or stop dates of medication ai·e described 
in Section 7.2.2. 
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8.5 
Extent of exposure 
8.5.1 
Duration of study drug exposure 
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Duration of study dmg exposure (in days) will be calculated as date of last study 
medication administration minus date of first study medication administration + 1 day, 
regardless of study dtug intenuption. 
Study dtug exposure will be summarised by treatment group and separated for the double-
blind and open label phase on the Safety Analysis Set using time intervals and summary 
statistics. Planned and actual dose as well as injections at all sites per subject and treatment 
cycle will be listed. 
8.5.2 Treatment compliance 
All study procedures are to be perfo1med under supervision at the study site, and thus, no 
separate procedures will be used to monitor subject compliance. 
8.6 
Efficacy analyses 
8.6.1 
Analysis methods 
The analyses of the primaiy and secondaiy outcome measures will be based on different 
statistical tests such as Cochran-Mantel-Haenszel test, Pearson Chi-Squai·e test, Wilcoxon 
Rattle Sum test and Fisher's exact test, if appropriate. Details for each efficacy endpoint 
will be provided in the following sections. Subgroup analyses will be described in section 
8.8. 
8.6.1.1 Multiplicity 
The testing of the primaiy and the five key secondaiy efficacy endpoints will be perfo1med 
with appropriate multiplicity control based on the FAS population. The results of each test 
result will only be considered confnmative if the previous test in the order showed a 
confnmatory result at a one-sided significance level of 0.025. If the one-sided p-value is 
lai·ger than 0.025 for any of the tests, the results of the subsequent tests will only be 
considered explorato1y, and not confnmato1y. The application of this hierarchical approach 
keeps the global significance level to 0.025 one-sided and requires no fmther adjustment of 
the significance level. 
The following order of tests will be applied: 
• 
Primaiy endpoint ( composite endpoint) 
• 
Key secondary endpoint 1 ( composite endpoint) 
• 
Key secondary endpoint 2 ( composite endpoint) 
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Key secondaiy endpoint 3 
3.1: The investigator's in-clinic assessments 
3.2: The subject's in-clinic assessments 
• 
Key secondary endpoint 4 ( composite endpoint) 
• 
Key secondary endpoint 5 
5.1: The modified Skindex-16 (GL-QoL) Emotional domain 
5.2: The modified Skindex-16 (GL-QoL) Functioning domain 
5.3: The modified Skindex-16 (GL-QoL) Overall score 
5.4: The F ACE-Q Appraisal of Lines Between Eyebrows scale 
5.5: The FACE-Q Age Appraisal VAS score 
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All other analyses (e.g., additional analyses of the primary and the five key secondaiy 
efficacy endpoints using other analysis populations or other statistical methods, analyses of 
additional secondary endpoints) will only be considered explorato1y. 
8.6.1.2 Treatment by center interaction analysis (multi-center study) 
Treatment-by-center interaction will be tested using the Breslow-Day test for homogeneity 
of the odds ratios for the primary efficacy endpoint. 
8.6.2 Analysis of primary efficacy endpoint(s) 
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 
using a significance level (a) of 0.025. Small sites with less than 3 placebo subjects will be 
combined. The null hypothesis Ho given below will be tested against the alternative 
hypothesis H1: 
Ho: PBoNTIA-DP~ PPlacebo 
H1: PBoNTIA-DP>PPlacebo 
The Cochran-Mantel-Haenszel test will be applied by the SAS procedme 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 procedme. Superiority of BoNT/A-DP over 
placebo will only be concluded if, besides statistical significance ( one-sided p-value 
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:::;0.025), the propo1iion ofresponders in the BoNT/A-DP treatment group is higher than for 
the placebo treatment group. 
The FAS will serve as the primruy 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 Exploratory Analyses on the Primary Endpoint Variable: 
Fmiher analyses on the primary endpoint variable are exploratory. A one-sided Pearson x,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. As a sensitivity 
analysis for the primru·y endpoint, a tipping point analysis will be perfo1med. Each missing 
value will be assigned to either a response or non-response, so that all possible 
combinations of replacing one 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. 
The Cls will also be calculated for the additional analyses as listed in the following: 
• 
The primary endpoint measme 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. This 
analysis will be perfo1med for the FAS, MF AS and PP populations. 
• 
The primary endpoint measme using the MFAS and the PP. 
• 
The primru·y endpoint measme applying the LOCF for week 4 visit. This analysis 
will be done for FAS, MF AS and PP populations. 
8.6.3 Analysis of secondary efficacy endpoint(s) 
The following order of tests will be defined for the analysis of the key secondruy 
endpoints: 
• 
Prima1y endpoint ( composite endpoint) 
• 
Key secondary endpoint 1 ( composite endpoint) 
• 
Key secondary endpoint 2 ( composite endpoint) 
• 
Key seconda1y endpoint 3 
3.1: The investigator's in-clinic assessments 
3.2: The subject's in-clinic assessments 
• 
Key secondary endpoint 4 ( composite endpoint) 
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Key secondary endpoint 5 
5.1: The modified Skindex-16 (GL-QoL) Emotional domain 
5.2: The modified Skindex-16 (GL-QoL) Functioning domain 
5.3: The modified Skindex-16 (GL-QoL) Overall score 
5 .4: The F ACE-Q Appraisal of Lines Between Eyebrows scale 
5 .5: The F ACE-Q Age Appraisal VAS score 
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For key secondary endpoints 2 - 4, the p-value to be considered within the hierarchical 
testing procedme is the one resulting from the Cochran-Mantel-Haenszel test as described 
for the primary efficacy endpoint in the first paragraph entitled "Primary Analysis" of 
section 8.6.2. 
Analysis of key secondmy endpoint 1: The percentage of responders at maximum frown (as 
defined above for the primary efficacy endpoint) at week 12 (after the first treatment with 
BoNTIA-DP or placebo). 
The same analyses, inclusive the additional exploratory analyses, as described for the 
primary endpoint will be conducted. 
Analysis of key secondary endpoint 2: The percentage of responders at maximum frown (as 
defined above for the primmy efficacy endpoint) 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 the additional exploratory analyses, as described 
for the prima1y endpoint will be conducted as explorato1y analyses. Subjects who were re-
treated before visit week 16 are considered to be non-responders in all these analyses. 
Analysis of key secondary endpoint 3: 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 the additional explorato1y analyses as 
described for the primary endpoint, will be conducted. 
The analysis using the investigator's in-clinic assessment will be conducted first with 
respect to the hierarchical order of key secondaiy endpoints, with the analysis using the 
subject's in-clinic assessment second. 
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All analyses (inclusive the additional explorato1y analyses) 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 
analyses of the subject's in-clinic assessment. 
For the primary analysis (to be considered within the hierarchical testing procedme), 
subjects with missing investigator in-clinic assessments of FWS score at rest 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 within the primary analysis. 
As a consequence, the primary analysis will lead to exactly the same results as the LOCF 
analysis and thus the LOCF analysis will be skipped. 
Analysis of key secondary endpoint 4: The percentage of responders at maximum frown (as 
defined above for the primary efficacy endpoint) at week 20 or later (after the first 
treatment). 
The analysis of visit week 20 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 explorato1y analyses as described 
for the primary endpoint, will be conducted as explorato1y analyses (for subgroups also). 
Analyses of other visits after first treatment but before re-treatment up to week 48 are 
explorato1y only based on the FAS using descriptive statistics only. Subjects with re-
treatment before the respective visit will be excluded from the analysis. Additional 
explorato1y analyses, as described for the primary endpoint, will not be conducted, with the 
exception of the calculation of 95% Cls. 
Analysis of key secondary endpoint 5: 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 BoNTIA-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 F ACE-Q Age Appraisal VAS scales will be analyzed according to the foreseen 
analysis approach of these tools, as described below. 
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Emotional and Social Functioning 
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The modified Skindex-16 (GL-QoL) Emotional and Functioning domain 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 constmct. Domain and overall 
scores will be calculated if at least two of each of three 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, if appropriate. Estimates of 'mild', 'moderate', and 
'severe' psychological impact, and of the minimal clinical impo1tant difference, will be 
used to aid interpretation of scores and will be considered explorato1y. 
The analysis will be conducted with respect to the hierarchical order of key secondary 
endpoints; the analysis using the Emotional domain first, the 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 perf01m ed. 
Concerns Relating to Glabellar Lines 
The F ACE-Q Appraisal of Lines Between Eyebrows scale and F ACE-Q Age Appraisal 
VAS scores will be derived in accordance with the developers' instmctions and missing 
data treated accordingly. The absolute change from baseline measured on the screening 
visit will be calculated for the F ACE-Q Appraisal of Lines Between Eyebrows scale and 
for the F ACE-Q Age Appraisal VAS score 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 perfo1med. This analysis will be conducted with 
respect to the hierarchical order of key secondaiy endpoints as well; the analysis of FACE-
Q Appraisal of Lines Between Eyebrows scale first, followed by the analysis of F ACE-Q 
Age Appraisal VAS scores. 
Exploratory Analyses 
Explorato1y analyses of modified Skindex-16 (GL-QoL) domain and overall score and 
F ACE-Q Appraisal of Lines Between Eyebrows scale and F ACE-Q Age Appraisal VAS 
will also be conducted using the MF AS and the PP population. The analyses described in 
the two previous sections will be repeated for these populations. 
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8.6.4 Additional secondary analyses 
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The additional secondary efficacy endpoints will be analyzed applying the appropriate 
statistical method for the comparison of both treatment rums. For propo1tions 
• 
of responders with a FWS score of 0 or 1 and an improvement >= 2 points in FWS 
score at maximum frown, 
• 
of subjects with >= 2 point reduction in FWS at maximum frown, 
• 
of subjects with a >= 1 point reduction in FWS at rest, and 
• 
of subjects with an improvement of >=2 points in FWS at maximum frown at 4 
weeks after re-treatment, 
the Cochran-Mantel-Haenszel test (with stratification variable site) and the Pearson x2-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 x2-test. Two-
sided 95% Cls for response rates will be calculated, where appropriate. Additionally the 
cumulative prop01tions 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 F ACE-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-sided McNemar test (using a significance level of 0.05) will be 
used to compare the response propoitions 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. 
8. 7 
Safety analyses 
This section describes the safety analyses that will be conducted on the double-blind and 
the open label treatment period, i.e., the safety analyses on all data collected during these 
treatment periods and all data collected in subjects who dropped-out during one of the 
treatment periods. 
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All definitions relative to safety endpoints are detailed in the following sections. 
Safety analyses will be conducted on the Safety Analysis Set and will be perfo1med for all 
safety variables specified below. 
All safety data will be summarized by treatment group. 
The safety analyses of changes from baseline to a specific time point in safety variables 
(e.g., laborato1y parameters, vital signs, and ECG) will only include subjects from the 
Safety Analysis Set who have data available for both the baseline and the time point under 
consideration unless othe1w ise specified. 
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. 
An additional safety evaluation will be perfo1med for laboratory data, vital signs, and ECG 
by defining cycle 2 day Oas baseline for subjects who switched from placebo to BoNT/A-
DP. 
8.7.1 
Treatment Exposure 
A summaiy table displaying the number of subjects by the number of treatment cycles will 
be prepai·ed. The duration of study drng exposure (calculated as described in section 8.5.1) 
during each treatment cycle will be analyzed by summary statistics. 
8.7.2 Adverse events (secondary safety endpoint 1) 
All AEs will be classified by SOC and PT according to MedDRA Version 19.0 or higher. 
In summaries by SOC and PT, adverse events will be s01ted by decreasing frequency 
within each SOC and PT. In summaries by PT, AEs will be s01ted by decreasing frequency 
within each PT. 
AE smnmai·y tables will be presented for TEAEs and AESis sepai·ately by treatment cycle 
and will include the number and percentage of subjects with any: 
• 
TEAE/AESI 
• 
TEAE/ AESI related to study medication (AE will be defined as related if causality 
is definitely, probably or possibly or if causality assessment is missing) 
• 
TEAE/AESI related to injection procedure (AE will be defined as related if 
causality is definitely, probably or possibly or if causality assessment is missing) 
• 
Severe TEAE/ AESI 
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• 
Severe TEAE/ AESI related to study medication 
• 
Severe TEAE/ AESI related to injection procedure 
• 
TEAE/ AESI leading to discontinuation 
• 
Study dmg related TEAE/AESI leading to discontinuation 
• 
Serious TEAE/ AESI 
• 
TEAE/AESI leading to death. 
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All TEAEs as well as all AESis will be summarized by SOC, PT and treatment group 
using frequency counts and percentages (i.e. number and percentage of subjects with an 
event). 
The number of events, as well as the number and rate of affected subjects will be repo1ied 
by SOC and PT for all TEAEs and for all AESis separately. 
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 
detennined whether an AE is treatment-emergent due to a paiiial onset date, then it will be 
counted as such. 
TEAEs and AESis 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 staiiing on or after first treatment up to before open label extension 
(first cycle), and events staiiing on or after re-treatment lmtil end of study (open label 
phase). If it cannot be dete1mined whether an AE struied during the first treatment cycle or 
the open label extension phase due to a partial onset date, then it will be counted as having 
struied during first treatment cycle. The assignment of AEs to the different cycles of the 
open label extension phase will be done similarly: AEs will be assigned to a ce1iain cycle if 
they staii on or after treatment of the respective cycle but before treatment of the next 
cycle. In case that there is no subsequent treatment cycle, all AEs (staiiing on or after the 
last treatment) until end of study will be assigned to the last cycle. 
Events of subjects who staiied 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. 
TEAEs and AESis (per SOC and PT) will also be summarized by seriousness, severity, 
relationship to study medication, and relationship to procedure using frequency counts and 
percentages (i.e. number and percentage of subjects with an event). 
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8.7.3 Antibody formation (secondary safety endpoint 2) 
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Serum samples will be tested for the presence of antibodies to botulinum toxin using an 
Anti Drug Antibody 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-drng antibodies, the other samples from the subject will be analyzed to detennine 
when antibodies developed. Senun 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. 
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-dtug antibodies, all analyzed samples will be analyzed descriptively by counts over 
time as well. 
8.7.4 Laboratory data (secondary safety endpoint 3) 
For the pmposes of summarization in both the tables and listings, all laboratory values will 
be presented in SI units. If a lab value is repo1ied using a nonnumeric qualifier e.g., less 
than ( <) a ce1tain value, or greater than (>) a ce1iain value, the given numeric value will be 
used in the smmnary statistics, ignoring the nonnumeric qualifier. 
Visit value and change and/or percent change from baseline (where applicable) dming the 
ti-eatment period will be summarized by treatment group using descriptive statistics for all 
laboratory parameters. 
All laboratory values will be classified as n01mal or abno1mal according to the central 
laborato1y nonnal ranges and indicated as clinically significant (CS) or not clinically 
significant (NCS) by the investigator. Quantitative laborato1y values will be sUllllllarized 
with means, standard deviations, medians, minima and maxima at baseline and over time 
and of absolute changes from baseline. Categorical variables will be sUllllllarized by counts 
and percentages of subjects in coITesponding categories. Shift tables illustrating changes 
with respect to the central laborat01y 1101mal ranges and the investigator assessment 
between baseline and post-baseline visits will be created: Number and percentage of 
subjects with 1101mal, CS and NCS laboratory values. 
8.7.5 Vital signs (secondary safety endpoint 3) 
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, 
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standard deviations, medians, minima and maxima of the time comse and of changes from 
baseline to each post-baseline visit by treatment cycle will be presented. 
8.7.6 Electrocardiograms (secondary safety endpoint 3) 
Nonnal/abno1mal shift tables will be created for the overall ECG inte1pretation by 
treatment group for all applicable time points. 
8.7.7 Physical examinations 
All physical examination data and abnonnalities will be listed only. 
8.8 
Other analysis 
8.8.1 Subgroups 
The following subgroup analyses will be perfo1med for the primary efficacy endpoint. 
Subgroup analyses a) and b) will as well be conducted for all key secondaiy endpoints: 
a) Subgroup analysis by geographic region, count1y, and site. 
Subgroup analyses will be conducted for geographic region (US/EU), country, and site. 
Sites with less than three placebo subjects will be combined. The x,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 x,2-test. Stratified 
analyses applying the Cochran-Mantel-Haenszel test will also be conducted using factor 
geographic region and countiy. 95% Cls will be presented, if applicable. The modified 
Skindex-16 (GL-QoL) and FACE-Q Appraisal of Lines Between Eyebrows scale and 
F ACE-Q Age Appraisal VAS scales will be analyzed by geographic region, counti·y, and 
site according to the forese.en analysis approach of these tools, as described in section 
8.6.3. 
b) Subgroup analysis by subjects with previous use of botulinum toxin versus na'ive 
subjects. 
Subgroup analyses will be conducted for subjects with ti·eatment with any serotype of 
botulinum toxin for any indication versus na'ive subjects. The x,2-test or Fisher's exact test 
(see above con esponding criteria to use Fisher) will be applied for each subgroup. No 
stratified analysis using factor pre-ti·eated/na'ive subjects is cmTently planned. 95% Cls will 
be presented, if applicable. The modified Skindex-16 (GL-QoL) and FACE-Q Appraisal of 
Lines Between Eyebrows scale and F ACE-Q Age Appraisal VAS scales will be analyzed 
by subjects with previous use of botulinum toxin versus na'ive subjects according to the 
foreseen analysis approach of these tools, as described in section 8.6.3. 
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c) Subgroup analysis by age groups. 
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Subgroup analyses will be conducted for subjects by age groups (below 65 years/ 65-74/ 
75-84/ 85 years and older). The x,2-test or Fisher's exact test (see above coITesponding 
criteria to use Fisher) will be applied for each subgroup. No stratified analysis using factor 
age is cmTently planned. 95% Cls will be presented, if applicable. 
d) Subgroup analysis by gender. 
Subgroup analyses will be conducted for subjects by gender (male/ female). The x,2-test or 
Fisher's exact test (see above coITesponding criteria to use Fisher) will be applied for each 
subgroup. No stratified analysis using factor gender is cmTently planned. 95% Cls will be 
presented, if applicable. 
e) Subgroup analysis by ethnicity. 
Subgroup analyses will be conducted for subjects by ethnicity (Hispanic or Latino/ Not 
Hispanic or Latino). The x,2-test or Fisher's exact test (see above coITesponding criteria to 
use Fisher) will be applied for each subgroup. No stratified analysis using factor ethnicity 
is cmTently planned. 95% Cls will be presented, if applicable. 
f) Subgroup analysis by Fitzpatrick skin type. 
Subgroup analyses will be conducted for subjects by Fitzpatrick skin type (Type I/ Type II/ 
Type III/ Type N I Type V/ Type VI). The x,2-test or Fisher's exact test (see above 
coITesponding criteria to use Fisher) will be applied for each subgroup. No stratified 
analysis using factor Fitzpatrick skin type is cmTently planned. 95% Cls will be presented, 
if applicable. 
8.9 
Interim analysis 
Not applicable. 
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9 
CHANGES TO PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
The following changes to the planned analysis from the study protocol are designated: 
• 
The definition of the SAF in section 6 was changed compared to the definition in 
section 12.2 of the study protocol in order to include all treated subjects in the 
safety analyses. 
• 
The analysis of antibody fo1mation described in section 8.7.3 was changed 
compared to the description in the study protocol. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 43 of 44 


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Statistical Analysis Plan (SAP) 
CROMA 
10 
REFERENCES 
ICALn-t • ~ \f ,; J'#fC'f"11CN 
:!.!!!: 
1. 
ICH 
Topic 
E3: 
Structure 
and 
Content 
of Clinical 
Study 
Repo1ts 
(CPMP/ICH/137/95- adopted December 1995). 
2. 
ICH Topic E9: Statistic.al Principles for Clinic.al Trials (CPMP/ICH/363/96 -
adopted March 1998). 
3. 
FDA: Code of Federal Regulations (CFR), pait 11 - adopted 15 September 2016. 
Statistical Analysis Plan 
Protocol Number: CPH-301-201030 
Version: FINAL 1.0, Date: 23 June 2017 
Page 44 of 44