Clinical trial NCT03806933
Conditions: Moderate to Severe Glabellar Frown Lines
Sponsor: Merz Aesthetics GmbH
Start date: 2019-01-23; Completion date: 2020-10-08
Enrollment: 241 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to investigate the safety and duration of effect following different doses of Botulinum Toxin A (NT 201) in the treatment of glabellar frown lines (GFL).

Detailed description:
This prospective, randomized, double-blind, multi-Center clinical study consists of a two stage experimental main period comparing different dose groups, followed by an optional open-label extension period (20 Units follow-up treatment).

Arms: arm 1: Stage 1 and 2. Intramuscular injection into the glabellar area. arm 2: Stage 1. Intramuscular injection into the glabellar area. arm 3: Stage 1. Intramuscular injection into the glabellar area. arm 4: Stage 2. Intramuscular injection into the glabellar area. arm 5: Open Label Extension Period. Intramuscular injection into the glabellar area.
Interventions: intervention 1: NT 201
Intervention descriptions: intervention 1: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% unpreserved Sodium Chloride (NaCl).

Protocol documents:
Prot_000.pdf: 
Merz Phrumaceuticals GmbH 
M602011015 
SOP/245/EN - CLINICAL STUDY PROTOCOL 
Version 2.0 (21-JUL-2023) 
A prospective, randomized, double-blind, multicenter study to investigate 
the safety and duration of effect of different NT 201 dose groups following 
the treatment of glabellar frown lines 
Development phase: 
Study identifier: 
NCT number: 
EudraCT number: 
IND number: 
Indication: 
Planned study period: 
Investigational product(s): 
Sponsor: 
Responsible for the clinical 
study protocol content at 
the sponsor: 
Version date: 
Phase 2 
M602011015 
NCT03806933 
2018-002743-28 
100288 
Glabellar frown lines 
First subject first visit: 
Last primaiy outcome visit: 
Last subject last visit: 
JAN-2019 
SEP-2020 
OCT-2020 
Clostridium botulinum neurotoxin type A 
(150 kDa), free from complexing proteins powder for 
solution for injection (NT 201) 
Merz Phaimaceuticals GmbH 
Eckenheimer Landsti·. 100 
60318 Frankfurt/Main Ge1many 
Telephone: 
+49 69 1503 0 
Telefax: 
+49 69 1503 200 
Clinical Proj ect Mana er: 
Medical Expert: 
Biostatistician: 
21-JUL-2023, Version 2.0 
30-APR-2020, Version 1.0, Amendment 2 
22-OCT-2019, Version 1.0, Amendment 1 
01-OCT-2018, Version 1.0 
CONFIDENTIAL AND PROPRIETARY 
Tue contents of this document ru·e confidential and proprietruy to Merz Phrumaceuticals. 
Unauthorized use, disclosme or reproduction is strictly prohibited. This document or parts thereof may 
not be disclosed to pait ies not associated with the clinicai investigation without the prior written consent 
of Merz Phannaceuticals. 
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SIGNATURE PAGE 
The study will be conducted in compliance with the clinical study protocol, ICH–GCP principles, the 
Declaration of Helsinki, and regulatory authority requirements. 
The following individuals are responsible for the content of the clinical study protocol: 


Merz Pharmaceuticals GmbH 
 
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Statement of Compliance 
Study site(s) 
 
I have thoroughly read and reviewed the clinical study protocol. Having understood the 
requirements and conditions of the clinical study protocol, I agree to perform the clinical 
study according to the clinical study protocol, the case report form, International 
Conference on Harmonization (ICH)–Good clinical practice (GCP) principles, the 
Declaration of Helsinki, and regulatory authority requirements. 
 
I have received the current investigator’s brochure (IB). Having been adequately 
informed about the investigational product (IP) development to date, I also agree to: 
 
• Sign this clinical study protocol before the study formally starts. 
• Wait until I have received approval from the appropriate independent ethics 
committees (IECs)/ institutional review boards (IRBs) before enrolling any subject in 
this study. 
 
• Obtain informed consent for all subjects prior to any study-related action performed. 
• Start the study only after all legal requirements in my country have been fulfilled. 
• Permit study-related monitoring, audits, IEC/IRB review, and regulatory inspections. 
• Provide direct access to all study-related records, source documents, and subject files 
for the monitor, auditor, IEC/IRB, or regulatory authority upon request. 
 
• Use the IP and all study materials only as specified in the clinical study protocol. 
• Report to the clinical CRO, within 24 hours, any adverse event (AE) that is serious, 
whether considered treatment related or not as well as any adverse event of special 
interest (AESI) (see Section 10.3 for definition). 
 
• For United States (US) studies: Prior to initiating the study, I will provide the sponsor 
with a written disclosure of any financial interest in accordance with 21 CFR Part 54 
and a signed Food and Drug Administration (FDA) 1572 form according to 21 CFR 
Part 312. 


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Furthermore, I understand that: 
 
• Changes to the clinical study protocol must be made in the form of an amendment 
that has the prior written approval of Merz and – as applicable – of the appropriate 
IEC/IRB and regulatory authority. 
 
• The content of the clinical study protocol is confidential and proprietary to Merz. 
• Any deviation from the clinical study protocol may lead to early termination of the 
study site. 
 
 
 
 
 
Principal investigator (print name) 
Date (dd-MMM-yyyy) 
 
 
 
Study site stamp (for German sites only): 
Signature 


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Changes to Previous Versions of this Protocol 
Version and 
Date 
Version 2.0, 
21-JUL-2023 
Version 1.0, 
30-APR-2020 
Version 1.0, 
22-OCT-2019 
Version 1.0, 
0l-OCT-2018 
CONFIDENTIAL 
Change 
Using the original 2018 (vl) clinical study protocol, as well as the two 
subsequent "stand alone" amendments/Summaiy of Changes documents from 
2019 and 2020, this compiled study protocol was required for appropriate and 
transparent public disclosure and alignment with the final Statistical Analysis 
Plan (2021, v3). 
A second protocol amendment became necessaiy due to govemment 
regulations and rest:rictions related to COVID-19. This amendment was needed 
to assure subjects' safety and mitigate the impact on safety and efficac 
assessments in case sub·ects could not attend on-site visits. 
Original version 
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List of abbreviations and definitions of terms 
 
 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical classification system of the World Health 
Organization 
BDRM 
Blind data review meeting 
β-HCG 
Beta-Human chorionic gonadotropin 
BoNT(/A) 
Botulinum neurotoxin (type A) 
CETS 
Combined endpoint treatment success 
CRO 
Contract research organization 
DEM 
Dose escalation meeting 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
EU 
European Union 
EudraCT 
European clinical trial database 
FAS 
Full analysis set 
FDA 
Food and Drug Administration, US 
FWS 
Facial wrinkle scale 
GCP 
Good clinical practice 
GFL 
Glabellar frown lines 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IND number 
Investigational new drug number, issued by the FDA 
IP 
Investigational product 
IRB 
Institutional review board 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Main period 
OLEX 
Open-label extension (period) 
PI 
Prescribing information 


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PRO 
Patient-reported outcome 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SES 
Safety evaluation set 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TEAESI 
Treatment-emergent adverse event of special interest 
TESAE 
Serious treatment-emergent adverse event 
U 
Unit 
US(A) 
United States (of America) 
V 
Visit 
WHO 
World Health Organization 
 
 
 


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Table of Contents 
1 
S ynops is .......................................................................................................... 9 
2 
S tudy Adminis trative Structure ...................................................................... 16 
3 
Ethics............................................................................................................. 20 
4 
Introduction ................................................................................................... 25 
5 
S tudy Objectives ........................................................................................... 30 
6 
Investigational Plan ....................................................................................... 31 
7 
S tudy Population .......................................................................................... 37 
8 
Treatments..................................................................................................... 44 
9 
Study Assessments and Visit Schedule ...................................................... 58 
10 
Safety Assessments .................................................................................... 75 
11 
Data Quality Assurance ............................................................................... 82 
12 
Statistical Methods ........................................................................................ 88 
13 
Data Handling and Recordkeeping ............................................................ 101 
14 
Publication Policy ....................................................................................... 104 
15 
References ................................................................................................. 105 
16 
Appendices ................................................................................................ 109 
 


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1 S YNOPS IS 
Study title 
 
A prospective, randomized, double-blind, multicenter study to investigate the safety and 
duration of effect of different NT 201 dose groups following the treatment of glabellar 
frown lines 
 
Study phase 
 
2 
 
Indication 
 
Glabellar frown lines (GFL) 
 
Study objectives 
 
Primary objective 
 
To assess the safety and duration of effect of different NT 201 dose groups following the 
treatment of GFL. 
 
Secondary objective 
 
To assess the efficacy of different NT 201 dose groups following the treatment of GFL. 
 
Study population, diagnosis, and main criteria for in- and exclusion 
 
The study will be a prospective, randomized, double-blind, dose-ranging, multicenter, 
phase 2 clinical study with two treatment stages. 
 
Only subjects meeting all of the inclusion and none of the exclusion criteria at the 
Screening Visit V1 (Day -3 to -14) and/or the Baseline Visit V2 (Day 1) will be considered 
for study enrollment for stage 1 or 2 respectively. 
 
Main inclusion criteria 
 
• Male or female subject 18 years or over. 
• Moderate (score = 2) to severe (score =3) GFL at maximum frown as assessed by 
investigator on the 4-point FWS. 
 
• Moderate (score = 2) to severe (score =3) GFL at maximum frown as assessed by 
subject on the 4-point FWS. 


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Main exclusion criteria 
 
• Previous treatment with Botulinum neurotoxin (BoNT) of any serotype in the 
facial area within the last 12 months before injection. 
 
• Previous treatment with any facial cosmetic procedure (e.g., chemical peeling, 
photo rejuvenation, mesotherapy, photodynamic therapy, laser treatment, tattooing 
of eyebrows) in the glabellar area within the last 12 months before injection. 
 
• Previous treatment with any biodegradable filler in the glabellar area within the 
last 12 months before injection. 
 
• Inability to substantially reduce GFL by physically spreading them apart as 
assessed by the investigator. 
 
• Excessively thick sebaceous skin or hypertrophic muscles in the upper third part 
of the face. 
 
• Any surgery or scars in the glabellar area. 
• Marked facial asymmetry. 
• Eyelid ptosis. 
• Marked brow ptosis and/or dermatochalasis. 
• Ongoing severe or unstable medical conditions, e.g., systemic infection, or 
pulmonary disease, at the discretion of the investigator. 
 
Study design 
 
This multicenter Phase 2 clinical study will consist of a Main Period and the subsequent 
optional open-label extension (OLEX) Period. The Main Period will have a prospective, 
randomized, double-blind, dose-ranging, design with two treatment stages. In stage 1, the 
dose groups 20 units (U), 50 U, and 75 U will be investigated. Once all subjects of stage 1 
completed Day 30±7 Follow-up Observational Visit V4, a dose escalation meeting (DEM) 
will be held. Stage 2 will be performed only if no safety concerns have been raised during 
DEM and will investigate the dose groups 20 U and 100 U. Subjects do not cross over from 
stage 1 to stage 2. A total number of up to 240 subjects with moderate to severe GFL at 
maximum frown as assessed by the investigator using the 4-point FWS is planned to be 
randomly assigned to one of up to four NT 201 dose groups (stage 1: 20 U, 50 U, 75 U and, 
if applicable, stage 2: 20 U and 100 U). 
 
Study procedures will be identical in both stages. The subjects will receive intramuscular 
injection of NT 201 according to their respective randomized dose groups administered at 


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the Baseline Visit V2 (Day 1) of stage 1 or stage 2. The injection at Baseline Visit V2 (Day 
1) of stage 1 or stage 2 and the following Observational Visits (up to V15) comprise the 
main period (MP) ofthe study. 
Additionally, subjects who have relapsed to baseline status, will have the option to receive 
a follow-u ti·eatment with the market a roved dose of 20 U NT 201 for their GF 
This injection and the subsequent 
constitutes an optional open-label extension (OLEX) period in this study. 
MP 
Stage 1 of the study 
fu stage 1 of the study, eligible subjects, who had a successful Screening Visit Vl (Day -
3 to -14), will be randomized at the Baseline Visit V2 (Day 1) to one of three dose groups 
of 20 U (n=30), 50 U (n=60) or 75 U NT 201 (n=60) according to the randomization ratio 
1:2:2. 
Once all emolled subjects for stage 1 have had their Day 30±7 Follow-up Observational 
Visit V 4, a blinded evaluation of safety data will be perfonned in a DEM. Based on the 
stage 1 data, a decision to proceed with stage 2 of the study with a dose group of 100 U NT 
201 will be made. 
Stage 2 of the study 
fu the case where no safety concems have been raised during DEM, stage 2 of the study 
will be started. After successful screening eligib]e subjects will be emolled and randomized 
at the Baseline Visit V2 (Day 1) to one oftwo dose groups of 20 U (n=30) or 100 U NT 
201 (n = 60) according to randomization ratio 1:2. 
The obse1vation period for each subject (in stage 1 and stage 2) will be at least 180 days. 
Subjects who have relapsed to baseline status of their GFL based on the investigator's 
assessment on the FWS at maximum frown up to Day 180, should complete the End of MP 
study visit at Day 180 of the study. Subjects who have not relapsed to baseline status of 
their GFL at Day 180 (V9) will continue to be obse1ved for up to 180 additional days. For 
subjects who have relapsed to baseline status of their GFL between Day 180 and Day 360 
the End ofMP can be perfo1med at each ofthe respective Obse1vational Visits. If no relapse 
to baseline status is measured, the End ofMP will be perfo1med at Day 360 (V15). 
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Optional OLEX: 
 
Subjects who have relapsed to baseline status of their GFL in the MP will have the option 
to receive a follow-up treatment with the market approved dose of 20 U NT 201 for their 
GFL between Day 180 and Day 360. An OLEX Follow-Up Visit V16 will be performed 
30 days after the optional injection to document the occurrence of adverse events 
(AEs)/adverse event of special interest (AESIs). 
 
Study duration for each subject (in stage 1 and stage 2) will be at least 180 days, plus the 
individual duration of screening (up to 14 days), plus OLEX follow-up for subjects who 
elect to receive an optional follow-up treatment. The overall maximum study duration will 
be up to 390 days in case the subject will receive an optional follow-up treatment plus the 
individual duration of screening (up to 14 days) for each subject. 
 
Subjects who withdraw or are withdrawn prematurely from the study will be requested to 
come to the End of MP study visit. Please note that subjects who receive the optional 
follow-up treatment but do not attend the OLEX Follow-Up Visit V16 for any reason will 
not be considered as discontinued prematurely from the study. 
 
Planned study period 
 
First subject first visit: 
JAN-2019 
Last primary outcome visit: SEP-2020 
Last subject last visit: 
OCT-2020 
 
Duration of treatment per subject 
 
There is one planned study treatment at the Baseline Visit V2 (Day 1) of stage 1 and stage 
2 respectively and one optional follow-up treatment for subjects who have relapsed to 
baseline status of their GFL in the MP. The overall study duration for each subject will be 
at least 180 days, plus the individual duration of screening (up to 14 days), plus 30 days 
OLEX follow-up for subjects who elect to receive an optional follow-up treatment. The 
overall maximum study duration could be up to 390 days for subjects who receive an 
optional follow-up treatment, plus the individual duration of screening (up to 14 days) for 
each subject. 
 
Variables for analysis 
Efficacy variables 
Primary efficacy variable 
Duration of effect as defined by time between treatment and relapse to baseline status. 
Effect is defined as improvement at maximum frown as assessed by the investigator on the 
FWS. 


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If no improvement is observed on the FWS at any point after treatment, the time will be 
set to 0. 
 
Secondary efficacy variables 
 
• 
Duration of effect whereby effect is defined by a score of none (0) or mild (1) 
at maximum frown as assessed by the investigator according to FWS 
 
This variable is defined as the time between treatment and the first point in time 
when the score is moderate (2) or severe (3) again. If no improvement is 
observed on the FWS at any point after treatment, the time will be set to 0 
 
• 
Duration of effect whereby effect is defined as 2-point improvement from 
baseline at maximum frown as assessed by the investigator according to FWS 
 
This variable is defined as the time between treatment and the first point in time 
when the improvement is less than 2 points again. If no improvement is 
observed on the FWS at any point after treatment, the time will be set to 0 
 
• 
Percentage of subjects rated as none (0) or mild (1) at maximum frown by 
investigator’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as none (0) or mild (1) at maximum frown by 
subject’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as at least 1-point improvement compared to 
baseline at maximum frown by investigator’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as at least 1-point improvement compared to 
baseline at maximum frown by subject’s rating on FWS Subject at Day 180 
(V9) 
 
Safety variables 
 
Primary safety variables 
 
Occurrences of treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), 
treatment-emergent adverse events of special interest (TEAESIs), related TEAEs and 
related TESAEs by dose group for the entire study period. 
 
An AE is considered treatment-emergent with onset or worsening on or after date of the 
first administration of investigational product (IP). 
 
Secondary safety variables 
 
Not applicable. 


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Total number of subjects and number of countries 
A total number of240 subjects will be randomized. 
Stage 1: fu total 150 subjects: 30 subjects for the <lose groups with 20 U and 60 subjects 
each for 50 U and 75 U (1 :2:2 randomization). 
Stage 2: fu total 90 subjects: 30 subjects for the <lose group 20 U and 60 subjects for 
100 U (1:2 randomization). 
The study will be conducted in the United States of America (USA) and Gennany. 
Number of study sites 
lt is planned to conduct the study in approximately 8 sites. 
Number of visits 
There will be u to 16 site visits during study course. 
lnvestigational product(s), dose, and route of administration 
fu this study, all subjects will receive active treatment with NT 201 (active ingredient: NT 
101, Clostridium botulinum neurotoxin type A (150kDa), free from complexing proteins) 
injected into the glabellar area after assignment to one of the following <lose groups: 20 U, 
50 U, or 75 U in stage 1 and 20 U or 100 U in stage 2 at Baseline Visit V2 (Day 1) of the 
respective stage. Subjects (in stage 1 and stage 2) who have relapsed to baseline status in 
the MP will have the option to receive a follow-up treatment with the market approved 
<lose of 20 U NT 201 for their GFL between Day 180 and Day 360. 
Statistical analysis methods 
Efficacy variables 
The efficacy analyses will be based on the füll analysis set (F AS). 
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Primary efficacy variable 
 
The primary endpoint will be described by Kaplan-Meier Curves per group and the 
respective medians of times. 
 
pairwise log-rank tests and 
Cox proportional hazards regression will be applied to compare differences between high 
dose groups and the 20 U group to explore statistical significance. 
 
Secondary efficacy variables 
 
The secondary duration of effect variables will be analyzed in analogy to the primary 
variable. 
 
For the percentages of subjects fulfilling the criteria as described in the secondary efficacy 
variables two-sided 95% Pearson-Clopper confidence intervals will be computed for each 
dose group. 
 
Safety variables 
 
Primary safety variable 
 
All safety analyses will be conducted on the safety analysis set (SES). Incidences (absolute 
and percentage) of TEAEs, TEAESIs, TESAEs, and related TEAEs will be calculated on 
the level of system organ class (SOC) and preferred term (PT). 
 
Secondary safety variables 
 
Not applicable 


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2 STUDY ADMINISTRATIVE STRUCTURE 
2.1 
Interna! responsibilities 
Name 
Merz Phannaceuticals GmbH 
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Function 
Sponsor 
Clinical project manager 
Clinical project director 
Merz No1th America 
Medical expe1t 
Biostatistician 
Product safety officer 
Regulatory affairs 
manager 
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Address 
Eckenheimer Landstrasse 100 
60318 Frankfurt/Main 
Germany 
Telephone: +49-69-1503-0 
Telefax: 
+49-69-1503-200 
Telephone: 
Telefax: 
Email: 
Telephone: 
Mobile: 
Email: 
Telephone: 
Telefax: 
Email: 
Telephone: 
Telefax: 
Email: 
Telephone: 
Telefax: 
Email: 
Telephone: 
Telefax: 
Email: 
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External responsibilities 
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The administrative stiuctme for extemal responsibilities includes, but is not limited to, the 
following paiticipants: 
The sponsor will maintain a list of all principal investigators and of all independent ethics 
committees (IECs)/institutional review boai·ds (IRBs). CmTiculum vitae of each 
investigator, names of all investigators as well as names and addresses of each IEC/IRB as 
well as additional vendors can be found in the trial master file. 
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2.3 
Committees 
 
No external committees are planned during this study. A DEM will be performed during 
the study. For more information, see Section 12.4.7.3. 


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3 ETHICS 
 
3.1 
Independent Ethics Committee/Institutional Review Board 
 
The following documents must be submitted to the responsible IEC/IRB and approval 
obtained: 
 
• The clinical study protocol. 
• Any amendment to the clinical study protocol that is not solely of an administrative 
nature. 
 
• The investigator’s brochure (IB) and all updates. 
• Subject information and informed consent forms, as well as updates (if applicable). 
• All subject recruitment procedures and any advertisement used to recruit subjects (if 
applicable). 
 
• Any other required documents. 
If applicable, and in accordance with local legal requirements, the above documents also 
may be submitted to the respective regulatory authority(ies) for separate approval. 
 
3.2 
Ethical conduct of the study 
 
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, and are consistent with International Conference on 
Harmonization (ICH)-Good clinical practice (GCP) and applicable regulatory 
requirements. Regulatory authorities will be notified and consulted as required prior to, 
during, and after the conduct of the study. 
 
All required approvals, favorable opinions, or additional requirements of the appropriate 
IRB, EC, or other regulatory authority will be obtained prior to initiation of the trial. 


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3.3 
Subject information and informed consent 
 
3.3.1 
Subject information 
 
Prior to study enrollment, the subject will be given full verbal and written information on 
the nature, objective, significance, expected benefits, potential risks, and expected 
consequences of the study and their rights as study participants. This verbal and written 
information will be provided by the investigator (or authorized sub-investigator if 
applicable) according to the provisions set forth in the Declaration of Helsinki. The 
obligations of the investigator are set forth in the clinical study protocol, the ICH-GCP 
principles (effective as of 17-JAN-1997) and the respective national regulations governing 
medical research and experimentation on humans. 
 
Each subject will have the opportunity to question the investigator (or authorized designee) 
about the study prior to giving consent. 
 
 
 
3.3.2 
Informed consent 
 
Informed consent will be obtained: 
 
• In writing directly from the subject. 
The consent must be confirmed by the investigator (or authorized designee in accordance 
with local requirements) who conducted the informed consent briefings. The informed 
consent process must be traceable from the available documentation. At a minimum, this 
documentation should include information about when the subject was first informed about 
the study and who supplied the information. The subject will be given a copy of the signed 
and dated written informed consent form as well as all consent form updates (if applicable). 
 
During the course of the study, the subject will be informed in a timely manner if 
information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. In case of AEs, or poor tolerability to the IP, the subject should 
inform the investigator, who then will make a judgment whether continuing in the study 
serves the subject’s best interests. The subject, however, is free to withdraw consent at any 
time and for any reason, whether expressed or not. 
 
 
 
This applies to sites that are temporarily closed for subject on-site visits or have subjects 
under a Stay-at-Home-Order or subjects who choose not to come to the site due to the 
pandemic. 
 
 


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To assure subject's safety, sites will monitor subject's safety via phone calls at planned 
visit dates based on subject's verbal consent. 
a) being called for safety assessments (AEs, AESis, change in medication and non-drng 
ti-eatment, and occmTence of pregnancy) via phone and 
After the verbal consent, the subject must also confnm his/her consent electrnnically in 
writing (via email) before sending out the documents required for the self-assessment to 
the subject. 
During the next on-site visit, subject's consent to the phone visit and / or the self-
assessment must be confnmed by the investigator and the subject in a signed supplemental 
ICF according to the procedures described above, including the requirements for 
trnceability. 
Eve1y effo1i should be made to contact subjects via phone or letter. At least 3 documented 
attempts to contact the subject should be made. All the attempts are to be documented in the 
subject's source documentation. 
3.3.3 
Subject card 
A subject card will be given to all subjects, who will be instrncted to keep it in their 
possession at all times. The subject card will contain the following printed info1m ation: 
• 
The name, address, and telephone number of the investigator or institution, as the 
main contact for product infonnation and emergency unblinding. 
• 
A 24-hour hotline number for emergencies. 
3.3.4 
Post-study treatment 
No specific post-study airnngements ai·e made and no specific post-study cai·e will be 
peifonned after this study. After study discontinuation, the subjects will be treated by their 
physician according to their medical condition and standard treatments in the countiy 
concemed. 
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3.3.5 
Subject privacy 
 
The subject will be informed of procedures to protect subject privacy. Although recorded 
data will be passed on in a coded version (pseudonymized) only to authorized individuals, 
re-identification by the investigator (e.g., in case of emergencies) will be possible by the 
specific number assigned to the subject (see Section 8.2.1). Access to non-coded data will 
be allowed solely to check validity, and such access will be limited strictly to authorized 
individuals (e.g., individuals authorized by the sponsor (e.g. (medical) monitors), auditors, 
regulatory authorities, or members of IECs/IRBs) who have been bound to confidentiality. 
If the results of the study are published, the subject’s identity will remain confidential. 
 
 
3.3.6 
Contact point 
 
All subjects will be provided in the subject informed consent form with a contact address 
where they may obtain further general information regarding clinical studies. 
 
 


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3.4 
Insurance 
 
From the beginning of the study until its termination, each subject is insured against any 
health impairment occurring as a result of participation in the study in accordance with the 
laws and regulations of the country in which the study is performed. 
 
The subject will be informed by the investigator and through the subject’s informed consent 
form about the existence of this insurance and the resulting obligations. The required 
insurance documents will be handed out to the subject, if requested by the subject or if 
required by local law (as is the case e.g. in Germany). 
 
Any medical or non-medical deviation from the clinical study protocol that is deemed to 
have occurred through the subject’s own fault may not be covered by this insurance. 
 
The sponsor is usually not liable for injuries/cases of death that occur solely as a 
consequence of the subject’s underlying disease or condition, or from diagnostic or 
therapeutic measures not specifically required by the clinical study protocol. The sponsor 
is also usually not liable for events resulting from negligence of the investigator, clinical 
study staff, and/or CRO, including failure to act according to ICH-GCP principles or to 
comply strictly with the clinical study protocol. 
 
 
 
3.5 
Financing 
 
The financial aspects of the study will be documented in an agreement between the sponsor, 
the CRO(s), and each investigator or any other involved party, and must be confirmed in 
writing before the study commences. 
 
 


Merz Phrumaceuticals GmbH 
M602011015 
4 INTRODUCTION 
4.1 
Study background 
Investigational product 
SOP/245/EN - CLINICAL STUDY PROTOCOL 
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Botulinum neurotoxin type A (BoNT/A) is synthesized by a wild-type strnin of the 
anaerobic bacterium Clostridium botulinum. BoNT/A is a pa1i of a high molecular weight 
complex, which is fo1med by several hemagglutinins and other non-toxic non-
hemagglutinin proteins. 
BoNT/A acts selectively on peripheral cholinergic nerve endings, resulting in a temporaiy 
reduction in muscle contraction. Over the years, a lot of indications in the field of aesthetic 
dennatology and plastic surge1y were found for BoNT/A prepai·ations such as 
hyperfunctional GFL due to muscle overactivity and ai·e treated commonly in daily practice 
and reseai·ch [Imhof 2013, Jones 2010, Nestor 2011, Nettai· 2011, Prager 2013, 
Tamburic 2012]. 
NT 201 (United States Adopted Name [USAN]: incobotulinumtoxinA) is a highly purified, 
freeze-dried fo1mulation of BoNT / A and was first a 
roved on 31-MA Y-2005 in Gennan . 
, 
lll 
Cosmetic (Canada only for aesthetic use) and Xeomeen (Belgium and Mexico only). 
Medical background 
Ve1iical GFL between the eyebrows ai·e caused by contraction of the conugator muscles 
located above both eyebrows and the procems muscle at the root of the nose [Canuthers 
1996]. In subjects suffering from expression related GFL due to muscle overactivity, facial 
lines in this ai·ea become static lines fixed in the skin at rest early in the aging process. 
E ective management o 
acia mes reqmres approac es mc u mg aest etic an 
surgical de1matological treatments such as peels, laser resurfacing, fillers, and surgical 
treatments such as rhytidectomy, eyebrow lift, and blepharoplasty [Cather 2002]. Since 
surgical techniques involve risks and recove1y time, and rejuvenation and filler techniques 
may not achieve fully satisfacto1y results, minimally invasive local injection treatment with 
BoNT/A rapidly becaine the standai·d treatment when the first representative of this dmg 
dass was approved for treatment of GFL. 
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BoNT/A treatment is a minimally invasive aesthetic procedure and at 7 million was the 
leading non-surgical cosmetic procedure in 2016 in the USA [American Society of Plastic 
Surgeons 2017]. 
 
GFL are the historically first and most frequently treated aesthetic indication. 
 
Treatment of GFL mainly targets the corrugators and procerus muscles [Carruthers 1996]. 
The usual number of injection sites ranges from five to seven, with men typically requiring 
more sites and a higher dose [Jones 2017]. In GFL, local muscle relaxation is manifested 
as a reduction in the corresponding facial lines. The approved standard dose of NT 201 in 
this indication is 20 U [Merz Pharmaceuticals GmbH 2017, Merz Pharmaceuticals LLC 
2018]. According to the EU summary of product characteristics (SmPC) the dose may be 
increased by the physician to up to 30 U if required by the individual needs of the patients. 
According to the American Consensus group about 30% of panel members use higher 
doses than the approved dose [Carruthers 2004b]. 
 
 
 
 
 
 


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4.3 
Risk-benefit assessment 
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There is an increasing demand for longer druration of effect followin 
BoNT / A because this si ificantl influences atient satisfaction. 
Previous studies have indicated that a longer duration of effect might be achieved with 
increasing <loses of BoNT / A while maintaining an acceptable safety profile. Doses of up 
to 80 U in the ti-eatment of GFL in 1:Il~ere shown to be safe and well tolerated 
[Canuthers 2005a, Canuthers 2005~
]. 
fu general, NT 201 is safe and well tolerated in the approved indications including facial 
aesthetic indications such as GFL and upper facial lines (please refer to the cunent IB). 
Doses of up to 64 U NT 201 in the indication u 
er facial lines have been found tobe safe 
and well tolerated 
and are ah-eady approved in the EU. And, 
as outlined above, there is literature evidence that <loses of up to 80 U are safe. Therefore, 
75 U is a reasonable highest <lose in the first stage of the design. 
The mechanism of action and potential AEs following treatment with BoNT/A are well 
known and qualitatively no new AEs are expected in this study. Common undesirable 
effects after NT 201 injection include local, generalized, or procedural AEs such as 
injection site hematoma, injection site e1ythema, and ecchymosis. Local AEs are usually 
mild and tem orai in nature and enerall resolve s ontaneousl without intervention. 
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Most of the complications of BoNT/A injections are related to needle misplacement 
[Alimohammadi 2017, Brodsky 2012, Rohrich 2003]. Detailed knowledge of the exact 
anatomical relationships between the muscles to be in' ected is ve1 im 01iant to avoid the 
develo ment of adverse effects. 
For this study only investigators experienced in the treatment of GFL with BoNT/A will 
be selected. To ensure exact placement of the injections to targeted muscles, training of 
investigators during the investigator meetings will focus on individual anatomy of the 
underlying facial musculature and the physiologic interactions of the muscles. Moreover 
precise and standardized injection technique will be demonstrated during these trainings. 
fu this respect, it should fmther be considered that treatment areas and injection points are 
in line with the approved label claims in the EU SmPC and the US prescribing info1mation 
(PI) as well as with international guidelines. Hence, the study design will not induce further 
procedure related risks. 
fu conclusion the sponsor believes that this clinical study M602011015 is carefully 
designed to minimize risks and to maximize potential benefits for the subjects. Based on 
available evidence, the benefit-risk-balance is considered as positive. 
The COVID-19 pandemic may impact the conduct of this clinical trial. Subjects may no 
longer be able to come to the investigational site for planned safety and efficacy follow up 
visits due to quarantines, site closures, or travel limitations. Since ensuring the safety of 
the subjects is paramount, mitigation measures will be implemented. Subjects' safety will 
be monitored via phone calls at planned visit dates based on subjects' consent. Efficacy 
based on investigator assessments will not be possible under the circumstances mentioned 
above, however subjects' self-assessments can also be perfonned safely at home. 
Therefore, subjects will be asked ifthey consent to perfo1m their self-assessments at home. 
On-site visits should be perfo1med at the earliest possible date the subject is able to safely 
come to the site again. fu conclusion the measures as outlined above are deemed 
appropriate to assure the safety of trial subjects and reduce the amount of missing data due 
to COVID-19 pandemic. 
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4.4 
Justification of doses 
 
 
 
 
In everyday practice some physicians do already use higher doses than the approved dose 
of 20 U in the treatment of GFL. According to the Consensus Recommendations on the use 
of BoNT/A in facial aesthetics [Carruthers 2004b] 30% of the panel members use doses of 
up to 120 U in the treatment of GFL. 
 
The doses in this study were chosen in reference to publications and common use in 
aesthetic medicine. 


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5 S TUDY OBJ ECTIVES 
Primary objective 
 
To assess the safety and duration of effect of different NT 201 dose groups following the 
treatment of GFL. 
 
Secondary objective 
 
To assess the efficacy of different NT 201 dose groups following the treatment of GFL. 


Merz Phrumaceuticals GmbH 
M602011015 
6 
INVESTIGATIONAL PLAN 
6.1 
Overall study design 
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This multicenter Phase 2 clinical study will consist of a Main Period and the subsequent 
optional open-label extension (OLEX) Period. The Main Period will have a prospective, 
randomized, double-blind, dose-ranging, design with two treatment stages. fu stage 1, the 
<lose groups 20 U, 50 U, and 75 U will be investigated. Once all subjects of stage 1 
completed Day 30±7 Follow-up Observational Visit V4, a DEM will be held. Stage 2 will 
be perfo1med only if no safety concems have been raised during DEM and will investigate 
the <lose groups 20 U and 100 U. Subjects do not cross over from stage 1 to stage 2. A total 
number ofup to 240 subjects with moderate to severe GFL at maximum frown as assessed 
by the investigator using the 4-point FWS is planned to be randomly assigned to one of up 
to four NT 201 <lose groups (stage 1: 20 U, 50 U, 75 U and, if applicable, stage 2: 20 U and 
100 U). 
Study procedures will be identical in both stage-
. Tue subjects will receive 
intramuscular injection of NT 201 according to ~
e randomized <lose groups 
administered at the Baseline Visit V2 (Day 1) of stage 1 or stage 2. Tue injection at Baseline 
Visit V2 (Day 1) of stage 1 or stage 2 and the following Observational Visits (up to V15) 
comprise the MP ofthe study. 
Additionally, subjects who have relapsed to baseline status in the MP, will have the option 
to receive a follow-u treatment with the market a 
roved <lose of 20 U NT 201 for their 
GF 
This injection and the subsequent follow-up visit 
constltutes an opbona OLEX peno m this study. For more infonnation on dosage, 
fo1mulation, route of administration, and treatment groups, see Section 8. 
MP: 
Stage 1 of the study 
fu stage 1 of the study, eligible subjects, who had a successful Screening Visit VI (Day -
3 to -14), will be rando1nized at the Baseline Visit V2 (Day 1) to one ofthree <lose groups 
of 20 U (n=30), 50 U (n=60) or 75 U NT 201 (n=60) according to the randoinization ratio 
1:2:2. 
Once all emolled subjects for stage 1 have had their Day 30±7 Follow-up Observational 
Visit V 4, a blinded evaluation of safety data will be perfo1med in a DEM. Based on the 
stage 1 data, a decision to roceed with sta e 2 of the stud with a <lose 
·ou of 100 U NT 
201 will be made 
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In addition to the blinded safety data evaluation (once all subjects of stage 1 completed 
Day 30±7 Follow-up Observational Visit V4), an interim analysis will be performed once 
complete 180-day data (V9) of stage 1 are available. Data will be unblinded for sponsor 
staff and vendor data management and biostatistics staff only with regard to stage 1 
subject’s assignment to treatment groups. The blind for subjects in stage 2 will be 
maintained. Stage 2 subjects, if applicable, will not be included in the 180-day interim 
analysis. For more details see Section 12.4.7.2. 
An interim analysis of complete Stage 1 MP data will be performed as soon as data until 
and including the End of MP visit V15 from Stage 1 subjects’ are completely available 
(except for missingness due to premature study discontinuation or intermittently missing 
visits). The analysis of Stage 1 MP data will serve to get further insights regarding duration 
of effect and occurrence of TEAEs over the entire Main Period of up to 360 days. 
Knowledge gained form the interim analysis at End of MP of Stage 1 will be useful to 
decide whether it is still meaningful to motivate affected Stage 2 subjects to re-assume on-
site visits depending on the number of missing visits for the primary efficacy variable. 
Since ensuring the safety of subjects is paramount, this analysis will be valuable to balance 
the potential risks of further onsite visits against benefits such as avoidance of missing data 
and premature study discontinuations. Investigators and subjects, site staff and blinded 
monitor will be kept blinded throughout for both stages until final unblinding. The blind 
for subjects in Stage 2 will be completely maintained. 
 
Stage 2 of the study 
 
In the case where no safety concerns have been raised during DEM (see Section 12.4.7.3), 
stage 2 of the study will be started. After successful screening, eligible subjects will be 
enrolled and randomized at the Baseline Visit V2 (Day 1) to one of two dose groups of 20 
U (n=30) or 100 U NT 201 (n = 60) according to randomization ratio 1:2. 
 
 
The observation period for each subject (in stage 1 and stage 2) will be at least 180 days. 
Subjects who have relapsed to baseline status of their GFL based on the investigator’s 
assessment on the FWS at maximum frown up to Day 180, should complete the End of MP 
study visit at Day 180. Subjects who have not relapsed to baseline status of their GFL at 
Day 180 (V9) will continue to be observed for up to 180 additional days. For subjects who 
have relapsed to baseline status of their GFL between Day 180 and Day 360 the End of MP 
can be performed at each of the respective Observational Visits. If no relapse to baseline 
status is measured, the End of MP will be performed at Day 360 (V15). 
 
 
 
 
 


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Optional OLEX: 
 
Subjects who have relapsed to baseline status of their GFL in the MP will have the option 
to receive a follow-up treatment with the market approved dose of 20 U NT 201 for their 
GFL between Day 180 and Day 360. An OLEX Follow-Up Visit V16 will be performed 
30 days after the optional injection to document the occurrence of AEs/AESIs. 
 
Study duration for each subject (in stage 1 and stage 2) will be at least 180 days, plus the 
individual duration of screening (up to 14 days), plus 30 days OLEX follow-up for subjects 
who elect to receive an optional follow-up treatment. The overall maximum study duration 
will be up to 390 days in case the subject will receive an optional follow- up treatment plus 
the individual duration of screening (up to 14 days) for each subject. 
 
Subjects who withdraw or are withdrawn prematurely from the study will be requested to 
perform the End of MP study visit. Please note that subjects who receive the optional 
follow-up treatment but do not attend the OLEX Follow-Up Visit V16 for any reason will 
not be considered as discontinued prematurely from the study. 
 
The study will be conducted in approximately 8 study sites in USA and Germany. 
 
6.1.1 
End of study 
 
The end of study is defined as the last visit of the last subject. 
 
 


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6.2 Discussion of study design, including choice of control groups 
 
This prospective, randomized, double-blind, dose-ranging, multicenter, phase 2 clinical 
study is designed to investigate the safety and duration of effect of different NT 201 dose 
groups following the treatment of GFL. 
 
The recommended dose of 20 U NT 201 used in the US and the 20 to 30 U used in the EU 
for the treatment of GFL has been proven effective and safe in numerous clinical studies 
and there is a long term experience in clinical practice. In this study, higher doses of NT 
201 (50 U, 75 U, and 100 U) are compared to this currently approved dose. The focus of 
the study is the safety and duration of effect. 
 
To reduce the risk of subjects, a two-stage design was  chosen and the highest  dose   (100 
U) is only investigated when acceptable safety based on predesigned criteria was proven 
for the 50 U and 75 U doses (see Section 12.4.7.3). To ensure blinding and comparability 
of the results, subjects will be enrolled in the 20 U dose group in both stages. 
 
The DEM will be performed when all enrolled  subjects  for  stage  1  have  had  their Day 
30±7 Follow-up Observational Visit. Selection of this time point ensures timely decision 
on the continuation with stage 2 as well as an accurate measurement of safety as the 
treatment will already have reached its peak effect. 
 
Both stages use a randomized double-blind design. Although an unblinded interim analysis 
will be performed on the 180-day data of stage 1 subjects, the blind will be maintained for 
investigators, subjects, site staff and monitors to ensure unbiased continuation of the study. 
 
Subjects will be enrolled regardless of gender, age, ethnic background and pre-treatment 
status to represent the average target population that is seeking GFL treatment. 
 
Wash out  period  for  BoNT/A  treatment  in  the  targeted  areas  before  the  study  is  12 
months, ensuring that no BoNT/A activity from former treatments is left. 
 
The primary efficacy endpoint of the study is duration of effect. The observation period of 
up to one year, represents a reasonable time that the IP will have worn off in most of the 
treated subjects, considering the higher doses applied, and ensuring that the primary 
efficacy endpoint can be measured in a reasonable number of subjects. 
 
subjects who have relapsed 
to baseline status in the MP will have the option to receive a follow-up treatment with the 
market approved dose of 20 U NT 201 for their GFL between Day 180 and Day 
360. 
 


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7 S TUDY POP ULATION 
 
7.1 
Selection of study population 
 
Subjects with moderate (score = 2) to severe (score = 3) GFL at maximum frown as 
assessed by the investigator and subject using the 4-point FWS at screening will be enrolled 
in this study. 
 
Treatment-naïve subjects or pre-treated (non-naïve) subjects may enter the study. Pre- 
treated subjects must not have received treatment with BoNT of any serotype in the facial 
area within the last 12 months before injection. 
 
To support the recruitment process, recruitment advertisements approved by the 
responsible IECs/IRBs will be published as required. 
 
Distribution of gender 
 
No stratification regarding gender is planned. Subjects will be recruited regardless of their 
gender, ethnicity and age. This study population will therefore be expected to be a 
representative sample of the target population for the indication of moderate to severe GFL. 
 
7.2 
Inclusion criteria 
 
Only subjects meeting all of the following inclusion criteria at the Screening Visit V1 (Day 
-3 to -14) and/or the Baseline Visit V2 (Day 1) (as indicated below) will be considered for 
study enrollment for stage 1 or 2 respectively. 
 
 


Merz Phrumaceuticals GmbH 
M602011015 
Male or female subject 18 years or over. 
Moderate (score = 2) to severe (score 
=3) GFL at maximum frown as assessed by 
investigator on the 4-point FWS. 
Moderate (score = 2) to severe (score 
=3) GFL at maximum frown as assessed by 
subject on the 4-point FWS. 
7.3 
Exclusion criteria 
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Efficacy 
X 
X 
Efficacy 
X 
X 
Subjects meeting any of the following criteria at the Screening Visit VI (Day -3 to -14) 
and/or the Baseline Visit V2 (Day 1) (as indicated below) will not be included as subjects 
in this study for stage 1 or 2 respectively: 
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Version 2.0 (21-JUL-2023) 
Exclusion Criteria 
Previous treatment with BoNT of any serotype 
in the facial area within the last 12 months 
before injection. 
Rationale 
Efficacy 
Previous treatment with any facial cosmetic 
Efficacy 
procedure (e.g., chemical peeling, photo 
rejuvenation, mesotherapy, photodynamic 
therapy, laser treatment, tattooing of eyebrows) 
in the glabellar area within the last 12 months 
before in'ection. 
Previous treatment with any biodegradable 
Efficacy 
filler in the glabellar area within the last 12 
months before injection. 
Inability to substantially reduce GFL by 
Efficacy 
physically spreading them apait as assessed by 
the investi ator. 
Excessively thick sebaceous skin or 
Efficacy 
hype1trophic muscles in the upper third pait 
Marked brow ptosis and/or 
Safety concem 
de1matochalasis. 
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Screening 
Baseline 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Ongoing severe or unstable medical 
conditions, e.g., systemic infection, or 
puhnonaiy disease, at the discretion of the 
investigator. 
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Safety concem 
X 
X 
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7.4 
Removal of subjects from treatment or assessment 
 
7.4.1 
Discontinuation of subject’s study participation 
 
In accordance with the Declaration of Helsinki and the informed consent form, the subject 
may end his/her participation in the study at any time without any penalty or loss of benefits 
to which the subject is otherwise entitled (see Section 7.4.3). Both the fact and the reason(s) 
why the subject’s participation in the study was prematurely discontinued must be recorded 
in the source documentation (e.g. subject file) and the electronic case report form (eCRF). 
Date and discontinuation circumstances should be stated. 
 
The investigator must discontinue the subject’s study participation at any time, if any of 
the following occurs: 
 
• Withdrawal of informed consent. 
• Pregnancy prior to injection of IP (in case of pregnancy after a subject has received 
an injection the subject can continue with applicable study visits until the end of the 
study but without any invasive procedure, e.g. injections, blood draw, or any other 
interventional procedure). However the subject is free to discontinue the study at any 
time. 
 
• Any AE for which treatment continuation would constitute an unacceptably high risk 
for the subject. 
 
Deviations from this study protocol, or conditions comprising exclusion criteria established 
in Section 7.3 that arise after the subject has been included in the study may (but will not 
necessarily) lead to the discontinuation of subject’s study participation. All such conditions 
must be properly documented. 
 
Subjects who discontinue the study because of AEs will be treated according to standard 
clinical procedures and will be followed up until the End of MP if no optional treatment 
was received or the OLEX Follow-up Visit V16 if optional treatment was received (see 
Section 6.1) as described in Section 10.1. All pertinent information concerning the AE will 
be documented in the source documentation as well as in the eCRF AE report form. 
 
Following discontinuation the End of MP is to be documented. The investigator is required 
to make every effort to contact subjects lost to follow-up, and all such efforts are to be 
documented in the source documentation (e.g., times and dates of telephone contact, copies 
of letters). Please note that subjects who receive optional follow-up treatment but do not 
attend the OLEX Follow-Up Visit V16 for any reason will not be considered as 
discontinued prematurely from the study. 


Merz Pharmaceuticals GmbH 
 
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M602011015 
 
Version 2.0 (21-JUL-2023) 
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7.4.2 
Premature termination or suspension of the study or 
closure/suspension of a study site 
 
The study or a study site can be prematurely terminated or suspended by the sponsor. 
Reasons for termination of the study or closure of a study site may include, but are not 
limited to, the following: 
 
• Subject enrollment is unsatisfactory. 
• The risks and benefits of continuing the study have been reassessed, and the risks 
outweigh any potential benefits. 
 
• The incidence of AEs constitutes a potential health hazard to the subjects. 
• New scientific data on the IP(s) do not justify a continuation of the study. 
• The investigator or study site exhibits serious and/or persistent non-adherence to the 
clinical study protocol, the Declaration of Helsinki, ICH–GCP, and/or applicable 
regulatory requirements. 
 
• The sponsor decides to terminate the study at any time for any other reason. 
Furthermore, the study may be prematurely ended if the regulatory authority or the 
IEC/IRB has decided to withdraw or suspend approval for the study, the study site, or the 
investigator. 
 
If the study is prematurely terminated or suspended for any reason, the investigator must 
inform the subjects and ensure appropriate follow-up treatment. Within the timeframes 
noted in applicable regulations, the sponsor will promptly inform the investigators, study 
sites, the IEC/IRB, and regulatory authorities of the termination or suspension of the study, 
as well as provide reasons for the action. 
 
7.4.3 
Provision of care for subjects after discontinuation of the study 
 
After study discontinuation, the subjects will be treated by their physician according to 
their medical condition and standard treatments in the country concerned. 


Merz Phrumaceuticals GmbH 
M602011015 
8 TREATMENTS 
SOP/245/EN - CLINICAL STUDY PROTOCOL 
Version 2.0 (21-JUL-2023) 
8.1 
lnvestigational product(s) 
8.1.1 
Description of investigational product(s) 
fuvestigational product: 
futemational non-proprieta1y 
name of active ingredient: 
Excipients: 
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Template: tem-csp-v3.0-20150713 
NT 201, 
(active 
ingredient: 
NT 101, 
Clostridium 
botulinum neurntoxin!III
A 
150kDa), free from 
complexing proteins ), 
powder for solution 
for injection (manufacture 
y Merz P anna GmbH & Co. 
KGaA, 
Am 
Pha1mapark, 
06861 
Dessau-Rosslau, 
Ge1many) is refoased by Merz Phaimaceuticals GmbH, 
Eckenheimer Landstr. 100, D-60318 Frankfiui/Main, 
Ge1many. 
An international non-proprietaiy naine for the drng 
substance has not been assigned. Tue assigned United 
States Adopted Naine (USAN) for the active ingredient is 
incobotulinumtoxinA. 
Sucrose, human senun albumin. 
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8.1.1.1 
lnstructions for preparation 
SOP/245/EN - CLINICAL STUDY PROTOCOL 
Version 2.0 (21-JUL-2023) 
Preparation of the IP will be perf01med by an unblinded study nurse or phaimacist, who 
receives a precise training. The unblinded study muse/phaim acist must be a sepai·ate person 
not involved in any other study procedures to ensure blinding of the investigators, other 
study staff, and subjects. By using the IWRS the <lose group according to randomization 
and the medication nlllllber of the medication box to be used will be provided following 
log-in with a separate password for the unblinded staff. Tue unblinded study 
nurse/pha1macist will then reconstitute the IP for each subject according to the randoinized 
<lose group assignment. Tue syringe to be used for injection must be labelled with the 
medication nlllllber provided with the IP kit. Reconstitution according to each <lose group 
assigned by IWRS will be doclllllented in a separate unblinded folder not accessible to 
blinded study staff. Tue medication number for each subject will be recorded in the eCRF. 
The investigator will be blinded to <lose group as only the syringe will be provided for 
treatment. 
For the optional follow-up treatment with the approved standard <lose of 20 U NT 201 
reconstitution and administration must follow the a roved label. 
Ass1gnment o t e 
medication nlllllber will be perfo1med by the IWRS. As all subjects will receive the saine 
<lose for this follow-up injection, no other procedures on treatment assignment ai·e 
necessa1y. 
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Version 2.0 (21-JUL-2023) 
All injectable solutions should be clear, colorless, and :free :from paiiiculate matter, 
othe1wise it has to be discarded. 
The IP should be reconstituted sho1ily before injection. However, the reconstituted solution 
can be stored in the original vial for up to 24 hours in a re:frigerator at 2-8°C (36- 46°F). 
Any deviation should be documented on the drug accountability log. Reconstituted study 
medication is not to be stored in syringes. Any used syiinges, spillages, or other materials 
that have been in contact with the IP must be disposed adequately. Any reconstituted IP if 
(paiiially) used or unused must be inactivated appropriately at the site, 
e.g. by autoclaving (please also refer to Section 8.1.5). 
8.1.1.2 
lnstructions for administration 
For safety reasons, emergency equipment for treatment of anaphylactic reactions 
e available at site. 
The treatment will be administered to five intramuscular injection sites into the procerns 
and c01n1gator muscles. As the position and the size of these muscles can differ, the 
investifator should identify the muscles by touching and holding them gently between the 
finger1 
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Only medical doctors trained and experienced in aesthetic BoNT treatment are allowed to 
inject subjects. The number of investigators responsible for these tasks should be as small 
as possible. 
 
The investigator will use the IP(s) and all study materials only within the framework of the 
clinical study and in accordance with this clinical study protocol. 


Merz Phrumaceuticals GmbH 
M602011015 
8.1.2 
Packaging and labeling 
SOP/245/EN - CLINICAL STUDY PROTOCOL 
Version 2.0 (21-JUL-2023) 
o con ms a s 1c er w1 
the medica 10n num er or 
labeling of th 
inge. Assignment of the medication number to the 
subject is given to the investigator via the IWRS or is given to the investigator on a printed 
. 
. 
. 
' 
. 
. 
. 
The investigator must administer the IP to the subject during the injection visits only. IP 
must not be handed over to subjects. 
The IWRS will assign IP to each subject at baseline or at Vl 5 for the optional follow-up 
treatment. If an IP vial should be broken, or becomes unusable for any reason, the 
medication-box / vial must be replaced from the site stock of study medication and the 
medication number and reason for unusability will be recorded in the IWRS. 
The study medication must be labeled according to regulato1y requirements in the 
paiticipating countries. The label will include as minimum infonnation the naine and 
address of the sponsor, study reference number, European clinical trial database 
(EudraCT)/ Investigational new drng (IND) number, medication number, the dosage f01m, 
route of administration, quantity of dosage units, batch number, directions for use, storage 
conditions, period of use, and the waining 'For clinical study use only'. German labels will 
include the name and address of the CRO. Labels for USA only, must include: 'Caution: 
New Drng - Limited by Federal (or US) law to investigational use'. Parts of the study 
medication ma be sub· ect to a reduced labelin accordin to the a licable regulations. 
8.1.3 
Storage of investigational product(s) 
The IP will be shipped at ambient temperature. Shipment will be perfo1med under 
temperature control. Unopened vials should be stored within a temperature range from +2 
to +25°C (36-77°F). lt is recommended not to freeze the study medication. During storage 
the minimum/maximum temperature must be recorded in a temperature log. During 
storage at the site the temperature log must be maintained weekly on a predefined business 
day (e.g. eve1y Thursday ± one business day). For storage ofreconstituted IP, see Section 
8.1.1.1. IP must be stored in a locked place during all study periods. 
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8.1.4 
Accountability for investigational product(s) 
 
It is the responsibility of the investigator or pharmacist according to local law to ensure 
that a current record of inventory/drug accountability is maintained. Inventory records must 
be readily available for inspection by the unblinded study monitor and are open to 
inspection by the FDA or other regulatory authorities at any time. Each shipment of 
materials for the study will contain an ‘IP supply and return form’ to assist the investigator 
in maintaining up-to-date and accurate inventory records. This form includes the following 
information: study number, dates, quantities, batch number, expiration date, and the 
medication number assigned to the IP. 
 
Upon receipt of the IP(s), the investigator - pharmacist according to local law - must 
visually inspect the shipment and verify the number and condition of the IP(s), and 
acknowledge the receipt in the IWRS. An ‘IP supply and return form’ must be completed 
and signed by the investigator or authorized site staff or pharmacist according to local law. 
The original completed and signed form must be filed with the inventory/drug 
accountability records. Instead of paper forms IWRS print-outs can be used, if applicable. 
 
To ensure proper storage and to verify the inventory, a drug supply inspection will be 
conducted at regular intervals by the unblinded monitor. The results of the inspection will 
be made available to the authorized individuals (e.g., unblinded monitor, auditor, and 
regulatory authorities) on request throughout the study. 
 
For further details, see Section 8.2.5. 
 
8.1.5 
Destruction of investigational product(s) 
 
Any used syringes, spillages, or other materials that have been in contact with the IP must 
be disposed adequately. Any reconstituted IP if (partially) used or unused must be 
inactivated appropriately at the site, e.g. by autoclaving
 
. 
 
 
 
 
 
 
 


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fu cases where reconstituted product has been spilled, diy, absorbent material should be 
used. If the product comes into contact with skin, the affected area should be abundantly 
rinsed with water. If product gets into the eyes, they should be rinsed thoroughly with 
plenty ofwater or with an ophthalmic eyewash solution. If product comes into contact with 
a wound or damaged skin, the area should be rinsed thoroughly with plenty of water and 
appropriate medical steps according to the <lose injected should be taken. 
Upon the completion or tennination of the study, all used and unused vials of IP must be 
retumed to the sponsor or another authorized party. Destiuction of IP(s) at the study site 
may be allowed if written authorization is provided by the sponsor. If destiuction at the 
study site is agreed upon, then a ce1tificate of destiuction must be given to the sponsor. 
8.2 Treatments administered 
During this study, all subjects will receive active ti·eatinent with NT 201 once at the 
Baseline Visit V2 (Day 1) of stage 1 or stage 2. 
· 
· 
· 
· 
·eatinent with NT 201 at th 
· 
· · 
~ected into the glabellar are 
<lose ·ou s: 
Subjects (in stage 1 and stage 2) who have relapsed to baseline status in the MP will have 
the option to receive a follow-up ti·eatment with the market a roved <lose of 20 U NT 201 
for ti·eatment of their GFL between Da 180 and Da 36 
8.2.1 
Methods of assigning subjects to treatment groups 
This study is planned as a multinational, multicenter study. At the Baseline fujection Visit 
(V2; Day 1) of each stage, subjects will be randomly assigned to <lose groups sti·atified by 
center by using IWRS. For stage 1, groups 20, 50 and 75 U will be randomized with a 
randomization ratio of 1 :2:2. For stage 2, subjects will be assigned randomly to the groups 
20 U or 100 U with a randomization ratio 1 :2. Randomized subjects discontinued from the 
study will not be replaced. 
Randomization in blocks of appropriate size and by IWRS will ensure appropriate conti·ol 
of sti·atification. Tue block size will not be disclosed to investigators until the study is 
unblinded. Subjects will receive a subject /screening number through the IWRS, as well as 
a randomization number, if randomized. 
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The investigator will enter the subject in the IWRS and confüm successful screening. Tue 
IWRS will then assign to each subject a randomization number and the unique medication 
number of the IP kit tobe used for injection. The screening, randomization, and medication 
numbers will be recorded in the eCRF. 
The unblinded study nurse/phaimacist responsible for preparation of the IP will add a 
sticker with the medication number (provided in the IP kit) on the ready for use syringe to 
ensure conect assignment to the subject by the investigator or a printed note accompanying 
the syringe stating subject/screening number and medication number. 
Subjects who are withdrawn prematurely will retain their screening and randomization 
numbers, if applicable. 
The randomization schedules for stage 1 and 2, respectively, will be sealed and locked at 
the sponsor's site and will not be accessible to any blinded functions in the study prior to 
applicable unblinding. 
As all subjects will receive 20 U ofNT 201 in the optional follow-up treatment, no fmiher 
randomization is required. The unique medication number of the IP kit for the optional 
follow-up treatment as assigned to the subject by IWRS will the recorded in the eCRF. 
8.2.2 
Selection of doses in the study 
In the present study 20 U, 50 U and 75 U NT 201 are used in stage 1 and 20 U and 100 U 
are used in stage 2. 
The dose of 20 U is the cmTently approved dose of NT 201 for the treatment of GFL. 
According to the Consensus Recommendations on the use of BoNT/A in facial aesthetics 
[Canuthers 2004b 30% of anel members use doses of u to 120 U in the treatment of 
GFL. 
The optional follow-up treatment is administered with the approved standai·d dose of20 
U NT 201. Reconstitution and administration follows the approved labe 1. 
8.2.3 
Selection and timing of doses for each subject 
In this study, all sub'ects will receive active treatment with NT 201 injected into the 
glabellar ai·ea 
in one of following dose 
groups: 20 U, 50 U, or 75 U in stage 1 and 20 U or 100 U in stage 2 at the Baseline Visit 
V2 (Day 1) of the respective stage. 
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Subjects (in stage 1 and stage 2) who have relapsed to baseline statlls in the MP will have 
the option to receive a follow-up treatment with the market approved <lose of 20 U NT 201 
for their GFL between Day 180 and Day 360. 
For more details see Section 8.1.1.2 and Section 8.2.1. 
8.2.4 
Duration of treatment per subject 
There is one planned study ti-eatment at the Baseline Visit V2 (Day 1) of stage 1 and stage 
2 and one optional follow-up ti·eatment for subjects who have relapsed to baseline status of 
their GFL in the MP. Tue overall study duration for each subject will be at least 180 days, 
plus the individual duration of screening (up to 14 days), plus 30 days OLEX follow-up for 
subjects who elect to receive an optional follow-up ti·eatment. Tue overall maximum study 
duration could be up to 390 days for subjects who receive an optional follow-up ti·eatment, 
plus the individual duration of screening (up to 14 days) for each subject. 
8.2.5 
Treatment compliance 
The IP(s) will be administered by inh'amuscular injection perfo1med by the investigator 
during the subject's visit to the investigationa[ site. Thus, füll treatment compliance is 
assured for each individual subject. 
At the beginning of the study, the site will receive dmg accountability fo1ms to document 
how and when IP is administered to subjects, or remains unused. These fonns will be made 
available to the authorized individuals (e.g., monitor, auditor) and will include the 
following infonnation: study number, dates, quantities, and the medication number 
assigned to the IP and study subjects. IWRS print outs can also be used for documentation. 
8.2.6 
Treatment of overdose 
An overdose is defined as any deviation from the specified <lose in the protocol ( <loses that 
are higher than recommended). Any overdose must be recorded in the IP section of the 
eCRF and the source documents. Any case of overdose leading to AEs, SAEs or AESis 
must be reported to the CRO in an expedited manner using the appropriate repoiting fo1m 
(see Section 10.1). 
As ti·eatment with IP is perfonned exclusively in a clinical setting under the supervision of 
ti·ained medical personnel, the risk of overdose in this study is estimated tobe ve1y low. 
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There is no significant information regarding overdose from clinical studies in adults with 
GFL as they will be treated in this clinical study. In the event of an overdose, the 
investigator/treating physician should closely monitor the subject for any AE/SAE and 
document the quantity of the excess dose. Excessive doses of NT 201 may be expected to 
produce neuromuscular weakness with a variety of symptoms. Signs include acute 
symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, 
dysphonia, and dysphagia, which would typically occur 12 to 72 hrs after exposure [Arnon 
2001]. Furthermore, signs and symptoms of overdose can result in ptosis, generalized 
muscle weakness and paralysis of respiratory muscle leading to aspiration pneumonia. 
Clinical cases of iatrogenic botulism after BoNT injection were reported for four adult 
patients whose clinical signs were consistent with those of naturally occurring botulism 
[Chertow 2006]. 
 
Symptoms of overdose are not immediately apparent following injection. By the time 
symptoms of intoxication are observed, treatment with anti-toxin will no longer be 
effective because the neurotoxin has already irreversibly blocked the transmitter release. 
Compounds releasing acetylcholine (e.g., physostigmine, guanidine, 3,4- diaminopyridine) 
might be helpful. However, there is no experience with a specific antidote to BoNT 
including NT 201 in the clinical management of overdose. A published case report 
describes the successful treatment of dysphagia with intranasal neostigmine [Marchini 
1997]. 
 
Subjects should be advised to seek immediate medical care if symptoms such as 
swallowing difficulties, speech or breathing problems occur. Subjects will receive a subject 
card with contact information in case of emergency (see Section 3.3.3) if additional 
information on the scope of the study should be required. 
 
Should accidental injection or oral ingestion occur, the subject should be medically 
supervised for several weeks for signs and symptoms of excessive muscle weakness or 
paralysis. Symptomatic treatment may be necessary. Respiratory support may be required 
where excessive doses cause paralysis of the respiratory muscles. Antitoxin would not 
reverse any BoNT-induced effects already apparent by the time of antitoxin administration. 
 
8.3 
Previous and concomitant therapies 
Before enrollment, the subject’s medical history should include a detailed list of all 
medications (including rescue medication) that the subject was taking for a period of at 
least 30 days prior to screening. The record should include the drug name (trade or generic), 
route of administration (e.g., intravenous, oral), total daily dose/unit (expressed in mg, mL, 
or IU), indication, the start and stop date (day, month, and year) for each 


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medication. At the end of the study an additional statement will be entered to indicate 
whether the intake/use of the medication is ongoing at the end of the study. Similar 
infonnation should be collected and assessed fm any non-dmg therapies that may have an 
effect on study results. 
revious treatments should be checked and listed before 
emollmen 
• 
Previous treatment with BoNT of any serotype at any body region at any tim~ . 
, including also biodegradable fille and inse1tion of pe1manent material 
(such as silicone, polyacrylamide etc) in the glabellar area at any time. 
The following procedures and concomitant medications are not pennitted during the 
study (please see also Section 7.3): 
• 
Procedures in the face that may violate in- and exclusion criteria. For details, please 
refer to in- and exclusion criteria. 
• 
Any other investigational drng. 
• 
Aminoglycoside antibiotics, or other agents that might interfere with neuromuscular 
function (e.g., D-penicillinamine, curarine-type muscle relaxants, succinylcholine) or 
might interfere with the action of BoNT (e.g., chloroquine) within 14 days prior to 
injection and during the entire course of the study. 
• 
Other agents that might interfere with neuromuscular function, i.e. drngs listed in 
World Health Organization (WHO) Anatomical Therapeutic Chemicalclassification 
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(ATC class M03 Agents that might induce the production of antibodies against 
acetylcholine receptors (e.g., D-penicillamine) (please see Section 16.3). 
 
• BoNT treatment of any serotype at any body region. 
The following concomitant non-drug therapies are not permitted during the study (please 
see also Section 7.3): 
 
• Treatment with any cosmetic procedure in the face (e.g., dermal filling, chemical 
peeling, photo rejuvenation, mesotherapy, photodynamic therapy, laser treatment). 
 
• Any surgery in the face. 
Therapy changes (including changes of regimen) during the study are to be documented 
in the source documentation and in the eCRF. 
 
8.4 
Restrictions during the study 
 
Not applicable. For restrictions regarding previous and concomitant therapies, see 
Section 8.3. 
 
 
 
 
 


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9 S TUDY ASSESSMENTS AND VISIT SCHEDULE 
9.1 
Assessments 
Assessments perfo1med by the subject should always be done independently from the 
investigator and study staff at the beginning of a study visit before any assessments 
peifonned by the investigator take place to guarantee inde endence of self-ratin s as 
described in more detail in the outcome manual . 
0 
facilitate consistent conditions for all subjects all make-up and evident jewehy has tobe 
removed from the face prior to any clinical assessments and self-assessments. The study 
staff will ensure the subject can perfo1m assessments independently at a place with 
adequate lighting and without disturbance at the beginning of the respective study visit. 
Furthennore, a minor will be provided so that subjects can control respectively for their 
-
GFL appearance. 
If on-site visits due to COVID-19 restrictions are not possible, efficacy live assessments 
by the investigator cannot be perfo1med and will inevitably lead to missing data. 
Subjects who provide their consent for self-assessment of efficacy at home will be re-
instrncted on how to perfonn their self-assessments during the safety call. Subjects will be 
reminded to wear no make-up and evident jewehy during self-assessment. Moreover, 
subjects will be requested to perfo1m their self-assessment at a lace with adequate lighting 
and without disturbance and to use a minor to assess their 
GFL a earance . 
• 
ub · ects will be asked to fill in, sign and date the questionnaire 
at the time of the planned study visit dates, if possible during/sho1tly after the 
respective saf~uments sent to the subjects (FWS PhotoGuide, completed 
questionnaire-) will be retumed to the investigational site at next possible 
on-site visit. 
Tue eCRF should be updated by the site staff to collect reasons for missing data: For each 
planned study visit that was not perfo1med at the study site, the site staff should document 
whether it was perfo1med as viitual visit due to COVID-19 pandemic, not perfo1med due 
to COVID-19 pandemic or not perfonned (due to other reasons). Also, it should be 
documented if a subject is discontinued from the study due to COVID-19 pandemic. 
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9.1. 1 
Clinical assessments 
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At the Screening Visit VI (Day -3 to -14), the subject's demographic data, relevant medical 
histo1y , concomitant diseases, and all concomitant therapies (medications and non-dmg 
treatments) planned during the study will be recorded. All prior medication(s) used by the 
subject during the last 30 days prior to the Screening Visit VI (Day -3 to -14) must be 
documented. Previous treatments with BoNT treatment of an 
e and for an bod 
in the glabellar area must be recorded regardless of time of application 
. A review of this info1mation will allow the investigator to assess whether 
t e su ~ect s ould be enrolled. Other data will be collected as required, including 
info1mation obtained from physical examinations, vital signs, and body weight and height 
measurement (see below). If counseling of subjects is deemed necessaiy, either before 
enrollment or during the study, counseling will be made available by the investigator 
involving other medical specialists, if necessa1y. 
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9. 1.1. 1 
Facial Wrinkle Scale (FWS) 
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The FWS is a widely used 4-point standardized assessment scale for the assessment of the 
severity of GFL, which has been used in several studies investigating facial wrinkle 
treatment [ Ascher 2004, Canuthers 2004a, Rzany 2006] including respective GFL studies 
with NT 201 [Canuthers 2013, Hanke 2013]. Analogue investigator (investigator's FWS) 
and subject (subject's FWS) versions will be used (see Section 16.4). 
9.1.1.1 .1 
lnvestigator's Facial Wrinkle Scale (FWS) 
A photo guide comprising sample photos of each of the four grades will suppo1i the rating 
by FWS together with descriptors for the four severity grades. Tue investigator must use 
the FWS photo guide together with the respective severity grade descriptors for each 
assessment. 
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Investigators must pass the prior training qualification for use of the FWS before their first 
study rating. 
 
Ratings at Baseline Visit V2 (Day 1), Day 30±7 (V4), Day 120±7 (V7), Day 180±7 (V9) 
and the End of MP in an individual subject should be performed by the same investigator. 
For the sake of consistency all efforts should be taken that all FWS assessments in an 
individual subject will be performed by the same investigator. 
 
9.1.1.1.2 
Subject’s Facial Wrinkle Scale (FWS) 
 
The subject will self-assess GFL 
at maximum frown according to the subject’s 
FWS together with the photo guide as reference. The descriptors for each scale grade will 
be provided together with instructions on how to perform the assessments on a separate 
subject rating sheet. The site staff will be trained during the investigator meeting or the site 
initiation visit on how to instruct the subject on the self-assessment. 
 
 
 
 
 
 
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9.1.1.5 Physical Examination 
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The investigator will perfonn physical examinations for subjects at the Screening Visit Vl 
(Day -3 to -14) and the End ofMP. The physical examination will cover standard physical 
examinations. Any abnonnal findings will be documented in the subject's medical file. The 
investigator will confnm the conduct of these investigations in the eCRF. 
9.1.1.6 Vital Signs 
Vital signs (i.e., blood pressme and heart rate) will be assessed at each visit :from the 
Screening Visit Vl (Day -3 to -14) to Day 180 (V9), and at End ofMP. Vital signs will be 
recorded in sitting or lying position after the subject has rested for at least 5 minutes. 
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9. 1. 1. 7 Body height and weight 
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Body height will be assessed at the Screening Visit Vl (Day -3 to -14) and weight will be 
assessed at the Screening Visit Vl (Day -3 to -14) and End ofMP. 
9.1.2 
Laboratory evaluations 
9. 1.2.1 
Clinical and research /aboratory eva/uations 
Blood samples for evaluation of clinical biochemistiy and hematology (approx. 9 mL) plus 
sennn pregnancy test (1 mL), if applicable, will be collected at the Screening Visit Vl (Day 
-3 to -14) and the End ofMP. 
Pregnancy testing (to be done prior to enrollment, with results available prior to 
administi·ation ofIP[ s]) will be perfo1med in female subjects with childbearing potential in 
sernm at the Screening Visit Vl (Day-3 to -14) and the End of MP. A mine pregnancy test 
will be peifo1med at the Baseline Visit V2 (Day 1) prior to injection and prior to optional 
follow-up u-eatment, if applicable. 
The samples for hematology and clinical biochemistiy, including sernm pregnancy test (if 
applicable), will be analyzed at the central labornto1y . Details with regard to the methods 
of sampling will be described in the respective laborato1y manual. 
If laborato1y evaluations are missing or are unreliable (e.g. due to failed analysis) a re-test 
of these parameters has to be perfonned in the centi·al laborato1y. Reliable laborato1y 
results for all required parameters have tobe available prior to the subjects' Baseline Visit 
V2 (Day 1). Tue results of the re-test will be entered in the study database. 
An additional safety laborato1y assessment can be perfo1med in the course of an AE if 
deemed necessaiy by the investigator and can be evaluated either in a local or the centi·al 
laborato1y. Results of these additional assessments will not be entered in the study database 
but can be added to the safety database optionally if values are paii of safety repo1iing. 
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9.1.3 
Pharmacodynamics 
 
Not applicable 
 
9.1.4 
Pharmacokinetics 
 
Not applicable. 
 
9.1.5 
Pharmacogenetics 
 
Not applicable. 


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9.1.6 
blood volume 
 
Blood samples will be taken for general safety testing (clinical biochemistry and 
hematology) and also for serum pregnancy testing. 
 
 
 
 
The blood amount corresponds to routine laboratory practice. 
 
Additional blood sampling may be necessary in case of missing values e.g. due to failed 
analysis. 
 
9.1.7 
Specimen preparation, handling, storage, and shipping 
 
Blood samples for clinical chemistry, hematology, and β-HCG will be determined by a 
central laboratory and will be handled according to the manual of the central laboratory. 
 
9.2 
Visit schedule 
 
Study procedures will be 
identical in stage 1 and stage 2 (if applicable). 
 
The purpose of the Screening Visit V1 (Day -3 to -14) is to determine subject eligibility 
for study participation. The screening evaluation must be completed between Day -14    to 
-3 prior to Baseline. Subjects who fail screening are allowed to be re-screened one time. 
Subjects who are re-screened will be assigned a new screening number. 
 
Baseline is defined as Day 1, which is the day of randomization and first administration 
of the IP. 
 
The clinical study protocol allows a window of ±7 days in scheduling of study visits for all 
post-baseline visits, except V3, where only a ±1 day window is allowed. The IP(s) should 
be injected at the study site by the investigator trained and experienced in aesthetic BoNT 
treatment. Following administration of IP(s), subjects will be observed 
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for a minimum of 30 minutes at the site and will be asked by the investigator if any AEs 
have occuned since the administration of study treatment. 
for all subjects who relapsed to baseline based on the investigator's assessment on the FWS 
at maximum frown. 
If planned on-site visits cannot be perfo1med due to COVID-19 situation, safety data will 
be collected via phone calls and the subjects will do their self-assessments at home if they 
previously consented to this procedure. 
fu addition, on-site visits should be perfonned at the earliest possible date that the subject 
is able to safely come to the site again. Any missing visit data and the reason should be 
documented as instrncted in Section 9 .1. 
Additionally, subjects (in stage 1 and stage 2) who have relapsed to baseline status in the 
MP will have the option to receive a follow-up treatment with the market approved dose of 
20 U NT 201 for their GFL between Day 180 and Day 
360. An OLEX Follow-up Visit V16 will be perfo1med for all subjects who receive the 
optional follow-up ti·eatment. 
Unscheduled visits may be required in the case of AEs or premature discontinuation of the 
study. fu this case, a final assessment will be perfo1med as soon as possible. If additional 
safety follow-up is necessaiy after this assessment, subjects may be contacted by telephone 
or assessed in the clinic, depending on the nature of the follow-up required. 
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10 SAFETY ASSESS MENTS 
 
10.1 
Definition of an adverse event 
 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product. An AE does not necessarily have a causal relationship with the treatment. Thus, 
an AE can be any unfavorable and unintended sign, symptom, or disease (including 
intercurrent illness); deterioration of a pre-existing illness; accident; any suspected drug 
reaction; or a clinically relevant change of laboratory values whether or not considered 
related to the IP(s) or study procedure. 
 
Changes in efficacy variables (e.g., subject-reported outcome variables [questionnaires and 
scales] during the course of the study) need not be documented as AEs, because these 
changes will be recorded as efficacy variables. Elective treatments planned before 
screening and which are documented in the subject’s source data are usually not regarded 
as AEs. 
 
The period of observation for an AE extends from the time when the informed consent 
form was signed until the End of MP if no optional treatment was received or the OLEX 
Follow-up Visit V16 if optional treatment was received (see Section 6.1). Any medical 
occurrence during the observation period is an AE and has to be documented in the 
subject’s file. For screening failures AEs are not to be documented in the eCRF. For 
randomized subjects that experienced AEs during the screening period these have to be 
entered into the eCRF. Non-serious AEs will not be followed up after the End of MP or the 
OLEX Follow-up Visit V16 if optional treatment was received. 
 
Pre-existing conditions noted in the medical history should not be reported as an AE, unless 
the condition worsens or the disease reoccurs during the observation period. To determine 
whether a condition has worsened, it is compared to the condition of the subject at 
screening. Abnormal laboratory values obtained during the subject’s screening period will 
only meet AE criteria if newly detected and if considered clinically significant. However, 
if laboratory values resulting from pre-existing conditions worsen to clinical relevance 
during the course of the study AE criteria are met. 
 
Data pertaining to AEs will be collected during each study visit on the basis of the subject’s 
spontaneous report, through investigator inquiry, or discovered in the course of 
examinations performed during the visit. 
 
If on-site visits are not possible due to COVID-19 pandemic and the subject provides 
his/her consent to safety assessments on the phone, safety assessments (AEs, change in 
medication and non-drug treatment, and occurrence of pregnancy) will be performed via 
phone calls and the results documented in the source data first and in the eCRF 
subsequently (see also Section 11.2). 
  


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For all adverse events that are collected during telephone visits, it is up to the medical 
judgement of the investigator to refer a subject to a specialist if deemed necessary, thus 
ensuring the safety of the subject and the accuracy of the data. 
 
The investigator will assess and record any AE in detail in the source documentation and 
on the eCRF AE report form. The following information must be recorded: 
 
• AE diagnosis or main symptom. 
•  
• Date of onset. 
 
• Date of worsening. 
• Intensity (maximum observed; see Section 10.1.1). 
• Causal relationship (not related, related). 
• Serious (yes or no). 
• Outcome (see Section 10.1.3). 
• AE leading to discontinuation of the study (yes or no). 
• Stop date. 
After completion of all scheduled visit assessments the investigator must document any 
AEs arising from these assessments. 
 
In case of an SAE, or AE of special interest 
the 
investigator must also complete an SAE report form or AE of special interest report form 
and report it to the CRO immediately, as described in Section 10.2. 
 
Treatment of overdose with IP(s) is described in Section 8.2.6. 
 
10.1.1 
Definition of intensity 
 
The clinical intensity of an AE will be classified on the basis of its associated signs and 
symptoms, as follows: 
 
Mild: 
Signs and symptoms that can be easily tolerated. Symptoms can be 
ignored and disappear when the subject is distracted. 
 
Moderate: Signs and symptoms that cause discomfort and interfere with normal 
functioning, but are tolerable. They cannot be ignored and do not disappear 
when the subject is distracted. 
 


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Severe: 
Signs and symptoms that affect usual daily activity and incapacitate the 
subject, thereby interrupting his/her daily activities. 
 
The definitions above are difficult to apply for some data (e.g., clinically relevant 
laboratory values that are documented and evaluated on the eCRF AE report form). In such 
situations, the investigator should make a judgment based on clinical experience. 
 
10.1.2 
Definition of causal relationship with investigational product(s) 
 
An AE is considered to be ‘related’ to IP(s) if a causal relationship between the IP(s) and 
an AE is at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
 
The expression ‘reasonable causal relationship’ is meant to imply that there are facts 
(evidence) or arguments to suggest a causal relationship (ICH E2A guideline). Otherwise, 
the AE should be considered as ‘not related.’ 
 
10.1.3 
Categories of outcome 
 
The reportable outcomes and/or sequelae of an AE are as follows: 
 
• Recovered/resolved. 
• Recovering/resolving. 
• Not recovered/not resolved. 
• Recovered/resolved with sequelae. 
• Fatal. 
• Unknown. 
If there is more than one AE, only the AE leading to death will be recorded as having a 
‘fatal’ outcome. 
 
10.2 Definition of a serious adverse event 
 
An SAE is any untoward medical occurrence, at any dose, that: 
 
• Results in death. 
• Is life-threatening.8 
• Requires inpatient hospitalization, or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 


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• Is a congenital anomaly/birth defect. 
 
8 The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have caused death if 
it were more severe. 
 
• Consists of any other medically important condition.9 
In case of death, an autopsy report should be submitted (if available). The date and cause 
of death should be recorded. 
 
Hospitalizations for elective treatments planned before screening and which are 
documented in the subject’s source data are usually not regarded as SAEs. 
 
All SAEs that occur during the study period whether considered to be related to IP(s) or 
not, must be reported by telefax or e-mail within 24 hours of knowledge of the event. SAE 
report forms are provided in the investigator’s site file. 
 
Although all information required for completion of an SAE report form may not be 
available within the specified time period, an initial report should be submitted if the 
following minimum information is available: 
 
• An identifiable subject (number). 
• A suspect product. 
• An identifiable reporting source (investigator/study site identification). 
• An event or outcome that can be identified as serious. 
 
 
 
 
 
 
9 According to ICH E2A, CPMP/ICH/377/95: ‘Medical and scientific judgment should be exercised in 




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AESIs should be documented on the general pages of the AE CRF as well as in the subject’s 
file. 
 
The AE form in the eCRF as well as the pages for medical history / concomitant diseases 
and for previous / concomitant medication and non-drug treatment are to be faxed/sent 
along with the AESI reporting form. 
 
 


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10.4 Expected adverse events 
 
Expected AEs are those listed in the reference safety information of the current IB [Merz 
Pharmaceuticals GmbH 2018]. 
 
10.5 Unexpected adverse events 
 
An unexpected AE is an AE not previously reported in nature, severity, or incidence in the 
reference safety information of the current IB [Merz Pharmaceuticals GmbH 2018]. 
 
10.6 Pregnancy 
 
Each pregnancy that starts during the study must be reported by the investigator to the CRO 
within 24 hours of learning of its occurrence. Pregnancies and pregnancy follow-up should 
be reported on a pregnancy monitoring form. Pregnancy follow-up should describe the 
outcome of the pregnancy, including any voluntary or spontaneous discontinuation; details 
of the birth; the presence or absence of any congenital abnormalities, birth defects, maternal 
or newborn complications, and their relation to the IP(s). Each normal pregnancy is to be 
reported as a non-serious AE (drug exposure  before or during pregnancy). Any abnormal 
pregnancy or pregnancy outcome is to be reported as SAE (on an SAE -form). 
 
In case a pregnancy occurs prior to injection, the subject must not receive any injection 
treatment and the End of MP will be conducted right away without any invasive procedures 
(such as blood drawing) performed. 
 
If a pregnancy occurs after a subject has received injection, the subject can continue with 
applicable study visits until the end of the study but without any invasive procedure (e.g. 
injections, blood drawing). However, the subject is free to discontinue the study at any 
time. 


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11 DATA QUALITY ASSURANCE 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any time, 
even after the end of study. The investigator is to notify the sponsor immediately of any 
such inspection. The investigator and institution will permit study-related monitoring, 
audits, reviews by the IEC/IRB and/or regulatory authorities, and will allow direct access 
to source data and source documents for such monitoring, audits, and reviews. 
 
11.1 Standardization procedures 
 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, central laboratories, centralized 
evaluations, and validation methods). 
 
This study will be monitored regularly by qualified monitors from the CRO according to 
ICH-GCP and the respective Standard operating procedures (SOPs) (see Section 11.4). 
 
11.2 Source documentation requirements 
All data collected from a subject during the course of this clinical study should be retained 
in the respective source documentation (e.g. subject file). This includes a copy of the letter 
sent to the subject’s primary physician about the subject’s participation in the study 
(provided the subject has a primary physician and has agreed to the general practitioner 
being informed). The source documentation must also contain a descriptive statement on 
the informed consent procedure (see Section 3.3.2). The investigator must also confirm by 
written statement in the source documentation that all inclusion criteria and all exclusion 
criteria were checked prior to randomization of the subject. In addition to this statement, 
the subject’s meeting or non-meeting of the in- and exclusion criteria and eligibility criteria 
have to be traceable on the basis of the documentation in the subjects file. The childbearing 
potential of female subjects must be noted in the source documentation. The site will keep 
a source data location list which will outline for the different data categories including 
electronic data (e.g. demographics, medical history, and AEs etc.) which document serves 
as source for these data (e.g. subject file, laboratory report). Scales assessed by 
investigators and subjects on paper forms 
will be considered 
as source data and will be transferred into the eCRF by the site. 
 
If a study site is using an electronic system for documenting source data, a member of the 
site staff must print out the source data after each visit. The paper print-outs  must overlap, 
if possible (i.e., must contain at least the last row of data from the subject’s previous visit). 
If it is not possible to obtain overlapping paper print-outs, the completeness of source data 
must be ensured by other suitable means. The print-out must be signed and dated by a 
member of the site staff who can confirm the accuracy and 


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completeness of data in the paper print-out. The monitor will also sign and date after 
verifying the source data. The paper print-out should be stored in the investigators site file. 
If source data information is entered retrospectively, this must be done directly on the paper 
print-out and should be initialed and dated. The same applies to any corrections of initial 
data. 
 
If the site is using a validated computer system including audit trail with a separate access 
for the monitor (i.e., the monitor can only access the data of the study subjects), then no 
such paper print-outs are required. 
 
To assure subject’s safety, sites that are temporarily closed for subject on-site visits or have 
subjects under a Stay-at-Home-Order or subjects who choose not to come to the site due to 
the pandemic will monitor subject’s safety via phone calls at planned visit dates. 
  
During the next on-site visit, subject’s consent to the phone visit and / or the self-
assessment must be confirmed by the investigator and the subject in a signed supplemental 
ICF according to the procedures described above, including the requirements for 
traceability.  
 
If safety assessments were performed via phone, it must be documented in the eCRF that 
the visit was virtually conducted by phone due to COVID-19 pandemic. If a planned visit 
cannot be performed at all, it must be documented in the eCRF whether this was due to 
COVID-19 pandemic or due to other reasons.  
 
Every effort should be made to contact subjects via phone or letter. At least 3 documented 
attempts to contact the subject should be made. All the attempts are to be documented in 
the subject’s source documentation. 
 
11.3 Data management 
 
Data required according to this protocol is to be recorded in the web-based eCRFs 
(electronic data capture system)
. All 
users who will enter data into the eCRF will be previously trained. After the successful 
completion of the training all participants will receive a training certificate, which will be 
a prerequisite for the access to the eCRF. The access to the eCRF is password-controlled 
and conforms with CFR part 11. 
 
Plausibility checks will be performed according to a data validation plan. Inconsistencies 
in the data will be queried to the investigators via the electronic data capture system; 
answers to queries or changes to the data will also be documented in this system directly 
by an authorized member of the investigator’s site staff. The audit trail in the electronic 
data capture system documents all changes. Edit checks will generate automatic queries 
during data entry when a field is not populated according to specifications defined in the 
data validation plan.  
 


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Manual queries (to be answered by site staff) can be raised during source data verification, 
medical or safety review and data management review. 
 
AEs, medical history/concomitant diseases and non-drug treatment will be coded according 
to the MedDRA version in effect at the time the database is closed. 
 
Laboratory data will be received electronically and merged with the eCRF data (but not 
uploaded into the EDC system). Plausibility checks will be performed to ensure correctness 
and completeness of these data. The data management / biostatistics vendor 
 
will be responsible for data-processing. 
 
After all necessary data for DEM (when all enrolled subjects for stage 1 have had their Day 
30±7 Follow-up Observational Visit V4) have been entered, a database snapshot will be 
taken. 
 
For the final analysis, after all data are entered and all queries are solved, the database will 
be closed. After database close, unblinding will take place. In case of any changes to the 
data after database close, these changes will be documented according to respective SOP. 


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An analogous procedure will be applied prior to the interim analysis after 180 days (V9) 
of stage 1. Once the data is cleaned, a database snapshot is saved. 
 
11.4 Monitoring 
 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP guidelines and the respective SOPs. During these visits, the monitor will prepare the 
study site for the conduct of the study, check for subject eligibility, for the integrity of the 
source data with the eCRF entries, for compliance with the clinical study protocol, ICH- 
GCP principles, the Declaration of Helsinki, and regulatory authority requirements. 
Monitoring will also be aimed at detecting any misconduct or fraud. 
 
In addition, the monitor will check whether all AEs and SAEs have been reported 
appropriately within the time periods required. 
 
The investigator and all staff will be expected to cooperate with the monitor by providing 
any missing information whenever possible. The investigator must be available to answer 
questions arising during regular monitoring visits. In addition, the investigator is required 
to: 
 
• Have all data properly recorded in the source documentation and the eCRF prior to 
each monitoring visit. 
 
• Have the source documentation available at the monitoring visits. 
• Record all IP(s) dispensed in the eCRF and the drug inventory records. 
Regular monitoring tasks will be performed by a blinded monitor. Compliance with the 
IWRS randomization and inventory/drug accountability will be monitored by an unblinded 
monitor. 
 
All subjects who are screened, but not included in the study, will be listed on the subject 
screening/enrollment log. 
 
Monitoring will be systematic, prioritized, and risk-based. Further details of monitoring 
activities will be provided in the monitoring manual, which describes the procedures to 
identify, evaluate, control, and report risks to critical processes and data on an ongoing 
basis throughout all stages of the trial’s life-cycle. 
 
Off-site and centralized monitoring are already conducted during the study as described in 
the monitoring manual and will be continued to be performed while on-site monitoring 
visits are not possible due to COVID-19 restrictions. If no on-site source data verification 
[SDV] is possible due to COVID-19 restrictions, a “data confirmation call” will be 
arranged with the site and documented. During this call, site personnel will be  
 
 


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asked to read aloud selected data from the source data to the study monitor; the study 
monitor will compare these data with the eCRF entries. During the next on-site visit, the 
CRA will verify the data fields confirmed via phone when reviewing the source data in 
person to complete the SDV process on-site and will tick the respective SDV-data fields in 
the eCRF at that time. Details of “data confirmation call” will be provided in the monitoring 
manual.  
 
During COVID-19 pandemic the monitors are in close contact with site staff to monitor 
the local situation and well-being of study subjects and staff. On-site monitoring visits will 
be done as soon as possible. 


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11.5 Auditing 
 
Audits will be performed according to the corresponding audit program, which will include 
the possibility that a member of the sponsor’s quality assurance function may arrange to 
visit the investigator in order to audit the performance of the study at the study site, and all 
study documents originating there. Auditors will conduct their work independently of the 
clinical study and its performance. 
 
Audits may also be performed by contract auditors. In this case, the sponsor’s quality 
assurance function will agree with the contract auditor regarding the timing and extent of 
the audit(s). For audits at the study site, the monitor will usually accompany the auditor(s). 


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12 STATIS TICAL METHODS 
This section describes the statistical analyses intended at the time of study planning. 
Further details on the statistical and analytical aspects will be presented in the SAP. 
 
Any deviations from planned analyses, the reason(s) for such deviation(s), and all 
alternative or additional statistical analyses that may be performed before database close 
or unblinding, respectively, will be described in amendments to the clinical study protocol 
or the SAP. All deviations and/or alterations will be summarized in the clinical study report. 
 
12.1 Determination of sample size 
 
 
 
In total, 60 subjects in the high dose groups are deemed required for the objectives of the 
study. For the low dose group, 30 subjects suffice in case the study stops after stage 1 as 
the side effects and efficacy of a dose of 20 U are well characterized in previous studies. 
 
12.2 Analysis sets 
 
Safety evaluation set 
 
The SES is the subset of all subjects who were exposed to study medication. 
 
Full analysis set 
 
The FAS is the subset of subjects in the SES for whom any efficacy variable is available 
(i.e., all subjects who have a baseline and at least one post-baseline value of any efficacy 
variable). 


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12.3 Variables for analysis 
 
12.3.1 
Efficacy variables 
 
12.3.1.1 
Primary efficacy variable 
 
Duration of effect as defined by time between treatment and relapse to baseline status. 
Effect is defined as improvement at maximum frown as assessed by the investigator on the 
FWS. 
 
If no improvement is observed on the FWS at any point after treatment, the time will be 
set to 0. 
 
12.3.1.2 
Secondary efficacy variables 
 
• 
Duration of effect whereby effect is defined by a score of none (0) or mild (1) 
at maximum frown as assessed by the investigator according to FWS 
 
This variable is defined as the time between treatment and the first point in time 
when the score is moderate (2) or severe (3) again. If no improvement is 
observed on the FWS at any point after treatment, the time will be set to 0 
 
• 
Duration of effect whereby effect is defined by 2-point improvement from 
baseline at maximum frown as assessed by the investigator according to FWS 
 
This variable is defined as the time between treatment and the first point in time 
when the improvement is less than 2 points again. If no improvement is 
observed on the FWS at any point after treatment, the time will be set to 0 
 
• 
Percentage of subjects rated as none (0) or mild (1) at maximum frown by 
investigator’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as none (0) or mild (1) at maximum frown by 
subject’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as at least 1-point improvement compared to 
baseline at maximum frown by investigator’s rating on FWS at Day 180 (V9) 
 
• 
Percentage of subjects rated as at least 1-point improvement compared to 
baseline at maximum frown by subject’s rating on FWS Subject at Day 180 
(V9) 


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12.3.2 
Pharmacodynamic variables 
 
Not applicable. 
 
12.3.3 
Pharmacokinetic variables 
 
Not applicable. 
 
12.3.4 
Pharmacogenetic variables 
 
Not applicable. 


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12.3.5 
Safety variables 
 
12.3.5.1 
Primary safety variables 
Occurrences of TEAEs, TESAEs, TEAESIs, related TEAEs and related TESAEs by dose 
group for the entire study period. 
 
An AE is considered treatment-emergent with onset or worsening on or after date of the 
first administration of IP. 
 
12.3.5.2 
Secondary safety variables 
 
Not applicable. 
 
 
12.4 Statistical analysis methods 
 
Analyses will be performed after all subjects of stage 1 have had their Day 180 assessments 
(interim analysis) and after all subjects of stage 1 and stage 2 (if applicable) have had their 
last visit (End of MP or OLEX Follow-Up Visit V16, as applicable). If not otherwise 
specified the data from stage 1 and stage 2 in the 20 U groups will be pooled in case stage 
2 is started. Otherwise, the dose groups will be presented as randomized for stage 1 only. 
 


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To get early insights, into duration of effect of NT 201 based on the primary efficacy 
parameter and the occurrence of treatment emergent adverse events (TEAEs) over the 
entire Main Period of 360 days, it is planned to perform an interim analysis of complete 
MP data from Stage 1, where doses up to 75 U were administered. 
 
12.4.1 
Efficacy variables 
 
The efficacy analyses will be based on the FAS (see Section 12.2). 
 
Statistical tests will be two-sided hypothesis tests for between-treatment differences in 
general. Continuous variables (values and changes from baseline) will be summarized by 
N, mean, standard deviation, median, quartiles, minimum, and maximum. For qualitative 
variables, absolute and percent frequencies (N, %) and, if applicable, shift tables will be 
displayed. Confidence limits 
will be given, where appropriate. 
 
12.4.1.1 
Primary efficacy variable 
 
The primary endpoint is the duration of effect defined in Section 12.3.1.1. This will be 
described by Kaplan-Meier Curves per group and the respective medians of times. 
 
pairwise log-rank tests will 
be applied to compare differences between high dose groups and the 20 U group to explore 
statistical significance. The 20 U group data will be pooled from stage 1 and 2, if applicable. 
 
For the primary endpoint a Cox proportional hazards regression will be applied with 
covariates dose group (20, 50, 75, 100 U), center, and baseline FWS score at maximum 
frown as assessed by the investigator. Here, the pooled 20 U group will be used as reference 
group. To explore potential stage effects, a sensitivity analysis will use dose groups 20 
(stage 1), 20 (stage 2), 50, 75 and 100 U with 20 (stage 1) as reference group. Depending 
on the outcome further exploration might be needed 
 
 
12.4.1.2 
Secondary efficacy variables 
 
The secondary duration of effect variables will be analyzed in analogy to the primary 
variable. However, the Cox proportional hazards regression analysis will be limited to 
pooling the 20 U groups of both stages. 
 
For the percentages of subjects fulfilling the criteria as described in the secondary efficacy 
variables two-sided 95% Pearson-Clopper confidence intervals will be computed for 
responder rates in each dose group. 
 
 
 
 


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12.4.2 
Pharmacodynamic variables 
 
Not applicable. 
 
12.4.3 
Pharmacokinetic variables 
 
Not applicable. 
 
12.4.4 
Pharmacogenetic variables 
 
Not applicable. 
 
12.4.5 
Safety variables 
 
All safety analyses will be conducted on the SES. Continuous safety variables will be 
analyzed using summary statistics. Categorical variables will be analyzed using absolute 
and relative frequencies. 
 
No inferential statistical methods will be applied. 
 
12.4.5.1 
Primary safety variable 
 
Incidences (absolute and percentage) of TEAEs, TEAESIs, TESAEs, and related TEAEs 
will be calculated on the level of SOC and PT. 
 
In addition, incidences for TEAE will also be presented by worst intensity and by worst 
causal relationship. 
 
 
 
 
All incidences will be presented by dose group and overall. 


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Related TESAEs, deaths and TEAEs leading to premature discontinuation will be listed 
only. 
 
For details on the safety evaluation for the DEM, see Section 12.4.7.2.1. 
 
For details on the safety analyses for the interim analysis (after Day 180 of stage 1), see 
Section 12.4.7.2.2. 
 
12.4.5.2 
Secondary safety variables 
 
Not applicable. 
 
 
 
 
 
 
 
12.4.7 
Special statistical/analytical issues 
 
12.4.7.1 
Discontinuations and missing data 
 
With relevance to efficacy objectives treatment will be applied only once and hence cannot 
be discontinued. Therefore, no premature discontinuation from treatment can occur. 
Missing values likewise occur at random or because the subject completes the study early 
due to relapse to baseline. The latter will not impact the primary analysis of duration of 
effect since this was completely captured. Hence, for any Kaplan-Meier analysis and 
inferential statistics intermittent missing data will be ignored and monotone missingness 
be considered as censored. 


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Due to the COVID-19 pandemic, a considerable amount of missing data is expected for 
subjects from Stage 2. Restrictions related to COVID-19 in both the US and in Germany 
(temporarily closed sites, stay-at-home orders, quarantines imposed to subjects suspected 
to be infected) may make it impossible for many subjects to attend all planned on-site visits. 
Since live assessments by investigators cannot be performed remotely, this will inevitably 
lead to missing data. 
Handling of missing data due to the COVID-19 pandemic in the final statistical analysis 
will depend on the number and pattern of missing values, which will be thoroughly 
described in the clinical study report. Decisions on any additional analyses to account for 
missingness due to COVID-19 will be made at the latest during the BDRM for the final 
analysis and described in an amendment to the SAP, which will be finalized prior to 
database close for the final analysis (see also section 12.4.7.6). 
 
12.4.7.2 
Interim analyses 
 
12.4.7.2.1 
Dose Escalation Meeting 
 
A blinded evaluation of safety data will be performed in a DEM when all enrolled subjects 
for stage 1 have had their Day 30±7 Follow-up Observational Visit V4. Based on the stage 
1 data, a decision to proceed with stage 2 of the study with a dose group of   100 U NT 201 
will be made. The evaluation includes blinded safety data of stage 1 subjects of the 20 U, 
50 U, and 75 U NT 201 dose group up to Follow-up Observational Visit V4, Day 30±7. 
 


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For more details, see Section 12.4.7.3. 
 
For this DEM the following data will be presented overall for the pooled blinded data: 
 
• 
Subject disposition and demographic data 
 
• 
Listings of medical history, concomitant diseases, previous and concomitant 
treatments 
 
• 
Incidences of TEAEs, TEAESIs, TESAEs, and related TEAEs by SOC and 
PT 
 
• 
Listings of TEAE, TEAESIs, TESAEs, Deaths and AEs leading to premature 
discontinuation 
 
12.4.7.2.2 
Interim analysis after Day 180 of stage 1 
 
An interim analysis of complete 180-day data (V9) of stage 1 will be performed. This 
interim analysis will serve to get early insights regarding the benefit-risk assessment and 
duration of effect of the dose groups investigated in the stage 1. However, it is not the aim 
of this analysis to decide on premature termination of the study. 
 
Data will be unblinded for sponsor staff and vendor data management and biostatistics staff 
only as required for the sake of the interim analysis. 
 
For data of Stage 1 until Day 180, the blind will not be broken until a BDRM focusing on 
the interim analysis has convened, the first version of the SAP has been finalized, and a 
database snapshot has been saved. After the blind is broken, the statistical analysis of Stage 
1 Day 180 results will proceed. 
 
The study will be continued and investigators, subjects, site staff and monitors (except the 
unblinded monitor responsible for IWRS compliance) will be kept blinded with regard to 
stage 1 subject’s assignment to treatment groups. Stage 2 subjects, if applicable, will not 
be included in the 180-day interim analysis. The blind for subjects in stage 2 will be 
maintained. Moreover, the blindness of investigators and subjects, site staff and blinded 
monitor will be maintained throughout for both stages until final unblinding. 
 
For the remaining data, the blind will not be broken until the final BDRM has convened, 
the final version of the SAP has been finalized, and the database has been closed. After the 
blind is broken, the overall statistical analysis of results will proceed. The SAP might be 
amended to stage 2 specific aspects before unblinding of stage 2. 
 
As the blind of the subjects of Stage 2 will be maintained and procedures for Stage 2 will 
be very advanced when results are disseminated there is no impact on validity of stage 2 
data and the credibility of study results. 
 
 






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12.4.7.4 
Multiple comparisons/multiplicity 
 
 
no multiplicity adjustment is foreseen. 
 
12.4.7.5 
Examination of subgroups 
 
Subgroup analyses will be specified in the SAP. 
 
12.4.7.6 
Additional analyses due to outbreak of COVID-19 pandemic  
Due to the COVID-19 pandemic, a considerable amount of missing data is expected for 
subjects from Stage 2 (see also section 12.4.7.1). This especially applies to efficacy variables 
that are based on live assessments by investigators, which cannot be performed remotely. 
The primary as well as several secondary
efficacy parameters will be affected. It 
should be noted that under specific circumstances, subsequently missing live ratings on the 
FWS by the investigator are likely to introduce bias to the assessment of the primary and 
secondaryduration of effect variables. If relapse to baseline status is first assessed only after 
several intermittently missing follow-up visits due to canceled on-site visits, the time to 
relapse will be overestimated. 
 
Data from Main Period of Stage 1 are in contrast not affected by this or any other kind of 
bias caused by COVID-19 pandemic because Stage 1 subjects did not miss any MP visits 
due to COVID-19 outbreak. Therefore, conduct of separate analyses of data from Stage 1 
and Stage 2 subjects will likely be necessary in addition to pooled analyses as planned for 
the final analysis of the study; this decision will be taken at the latest during the BDRM for 
the final analysis (see below). However, for reasons outlined in the following, it appears 
reasonable to perform an interim analysis of Main Period data from Stage 1 as soon as MP 
data from all Stage 1 subjects are available and cleaned. 
 
 As described in the newly added section 12.4.7.2.3 above, the additional interim analysis 
of complete MP data from Stage 1 will focus on the assessment of duration of effect of NT 
201 according to the primary efficacy parameter and on occurrence of treatment emergent 
adverse events (TEAEs), especially treatment-related TEAEs, over the 360 Day follow-up 


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period. Efficacy and safety data from Stage 1, where doses up to 75 U were applied, can 
give further insights into the efficacy and safety profile of NT 201. Depending on the future 
development of the COVID-19 pandemic and related restrictions in both countries this can 
be very valuable to decide whether resumption of on-site visits for Stage 2 subjects with 
intermittently missing on-site visits still appears meaningful and might outweigh the specific 
efforts and risks associated with travelling during the COVID-19 pandemic. Insights from 
the interim analysis at End of MP of Stage 1 might be valuable to decide whether affected 
Stage 2 subjects should be motivated to re-assume on-site visits after a certain time period 
with missing efficacy data according to investigator’s assessments. 
 
Any further additional statistical analyses planned to analyze the impact of missingness (see 
also section 12.4.7.1) and/or potential bias on data assessment due to COVID-19 pandemic 
(e.g. heterogeneity of Stage 1 and Stage 2 subjects due to COVID-19 related restrictions) 
will be decided upon at the latest during the BDRM for the final analysis. 
 
Depending on the amount of missing data and pattern of missingness, this might include 
separate analyses of Stage 2 subjects only. Any additionally planned analyses will be 
thoroughly described in an updated version of the statistical analysis plan, which will be 
finalized prior to database close for the final analysis.  
13 DATA HANDLING AND RECORDKEEPING 
By signing and dating the eCRF, the investigator will confirm that all investigations have 
been completed and conducted in compliance with this clinical study protocol, and that 
reliable and complete data have been entered into the eCRF. 
 
13.1 
Corrections to data 
 
All data required by this clinical study protocol are to be recorded in the eCRF as soon as 
possible. However, direct entries are not allowed; data must be transcribed from the source 
documentation (e.g., subject file, questionnaires and scales) to the eCRF. 
 
If corrections are necessary, an authorized member of the investigator’s site staff will enter 
the correct data into the web-based eCRF. The audit trail in the EDC system documents all 
changes. Edit checks issue automatic queries during data entry when a field is not populated 
to specifications defined in the data validation plan. Manual queries (to be answered by site 
staff) can be raised during source data verification, medical or safety review, and data 
management review. 
 
The data management / biostatistics vendor 
will 
be responsible for data processing. Final database close will occur only after quality 
assurance procedures have been completed. 
 


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13.2 
Record-keeping 
 
Upon closure of the study, the investigator must maintain all study-site records in a safe 
and secure location. The investigator is responsible for the integrity, retention, and security 
of all study-related records. The investigator must ensure that any reproductions of the 
original records are legible and provide a true and accurate copy of the original. Accurate, 
complete, and current records must be stored in such a way as to permit easy and timely 
retrieval for the sponsor or any applicable regulatory authorities. 
 
Essential documents should be retained until at least two years after the last approval of a 
marketing application (whether pending or contemplated) in an ICH region, or at least two 
years have elapsed since the formal discontinuation of IP clinical development. However, 
these documents are to be retained for a longer period, if required by applicable regulatory 
requirements or by agreement with the sponsor. 
 
Essential documents at the study site include (among other documents): 
 
• Source documentation (e.g. subject file, questionnaires and scales). 
 
• Subject identification code list (respective template provided to the investigator along 
with the Investigator’s site file, at the beginning of the study), which identifies the 
subject by number, name, and date of birth. 
 
• A signed copy of the final clinical study protocol and any amendment. 
• CDs/DVDs with PDF-files containing subjects’ eCRF data and audit trail (preferably 
provided to site during close-out visit), and any associated subject-related source data 
(or, where applicable, authorized copies of source data). 
 
• Signed informed consent forms. 
• Copies of site investigators’ and co-workers' curricula vitae. 
• Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies). 
 
• Copies of laboratory normal ranges and methods 
• Copies of study supply receipt forms and drug inventory forms. 
• Copies of all correspondence between the investigator and the monitor, and between 
the investigator and the sponsor. 
 
• Copies of safety information reported during the study and submitted by the sponsor. 
The investigator must notify the sponsor in the event of any changes to archival 
arrangements due to withdrawal of the investigator’s responsibility for keeping study 


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records to ensure that suitable arrangements for the retention of study records are made. 
 
13.3 
Destruction of study documents 
 
Study documents may not be destroyed by study site personnel before end of the retention 
period specified above without the prior written consent of the sponsor. The principal 
investigator must inform the sponsor in due time if the principal investigator leaves the 
institution during the retention period. This rule also applies if the institution closes within 
the retention period. 


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14 P UBLICATION POLICY 
The study results will be published in the public domain, and publishing details will be 
given in the clinical study agreement. Publications concerning study results must be 
approved in advance by the sponsor in writing. 
 
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 
 
The sponsor ensures that the study is registered and study results are disclosed in at least 
one public clinical study registry, in accordance with national/international regulations and 
other requirements. Study registration may include a list of the study sites, as applicable. 


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15 REFERENCES 
Alimohammadi M, Punga AR. Neurophysiological Measures of Efficacy and Safety for 
Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations. Toxins. 
2017;9(11). 
 
American Society of Plastic Surgeons. 2016 National Plastic Surgery Statistics. 2017. 
 
Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: 
Medical and public health management. JAMA. 2001;285(8):1059-70. 
 
Ascher B, Zakine B, Kestemont P, Baspeyras M, Bougara A, Santini J. A multicenter, 
randomized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of 
botulinum toxin A in the treatment of glabellar lines. J Am Acad Dermatol. 
2004;51(2):223-33. 
 
Brodsky MA, Swope DM, Grimes D. Diffusion of botulinum toxins. Tremor and other 
hyperkinetic movements. 2012;2. 
 
Carruthers A, Bogle M, Carruthers JD, et al. A randomized, evaluator-blinded, two- center 
study of the safety and effect of volume on the diffusion and efficacy of botulinum toxin 
type A in the treatment of lateral orbital rhytides. Dermatol Surg. 2007;33(5):567- 71. 
 
Carruthers A, Carruthers J. Prospective, double-blind, randomized, parallel-group, dose- 
ranging study of botulinum toxin type A in men with glabellar rhytids. Dermatol Surg. 
2005a;31(10):1297-303. 
 
Carruthers A, Carruthers J, Coleman WP, 3rd, et al. Multicenter, randomized, phase III 
study of a single dose of incobotulinumtoxinA, free from complexing proteins, in the 
treatment of glabellar frown lines. Dermatol Surg. 2013;39(4):551-8. 
 
Carruthers A, Carruthers J, Lowe NJ, et al. One-year, randomised, multicenter, two- period 
study of the safety and efficacy of repeated treatments with botulinum toxin type A in 
patients with glabellar lines. Journal of Drug Assessment. 2004a;7:1-20. 
 
Carruthers A, Carruthers J, Said S. Dose-ranging study of botulinum toxin type A in the 
treatment of glabellar rhytids in females. Dermatol Surg. 2005b;31(4):414-22; discussion 
22. 
 
Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. 
Journal of the American Academy of Dermatology. 1996;34(5 Pt 1):788-97. 
 
Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of 
botulinum toxin type A in facial aesthetics. Plast Reconstr Surg. 2004b;114(6):1S-22S. 


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Cather JC, Menter A. Update on botulinum toxin for facial aesthetics. Dermatol Clin. 
2002;20(4):749-61. 
 
Chertow DS, Tan ET, Maslanka SE, et al. Botulism in 4 adults following cosmetic 
injections with an unlicensed, highly concentrated botulinum preparation. JAMA. 
2006;296(20):2476-9. 
 
Food and Drug Administration. GUIDANCE FOR INDUSTRY - Patient-Reported 
Outcome Measures: Use in Medical Product Development to Support Labeling Claims. 
2009. 
 
Hanke CW, Narins RS, Brandt F, et al. A randomized, placebo-controlled, double-blind 
phase III trial investigating the efficacy and safety of incobotulinumtoxinA in the treatment 
of glabellar frown lines using a stringent composite endpoint. Dermatol Surg. 
2013;39(6):891-9. 
 
Hersant B, Abbou R, SidAhmed-Mezi M, Meningaud JP. Assessment Tools for Facial 
Rejuvenation Treatment: A Review. Aesthetic Plast Surg. 2016;40(4):556-65. 
 
 
 
Imhof M, Kuhne U. Introduction of the Microdroplet Technique with Incobotulinumtoxin 
A for the Treatment of Crow's Feet. The Journal of clinical and aesthetic dermatology. 
2013;6(7):40-4. 
 
Jones D. Commentary: Are Aesthetic Grading Scales only a Research Tool? Dermatologic 
Surgery. 2010;36:1817-8. 
 
Jones DH, Kerscher M, Geister T, Hast MA, Weissenberger P. Efficacy of 
IncobotulinumtoxinA for the Treatment of Glabellar Frown Lines in Male Subjects: Post- 
Hoc Analyses From Randomized, Double-Blind Pivotal Studies. Dermatol Surg. 2017;43 
Suppl 2:S235-S41. 
 
 


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Marchini C. Intranasal neostigmine therapy of botulinum toxin (BTX) treatment dysphagia 
[letter]. Clinical Neuropharmacology. 1997;20(3):279-80. 
 
Merz Pharmaceuticals GmbH. Xeomin® SmPC. 2017:1-31. 
Merz Pharmaceuticals GmbH. Investigator´s Brochure NT 201 (tradename: XEOMIN ®, 
XEOMEEN ®, BOUCOUTURE ®). 2018 
 
Merz Pharmaceuticals LLC. Prescribing information Xeomin®. 2018. 
Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double- 
blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast 
for the correction of nasolabial folds. Dermatol Surg. 2003;29(6):588-95. 
 
Nestor MS, Ablon GR. Duration of action of abobotulinumtoxina and onabotulinumtoxina: 
a randomized, double-blind study using a contralateral frontalis model. The Journal of 
clinical and aesthetic dermatology. 2011;4(9):43-9. 
 
Nettar KD, Yu KC, Bapna S, Boscardin J, Maas CS. An internally controlled, double- blind 
comparison of the efficacy of onabotulinumtoxinA and abobotulinumtoxinA. Arch Facial 
Plast Surg. 2011;13(6):380-6. 
 
 
Prager W, Bee EK, Havermann I, Zschocke I. Onset, longevity, and patient satisfaction 
with incobotulinumtoxinA for the treatment of glabellar frown lines: a single-arm, 
prospective clinical study. Clinical interventions in aging. 2013;8:449-56. 
 
 
Rohrich RJ, Janis JE, Fagien S, Stuzin JM. The cosmetic use of botulinum toxin. Plast 
Reconstr Surg. 2003;112(5 Suppl):177S-92S. 
 
Rzany B, Ascher B, Fratila A, Monheit GD, Talarico S, Sterry W. Efficacy and safety of 
3- and 5-injection patterns (30 and 50 U) of botulinum toxin A (Dysport) for the treatment 
of wrinkles in the glabella and the central forehead region. Arch Dermatol. 
2006;142(3):320-6. 


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Sloop RR, Escutin RO, Matus JA, Cole BA, Peterson GW. Dose-response curve of human 
extensor digitorum brevis muscle function to intramuscularly injected botulinum toxin type 
A. Neurology. 1996;46(5):1382-6. 
 
Tamburic S, Grant-Ross P, Labedzka M, Daniels G. Exploring the effects of non-medical 
versus medical approaches to the management of skin aging in women over sixty. 
International journal of cosmetic science. 2012;34(5):481-8. 
 


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16 APPENDICES 
 
 
 
 
 
 
 

SAP_001.pdf: 
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Merz Pharmaceuticals GmbH 
Statistical Analysis Plan 
A prospective, randomized, double-blind, multicenter study to investigate the 
safety and duration of effect of different NT 201 dose groups following the 
treatment of glabellar frown lines  
Phase 2 
M602011015 / NCT03806933  
Version 3.0, Final 
Date: 14-JAN-2021 
Author:
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary to Merz Pharmaceuticals GmbH. 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not be 
disclosed to parties not associated with the clinical investigation without the prior written consent of Merz 
Pharmaceuticals GmbH. 




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TABLE OF CONTENTS
SIGNATURE PAGE........................................................................................................... 2 
1 
LIST OF ABBREVIATIONS ................................................................................... 5 
2 
GENERAL AND TECHNICAL ASPECTS............................................................ 7 
3 
Clinical Study Design and Objectives ...................................................................... 7 
3.1 
Clinical Study Design.............................................................................................. 7 
3.2 
Clinical Study Objectives........................................................................................ 9 
4 
Determination of Sample Size................................................................................... 9 
5 
Analysis Sets ............................................................................................................. 10 
Safety Evaluation Set (SES).............................................................................................. 10 
Full Analysis Set (FAS) .................................................................................................... 10 
6 
Variables for Analysis.............................................................................................. 11 
6.1 
Efficacy Variables................................................................................................. 11 
 
Primary Efficacy Variable(s) .......................................................................... 12 
 
Secondary Efficacy Variables ......................................................................... 13 
6.2 
Safety Variables .................................................................................................... 16 
 
Primary Safety Variable(s).............................................................................. 16 
 
Secondary Safety Variables ............................................................................ 17 
7 
Statistical Analysis Methods ................................................................................... 20 
7.1 
Efficacy Variables................................................................................................. 20 
 
Primary Efficacy Variable(s) .......................................................................... 22 
 
Secondary Efficacy Variables ......................................................................... 24 
7.2 
Safety Variables .................................................................................................... 26 
 
Primary Safety Variable(s).............................................................................. 27 
 
Secondary Safety Variables ............................................................................ 28 
7.4 
Special Statistical/Analytical Issues...................................................................... 30 
 
Discontinuations and Missing Data................................................................. 30 
 
Interim Analyses ............................................................................................. 33 
 
Data Monitoring Committee ........................................................................... 37 
 
Multiple Comparisons/Multiplicity................................................................. 37 
 
Pooling of sites................................................................................................ 37 
 
Additional analyses due to outbreak of COVID-19 pandemic ....................... 38 


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9 
Changes to Former Versions ................................................................................... 40 
10 References ................................................................................................................. 43 
Appendix 
... 44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 LIST OF ABBREVIATIONS 
 
ADTTE 
Analysis dataset for time to event 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical classification system of the World 
Health Organization  
BDRM 
Blind data review meeting 
BMI 
Body mass index 
BoNT 
Botulinum neurotoxin 
CETS 
Combined endpoint treatment success 
CSP 
Clinical study protocol 
DEM 
Dose escalation meeting 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
FWS 
Facial wrinkle scale 
GFL 
Glabellar frown lines 
IP 
Investigational product 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MP 
Main period 
n 
Number of non-missing observations 
n miss 
Number of missing observations 
NT 201 
Clostridium botulinum neurotoxin type A (150 KD, free of 
complexing proteins) powder for solution for injection 
OLEX 
Open-label extension 
PDF 
Portable document format 
PT 
Preferred term 
Q1 
First quartile 
Q3 
Third quartile 
SADR 
Serious adverse drug reactions 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System software 


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SDTM 
Study data tabulation model 
SES 
Safety evaluation set 
SOC 
System organ class 
TFLs 
Tables / figures / listings 
TEAE 
Treatment emergent adverse event 
TEAESI 
Treatment emergent adverse event of special interest 
TESAE 
Treatment emergent serious adverse event 


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2 GENERAL AND TECHNICAL ASPECTS 
The objective of this statistical analysis plan (SAP) is to specify the statistical analyses with 
appropriate detail and precision to serve as a guideline for statistical programming and creation of 
tables, figures, and listings for clinical study protocol (CSP) M602011015, dated 01-OCT-2018, 
amendments 1 and 2 to CSP, dated 22-OCT-2019 and 30-APR-2020, respectively.  
All programs will be written using Statistical Analysis System Software (SAS®) version 9.4 or 
higher. A preferred font size of 10 points will be used for the tables and figures in section 14, 
corresponding to a line size of 111 digits and a page size of 42 lines for an output in A4 landscape 
format. For listings, a standard font size of 10 points with the line size and page size as defined 
above will be used to produce the output in A4 format. Individual SAS programs will be written 
for all tables, figures, and listings. 
 
 
 
 
 
 
 
 
 
 
 
3 CLINICAL STUDY DESIGN AND OBJECTIVES 
3.1 Clinical Study Design 
This multicenter Phase 2 clinical study consists of a Main Period (MP) and the subsequent optional 
open-label extension (OLEX) Period. The Main Period has a prospective, randomized, double-
blind, dose-ranging, design with two treatment stages. In stage 1, the dose groups 20 U, 50 U, and 
75 U are investigated. Once all subjects of stage 1 completed Day 30±7 Follow-up Observational 
Visit V4, a dose escalation meeting (DEM) was held. Stage 2 is performed only if no safety 
concerns have been raised during DEM and investigates the dose groups 20 U and 100 U. Subjects 
do not cross over from stage 1 to stage 2. A total number of up to 240 subjects with moderate to 
severe glabellar frown lines (GFL) at maximum frown as assessed by the investigator using the 4-
point Facial wrinkle scale (FWS) will be randomly assigned at 9 study sites in USA and Germany. 
Study procedures will be identical in both stages. The subjects will receive intramuscular injection 
of NT 201 according to their respective randomized dose groups administered at the Baseline Visit 
V2 (Day 1) of stage 1 or stage 2. The injection at Baseline Visit V2 (Day 1) of stage 1 or stage 2 
and the following Observational Visits (up to V15) comprise the MP of the study.  
Additionally, subjects who have relapsed to baseline status in the MP, will have the option to 
receive a follow-up treatment with the market approved dose of 20 U NT 201 for their GFL 
 


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. This injection and the subsequent follow-up visit constitute an optional 
OLEX period in this study. 
MP: 
Stage 1 of the study 
In stage 1 of the study, eligible subjects, who had a successful Screening Visit V1 (Day -3 to -14), 
were randomized at the Baseline Visit V2 (Day 1) to one of three dose groups of 20 U (n=30), 50 
U (n=60) or 75 U NT 201 (n=60) according to the randomization ratio 1:2:2.  
Once all enrolled subjects for stage 1 had their Day 30±7 Follow-up Observational Visit V4 
completed, a blinded evaluation of safety data was performed in a DEM. Based on the stage 1 data, 
a decision to proceed with stage 2 of the study with a dose group of 100 U NT 201 was made. No 
safety concerns were raised.  
In addition to the blinded safety data evaluation (once all subjects of stage 1 completed Day 30±7 
Follow-up Observational Visit V4), an interim analysis will be performed once complete 180-day 
data (V9) of stage 1 are available. Data will be unblinded for sponsor staff and vendor data 
management and biostatistics staff only with regard to stage 1 subject’s assignment to treatment 
groups. The blind for subjects in stage 2 will be maintained. Stage 2 subjects will not be included 
in the 180-day interim analysis. 
An interim analysis of complete stage 1 MP data will be performed as soon as data until and 
including the End of MP visit V15 from stage 1 subjects are completely available (except for 
missingness due to premature study discontinuation or intermittently missing visits). The analysis 
of stage 1 MP data will serve to get further insights regarding duration of effect and occurrence of 
TEAEs over the entire Main Period of up to 360 days. Knowledge gained from the interim analysis 
at End of MP of stage 1 will be useful to decide whether it is still meaningful to motivate stage 2 
subjects affected by COVID-19 (see section 7.4.7) to re-assume on-site visits depending on the 
number of missing visits for the primary efficacy variable. Since ensuring the safety of subjects is 
paramount, this analysis will be valuable to balance the potential risks of further on-site visits 
against benefits such as avoidance of missing data and premature study discontinuations. 
Investigators and subjects, site staff and blinded monitor will be kept blinded throughout for both 
stages until final unblinding. The blind for subjects in stage 2 will be completely maintained. 
Stage 2 of the study  
No safety concerns were raised during DEM. Therefore, stage 2 of the study was started. After 
successful screening, eligible subjects are enrolled and randomized at the Baseline Visit V2 (Day 
1) to one of two dose groups of 20 U (n=30) or 100 U NT 201 (n = 60) according to randomization 
ratio 1:2.  


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The observation period for each subject (in stage 1 and stage 2) will be at least 180 days. Subjects 
who have relapsed to baseline status of their GFL based on the investigator’s assessment on the 
FWS at maximum frown up to Day 180, should complete the End of MP study visit at Day 180. 
Subjects who have not relapsed to baseline status of their GFL at Day 180 (V9) will continue to 
be observed for up to 180 additional days. For subjects who have relapsed to baseline status of 
their GFL between Day 180 and Day 360 the End of MP can be performed at each of the respective 
Observational Visits. If no relapse to baseline status is measured, the End of MP will be performed 
at Day 360 (V15). 
Optional OLEX: 
Subjects who have relapsed to baseline status of their GFL in the MP will have the option to receive 
a follow-up treatment with the market approved dose of 20 U NT 201 for their GFL between Day 
180 and Day 360. An OLEX Follow-Up Visit V16 will be performed 30 days after the optional 
injection to document the occurrence of adverse events (AEs)/ adverse events of special interest 
(AESIs).  
Study duration for each subject (in stage 1 and stage 2) will be at least 180 days, plus the individual 
duration of screening (up to 14 days), plus 30 days OLEX follow-up for subjects who elect to 
receive an optional follow-up treatment. The overall maximum study duration will be up to 390 
days in case the subject will receive an optional follow-up treatment plus the individual duration 
of screening (up to 14 days) for each subject.  
Subjects who withdraw or are withdrawn prematurely from the study will be requested to perform 
the End of MP study visit. Please note that subjects who receive the optional follow-up treatment 
but do not attend the OLEX Follow-Up Visit V16 for any reason will not be considered as 
discontinued prematurely from the study. 
3.2 Clinical Study Objectives 
The primary objective is to assess the safety and duration of effect of different NT 201 dose groups 
following the treatment of GFL. 
The secondary objective is to assess the efficacy of different NT 201 dose groups following the 
treatment of GFL. 
 
4 DETERMINATION OF SAMPLE SIZE 


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In total, 60 subjects in the high dose groups are deemed required for the objectives of the study. 
For the low dose group, 30 subjects suffice in case the study stops after stage 1 as the side effects 
and efficacy of a dose of 20 U are well characterized in previous studies. 
 
5 ANALYSIS SETS 
The following analysis sets will be defined for the statistical analysis of this clinical study: 
Safety Evaluation Set (SES) 
The SES is the subset of all subjects who were exposed to study medication. 
Analyses based on the SES will use the actual treatment that a subject received at Day 1 (V2) to 
define the treatment group. 
Full Analysis Set (FAS) 
The FAS is the subset of subjects in the SES for whom any efficacy variable is available (i.e., all 
subjects who have a baseline and at least one post-baseline value of any efficacy variable). 




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Primary Efficacy Variable(s)
The primary efficacy variable is the duration of effect as defined by time between treatment and 
relapse to baseline status. Effect is defined as improvement at maximum frown as assessed by the 
investigator on the FWS. If no improvement is observed on the FWS at maximum frown at any 
point after treatment, the time will be set to 0.
Remarks:
“Time between treatment and relapse to baseline status” is assessed as the time between treatment 
and first occurrence of relapse to baseline status, and “improvement […] on the FWS” means any 
improvement, i.e., an improvement of at least one point on the FWS. 


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In case no improvement is observed at any point after treatment, the respective subjects will be 
assigned an event of relapse on the day of treatment and the corresponding time will be set to 0.
Secondary Efficacy Variables
The secondary efficacy variables are:
•
Duration of effect, whereby effect is defined by a score of none (0) or mild (1) at 
maximum frown as assessed by the investigator according to FWS 
This variable is defined as the time between treatment and the first point in time when 
the score is moderate (2) or severe (3) again. If no effect is observed on the FWS at any 
point after treatment, the time will be set to 0.
•
Duration of effect whereby effect is defined by 2-point improvement from baseline at 
maximum frown as assessed by the investigator according to FWS 
This variable is defined as the time between treatment and the first point in time when 
the improvement is less than 2 points again. If no improvement (e.g. difference to 
baseline <=1) is observed on the FWS at any point after treatment, the time will be set 
to 0.
•
Percentage of subjects rated as none (0) or mild (1) at maximum frown by investigator’s 
rating on FWS at Day 180 (V9) 
•
Percentage of subjects rated as none (0) or mild (1) at maximum frown by subject’s 
rating on FWS at Day 180 (V9) 
•
Percentage of subjects rated as at least 1-point improvement compared to baseline at 
maximum frown by investigator’s rating on FWS at Day 180 (V9)
•
Percentage of subjects rated as at least 1-point improvement compared to baseline at 
maximum frown by subject’s rating on FWS Subject at Day 180 (V9)


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6.2
Safety Variables
Per CSP version 1.0, it was foreseen to collect all safety data during on-site visits. In amendment 
2 of the CSP, the following strategy to mitigate impact of COVID-19 pandemic on safety of study 
participants and on completeness of safety data was specified: If planned on-site visits cannot be 
performed due to COVID-19 situation, safety data (AEs, change in medication and non-drug 
treatment, and occurrence of pregnancy) will be collected via phone calls provided the subject 
consented. In addition, on-site visits should be performed at the earliest possible date when the
subject is able to safely come to the site again. 
Primary Safety Variable(s)
The primary safety variables are the occurrences of treatment emergent adverse events (TEAEs),
treatment emergent serious adverse events (TESAEs), treatment emergent adverse events of 
special interest (TEAESIs), related TEAEs and related TESAEs by dose group for the entire study 
period. 
An AE is considered treatment-emergent with onset or worsening on or after date of the first 
administration of investigational product (IP). Each documented worsening of an AE will be 
counted and presented as separate AE. The start date of the AE will be the date of worsening.


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Secondary Safety Variables
Not applicable.


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7 STATISTICAL ANALYSIS METHODS 
In general for the final analysis, the dose groups of 20 U from stage 1 and stage 2 will be pooled 
in all efficacy and safety analyses if not described differently below. For the interim analyses of 
stage 1 at Month 6 and at End of MP (see section 7.4.2), subjects randomized into the 20 U group 
stage 1 (FAS analysis) or treated with 20 U in stage 1 (SES analysis) will be presented as dose 
group 20 U. 
7.1 Efficacy Variables 
The efficacy analyses will be based on the FAS and will be done by randomized treatment group 
(20 U [for final analysis pooled over stages 1 and 2 if not stated otherwise below], 50 U, 75 U, 100 
U). Statistical tests will be two-sided hypothesis tests for between-treatment differences in general. 
Continuous variables (values and changes from baseline) will be summarized by number of values 
analyzed (n), mean, standard deviation, median, quartiles, minimum, and maximum. 
 
 
 
 
 
For qualitative variables, absolute and percent frequencies (n, %) and, if applicable, shift tables 
will be displayed. Confidence limits 
will be given, where appropriate.  
 
 
Mean, first quartile (Q1), median, and third quartile (Q3) will be reported to one decimal place 
more than the data were collected, for the standard deviation two decimal places more will be 
displayed; for derived data, an adequate number of decimal places will be chosen. Percentages will 
be calculated using the denominator of all subjects in a specified population and treatment group. 
The denominator will be specified in a footnote to the tables for clarification if necessary. 
Percentages will be reported to one decimal place. 
Efficacy analysis will be based on the MP solely, ending with the End of MP visit. (As specified 
in the CSP, the End of MP visit is performed between Day 180±7 and 360±7, depending on when 
the individual subject relapsed to baseline according to the investigator’s assessment on the FWS 
at maximum frown.) Generally, only data from visits until regular End of MP will be used for 


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efficacy analyses, i.e. data from erroneously performed visits after occurrence of relapse6 (V10 to 
V14 and/or from End of MP visit) will be listed only.  
                                                          
6 based on investigator’s FWS scores at maximum frown 


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Primary Efficacy Variable(s)
The primary variable is the duration of effect defined in section 6.1.1, with effect being defined as 
improvement at maximum frown as assessed by the investigator on the FWS. Duration of effect 
will be described by Kaplan-Meier Curves per group and the respective medians of times with 
associated 2-sided 95% confidence interval.
pairwise log-rank tests will be applied 
to compare differences between high dose groups (50 U, 75 U and 100 U) and the 20 U group to 
explore statistical significance. The 20 U group data will be pooled from stage 1 and 2 for the final 
analysis.
For the primary endpoint, a Cox proportional hazards regression model will be applied to the data 
with covariates dose group (20, 50, 75, 100 U), study site8, and baseline FWS score at maximum 
frown as assessed by the investigator.
The timing and censoring variables for the Kaplan-Meier analysis and the Cox regression model 
will be calculated
8 The term “center” as used in the description of this model in the CSP was replaced by the “study site” to increase 
consistency with other parts of the CSP and throughout this SAP. The meaning remains the same.


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For the Cox regression analysis in the final analysis, the pooled 20 U group will be used as 
reference group. Hazard ratios will be calculated for each dose group to the reference group 
including Wald 95% confidence intervals and two-sided p-values. 
For the Cox regression analysis in the interim analysis, the 20 U group will be used as reference 
group. Hazard ratios will be calculated for each dose group to the reference group including Wald 
95% confidence intervals and two-sided p-values. 
To explore potential stage effects in the final analysis, a sensitivity analysis will use dose groups 
20 (stage 1), 20 (stage 2), 50, 75 and 100 U with 20 (stage 1) as reference group. Depending on 
the outcome further exploration might be needed.  
A further sensitivity analysis will be performed to assess the impact of the COVID-19 pandemic 
on the primary efficacy analysis. To this end, for each subject with missing values due to COVID-
19 pandemic (i.e., in case visits not performed due to COVID-19 or performed virtually due to 
COVID-19 so that live assessments by investigator could not be performed or discontinuation due 
to COVID-19 before relapse to baseline status), it will be checked whether values are missing from 
one or more visits directly preceding the visit when relapse to baseline was observed. While 
intermittently missing values due to COVID-19 (as well as continuous missingness resulting from 
premature discontinuation due to COVID-19) are generally assumed to be missing at random, this 
specific pattern of intermittent missingness might lead to bias in assessment of duration of effect. 
Specifically, the time to relapse to baseline status might be overestimated. Therefore, a sensitivity 
analysis will be conducted with time to relapse to baseline status from affected cases being 
censored at the first visit of those subsequent visits with missing values that directly precede the 
visit when relapse to baseline was observed. By this means, any overestimation of duration of 
effect resulting of a possibly delayed observation of relapse to baseline will be ruled out. If the 
first visit of those subsequent visits with missing values that directly precede relapse was 
performed virtually due to COVID-19 pandemic, the actual visit date will be used for censoring. 
In case the respective visit was not performed due to COVID-19 pandemic, time to relapse will be 
censored at the nominal visit date (calculated as injection date + number of days according to visit 
schedule in the study protocol - 1). The censoring variable CSNR will be set to 3. 
The need for further sensitivity analyses was discussed during BDRMs. During the BDRM for the 
final analysis performed on 7-JAN-2021, it was confirmed that all randomized subjects fulfill the 


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requirements to be included in the FAS. Furthermore, details on premature study discontinuations, 
amount, patterns and reasons for missing data on the FWS at maximum frown as assessed by the 
investigator and relatedness to COVID-19 pandemic as well as any identified intercurrent events 
were closely reviewed and discussed. It was concluded that the assumption of random missingness 
underlying the primary duration of effect analysis appears reasonable and that the above-specified
analysis to account for a specific pattern of missingness due to COVID-19 pandemic was deemed 
adequate and sufficient to assess the impact of the COVID-19 pandemic on the primary efficacy 
analysis (see also section 7.4.7 below). No intercurrent events with relevant impact on 
interpretation of analysis results were identified. Thus, no additional sensitivity analyses were 
considered necessary.
Secondary Efficacy Variables
The secondary duration of effect variables (see section 6.1.2) will be analyzed in analogy to the 
primary efficacy variable. However, for the final analysis, the Cox regression analysis will be 
limited to pooling the 20 U groups of both stages.
Duration of effects for each definition will be calculated as described in section 7.1.1, timing and 
censoring variables will be defined in analogy to the primary efficacy variable.
Kaplan Meier and Cox regression analyses will be performed as described above, except for the 
sensitivity analysis with separate 20 U groups from stage 1 and 2, which will be only done for the 
primary variable.
For the percentages of subjects fulfilling the criteria as described in the secondary efficacy 
variables (see section 6.1.2), two-sided 95% Pearson-Clopper confidence intervals will be 
computed for percentages of subjects showing an effect in each dose group. 


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7.2 Safety Variables 
All safety analyses will be performed on the SES and will be done overall and by actual dose group 
20 U [for final analysis pooled over stages 1 and 2 if not stated otherwise below], 50 U, 75 U, 100 
U). Analyses of AEs will be based on MP as well as the optional OLEX period, if applicable. 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA, 
version 23.1) using the version and the update strategy as defined in the data management plan. 
Only TEAEs will be summarized, which are defined as AEs with onset or worsening after the first 
administration of IP. Incidences will be calculated for TEAEs on the system organ class (SOC) 
level and on the preferred term (PT) level (i.e., total and percentage, by intensity, and by 
relationship). Listings and (as applicable) tables displaying incidences for TEAEs leading to 
discontinuation, serious TEAEs, TEAEs of special interest, and deaths will also be provided. 
Additionally the number and percentage of subjects with at least one non-serious TEAE with 
incidence ≥ 5% will be displayed by SOC and PT (final analysis only). Time to onset and duration 
of TEAEs will be listed, and a by subject listing of TEAEs related to COVID-19 pandemic will be 
provided. 
Calculation of time to onset/duration of AEs (days): 
 Time to onset of an AE is defined as start date of AE - date of first administration of study 
drug [+ 1 for AE starting after start of treatment] 
 The duration will be calculated as stop date - onset date + 1.  
If a subject has more than one outcome within a preferred term (PT) only the worst outcome will 
be used in the frequency tables. Also on subject level only the worst outcome category per subject 
will be counted in the frequency table. The worst outcome is defined in the following order: 
 recovered/resolved  


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
recovered/resolved with sequelae

recovering/resolving

not recovered/not resolved 

unknown

fatal.
In case of missing intensity or missing causal relationship of an AE the worst case principle will 
be applied, i.e. a missing intensity will be set to “severe” and a missing causal relationship will be 
set to “related”.
Laboratory evaluations and vital signs (values and changes from baseline) will be analyzed 
descriptively by treatment and study visit. Visits as documented in the eCRF will be used, i.e. visit 
“End of MP” and not “V15” will be analyzed. The same applies to analysis of TEAE incidence by 
time interval.
Primary Safety Variable(s)
Incidences (absolute and percentage) of TEAEs, TEAESIs, TESAEs, and related TEAEs will be 
calculated on the level of system organ class (SOC) and preferred term (PT). In addition, 
incidences for TEAE will also be presented by worst intensity and by worst causal relationship. In 
general, incidences for TEAEs will be reported by the following actual dose groups: 20 U [pooled 
over stage 1 and stage 2], 50 U, 75 U, 100 U. To explore potential stage effects, incidences for 
TEAE by worst causal relationship will additionally be provided separately for actual 20 U dose 
groups from stage 1 and stage 2.11
The following AE summary tables will be created by actual dose group and overall (entire study 
period), whereby in general the dose groups 20 U pooled, 50 U, 75 U, 100 U will be used:

TEAEs, subjects with TEAEs and number of TEAEs by SOC and PT.
11 This analysis was added after finalization of the CSP.


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
TEAEs, subjects with TEAEs by PT.

TEAEs, subjects with TEAEs and number of TEAEs by SOC and PT 

Non-serious TEAEs, 
by 
SOC and PT.

TEAEs by worst intensity, subjects with TEAEs.

TEAEs by worst causal relationship, subjects with TEAEs (20 U stage 1, 20 U stage 2, 20 
U pooled, 50 U, 75 U, 100 U).

Treatment related TEAEs by SOC and PT.

Treatment related TEAEs occurring between baseline and Day 180 (V9 or End of MP), by 
SOC and PT.

Treatment related TEAEs occurring between baseline and End of MP, by SOC and PT.

TEAEs by worst outcome, subjects with TEAEs.

TESAEs, subjects with TESAEs by SOC and PT.

TESAEs, listing of subjects.

Related serious TEAEs, listing of subjects.

Deaths, listing of all serious TEAEs leading to death.

TEAEs leading to discontinuation, listing of subjects.

TEAESIs, subjects by SOC and PT.

TEAESIs, listing of subjects
Related TESAEs, deaths, TEAEs leading to premature discontinuation and TEAEs related to 
COVID-19 will be listed only.
Secondary Safety Variables
Not applicable


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7.4
Special Statistical/Analytical Issues
Discontinuations and Missing Data
With relevance to efficacy objectives, the treatment will be applied only once and hence cannot be 
discontinued. Therefore, no premature discontinuation from treatment can occur. Missing values 
likewise occur at random or because the subject completes the study early due to relapse to
baseline. The latter will not impact the primary analysis of duration of effect since this was 
completely captured. Hence, for any Kaplan-Meier or Cox regression analysis and inferential 
statistics, intermittent missing data will be ignored and monotone missingness be considered as 
censored.
Intermittently missing values due to COVID-19 pandemic (resulting from missing visits not 
performed due to COVID-19 pandemic or visits performed virtually due to COVID-19 pandemic, 
thus precluding live assessments by the investigator as needed for the primary efficacy variable) 
as well as monotonously missing values resulting from premature discontinuation due to COVID-
19 pandemic are as well considered missing at random. However, a specific pattern of missing 
values might introduce bias to assessment of the primary variable of duration of effect: If data are 
missing from visits directly preceding the visit when relapse to baseline status is observed, time to 
relapse to baseline status might be overestimated. A sensitivity to assess such impact on missing 


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values due to COVID-19 pandemic on the primary duration of effect variable is described in 
section 7.1.1. 


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Handling of missing values due to the COVID-19 pandemic
Due to the COVID-19 pandemic, a considerable amount of missing data is expected for subjects 
from stage 2. Restrictions related to COVID-19 in both the US and in Germany (temporarily closed 
sites, stay-at-home orders, quarantines imposed to subjects suspected to be infected) may make it 
impossible for many subjects to attend all planned on-site visits. Since live assessments by 
investigators cannot be performed remotely, this will inevitably lead to missing data. 
Handling of missing data due to the COVID-19 pandemic in the final statistical analysis will 
depend on the number and pattern of missing values, which will be thoroughly described in the 
clinical study report. 
Also, reasons for missing data will be described. As specified in CSP amendment 2, for each 
planned study visit that was not performed at the study site, the site staff should document whether 
it was performed as virtual visit due to COVID-19 pandemic, not performed due to COVID-19
pandemic (with specific reason) or not performed (due to other reasons). Also, it should be 
documented if a subject is discontinued from the study due to COVID-19 pandemic, again with 
specific reason.
During the BDRM for the final analysis performed on 7-JAN-2021 (see also section 7.1.1 above
and section 7.4.7 below), the sensitivity analysis described in section 7.1.1 to account for a specific 
pattern of missingness due to COVID-19 pandemic was considered adequate and sufficient to 
assess the impact of COVID-19 pandemic on primary efficacy analysis. No additional sensitivity 
analyses were deemed necessary by BDRM participants.
Interim Analyses
Dose Escalation Meeting
A blinded evaluation of safety data was performed on 24th July 2019 in a DEM when all enrolled 
subjects for stage 1 had their Day 30±7 Follow-up Observational Visit V4 completed. Based on 
the stage 1 data, a decision to proceed with stage 2 of the study with a dose group of 100 U NT 201
was made. The evaluation included blinded safety data of stage 1 subjects of the 20 U, 50 U, and 
75 U NT 201 dose group up to Follow-up Observational Visit V4, Day 30±7. 
For this DEM the following data was presented overall for the pooled blinded data:


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• 
Subject disposition and demographic data  
• 
Listings of medical history, concomitant diseases, previous and concomitant treatments 
• 
Incidences of TEAEs, TEAESIs, TESAEs, related TESAEs and related TEAEs by SOC 
and PT 
• 
Listings of TEAE, TEAESIs, TESAEs, Deaths and AEs leading to premature 
discontinuation  
The DEM received complete blinded safety data of stage 1 subjects of the 20 U, 50 U, and 75 U 
NT 201 dose group up to Follow-up Observational Visit V4, Day 30±7. Based on the stage 1 data, 
it was decided to proceed with stage 2 of the study with a dose group of 100 U NT 201. 
 
Interim Analysis after Day 180 of stage 1 
An interim analysis of complete 180-day data (V9) of stage 1 was performed. This interim analysis 
served to get early insights regarding the benefit-risk assessment and duration of effect of the dose 
groups investigated in the stage 1. However, it was not the aim of this analysis to decide on 
premature termination of the study.  
Data was unblinded for sponsor staff and vendor data management and biostatistics staff only as 
required for the sake of the interim analysis.  
For data of stage 1 until Day 180, the blind was not be broken until a BDRM focusing on the 
interim analysis had convened, the first version of the SAP had been finalized, and a database 
snapshot had been saved. After the blind was broken, the statistical analysis of stage 1 Day 180 
results proceeded.  
The study continued and investigators, subjects, site staff and monitors (except the unblinded 
monitor responsible for interactive web response system [IWRS] compliance) were kept blinded 
with regard to stage 1 subject’s assignment to treatment groups. Stage 2 subjects were not included 
in the 180-day interim analysis. The blind for subjects in stage 2 is maintained. Moreover, the 
blindness of investigators and subjects, site staff and blinded monitor will be maintained 
throughout for both stages until final unblinding.  


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For the remaining data, the blind will not be broken until the final BDRM has convened, the final 
version of the SAP has been finalized, and the database has been closed. After the blind is broken, 
the overall statistical analysis of results will proceed. The SAP might be amended to stage 2 
specific aspects before unblinding of stage 2. 
As the blind of the subjects of stage 2 will be maintained and procedures for stage 2 will be very 
advanced when results are disseminated, there is no impact on validity of stage 2 data and the 
credibility of study results. 
For this interim analysis the following data were be presented based on the data up to Day 180 of 
stage 1: 
• 
Subject disposition and demographic data  
• 
Primary and secondary duration of effect variables  
o Kaplan-Meier estimates 
o Pairwise log-rank test vs. 20 U group 
o Cox regression results with dose group, FWS score at baseline, and study site12 as 
fixed effects 
• 
Investigator’s FWS and subject’s FWS at maximum frown
: Summary 
statistics and frequency tables for scores and percentages of subjects fulfilling criteria 
as defined for secondary 
variables including 95% confidence intervals 
• 
Listings of medical history, concomitant diseases, previous and concomitant 
therapies
• 
Incidences of TEAE, TEAESIs, TESAEs, and related TEAEs by SOC and PT 
• 
Listings of SAEs, Deaths and AEs leading to premature discontinuation  
 
                                                          
12 The term “center” as used in the CSP to refer to this fixed effect was replaced by “study site” to increase consistency 
with other parts of the CSP and throughout this SAP. The meaning remains the same. 


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For presentation of Kaplan-Meier and Cox regression analyses, the 20 U group of stage 1 served 
as reference group. 
The interim analysis was performed including all data 
up to V9 
(Day 180±7) from stage 1 whereby End of MP visit was included for subjects who have relapsed 
to baseline status at V9 (Day 180±7) according to the investigator’s assessment on the Facial 
Wrinkle Scale at maximum frown and completed End of MP at Day 180±7. Information on the 
main reason for end of study was included only for subjects who terminated the study before V9 
(Day 180±7), i.e. if the End of MP Visit was performed at Day 180±7. 
 
Interim Analysis after End of Main Period of stage 1 
An interim analysis of complete stage 1 MP data was performed as soon as data until and including 
the End of MP visit V15 from stage 1 subjects were completely available (except for missingness 
due to premature study discontinuation or intermittently missing visits). The analysis of stage 1 
MP data served to get further insights regarding duration of effect and occurrence of TEAEs over 
the entire Main Period of up to 360 days. As outlined and substantiated in more detail in the newly 
added section 7.4.7, this allowed for better-informed decision making during the further conduct 
of the study in stage 2 under the specific circumstances of the COVID-19 pandemic and related 
restrictions that might make it difficult or impossible for subjects to further attend on-site visits 
for a certain period of time. 
For the interim analysis of stage 1 at Day 180 (see previous section), the blind had already been 
broken for sponsor staff and vendor data management and biostatistics staff with regards to all 
subjects randomized in stage 1. Thus, no new subjects needed to be unblinded for this additional 
interim analysis at End of MP of stage 1. 
Data as needed for the analyses below have been cleaned. After a database snapshot had been 
saved, the statistical analysis of the entire MP of stage 1 were carried out. 
The study continued and investigators, subjects, site staff and monitors (except the unblinded 
monitor responsible for IWRS compliance) were kept blinded with regards to stage 1 subject’s 
assignment to treatment groups. Stage 2 subjects were not included in the interim analysis of stage 
1 MP data. The blind for subjects in stage 2 is maintained. Moreover, the blindness of investigators 
and subjects, site staff and blinded monitor will be maintained throughout both stages until final 
unblinding. 
For stage 2 subjects, the blind will not be broken until the final BDRM has convened, the final 
version of the SAP has been finalized, and the database has been closed. After the blind is broken, 
the overall statistical analysis of results will proceed. The SAP might be amended to stage 2 
specific aspects before unblinding of stage 2. 
As the blind of the subjects of stage 2 will be maintained and procedures for stage 2 will be very 
advanced when results of stage 1 MP are disseminated, there is no impact on validity of stage 2 
data and the credibility of study results. 
For this interim analysis the statistical evaluation were presented based on at least the following 
data up to End of MP of stage 1: 


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•
Subject disposition and demographic data
•
Primary duration of effect variable
o
Kaplan-Meier estimates
o
Pairwise log-rank test vs. 20 U group
o
Cox proportional hazards regression with dose group, center and baseline FWS 
score at maximum frown as assessed by the investigator as fixed effects
•
Incidences of TEAEs, TEAESIs, TESAEs, and related TEAEs by SOC and PT
Data Monitoring Committee
Except for the internal DEM committee (see section 7.4.2), no further committee is implemented 
for this study.
Multiple Comparisons/Multiplicity
no
multiplicity adjustment is foreseen. 
Pooling of sites
Site is planned to be included as fixed factor in the Cox regression model which will be applied 
for primary and secondary efficacy analyses.
Any decision to pool sites (e.g. due to small or unbalanced sample sizes between sites) was taken 
during the first BDRM performed on 16-JAN-2020. Sample sizes were found to be well balanced 
across sites per country. Therefore, no pooling of sites was considered necessary for the analyses.


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Additional analyses due to outbreak of COVID-19 pandemic
Due to the COVID-19 pandemic, a considerable amount of missing data was expected for subjects 
from stage 2 (see also section 7.4.1). This especially applies to efficacy variables that are based on 
live assessments by investigators, which cannot be performed remotely. The primary as well as 
several secondary 
parameters would be affected. It should be noted that under 
specific circumstances, subsequently missing live ratings on the FWS by the investigator are likely 
to introduce bias to the assessment of the primary and secondary duration of effect variables. If 
relapse to baseline status was first assessed only after several intermittently missing follow-up 
visits due to canceled on-site visits, the time to relapse might be overestimated.
Data from Main Period of stage 1 are in contrast not affected by this or any other kind of bias 
caused by COVID-19 pandemic because stage 1 subjects did not miss any MP visits due to 
COVID-19 outbreak. Therefore, conduct of separate analyses of data from stage 1 and stage 2 
subjects might be necessary in addition to pooled analyses as planned for the final analysis of the 
study; this decision was taken during the BDRM for the final analysis performed on 7-JAN-2021
(see below). However, for reasons outlined in the following, it appeared reasonable to perform an 
interim analysis of Main Period data from stage 1 as soon as MP data from all stage 1 subjects 
were available and cleaned.
As described in section 7.4.2 above, the additional interim analysis of complete MP data from 
stage 1 focused on the assessment of duration of effect of NT 201 according to the primary efficacy 
parameter and on occurrence of treatment emergent adverse events (TEAEs), especially treatment-
related TEAEs, over the 360 Day follow-up period. Efficacy and safety data from stage 1, where 
doses up to 75 U were applied, can give further insights into the efficacy and safety profile of NT 
201. Depending on the future development of the COVID-19 pandemic and related restrictions in 
both countries this was regarded as very valuable to decide whether resumption of on-site visits 
for stage 2 subjects with intermittently missing on-site visits still appeared meaningful and might 
outweigh the specific efforts and risks associated with travelling during the COVID-19 pandemic. 
Insights from the interim analysis at End of MP of stage 1 might be valuable to decide whether 
affected stage 2 subjects should be motivated to re-assume on-site visits after a certain time period 
with missing efficacy data according to investigator’s assessments.
Any further additional statistical analyses planned to analyze the impact of missingness (see also 
section 7.4.1) and/or potential bias on data assessment due to COVID-19 pandemic (e.g. 
heterogeneity of stage 1 and stage 2 subjects due to COVID-19 related restrictions) were to be 
decided upon at the latest during the BDRM for the final analysis. During this BDRM, conducted 
on 7-JAN-2021 (see also section 7.1.1 above), details on premature study discontinuations, 
amount, patterns and reasons for missing data and relatedness to COVID-19 pandemic as well as 
any identified intercurrent events were reviewed and assessed. It was concluded that the 
assumption of random missingness underlying the primary duration of effect analysis still appears
reasonable and that the planned analysis to account for a specific pattern of missingness due to 
COVID-19 pandemic (see section 7.1.1 above) is adequate and sufficient to assess the impact of 
the COVID-19 pandemic on the primary efficacy analysis. A separate analysis of U 20 Stage 1 
and 20 U Stage 2 for the primary efficacy variable is already included in section 7.1.1. No 


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intercurrent events with relevant impact on interpretation of analysis results were identified. For 
these reasons, no additional sensitivity analyses were deemed necessary by BDRM participants. 
All study subjects had their Screening visit V1 as well as their Baseline visit V2 when they received 
study treatment in MP before the first COVID-19 infections occurred in both Germany and the 
United States (US). The last subject included into this study was screened on 01-OCT-2019 and 
randomized on 10-OCT-2019. In Germany and in the US, the first COVID-19 cases were notified 
in January 2020 (Robert Koch Institute, 2020; Holshue et al. 2020). On March 11, 2020, the World 
Health Organization made the assessment that COVID-19 could be characterized as a pandemic. 
Due to this temporal sequence of events, it is evident that COVID-19 pandemic could not affect 
study treatment at Baseline Visit 2. Likewise, an impact of COVID-19 pandemic in terms of 
heterogeneity of baseline characteristics of subjects included prior to and during the pandemic can 
be ruled out. 
  


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9 CHANGES TO FORMER VERSIONS 
This update of the SAP became necessary due to amendment 2 of the CSP, dated 30-APR-2020. 
The main objective of CSP amendment 2 is to assure subjects safety during the COVID-19 
pandemic and to mitigate its impact on assessments of adverse events and on assessments of 
secondary 
efficacy parameters which based on subjects’ self-assessment in case subjects 
cannot attend on-site visits during the current situation.14  
The following changes to version 1.0 of the SAP were made: 
 Section 2: CSP amendment 2, dated 30-APR-2020, added. 
 Section 3.1: New subsection on interim analysis of complete stage 1 MP data added to the 
subsection on “MP: Stage 1 of the study”. 
                                                          
14 The primary efficacy parameter is also expected to be affected by restrictions due to the COVID-19 pandemic as 
mitigation measures such as, e.g., remote assessments, are not possible for live assessments by the investigator as 
needed for this parameter. However, subjects will be asked to come for an unplanned on-site visit at the earliest 
possible date that the subject is able to safely come to the site again. 


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 Section 6.1: New paragraph added to explain which efficacy assessments can be performed 
remotely and which ones will be missing if on-site visits due to COVID-19.  
 Section 6.2: New paragraph added to specify that and which kind of safety data will be 
collected via phone in case due to COVID-19 pandemic, planned on-site visits cannot be 
performed. 
 Section 7, second sentence: “For the interim analysis” changed to “For the interim analyses 
of stage 1 at Month 6 and at End of MP”. 
 Section 7.4.1: New subsection “Handling of missing values due to the COVID-19 
pandemic” added.  
 Section 7.4.2: New subsection “Interim Analysis after End of Main Period of stage 1” 
added.  
 Section 7.4.7 Additional analyses due to outbreak of COVID-19 pandemic added. 
The following changes to version 2.0 of the SAP were made: 
 Sections 6.2.1, 7.2 and 7.3: MedDRA version updated. 
 Section 6.2.3: Weight and body mass index added to vital sign parameters. 
 Section 6.2.3 and 7.2.3: Definition of baseline for analysis of clinical biochemistry and 
hematology. 
 Section 7.2.3: Definition of baseline for analysis of clinical biochemistry and hematology.  
 Section
7.2
 New variables related to impact of COVID-19 pandemic on study 
conduct added. 
 Section 7.1: More detailed specification of how visits not foreseen in the CSP, which were 
erroneously performed after V9 and relapse to baseline status, will be in handled efficacy 
analyses, for several special cases that did not yet occur when SAP version 1.0 was 
finalized after BDRM for the interim analysis at Month 6 of stage 1. 


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 Section 7.2: Specification that visits as documented in the eCRF will be used for TEAE 
incidence by time interval. 
 Section 7.2.1: 
 
Specification that TEAEs related to COVID-19 will be listed only. 
 Section 7.4.1: Assumptions regarding and handling of missing values due to COVID-19 
pandemic described (including reference to sensitivity analysis in section 7.1.1).  
 Section 7.4.7: Statement that and explanation why COVID-19 pandemic could not affect 
study treatment at Baseline Visit 2 and that an impact of COVID-19 pandemic in terms of 


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heterogeneity of baseline characteristics of subjects included prior to and during the 
pandemic can be ruled out.  
 Correction of minor typing errors. 
 Section 7.1/ 7.1.1/ 7.4.1: Decisions made during the BDRM for the final analysis were 
added
 
 
. 
 Section 7.4.6: Conclusion from first BDRM added that no pooling of sites was necessary. 
 
10 REFERENCES 
Robert Koch Institute (2020). Coronavirus Disease 2019 (COVID-19) Daily Situation Report of 
the Robert Koch Institute 08/09/2020 - UPDATED STATUS FOR GERMANY. URL: 
https://www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Situationsberichte/S
ept_2020/2020-09-08-en.pdf?__blob=publicationFile  (last access: 08-SEP-2020. 
Holshue, M.L. et al. (2020). First Case of 2019 Novel Coronavirus in the United States. The New 
England Journal of Medicine, 382;10; p.929-936.