A Phase I, Randomised, Double-blind, Parallel-group, Single-centre Comparative Study to Evaluate the Pharmacodynamic Profile of Dysport®, Botox®, and Xeomin® in the Extensor Digitorum Brevis (EDB) Model in Healthy Adult Male Participants
Phase: PHASE1
Conditions: Healthy Participants
Sponsor: Ipsen

IPSEN GROUP 
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Ipsen Protocol template version 7.0 
Protocol Title:  
A Phase I, Randomised, Double-blind, Parallel-group, Single-centre Comparative Study to 
Evaluate the Pharmacodynamic Profile of Dysport, Botox, and Xeomin in the Extensor 
Digitorum Brevis Model in Healthy Adult Male Participants 
 
Protocol Number: D-FR-52120-279 
 
Compound: IPN52120 (Dysport) 
 
Brief Title: A comparative study to evaluate the pharmacodynamic profile of Dysport, Botox 
and Xeomin in the extensor digitorum brevis model in healthy adult male participants 
 
Study Phase: I 
 
Acronym: Not Applicable 
 
Sponsor Name: Ipsen Innovation 
 
Legal Registered Address:  
5 Avenue du Canada 
91940 Les Ulis Cedex, France 
 
Regulatory Authority Identifier Number(s) 
 
 
EudraCT: 2021-000802-14 
 
  
 
Date and Version: Final – 30 April 2021; Version 1.0 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the sponsor’s prior written 
authorisation. 

I P S E N G R O U P 
D -F R -5 2 1 2 0 -2 7 9  
C O N FI D E N TI A L  
P R O T O C O L: FI N A L 3 0  A P RI L  2 0 2 1  
P A G E 2 /5 6  
 
I pse n Pr ot oc ol te m plate versi o n 7. 0 
S p o ns or Si g n at or y:  
 
 
 
 
 
 
 
 
 
I ps e n Bi osci e nce, I nc 
6 5 0 East Ke n dall S treet 
Ca m bri d ge, M assac h us etts 0 2 1 4 2  
U nite d States of A merica  
 
D ate  
 
 
 
 
 
 
 
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n:  
 
 
  
I ps e n I n n o vati o n 
5 A ve n ue d u Ca n a da  
9 1 9 4 0 Les Ulis Ce de x, Fra nce  
Tele p h o ne: 
 or 
 
E mail: 
 
P P D
P P D
P P D
P P D
P P D

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Ipsen Protocol template version 7.0 
Principal Investigator Signature Page 
I have read and agree to Protocol D-FR-52120-279 entitled “A Phase I, Randomised, 
Double-blind, 
Parallel-group, 
Single-centre 
Comparative 
Study 
to 
Evaluate 
the 
Pharmacodynamic Profile of Dysport, Botox, and Xeomin in the Extensor Digitorum Brevis 
Model in Healthy Adult Male Participants”. I am aware of my responsibilities as an investigator 
under the guidelines of Good Clinical Practice (GCP), local regulations (as applicable) and the 
study protocol. I agree to conduct the study according to these guidelines and to appropriately 
direct and assist the staff under my control, who will be involved in the study. 
 
NAME:  
 
TITLE: 
[PRINCIPAL] 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
 
OFFICE: 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 
[ ] 
 

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Ipsen Protocol template version 7.0 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 8 
1 
PROTOCOL SUMMARY ........................................................................................... 10 
1.1 
Synopsis .......................................................................................................................... 10 
1.2 
Schema ........................................................................................................................... 14 
1.3 
Schedule of Activities (SoA) ......................................................................................... 15 
1.4 
Brief Summary .............................................................................................................. 17 
2 
INTRODUCTION ........................................................................................................ 18 
2.1 
Study Rationale ............................................................................................................. 18 
2.1 
Background ................................................................................................................... 18 
2.2 
Benefit/Risk Assessment ............................................................................................... 19 
2.2.1 
Risk Assessment of the Impact of COVID-19 Vaccination on Study 
Participants .................................................................................................. 19 
3 
OBJECTIVES AND ENDPOINTS AND ESTIMANDS ........................................... 20 
4 
STUDY DESIGN ........................................................................................................... 21 
4.1 
Overall Design ............................................................................................................... 21 
4.2 
Scientific Rationale for Study Design .......................................................................... 21 
4.2.1 
Participant Population to be Studied.......................................................... 21 
4.3 
Justification for Dose .................................................................................................... 21 
4.4 
End of Study Definition ................................................................................................ 21 
5 
STUDY POPULATION ............................................................................................... 22 
5.1 
Inclusion Criteria .......................................................................................................... 22 
5.2 
Exclusion Criteria ......................................................................................................... 22 
5.3 
Lifestyle Considerations ............................................................................................... 23 
5.4 
Screen Failures .............................................................................................................. 23 
5.5 
Criteria for Temporarily Delaying Enrolment/Randomisation/Administration of 
Study Intervention Administration ............................................................................. 24 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ............................ 25 
6.1 
Study Intervention(s) Administered ............................................................................ 25 
6.2 
Preparation/Handling/Storage/Accountability .......................................................... 25 
6.2.1 
Investigational Medicinal Product Preparation ........................................ 26 
6.2.2 
Investigational Medicinal Product Storage and Security .......................... 26 
6.2.3 
Investigational Medicinal Product Accountability .................................... 26 
6.3 
Measures to Minimize Bias: Randomisation and Blinding ....................................... 26 
6.3.1 
Randomisation ............................................................................................ 26 
6.3.2 
Maintenance of Blinding ............................................................................ 27 
6.4 
Study Intervention Compliance ................................................................................... 28 
6.5 
Dose Modification ......................................................................................................... 28 
6.6 
Continued Access to Study Intervention after the End of the Study ....................... 28 

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6.7 
Treatment of Overdose ................................................................................................. 28 
6.8 
Concomitant Therapy ................................................................................................... 28 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 30 
7.1 
Discontinuation of Study Intervention ........................................................................ 30 
7.1.1 
Temporary Discontinuation ........................................................................ 30 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................ 30 
7.3 
Lost to Follow-up .......................................................................................................... 31 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................... 32 
8.1 
Efficacy/Pharmacodynamic Assessments ................................................................... 32 
8.1.1 
Compound Muscle Action Potential ........................................................... 32 
8.2 
Safety Assessments ........................................................................................................ 33 
8.2.1 
Physical Examinations ............................................................................... 33 
8.2.2 
Vital Signs ................................................................................................... 33 
8.2.3 
Electrocardiograms ..................................................................................... 33 
8.2.4 
Clinical Safety Laboratory Assessments .................................................... 33 
8.2.5 
SARS-CoV-2 Testing ................................................................................... 34 
8.3 
Adverse Events (AEs) and Serious Adverse Events (SAEs), and Other Safety 
Reporting ....................................................................................................................... 34 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information .... 34 
8.3.2 
Method of Detecting AEs and SAEs ........................................................... 34 
8.3.3 
Follow-up of AEs and SAEs ....................................................................... 35 
8.3.4 
Regulatory Reporting Requirements for SAEs .......................................... 35 
8.3.5 
Pregnancy .................................................................................................... 35 
8.3.6 
Adverse Events of Special Interest ............................................................. 36 
8.3.7 
Reporting of Study Intervention Errors Including Misuse/Abuse ............ 36 
8.4 
Pharmacokinetics .......................................................................................................... 36 
8.5 
Genetics .......................................................................................................................... 36 
8.6 
Biomarkers .................................................................................................................... 36 
8.7 
Immunogenicity Assessments ...................................................................................... 36 
8.8 
Health Economics OR Medical Resource Utilization and Health Economics ........ 37 
9 
STATISTICAL CONSIDERATIONS ........................................................................ 38 
9.1 
Statistical Hypotheses ................................................................................................... 38 
9.2 
Sample Size Determination .......................................................................................... 38 
9.3 
Analysis Sets .................................................................................................................. 39 
9.4 
Statistical Analyses ....................................................................................................... 39 
9.4.1 
General Considerations .............................................................................. 39 
9.4.1.1 
Pharmacodynamic Evaluation ..................................................................... 39 
9.4.2 
Analysis of Primary Endpoint(s) ................................................................ 40 
9.4.2.1 
Primary Estimand ........................................................................................ 40 
9.4.2.2 
Primary Analysis .......................................................................................... 40 

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9.4.2.3 
Convergence of the MMRM Model .............................................................. 40 
9.4.2.4 
Missing Data Handling ................................................................................ 41 
9.4.2.5 
Sensitivity and Supplementary Analyses ...................................................... 41 
9.4.3 
Analysis of Secondary Endpoints ............................................................... 41 
9.4.3.1 
Incidence of Recovery of CMAP Total Amplitude at Week 28 and Week 40
 ...................................................................................................................... 41 
9.4.3.2 
CMAP Total Amplitude at Week 40 ............................................................. 41 
9.4.3.3 
Time to Onset of Action ................................................................................ 42 
9.4.3.4 
Duration of Response ................................................................................... 42 
9.4.3.5 
Maximal Effect ............................................................................................. 42 
9.4.3.6 
Time to Maximal Effect ................................................................................ 42 
9.4.4 
Safety Analyses ............................................................................................ 42 
9.4.5 
Subgroups Analyse(s) ................................................................................. 42 
9.4.6 
Exploratory Analyse(s) ............................................................................... 42 
9.5 
Interim Analyses ........................................................................................................... 42 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS .................................................................................................... 43 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................. 43 
10.1.1 
Regulatory and Ethical Considerations ..................................................... 43 
10.1.2 
Financial Disclosure ................................................................................... 43 
10.1.3 
Contractual and Financial Details ............................................................. 43 
10.1.4 
Insurance, Indemnity and Compensation .................................................. 44 
10.1.5 
Informed Consent Process .......................................................................... 44 
10.1.6 
Data Protection ........................................................................................... 44 
10.1.7 
Dissemination of Clinical Study Data ........................................................ 45 
10.1.8 
Data Quality Assurance .............................................................................. 45 
10.1.8.1 
Study Monitoring ......................................................................................... 45 
10.1.8.2 
Information to Study Personnel ................................................................... 46 
10.1.8.3 
Investigator’s Regulatory Obligations ......................................................... 46 
10.1.9 
Source Documents ...................................................................................... 46 
10.1.9.1 
Recording of Study Data .............................................................................. 47 
10.1.9.2 
Data Management ........................................................................................ 47 
10.1.9.3 
Record Archiving and Retention .................................................................. 48 
10.1.10 
Study and Site Start and Closure ................................................................ 48 
10.1.11 
Publication Policy ....................................................................................... 49 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 50 
10.3 Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................ 51 
10.3.1 
Definition of AE .......................................................................................... 51 
10.3.2 
Definition of SAE ........................................................................................ 52 
10.3.3 
Recording and Follow-Up of AE and/or SAE ........................................... 53 

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10.3.4 
Reporting of SAEs ....................................................................................... 54 
10.4 Appendix 4: Adverse Events of Special Interest by Function Suggestive of 
Possible Remote Spread of Effect of Toxin ................................................................ 55 
11 
REFERENCES .............................................................................................................. 56 
 
LIST OF TABLES 
Table 1 
Schedule of Activities .......................................................................................... 15 
Table 2 
Objectives and Endpoints/Estmands ................................................................. 20 
Table 3 
Study Intervention Administered During the Study ........................................ 25 
Table 4 
Protocol-Required Safety Laboratory Tests ..................................................... 50 
 
LIST OF FIGURES 
Figure 1 
Study Schema ....................................................................................................... 14 
Figure 2 
Compound Muscle Action Potential .................................................................. 32 
 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
AE 
Adverse event 
AESI 
Adverse event of special interest 
BoNT 
Botulinum toxin 
BoNT-A 
Botulinum toxin type A 
CMAP 
Compound muscle action potential 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organisation 
ECG 
Electrocardiogram 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EDB 
Extensor digitorum brevis 
EoS 
End of study 
EU 
European Union 
EW 
Early withdrawal 
FDA 
Food and Drug Administration 
GCP 
Good clinical practice 
IB 
Investigator’s brochure 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Model for Repeated Measures 
PD 
Pharmacodynamics 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS® 
Statistical Analysis System® 
SoA 
Schedule of activities 

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ABBREVIATION 
Wording Definition  
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
U 
Units 
US(A) 
United States (of America) 
USPI 
United States Prescribing Information 

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• 
To assess safety 
• 
Type, incidence and severity of TEAEs, 
SAEs, AEs (or SAEs) leading to 
withdrawals  
• 
AESIs. 
AE=adverse event; AESI=adverse event of special interest; BoNT-A=botulinum toxin; CMAP=compound muscle action 
potential; EDB=extensor digitorum brevis; FDA=United States Food and Drug Administration; SAE=serious adverse 
event; TEAE=treatment-emergent adverse event 
 
The primary estimand and clinical question of interest related to the primary objective is: “What 
is the average difference between Dysport 40 U and the active comparators Botox 16 U and 
Xeomin 16 U in EDB CMAP total amplitude inhibition at Week 28 in healthy adult male 
participants”. A key intercurrent event for all estimands is study discontinuation for any reason 
before timepoint of assessment. 
 
Overall Design: 
This phase I, randomised, active-controlled, double-blind, parallel-group, single-centre 
comparative study will evaluate the pharmacodynamic profiles of Dysport, Botox and Xeomin 
in a human EDB model. Healthy male participants will be randomised to receive a single 
intramuscular injection of either Dysport 40 U, Botox 16 U or Xeomin 16 U in the EDB muscle.  
Compound muscle action potential of the EDB will be measured following supramaximal 
stimulation of the corresponding nerve at Baseline and each study visit. Measurements will be 
performed using surface electrodes placed over the belly part of the EDB and reference 
electrodes placed over the tendon of the corresponding muscle. 
 
Condition/Disease: Healthy participants  
 
Study Hypothesis: 
The higher quantity of neurotoxin in Dysport than Botox or Xeomin at the approved FDA dose 
used in therapeutic and aesthetic indications may contribute to the prolonged duration of action 
exhibited by Dysport compared with other botulinum toxin serotype A (BoNT-A) products 
[Field 2018]. Using the same dose ratio, this study aims to demonstrate a longer duration of 
action of Dysport compared to Botox and Xeomin in a well-known and recognised 
pharmacodynamic model in healthy male participants. 
 
Study Duration: This study will consist of a 14-day screening period, a double-blind period 
including treatment administration on Day 1 and follow-up period of 40 weeks. 
The total study duration will be approximately 10 months. 
 
Treatment Duration: Participants will receive a single study intervention administration on 
Day 1. 
 
Visit Frequency: Following injection of study intervention on Day 1, all participants will 
attend follow-up visits on Day 7 and then every 4 weeks (Week 4, 8, 12, 16, 20, 24, 28, 32 and 
36) until the end of study (Week 40). 
 

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Number of Participants:  
Approximately 48 participants will be screened to achieve 15 participants randomised to 
Dysport, 15 participants randomised to Botox and 15 participants randomised to Xeomin using 
a 
1:1:1 
randomisation 
ratio 
and 
assuming 
a 
screening 
failure 
rate 
of 
5%. 
 
Statistical Methods: 
Sample Size 
Using a 1:1:1 allocation ratio, 45 participants, 15 in each study intervention group provide at 
least 88% power (2-sided t-test, 5% significance level) to show superiority of Dysport 40 U 
over Botox 16 U and Dysport 40 U over Xeomin 16 U in each of the direct comparisons, 
assuming a true treatment difference of 18% relative change from baseline in EDB CMAP total 
amplitude and common standard deviation in all three treatment arms of 15%. 
Primary Analysis 
The primary endpoint, CMAP total amplitude at Week 28, measured as relative change from 
Baseline (%), will be analysed using a mixed-effects model for repeated measures (MMRM). 
The model will include fixed effects of treatment, time (corresponding to study visit), treatment-
by-time interaction and baseline CMAP total amplitude, as well as an unstructured covariance 
matrix to model the covariance structure of the repeated measures.  
Using the mixed-effects model described above, δdb = µdysport - µbotox and δdx = µdysport - µxeomin 
are the contrasts (i.e. mixed model Wald tests) of the Dysport versus Botox versus Xeomin 
comparisons in the primary endpoint at Week 28 of the study. Results of the primary analysis 
will contain an estimate of the treatment difference between Dysport and comparators Botox 
and Xeomin in CMAP total amplitude at Week 28, as well as standard error, 95% confidence 
interval, and p-value. 
The MMRM is implicitly handling missing data as missing at random (MAR) without explicit 
imputation. This missingness assumption appears meaningful given the long term 
pharmacodynamic effect of the investigated compounds: the effect of the drug will persist after 
discontinuation and is not expected, given the baseline profiles of the participant and 
assessments until the timepoint of discontinuation, to depend on whether the participant remains 
observable in the study or drops out. 
Multiple Testing 
To control for the family-wise type I error rate at the two-sided level α = 0.05, a 
Hochberg -procedure will be applied to investigate the two null hypotheses H0,db : δdb =0 and 
H0,dx : δdx =0. The testing procedure uses the following decision rules for the two p-values pdb 
and pdx  : 
• 
Both null hypotheses are rejected if max(pdb , pdx) ≤ α  
• 
Only the null hypothesis corresponding to the smaller p-value min(pdb , pdx) is rejected if 
min(pdb , pdx) ≤ α/2 and max(pdb , pdx) > α. 
 

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Intervention Groups and Duration: 
Intervention Name Unit Dose Strength 
Dose Level 
Route of 
Administration 
Dose Frequency 
Dysport 
300 U/vial 
40 U 
Intramuscular 
Single administration 
on Day 1 
Botox 
50 U/vial 
16 U 
Intramuscular 
Single administration 
on Day 1 
Xeomin 
50 U/vial 
16 U 
Intramuscular 
Single administration 
on Day 1 
U=units 
 
Data Monitoring/Other Committee: No 

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1.2
Schema
The scheme for the study is provided in Figure 1.
Figure 1
Study Schema
CMAP=compound muscle action potential; D=day; EBD=extensor digitorum brevis; W=week; V=visit

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1.3 
Schedule of Activities (SoA) 
The schedule of study procedures and assessments are summarised in Table 1. 
If the coronavirus disease 2019 (COVID-19) pandemic prevents participants from coming to the site, participants can have their study visit 
assessments performed remotely as judged appropriate by the investigator. This must be discussed with the sponsor before being implemented. In 
such a case, the investigator will perform a telemedicine visit and will make every effort, where applicable, to contact (subject to consent) the 
participant’s general practitioner or specialist physician to ensure all important medical information and safety event(s) occurring since the last 
visit are collected. Guidance on how to collect protocol planned assessments will be provided to the investigator in a separate document. Such 
document will be filed in the trial master file. Independent ethics committees (IECs)/institutional review boards (IRBs) will be notified of the 
changes as applicable locally. Of note, as the adapted visit deviates from the regular protocol plan, the changes will be recorded as protocol 
deviations related to COVID-19. 
Table 1 
Schedule of Activities 
Procedure 
SCR 
BSL 
Double-blind Period 
EoS 
/EW 
Notes 
Visit 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
 
Scheduled 
Day/Week 
Day -14 
to Day -1 
Day 1 
Day 7 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
 
Visit window (days) 
- 
- 
±1 
day 
± 3 days 
± 6 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight and 
height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol breath 
test/Drug test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study intervention 
administration  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 

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Procedure 
SCR 
BSL 
Double-blind Period 
EoS 
/EW 
Notes 
Visit 
Visit 1 
Visit 2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visit 
11 
Visit 
12 
Visit 
13 
 
Scheduled 
Day/Week 
Day -14 
to Day -1 
Day 1 
Day 7 
W4 
W8 
W12 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
 
Vital signs 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
Standing and supine blood 
pressures and heart rate. 
Measurements to be taken 
prior to sampling for 
laboratory tests where 
possible. 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology, blood 
chemistry, coagulation and 
serology 
SARS-CoV-2 Test 
X 
X* 
 
 
 
 
 
 
 
 
 
 
 
*To be performed predose. 
PCR test to be performed at 
screening and rapid antigen 
test at baseline. Additional 
testing can be performed if 
required or in the event of 
suspected COVID-19 
infection during the study.  
See Section 8.2.5. 
EDB CMAP 
recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior and 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
BSL=baseline; CMAP=compound muscle action potential; COVID-19=coronavirus disease 2019; ECG=electrocardiogram; EDB=extensor digitorum brevis; EoS=end of 
study; EW=early withdrawal; PCR=polymerase chain reaction; SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; SCR=screening; W=week 
 

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1.4 
Brief Summary 
This study is designed to investigate the comparative duration of action on CMAP of the EDB 
muscle injected with either Dysport 40 U, Botox 16 U or Xeomin 16 U applying a dose ratio of 
2.5:1:1 based on maximum recommended total doses in the USPI from FDA for adult upper 
limb spasticity and glabellar lines indications. 
Study details include: 
Study Duration: Approximately 10 months 
Treatment Duration: Single administration on Day 1 
Visit Frequency: Following injection of study intervention on Day 1, all participants will attend 
follow-up visits on Day 7 and then every 4 weeks (Week 4, 8, 12, 16, 20, 24, 28, 32 and 36) 
until the end of study (Week 40). 

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2 
INTRODUCTION 
Use of botulinum toxin type A (BoNT-A) for various therapeutic and aesthetic indications is 
well established. The most commonly used and commercially available BoNT-A products are 
Dysport® (manufactured by the sponsor), Botox® and Xeomin®. Each of these products has a 
unique manufacturing process. Excipients, formulation and non-interchangeable potency units 
of these BoNT-A products are different (e.g. formulation and purification). However, their 
mechanisms of action are the same and medicated by the 150 kDa BoNT-A neurotoxin. 
BoNT-As are neurotoxin complexes derived from the bacterium Clostridium botulinum. These 
products prevent acetylcholine release at neuromuscular junctions, blocking neuronal 
transmission which in turn results in weakness or paresis of the injected muscle. Over a period 
of months, the nerve function returns, thus treatment may need to be repeated periodically as 
required. 
Botulinum toxins are of significant value in the treatment of a variety of therapeutic indications 
including blepharospasm, hemifacial spasm, spasticity and cervical dystonia, as well as 
aesthetic indications (e.g. improvement in the appearance of moderate to severe glabellar or 
lateral canthal lines). 
In a recent study, it has been shown that Dysport may have a longer duration of action compared 
with other BoNT-A products due to a higher mean 150 kDa BoNT-A content per vial 
[Field 2018]. Accounting for the differences in potency and total recommended doses according 
to the United States Food and drug Administration (FDA) for therapeutic and aesthetic 
indications, study results suggest Dysport contains greater amounts of active neurotoxin when 
used at total FDA-recommended doses compared with Botox and Xeomin, thus prolonging the 
block of neurotransmitter release at the neuromuscular junction. 
The present study proposes to compare the duration of effect of three commercialized BoNT-A 
products (Dysport, Botox and Xeomin) administered into the extensor digitorum brevis (EDB) 
of healthy participants. Together with its nerve supply (peroneal nerve), this muscle is 
superficial and accessible for electrophysiological, hence commonly used by the scientific 
community for assessing the onset and quantifying the duration of effects following BoNT 
administration [Sloop 1996, Eleopra 1997a, 1997b, 2013, Pons 2019], comparing different 
subtypes of BoNT [Sloop 1997, Eleopra 1998, 2004] or even checking potency of BoNT 
formulations [Park and Ahn 2013]. 
2.1 
Study Rationale 
The purpose of this study is to investigate the comparative duration of action on compound 
muscle action potential (CMAP) of the extensor digitorum brevis (EDB) muscle injected with 
either Dysport 40 U, Botox 16 U or Xeomin 16 U applying a dose ratio of 2.5:1:1 based on 
maximum recommended total doses in the United States Prescribing Information (USPI) from 
the Food and Drug Administration (FDA) for adult upper limb spasticity and glabellar lines 
indications. 
Note: the units of study intervention to be used in this study are specific to each botulinum toxin 
and are not interchangeable.  
2.1 
Background 
In this study, it is planned to explore the pharmacodynamic profile of Dysport 40 U compared 
with Botox 16 U and Xeomin 16 U on CMAP of the EDB muscle. All three BoNT-A products 
share the same mechanism of action. However, based on recent study data it is hypothesised 
that, when given at the total recommended dose, Dysport may have a longer duration of action 
than other BoNTA products due to higher amounts of neurotoxin per vial [Field 2018]. Thus, a 
BoNT-A product with longer effect could allow for less frequent need for re-injection.  

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2.2 
Benefit/Risk Assessment 
This study will be conducted in healthy male participants. There is no benefit for this study 
population. 
Risks inherent to the administration of BoNT are those related to distant spread from the site of 
administration. In clinical practice, the risk of occurrence of such undesirable effects may be 
reduced by using the lowest effective possible dose and by not exceeding the maximum 
recommended dose per indication as indicated in the respective product labels. Doses that will 
be investigated in the present study have been shown to safe and well tolerated, also associated 
with a lack of local diffusion to the adjacent muscles [Pons 2019, Wohlfarth 2007].  
There have also been occasional reports of hypersensitivity. This potential risk will be mitigated 
by appropriate selection of participants.  
More detailed information about the known risks and reasonably expected adverse events may 
be found in the respective product labels for Dysport, Botox and Xeomin. 
Safety will be closely monitored during the study. Type, severity, seriousness, duration, 
reversibility and outcome of treatment-emergent AEs (TEAEs) and adverse events of special 
interest (AESIs), a well as TEAEs leading to withdrawals will be followed. In addition, all AEs 
will be monitored by the sponsor to determine if they meet the criteria of AESIs. 
2.2.1 
Risk Assessment of the Impact of COVID-19 Vaccination on Study Participants 
Currently there is no evidence of an increased safety risk in patients treated with BoNT prior to 
or following vaccination against COVID-19.  
The doses of study intervention (BoNT) to be used in the study have been shown to be safe 
when injected into the EDB muscle. At 40 U, there is no local diffusion of Dysport into adjacent 
muscles. However, as a precautionary measure and to help minimise confounding factors in the 
safety assessments, a COVID-19 vaccine should not be administered within 7 days before or 
after the study intervention injection. 

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4 
STUDY DESIGN 
4.1 
Overall Design 
This is a phase I, randomised, double-blind, parallel-group, single-centre comparative study to 
evaluate the pharmacodynamic profile of Dysport 40 U, Botox 16 U and Xeomin 16 U in the 
EDB model in healthy adult male participants.  
A total of 45 participants will be randomised to Dysport 40 U, Botox 16 U or Xeomin  16 U to 
be administered as a single injection on Day 1.  
The maximum duration of the study is approximately 10 months from screening to last study 
visit. The participants will be followed-up for 40 weeks. 
The study design is illustrated in Figure 1. 
4.2 
Scientific Rationale for Study Design 
The higher quantity of neurotoxin in Dysport than Botox or Xeomin at the approved FDA dose 
used in therapeutic and aesthetic indications may contribute to the prolonged duration of action 
exhibited by Dysport compared with other BoNT-A products [Field 2018]. Using the same dose 
ratio, this study aims to demonstrate a longer duration of action of Dysport compared to Botox 
and Xeomin in a well-known and recognized pharmacodynamic model in healthy male 
participants. 
This model uses the EDB muscle and records its compound muscle action potential (CMAP) 
following supramaximal stimulation of the corresponding nerve. The present design will 
capture the CMAP of injected EDB with either Dysport, Botox or Xeomin. The expected 
inhibition of the electrophysiological signal following BoNT administration will be followed 
in parallel study intervention groups and blinded conditions, up to 40 weeks after injection 
aiming at capturing recovery of the inhibition. 
4.2.1 Participant Population to be Studied 
This study will enrol healthy male participants between the ages of 18 to 65 years. All 
participants should be in good health as determined by medical history, physical examination, 
clinical laboratory testing, electrocardiograms, vital signs and investigator’s judgement. 
After completion of the study, no additional treatment or medical care is necessary. 
4.3 
Justification for Dose 
Dysport 40 U has already been shown to be well tolerated when injected into the EDB 
[Pons 2019], as well as demonstrating an absence of local diffusion to the adjacent muscles. 
This dose level was also associated to a remaining CMAP inhibition 6 months post-injection. 
When applying a ratio of 2.5 (Dysport) for 1 (Botox/Xeomin), which is based on the maximum 
recommended total doses in the USPI from the FDA from adult upper limb spasticity and 
glabellar lines indications, a dose of 16 U is selected for Botox and Xeomin. Doses of 16 U 
Botox or Xeomin were also shown to be safe when injected into the EDB [Wohlfarth 2007].  
4.4 
End of Study Definition 
The end of the study (EoS) is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA for the last participant. 
A participant is considered to have completed the study if he has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the SoA. 

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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Participant must be between18 to 65 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, vital signs and cardiac 
monitoring. 
Weight 
3. A body mass index (BMI) within the range 18 and 30 kg/m2 (inclusive). 
Sex 
4.  Participants are male. 
Informed Consent 
5. Capable of giving signed informed consent as described in Appendix 10.1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any medical condition that may put the participant at risk with exposure to BoNT, 
including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral 
sclerosis, or any other disease that might interfere with neuromuscular function. 
2. Complication or history of peripheral neuropathy (e.g. as a result of diabetes mellitus), 
nerve root impairment or muscle disease. 
3. Has or has a history of breathing problems, such as asthma or emphysema. 
4. Has or has a history of swallowing problems. 
5. Has or has a history of bleeding problems. 
6. Has or has a history of blurred or double vision. 
7. Has or has a history of dysarthria or dysphonia. 
Prior/concomitant Therapy 
8. Previous treatment with BoNT (any serotype) during the past 6 months. 
9. Has received a COVID-19 vaccine injection within 7 days before the planned study 
intervention injection or is planning/likely to be vaccinated within 7 days after the 
planned study intervention injection. 
10. Use of agents that could interfere with neuromuscular transmission, including calcium 
channel blockers, penicillamine, aminoglycosides, lincosamides, polymixins, 
magnesium sulphate, anticholinesterases, succinylcholine and quinidine. 
11. Use of concomitant therapy which, in the investigator’s opinion, would interfere with 
the evaluation of the safety or efficacy of the study intervention, including medications 

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affecting bleeding disorders (e.g. antiplatelet agents and/or anticoagulants given for 
treatment or prevention of cardiovascular/cerebrovascular diseases). 
12. Any planned surgery of the foot. 
Prior/concurrent Clinical Study Experience 
13. Use of any experimental device within 3 months or use of any treatment with an 
experimental drug within five times the documented terminal half-life of the respective 
drug or its metabolites or if the half-life is unknown within 3 months prior to the start 
of the study (prior to Baseline) and during the conduct of the study. 
14. Participation in a concurrent study of another investigational drug or device. 
Diagnostic Assessments 
15. Known positive for hepatitis B antigen, or hepatitis C virus antibody, or for human 
immunodeficiency virus (HIV) or a diagnosis of acquired immunodeficiency 
syndrome. 
16. Clinically diagnosed significant anxiety disorder, or any other significant psychiatric 
disorder (e.g. depression) that might interfere with the participant's participation in the 
study. 
Other Exclusions 
17. Known hypersensitivity to any of the components of the Dysport/ Botox/ Xeomin 
formulation (which includes human serum albumin, lactose, sucrose) or allergy to 
cow's milk protein. 
18. Has recent evidence of alcohol abuse, positive drugs of abuse screen, or other relevant 
neuropsychiatric condition in the opinion of the investigator. 
19. Has any mental condition rendering the participant unable to understand the nature, 
scope and possible consequences of the study. 
20. Is likely to be noncompliant or uncooperative during the study, in the judgment of the 
investigator. 
21. Resides in an institution by administrative or court order 
22. Is a sponsor employee or clinical research unit personnel directly affiliated with this 
study or is an immediate family member. Immediate family is defined as a spouse, 
parent, child or sibling whether biological or legally adopted. 
23. Any uncontrolled systemic disease or other significant medical condition which would 
be harmful for the participant to be entered into the study or continue participation are 
considered as exclusion criteria. 
5.3 
Lifestyle Considerations 
Besides restrictions already presented in the exclusion criteria (see Section 5.2), participants 
will be requested to abstain from alcohol for 24 hours prior to admission to the clinical research 
unit. Excessive alcohol consumption (>14 units per week) should be avoided for the duration 
of the study. Participants are also requested to abstain from recreational drugs abuse from 
48 hours prior to Day -1 and until discharge from the study. Participants will be requested to 
refrain from smoking while they are in the unit and should also refrain from vigorous physical 
activity from Screening until the completion of the study. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 

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participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, reason for screen failure, eligibility criteria and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
Rescreened participants will have to re-sign an (new) ICF and a new participant number will 
be allocated. All screening assessments need to be repeated for the rescreened participant. 
5.5 
Criteria for Temporarily Delaying Enrolment/Randomisation/Administration 
of Study Intervention Administration 
In case of suspected or confirmed COVID-19 (SARS-CoV-2) infection at the Baseline visit 
(Day 1), the study intervention administration may be temporarily postponed depending on the 
participant’s clinical presentation. See Section 7.1.1 for further details. 

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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention(s) Administered 
Table 3 
Study Intervention Administered During the Study 
Intervention 
name 
Dysport 
Botox 
Xeomin 
Type  
Biologic 
Biologic 
Biologic 
Dose formulation 
Lyophilised powder 
Lyophilised powder 
Lyophilised powder 
Unit dose 
strength(s) 
300 U/vial 
50 U/vial 
50 U/vial 
Dosage Level(s) 
40 U 
16 U 
16 U  
Dose Frequency 
Single administration on 
Day 1 
Single administration on 
Day 1 
Single administration on 
Day 1 
Route of 
administration 
Intramuscular injection 
Intramuscular injection 
Intramuscular injection 
Use 
Active-comparator 
Active-comparator 
Active comparator 
IMP and 
AMP/NIMP 
IMP  
IMP  
IMP 
Sourcing 
Provided by the sponsor 
Provided by the sponsor 
Provided by the sponsor 
Packaging and 
labelling 
Commercial product will 
be used. Study intervention 
will be provided in packs 
of 1 vial, labelled on 
primary and secondary 
packaging for clinical study 
purpose. 
Commercial product will 
be used. Study intervention 
will be provided in packs 
of 1 vial, labelled on 
primary and secondary 
packaging for clinical study 
purpose 
Commercial product will 
be used. Study intervention 
will be provided in packs 
of 1 vial, labelled on 
primary and secondary 
packaging for clinical 
study purpose. 
Storage 
requirements 
To be stored between 2°C 
and 8°C 
To be stored between 2°C 
and 8°C 
Room temperature (below 
25°C) 
AMP=auxiliary medicinal product; IMP=investigational medicinal product; NIMP=non-investigational 
medicinal product; U=units 
 
6.2 
Preparation/Handling/Storage/Accountability 
1. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. 
Only participants screened in the study and who meet the eligibility criteria may receive 
study intervention and only authorised site staff may supply or administer study 
intervention. All study intervention must be stored in a secure, environmentally 
controlled and monitored (manual or automated) area in accordance with the labelled 
storage conditions with access limited to the investigator and authorised site staff. 
3. 
The investigator, institution or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records). 
4. 
Further guidance and information for the preparation and management of the study 
intervention are provided in the “IMP handling manual”. 
5. 
The sponsor will provide guidance on the destruction of unused study intervention. If 
destruction is authorised to take place at the investigational site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 

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regulations, institutional policy and any special instructions provided by the sponsor. All 
destruction must be adequately documented. 
6.2.1 
Investigational Medicinal Product Preparation 
The investigator or an approved representative (e.g. pharmacist) will ensure that all IMPs are 
reconstituted by an independent reconstitutor (unblinded study staff) and dispensed by qualified 
staff members. Detailed instructions for storage, reconstitution and preparation before treatment 
administration will be provided in the “IMP handling manual” or similar documentation. 
The vial of Dysport will be reconstituted using sterile 0.9% sodium chloride solution for 
injection to a concentration of 200 U/mL for administration of a dose of 40 U in 0.2 mL. 
The vials of Botox and Xeomin will be reconstituted using sterile 0.9% sodium chloride 
solution for injection to a concentration of 80 U/mL for administration of a dose of 16 U in 
0.2 mL. 
A ready to administer syringe containing the study intervention will be provided to the injection 
responsible delegated person in order to maintain the blinding. 
6.2.2 
Investigational Medicinal Product Storage and Security 
The investigator or an approved representative (e.g. pharmacist) will ensure that all IMPs and 
any other study related material are stored in a secured area, under recommended temperature 
monitored storage conditions, in accordance with applicable regulatory requirements. 
All study interventions must be stored as indicated in Table 3. Sterile 0.9% sodium chloride 
solution for reconstitution can be stored at room temperature. 
6.2.3 
Investigational Medicinal Product Accountability 
All IMPs and any other study related material are to be accounted for on the IMP accountability 
log provided by the sponsor. Used vials, empty or not, must be retained at site in accordance 
with local regulations. It is essential that unused supplies, as well as used supplies or empty 
boxes of used supplies, are retained for verification (by sponsor’s unblinded representative). 
Unused supplies, as well as used supplies or empty boxes of used supplies, will be either 
destroyed at the site or in the local depot. Drug accountability records will be maintained by the 
independent reconstitutor (unblinded study staff) documenting the subject allocated treatment 
number and the number of vials used and not used. 
6.3 
Measures to Minimize Bias: Randomisation and Blinding 
6.3.1 
Randomisation 
The sponsor’s randomisation manager who is a statistician independent of the study will prepare 
the list of randomisation numbers for this study. It will be produced in blocks, on a balanced 
ratio [1 Dysport: 1 Botox: 1 Xeomin]. 
After eligibility is confirmed at Day 1, participants will be assigned a randomisation number 
and to the associated study intervention group, in sequential order within the centre. Each 
participant will be treated with the intervention allocated to this randomisation number. This 
will be done by an unblinded pharmacist (independent reconstitutor) in charge of the study 
intervention preparation, by considering the first unused treatment allocation envelope among 
the set of envelopes provided to the centre. The assigned randomisation number will have to be 
specified on the treatment kit, vial and syringe used for the study intervention reconstitution. 
The investigator, the unblinded pharmacist, and investigator staff will under no circumstances 
change the randomisation number or the study intervention group allocated to the participant. 
Recruitment will stop once 45 participants have been randomised. Randomised participants 
who terminate their study participation for any reason before starting intervention will retain 

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their randomisation number (the randomisation number will not be reused). The next participant 
will be assigned the next randomisation number.  
Randomised participants who discontinue the study early will not be replaced.   
The sponsor’s randomisation manager will keep the master list of randomisation numbers. 
Access to this list must be restricted until authorisation is given to release it for final analysis. 
6.3.2 
Maintenance of Blinding 
During the study, the sponsor, investigator (including study site personnel) and the participant 
will be blinded to the study intervention. To maintain the blind during the study only a qualified, 
trained and unblinded person independent of the injector and investigator will prepare (i.e. 
reconstitute) the study intervention and will have no further involvement in the study. This 
person will be fully trained in the method of preparing the study intervention and the importance 
of their role in maintaining the blind for the participant, the investigator and the rest of the team. 
In the event of a quality assurance audit, the auditor(s) will be allowed to access to unblinded 
study intervention records at the site to verify that randomisation/dispensing has been done 
accurately. 
Due to slight differences in colour between the study interventions and to maintain the blind 
during the study, the injector will also be independent from the investigator and be unblinded 
(note: the injector will be different from the person who will evaluate CMAP). Following 
injection of the study intervention, the injector will have no further involvement in the study.  
Two sets of individual code break envelopes (an envelope per randomisation number) will be 
prepared by the sponsor’s randomisation manager to enable emergency code break procedures 
for individual participants without compromising the blind of the study. One set will be 
provided to the investigational site and one set will be provided to the central department of 
pharmacovigilance at the sponsor. 
The code break material will be retained by the investigator (or representative) in a secured 
area.  
In case of an emergency, the investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. 
If a participant’s intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind.  
The investigator must reseal the envelope. The investigator will sign, date and provide reason 
for the code break on the emergency code break form and on the sealed envelope. The date and 
reason for identifying the intervention will be recorded in the eCRF. 
Once the study is complete, all code break material (sealed and opened) must be inventoried 
and returned to the sponsor. 
Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. 
If the SAE requires that an expedited regulatory report be sent to one or more regulatory 
agencies, a copy of the report, identifying the participant’s intervention assignment, may be 
sent to investigators in accordance with local regulations and/or sponsor policy.  

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6.4 
Study Intervention Compliance 
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision at the study site on Day 1. Therefore, participant compliance with study 
intervention is not expected to be an issue. The date, time and volume of administration will be 
recorded in the source documents and in the eCRF. The dose of study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention.  
6.5 
Dose Modification 
No dose modification will be required in this study. 
6.6 
Continued Access to Study Intervention after the End of the Study 
The participants will not receive any additional study intervention following the end of the 
study. 
6.7 
Treatment of Overdose 
For this study, any dose of Dysport, Botox or Xeomin greater than that defined in Section 6.1 
will be considered an overdose. 
In the event of an overdose, the investigator should: 
• 
Contact the medical monitor immediately. 
• 
Closely monitor the participant signs and/or symptoms of excessive muscle weakness or 
muscle paralysis. Note: symptoms of overdose may not present immediately following 
injection. Should accidental injection or ingestion occur the participant should be 
medically supervised for several weeks. 
• 
Document the quantity of the excess dose, as well as the duration of the overdose. See 
Section 10.3.1 for reporting requirements concerning overdose. 
6.8 
Concomitant Therapy 
Any prior medications/nondrug therapies used by the participant within 30 days prior to the 
Screening visit (and not continued during the study) or concomitant medications/nondrug 
therapies given during the study will be indicated on the eCRF. Dose and generic name or trade 
name will be indicated. 
The investigator will be advised not to use any dermal topics (including anaesthetic topics) on 
the participant prior to the injection of study intervention on Day 1. In addition, the following 
concomitant medications are not permitted during this study: 
• 
Any form of BoNT (other than the specific study intervention) for administration into 
any site of the body.  
• 
Any experimental new drug or device. 
• 
Medications 
that 
affect 
neuromuscular 
transmission, 
such 
as 
curare-like 
non-depolarising 
agents, 
lincosamides, 
polymyxins, 
anticholinesterases 
and 
aminoglycoside antibiotics, within the past 30 days of Baseline and during the study. 
• 
Medications that affect bleeding disorders (antiplatelet agents and/or anticoagulants 
given for treatment or prevention of cardiovascular /cerebrovascular diseases). 
• 
Concomitant medications for other purposes are allowed at the investigator’s discretion. 
It is recommended that the dosage for these medications is kept constant throughout the 
study. Where medically appropriate, all concomitant medications being taken by a 
participant at entry into the study should continue at the same dose. 

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Concomitant use of anticholinergic drugs (which may potentiate systemic anticholinergic 
effects) is permitted if the dosage has been stable for the 6 weeks prior to study intervention 
and is expected to remain at this stable dose throughout the study. 
Concomitant use of any vaccine against COVID-19 is permitted from 7 days after injection of 
study intervention. COVID-19 vaccination dates should not be delayed to enable study 
participation. Participants who are unable to adhere to the COVID-19 vaccination guidance 
outlined in this protocol should not be included in the study (also see Section 5.2). 

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7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
In this study, there will be only one treatment cycle administered on Day 1 of the study, thus 
discontinuation of the study intervention is not applicable. In the event, a participant is 
randomised, but does not receive study intervention, the participant will not remain in the study 
and the EoS/EW assessments will not be performed 
7.1.1 
Temporary Discontinuation 
In case of suspected or confirmed COVID-19 (SARS-CoV-2) infection at the Baseline visit 
(Day 1), the study intervention administration may be temporarily postponed depending on the 
participant’s clinical presentation. In some cases, the investigator may request a participant be 
retested before the intervention administration is administered. 
In the event of suspected or confirmed COVID-19 infection after study intervention 
administration on Day 1, the participant will be required to isolate for at least 14 days and have 
a negative SARS-CoV-2 test before returning to the study site for the next follow-up visit. A 
participant may be permanently discontinued at the discretion of the investigator if further study 
participation is deemed to be harmful for the participant, or other participants in the study and/or 
study site personnel. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
compliance reasons.  
• 
At the time of discontinuing from the study, if possible, an early withdrawal visit should 
be conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
• 
The reason for discontinuation will be recorded in the eCRF. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such withdrawal of consent. 
• 
If the participant withdraws consent, it should be explained in detail in the medical 
records by the investigator as to whether the withdrawal is only from further receipt of 
study intervention or also from study procedures and/or posttreatment study follow-up. 
This information must be entered in the eCRF.  
• 
If a participant withdraws from the study, he may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
A participant may discontinue participation in the study at any time for any reason (e.g. lack of 
efficacy, withdrawal of consent, adverse event (AE)). The investigator and/or sponsor can 
withdraw a participant from the study at any time for any reason (e.g. protocol violation or 
deviation noncompliance with the protocol conditions or AEs). All cases of discontinuation will 
be discussed between the investigator and the sponsor.  
If a participant decides to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the participant, all efforts will be made to complete and report 
the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the participant’s withdrawal should be made and an explanation given 
of why the participant is withdrawing or being withdrawn from the study.  

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The reason for and date of withdrawal from the study must be recorded on the electronic case 
report (eCRF). If a participant withdraws consent, every attempt will be made to determine the 
reason. If the reason for withdrawal is an AE or a clinically significant laboratory test 
abnormality, monitoring will continue until the event has resolved or stabilised, until the 
participant is referred to the care of a local health care professional, or until a determination of 
a cause unrelated to the IMP or study procedure is made. The specific AE or test result(s) must 
be recorded on the eCRF. All evaluations should be performed, according to the protocol, on 
the last day the participant receives IMP, or as soon as possible thereafter 
7.3 
Lost to Follow-up 
A participant will be considered lost to follow-up if he repeatedly fails to return for scheduled 
visits and cannot be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible. The site should counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, two certified letters to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• 
Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study.  
• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not receive study intervention. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.  
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 10.1 
(Section 10.1). 

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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA. Protocol waivers and 
exemptions are not allowed.
•
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study participation.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or to record reasons 
for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (e.g. blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA.
•
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 12 mL.
•
Repeat or unscheduled samples may be taken for safety reasons or in case of technical 
issues with the samples.
8.1
Efficacy/Pharmacodynamic Assessments
Planned timepoints for all pharmacodynamic assessments are provided in the SoA (see 
Section 1.3).
8.1.1
Compound Muscle Action Potential
The CMAP procedure will be performed on the injected foot by a neurophysiologist (different 
from the study intervention injector) at the study centre.
The effect in the EDB injected muscles will be quantified by the electrophysiologic evaluation 
of the CMAP peak-to-peak total amplitude (mV), elicited by supramaximal electrical 
stimulation of the peroneal nerve at the ankle. Latency for the M wave will also be collected 
(Figure 2).
Figure 2
Compound Muscle Action Potential

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Surface electrodes will be used as recording electrodes (placed over the muscle belly) and 
reference electrodes (placed over the tendon of the corresponding muscle). The point of 
maximum response of both EDB, as assessed during the screening period will be marked with 
indelible ink to allow recording from the same site on subsequent occasions. 
At each visit (including the screening visit), three measurements of CMAP will be carried out 
at approximately 2-minute intervals. The three values of CMAP recorded will be averaged to 
calculate the corresponding visit value.  
The intensity in mA required to cause supramaximal stimulation should be recorded for each 
CMAP assessments throughout the study. 
Surface skin temperature of the injected foot will be recorded and ascertained to be above 32°C 
prior to each CMAP test. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.3). 
8.2.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight will 
also be measured and recorded at Visit 1 only.  The investigator should pay special attention to 
clinical signs related to previous serious illnesses. 
8.2.2 
Vital Signs 
Vital signs (systolic and diastolic blood pressures and heart rate) will be recorded during the 
study. Vital signs will be measured with the participant standing and in a supine position after 
resting for 3 minutes. At Baseline (Day 1), vital signs will be recorded before treatment. 
8.2.3 
Electrocardiograms 
A 12-lead ECG will be recorded at a paper speed of 25 mm/sec at Visit 1 with the participant 
in a supine position after 5 minutes of rest. 
8.2.4 
Clinical Safety Laboratory Assessments 
• 
See Appendix 10.2 for the list of clinical laboratory tests to be performed and to the SoA 
(Section 1.3) for the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents.  
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the investigator or medical monitor. 
• 
If clinically significant/any values do not return to normal/baseline within a period of 
time judged reasonable by the investigator, the aetiology should be identified and the 
sponsor notified. 
• 
All protocol-required laboratory tests, as defined in Appendix 10.2, must be conducted 
in accordance with the SoA (Section 1.3). 
• 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g. SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 

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8.2.5 
SARS-CoV-2 Testing 
SARS-CoV-2 testing will be performed as outlined in the SoA (Section 1.3). Prior to the 
Screening visit, potential participants will be contacted by telephone and instructed not to visit 
the study site for at least 14 days if they have COVID-19 symptoms, have been in close contact 
with a positive individual, or have tested positive with COVID-19 following a SARS-CoV-2 
test in the last 2 weeks. At the Screening visit, participants will be scheduled at least 5 minutes 
apart from one another to lessen the likelihood of infection spread. Participants will have a swab 
of the nose or back of the throat tested for COVID-19 infection using reverse transcription 
polymerase chain reaction (PCR). 
Only participants who have a negative COVID-19 test at Screening will be allowed to attend 
the study site on Day 1 for study intervention administration. At the Baseline visit on Day 1, 
participants will be re-tested using a rapid SARS-CoV-2 antigen test (approximately 
15 minutes) and confirmed negative prior to injection of the study intervention. 
The investigator may request a participant be re-tested at any time during the study if required 
or in the event of suspected COVID-19 infection using PCR. 
8.3 
Adverse Events (AEs) and Serious Adverse Events (SAEs), and Other Safety 
Reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 10.3. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 10.3. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs/SAEs will be collected from the signing of the ICF until EoS/EW visit at the time 
points specified in the SoA (Section 1.3). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE section of the case report form. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours of awareness of the event, as indicated in 
Appendix 10.3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 
8.3.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 

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8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in 
Section 8.3.6), will be followed until resolution, stabilisation, the event is otherwise explained 
or the participant is lost to follow-up (as defined in Section 7.3). Further information on 
follow-up procedures is provided in Appendix 10.3. 
8.3.4 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g. summary or listing of SAEs) from the sponsor will 
review and then file it along with the package insert and will notify the IRB/IEC, if 
appropriate according to local requirements. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.3.5 
Pregnancy 
• 
Details of all pregnancies in female partners of male participants will be collected from 
the signing of the ICF and until completion of the study and within 90 days after the 
participants last dose of study intervention or completion of the study (whichever is 
greater). 
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate forms (SAE form in the eCRF and Drug Exposure Form – paper form) and 
submit it to the sponsor within 24 hours of learning of the female partner of male 
participant pregnancy (after obtaining the necessary signed informed consent from the 
female partner). 
• 
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• 
The pregnant female partner will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the pregnant female partner and 
the neonate and the information will be forwarded to the sponsor. 
• 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study pregnant female partners, he or she may learn of an SAE through 
spontaneous reporting. 

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8.3.6 
Adverse Events of Special Interest  
Adverse Events of Special Interest (AESI) for this study include: 
• 
AEs of possible remote spread effect of toxin 
• 
AEs suggestive of hypersensitivity reaction. 
These events must be collected in the eCRF. 
If they meet the seriousness criteria, they should also be reported as SAEs (refer to 
Appendix 10.3).  
Adverse events of special interest are AEs that may not be serious but are of special importance 
to a particular drug or class of drugs. Such events might be precursors to more serious medical 
conditions, for example, muscle pain and elevated creatine phosphokinase may be indicative of 
potential rhabdomyolysis.  
Other types of nonserious events may be important in and of themselves, such as those that 
could affect quality of life in a meaningful way (e.g. impotence, hair loss).  
Adverse events of special interests with BoNT are events that suggest a possible remote spread 
effect of the toxin and are presented by function in Section 10.4 (Appendix 4). These symptoms 
could be related to toxin spread and in case of occurrence they should be reported and monitored 
carefully until resolution. AEs suggestive of hypersensitivity reaction are also of special interest 
and will be analysed using the Medical Dictionary for Regulatory Activities (MedDRA) 
Hypersensitivity standardised MedDRA queries (SMQ) (narrow). All AEs will be monitored 
by the sponsor to determine if they meet the criteria of AESIs. 
8.3.7 
Reporting of Study Intervention Errors Including Misuse/Abuse 
• 
Medication errors are unintentional errors in the prescribing, dispensing, administration 
or monitoring of a study intervention (medicinal product) while under the control of a 
healthcare professional, participant or consumer (European Medicines Agency 
definition). 
• 
Misuse refers to situations where the study intervention is intentionally and 
inappropriately used not in accordance with the protocol. 
• 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
• 
Study intervention errors and uses outside of what is foreseen in the protocol will be 
recorded in the eCRF irrespective of whether associated with an AE/SAE or not. It will 
also be documented in the AE section of the eCRF if associated with an AE. It will be 
reported in the safety database only if associated with an SAE.  
• 
Misuse or abuse will be collected and reported in the safety database, whether associated 
or not with an AE/SAE, within 24 hours of investigator’s awareness. 
8.4 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.5 
Genetics 
Genetics are not evaluated in this study. 
8.6 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.7 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 

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8.8 
Health Economics OR Medical Resource Utilization and Health Economics 
Health Economics or Medical resource utilization and health economics parameters are not 
evaluated in this study.  

I P S E N G R O U P 
D -F R -5 2 1 2 0 -2 7 9  
C O N FI D E N TI A L  
P R O T O C O L: FI N A L 3 0  A P RI L 2 0 2 1  
P A G E 3 8 /5 6  
 
I pse n Pr ot oc ol te m plate versi o n 7. 0 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1  
St atistic al H y p ot heses  
T he pri mar y e n d p oi nt, C M A P t otal a m plit u de at Wee k 2 8, meas ure d as relati ve c ha n ge fr o m 
Baseli ne ( %), will be a n al yse d usi n g a mi x e d -effects m o del f or re peate d meas ures ( M M R M), 
δ d b =  µ d ys p ort - µ b ot o x a n d δ d x =  µ d ys p ort - µ xe o mi n are t he c o ntrasts (i.e. mi x e d m o del Wa l d tests) of 
t he D ys p ort vers us B ot o x vers us Xe o mi n c o m paris o ns i n t he pri mar y e n d p oi nt at Wee k 2 8 of 
t he st u d y. T w o ele me ntal n ull h y p ot heses will be i n vesti gate d,  
H 0, d b, 1 :    δ d b  = 0  a n d  
H 0, d x, 1 :    δ d x  = 0.  
T hese n ull h y p ot heses of n o differe nce  bet wee n t he res pecti ve treat me nt ar ms i n t he pri mar y 
e n d p oi nt will be teste d a gai nst t he res pecti ve t w o -si de d alter nati ve h y p ot h eses  
H A, d b, 1  :    δ d b  ≠ 0  a n d  
H A, d x, 1  :    δ d x  ≠ 0  
at a 5 % si g nifica n ce l e vel ( α = 0. 0 5) usi n g a M M R M m o del a n d mi x e d m o d el  Wal d tests of t he 
res pecti ve c o ntrast t he D ys p ort vers us B ot o x vers us Xe o mi n c o m paris o ns i n t he pri mar y 
e n d p oi nt at W ee k  2 8 of t he st u d y.  
T o c o ntr ol f or t he fa mil y -wis e t y p e  I err or rat e at t he t w o-si de d le vel α =  0. 0 5, a H oc h ber g 
pr oce d ure [D mitrie n k o a n d D’ A g osti n o 2 0 1 3 ] will be a p plie d t o i n vesti gate t he t w o n ull 
h y p ot hes es H 0, d b, 1 a n d H 0, d x, 1. T he testi n g pr oce d ure uses t he f oll o wi n g d ecisi o n r ules f or t he 
t w o p-val ues p d b a n d p d x: 
• 
B ot h n ull h y p ot hes es are rejecte d if ma x( p d b , pd x) ≤ α  
• 
O nl y t he n ull h y p ot hesis c orres p o n di n g t o t he s maller p -val ue mi n( p d b , pd x) is rejecte d if 
mi n( p d b , pd x) ≤ α/ 2 a n d ma x( pd b , pd x) > α. 
If b ot h n ull h y p ot heses of t he pri mar y e n d p oi nt are rejecte d, t h e n t he sa me H oc h ber g pr oce d ure 
will be a p plie d se q u e ntiall y t o t he t w o res p ecti v e n ull h y p ot h eses c o m p ari n g D ys p ort wit h 
B ot o x a n d wit h Xe o mi n f or sec o n dar y e n d p oi nts i n t he f oll o wi n g or der:  
1.  
C M A P t otal a m plit u de at Wee k 4 0 p ost -i njecti o n   
2.  
I n ci de nce of rec o ver y of C M A P t otal a m plit u de at Wee k 2 8 p ost-i njecti o n   
3.  
I n ci de nce of rec o ver y of C M A P t otal a m plit u de at Wee k 4 0 p ost-i njecti o n   
T he t w o n ull h y p ot heses of sec o n dar y e n d p oi nt k, k = 2,  3  are teste d wit h a H oc h ber g pr oce d ure, 
w he n b ot h n ull h y p ot hes es of e n d p oi nt k -1 are rejecte d.     
9. 2  
S a m ple Size D eter mi n ati o n  
A p pr o xi matel y 4 8 partici pa nts will be scree ne d t o ac hie ve 1 5 partici pa nts ra n d o mise d t o 
D ys p ort, 1 5 partici pa nts ra n d o mise d t o B ot o x a n d 1 5 partici pa nts ra n d o mise d t o Xe o mi n usi n g 
a 1: 1: 1 ra n d o misati o n rati o a n d ass u mi n g a s cree ni n g fail ure rat e of 5 %.   
T he sa m ple siz e cal c ulati o n is base d o n t h e pri mar y effi cac y esti ma n d a n d its e n d p oi nt rel ati ve 
c ha n ge fr o m bas eli ne i n E D B C M A P t otal a m plit u de at Wee k 2 8. Usi n g a 2 -si de d t-test at t he 
5 % si g nifi ca nce le v el, t h e c h ose n sa m ple siz e pr o vi des at least 8 8 % p o wer t o detect a treat me nt 
differe n ce of  1 8 % relati ve c ha n ge fr o m b aseli ne i n t he D ys p ort ar m t ha n i n a c o m parat or ar m 
ass u mi n g a c o m m o n  st a n dar d d e viati o n i n all tr eat me nt ar ms of 1 5 % as o bser ve d f or D ys p ort 
i n a hist orical st u d y 
 –  Part B. T he treat me nt differe n ce is base d o n t he 
o bser ve d a v era ge E D B C M A P t otal a m plit u de at 6 m o nt hs of D ys p ort 4 0 U (
 
–  Part B)  a n d of B ot o x a n d Xe o mi n 1 6 U i n W o hlfart h [ W o hlfart h 2 0 0 7 ]. T he p o wer a nal ysis 
was c o n d ucte d wit h N Q uer y versi o n 8. 4. 1. 0.  Gi ve n t he ma de ass u m pti o ns a n d t he sa m ple siz e 
of 1 5 partici p a nts per ar m t he pr o ba bilit y t o s h o w s u peri orit y of D ys p ort t o b ot h c o m parat ors 
C CI
C CI

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simultaneously is at least 81%, as shown in a simulation study conducted with software R 
version 4.0.3.  
9.3 
Analysis Sets 
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Screened 
All participants who signed an informed consent form 
Randomised  
The randomised set will contain all participants who are randomised to study 
treatment. A participant will be considered as randomised if a study 
intervention group has been randomly assigned. For analyses and displays, 
participants will be classified according to randomised treatment 
Safety 
The safety set will contain all participants who receive at least one dose of 
study medication. For analyses on the safety set, participants will be 
classified according to treatment received. If there is any doubt whether a 
participant was treated or not, he will be assumed treated for the purposes of 
analysis. 
Pharmacodynamic (PD) 
The PD analysis set will contain all participants from the randomised set 
who receive the appropriate dose of study treatment and have CMAP 
recorded for baseline and at least one post baseline assessment. 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be finalized prior to database lock and it will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
The COVID-19 pandemic may have an impact on this study. Participants substantially affected 
directly or indirectly by COVID-19 will be flagged with a protocol deviation. If the protocol 
deviation is major and is suspected to interfere with CMAP total amplitude, it will be handled 
as intercurrent event as described in Section 9.4.2.1. Further details will be provided in the SAP. 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s biometry 
department. Statistical evaluation will be performed using Statistical Analysis System (SAS)® 
version 9.4 or higher.  
9.4.1 
General Considerations 
Subject disposition will be summarized descriptively for all screened subjects. Discontinuations 
will be summarized descriptively for all randomized subjects.  Demographics and other baseline 
characteristics will be summarized descriptively in the randomized set by study intervention 
group and overall. 
Data collected in this trial will be summarized according to their nature as follows: 
• 
Continuous variables: arithmetic mean, standard deviation, minimum and maximum 
values, median and quartiles depending on the number of observations. 
• 
Categorical variables: absolute and relative frequencies. 
A summary table of protocol deviations and the corresponding listing will be prepared. 
9.4.1.1 
Pharmacodynamic Evaluation  
Individual pharmacodynamic endpoints will be tabulated by treatment and timepoint. For the 
EDB CMAP, three measurements of CMAP will be taken at each timepoint including baseline. 
The mean of these three measurements will be used to determine the parameter relative change 
from baseline in CMAP total amplitude, used in primary and secondary analyses of the EDB 
CMAP related endpoints. The baseline value used for the analyses will be the average of six 
measurements, the three measurements at screening and the three measurements at baseline. 

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At each visit time to latency will be evaluated. Skin temperature and stimulation intensity will 
be also collected for quality control and descriptive statistics. 
Individual pharmacodynamic endpoints will be tabulated by treatment allocation and timepoint.  
Further details on general statistical considerations will be specified in the statistical analysis 
plan (SAP). 
9.4.2 
Analysis of Primary Endpoint(s) 
9.4.2.1 
Primary Estimand 
The primary estimand has the following key attributes: 
• 
Population of interest: healthy adult male participants as defined by the listed 
inclusion/exclusion criteria in Section 5. 
• 
Variable/endpoint of interest: CMAP total amplitude at Week 28, measured as relative 
change from Baseline (%).  
a) Key Intercurrent event (ICE): study discontinuation 
b) Major protocol deviation interfering with CMAP total amplitude.  
• 
Treatment regimen: Dysport, Botox or Xeomin will be administered as described in 
Section 6 and potential intake of permitted concomitant medications (for a list see 
Section 6.8). 
• 
Population-level summary of the treatment effect of interest: the difference in average 
relative change from baseline in each study intervention group in CMAP total amplitude 
at the respective timepoint. 
For ICEs (a) and (b) a hypothetical strategy will be used, the treatment difference which would 
have been measured if the intercurrent event would not have happened is of interest and will be 
assessed taking into account the long term pharmacodynamic effect of the investigated 
compounds. This implies that assessments after the occurrence of a major protocol deviation 
interfering with CMAP total amplitude will be ignored for the primary analysis. 
9.4.2.2 
Primary Analysis 
The primary endpoint, CMAP total amplitude at Week 28, measured as relative change from 
Baseline (%), will be analysed using a mixed-effects model for MMRM. The model will include 
fixed effects of treatment, time (corresponding to study visit), treatment-by-time interaction and 
baseline CMAP amplitude, as well as an unstructured covariance matrix to model the 
covariance structure of the repeated measures.  
Using the mixed-effects model described above, the Dysport versus Botox and Dysport versus 
Xeomin comparisons in the primary endpoint at Week 28 of the study will be investigated using 
the according partial tests (i.e. mixed model Wald tests). Results of the primary analysis will 
contain an estimate of the treatment difference between Dysport and comparators Botox and 
Xeomin in CMAP total amplitude at Week 28, as well as standard error, 95% confidence 
interval, and p-value. 
9.4.2.3 
Convergence of the MMRM Model 
If the default Newton-Raphson algorithm used by statistical analysis software PROC MIXED 
fails to converge, the Fisher scoring algorithm up to iteration 2 will be used (via the 
SCORING=2 option of the PROC MIXED statement) to obtain the initial values of covariance 
parameters [Mallinckrodt 2008]. If this alternative also fails to converge, then in addition the 
no-diagonal factor analytic structure (via the TYPE=FA0(T) option of the REPEATED 
statement, where T is the number of post baseline measurement timepoints incorporated in the 

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MMRM analysis) will be used, which effectively performs the Cholesky decomposition of the 
covariance matrix and is numerically more stable. 
When the above strategies fail, then, in addition to the changes described above, a model with 
the less complex heterogeneous Toeplitz covariance structure (TOEPH) will be fitted. When 
the above strategies fail, then, in addition to the changes described above, a model with the less 
complex compound symmetry covariance structure (CS) will be fitted. When all above 
measures fail, then the primary endpoint, CMAP total amplitude at Week 28, measured as 
relative change from Baseline (%), will be analysed using an Analysis of Covariance 
(ANCOVA) model with covariates treatment and baseline CMAP amplitude.  
The first algorithm that leads to convergence in this sequence of fallback measures will be the 
algorithm used for the primary analysis of the study. 
9.4.2.4 
Missing Data Handling 
The MMRM is implicitly handling missing data as missing at random (MAR) without explicit 
imputation. This missingness assumption appears meaningful given the long term 
pharmacodynamic effect of the investigated compounds: the effect of the drug will persist after 
discontinuation and is not expected, given baseline profile of the participant and assessments 
until the timepoint of discontinuation, to depend on whether the participant remains observable 
in the study or drops out. 
In case of occurrence of a major protocol deviation interfering with CMAP total amplitude, 
CMAP data collected after the protocol deviation will be ignored, and will be handled by the 
model as MAR. This implements a ‘per protocol’ analysis assessing the treatment difference 
occurring in case participants adhere to the protocol by using a hypothetical handling strategy 
for this intercurrent event.  
9.4.2.5 
Sensitivity and Supplementary Analyses 
In case of occurrence of a major protocol deviation interfering with CMAP total amplitude, a 
supplementary analysis will be conducted using a treatment policy strategy to handle this 
intercurrent event. All collected CMAP data will be taken into account in this supplementary 
analysis, even when occurring after the protocol deviation. 
9.4.3 
 Analysis of Secondary Endpoints 
9.4.3.1 
 Incidence of Recovery of CMAP Total Amplitude at Week 28 and Week 40 
Recovery of CMAP total amplitude is defined as a return of total amplitude to at least 85% of 
the Baseline value. Incidence of recovery of CMAP total amplitude at Weeks 28 and 40 will be 
analysed for each of the two timepoints by estimating proportion of participants with recovery 
in each of the treatment arms, pD in the Dysport arm, pB in the Botox arm, pX in the Xeomin 
arm, as well as  the risk differences pD – pB and pD – pX  with point estimates as well as according 
exact (Clopper-Pearson) 95% confidence intervals for pD , pB  and pX and exact unconditional 
95% confidence interval for the risk differences.  
A Fisher’s Exact Test (one-sided, significance level 2.5%) will be used for testing each of the 
comparisons of Dysport to Botox or Xeomin respectively in the framework of the multiple 
testing procedure described in Section 9.1. 
9.4.3.2 
CMAP Total Amplitude at Week 40  
CMAP total amplitude at Week 40 will be analysed using the same MMRM model used for the 
primary analysis.  

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9.4.3.3 
Time to Onset of Action 
Time to onset of action will be analysed descriptively. Onset of action is defined as the first 
timepoint where EDB CMAP total amplitude is 85% or lower than the Baseline value. 
9.4.3.4 
Duration of Response 
Duration of response will be analysed descriptively. Duration of response is defined as the time 
between onset of action and recovery of CMAP total amplitude (where recovery is defined as 
return to at least 85% of the Baseline value).  
9.4.3.5 
Maximal Effect 
Maximal Effect for each participant is defined as the maximal measured inhibition of CMAP 
amplitude of stimulated EDB. Maximal Effect will be analysed descriptively. 
9.4.3.6 
Time to Maximal Effect 
Time to maximal effect will be analysed descriptively. Time to maximal effect is defined on an 
individual basis as the time between Baseline and the timepoint of maximal inhibition of CMAP 
amplitude of stimulated EDB. 
9.4.4 
Safety Analyses 
All safety analyses will be made on the Safety Population.  
Summary statistics will be presented by study intervention group and overall for vital signs, 
physical examination, at each assessment.  
Adverse Events 
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) (last applicable version) and will be classified by MedDRA preferred term and 
system organ class.  
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of study intervention, or  
• 
it was present prior to receiving the first dose of study intervention but the intensity 
increased during the active phase of the study. 
All AEs, TEAEs, treatment-related AEs and study procedure-related AEs will be summarised 
by system organ class and preferred term in tables with the number of subjects with at least one 
AE and total number of AEs, the number of subjects with at least one treatment-related AE and 
the number of treatment-related AEs, and the number of subjects with at least one study 
procedure-related AE and number of study procedure-related AEs. 
All AEs, treatment-related AEs, study procedure-related AEs and concomitant medications 
will be listed.  
9.4.5 
Subgroups Analyse(s) 
No subgroup analyses will be performed  
9.4.6 
Exploratory Analyse(s)  
Exploratory analyses including analysis of CMAP endpoints at timepoints different from 
Weeks 28 and 40 and latency of M-wave at all timepoints will be specified in the SAP. 
9.5 
Interim Analyses 
No interim analyses are planned.  

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10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
o 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g. advertisements) must be approved by the IRB/IEC before the study is 
initiated. 
• 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
• 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The investigator will be responsible for the following: 
o 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
applicable 
local 
regulations, 
ICH 
guidelines 
and 
the 
IRB/IEC 
requirements/procedures. 
10.1.2 
Financial Disclosure 
The investigator and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for one year after completion of the study. 
10.1.3 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included participant, based on the calculated costs of performing the study 
assessments in accordance with the protocol and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 

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10.1.4 
Insurance, Indemnity and Compensation 
The sponsor will provide product liability insurance for all participants included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 
10.1.5 
Informed Consent Process 
• 
The ICF and any participant recruitment materials must be in compliance with ICH GCP, 
local regulatory requirements, and legal requirements, including applicable privacy laws. 
• 
The ICF used during the informed consent process and any participant recruitment 
materials must be approved by the IRB/EC before use, and available for audit and 
inspection.  
• 
The investigator or his/her authorised representative will explain to the participant the 
nature and objectives of the study and possible risks associated with the participation. 
They will answer all questions raised by the participant regarding the study and allow 
sufficient time for discussion. 
• 
Participants must be informed that their participation is voluntary.  
• 
The investigator or his/her authorised representative will obtain written informed consent 
from each participant before any study-specific procedure is performed. The investigator 
will retain the original of each participant’s signed ICF.  
• 
A copy of the signed ICF(s) must be provided to the participant. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
The ICF will contain a separate section that addresses the use of all data for optional 
future research. These data may only be used for scientific health-related research to find 
new ways to detect, treat, prevent or cure health problems. Participants will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the study. A specific consent will be required to document a 
participant’s agreement to allow any data to be used for future research.  
A participant who is rescreened will be required to sign another ICF. 
If a pregnancy is reported for a female partner of a male participant during the study, the female 
partner will be asked to sign appropriate consent for the sponsor to follow the outcome of the 
pregnancy 
10.1.6 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the participant who will be required to give consent for their data to be used as described in the 
informed consent.  
The participant must be informed that his medical records may be examined by the sponsor’s 
auditors or other authorised personnel appointed by the sponsor, by appropriate IRB/IEC 
members, and by inspectors from regulatory authorities. 

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10.1.7 
Dissemination of Clinical Study Data 
The sponsor seeks to publish the results of its clinical trials in biomedical journals, whatever 
the outcome. Clinical trial results may also be presented at international congresses as posters 
or oral presentations. 
Protocol and result summary will be made publicly available on the US Clinical Trials Registry 
(ClinicalTrials.gov) and for studies run in the European Union (EU)/European Economic Area 
on the EU Clinical Trials Register (www.clinicaltrialsregister.eu). The sponsor also provides 
clinical trial information to other national clinical trial registries or databases according to local 
requirements/legislation. 
A clinical study report will be prepared if at least one participant has signed informed consent 
and received intervention, regardless of whether the study is completed or prematurely 
terminated. The clinical study report may be disclosed according to regulatory requirements.  
10.1.8 
Data Quality Assurance 
All participant data relating to the study will be recorded on electronic eCRF unless transmitted 
to the sponsor or designee electronically (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by electronically signing the eCRF. 
Guidance on completion of eCRFs will be provided in eCRF completion guidelines. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
authority inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g. risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
The sponsor assumes accountability for actions delegated to other individuals (e.g. Contract 
Research Organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study should 
be retained by the investigator according to the ICH-GCP guidelines, to local regulations, or as 
specified in the study agreement, whichever is longer. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
Reasons should be given on the relevant eCRF for any missing data and other protocol 
deviations. Any electronic queries and items not adequately explained will require additional 
electronic manual queries to be raised to the investigator by the monitor for 
clarification/correction. The investigator must ensure that queries are dealt with promptly. All 
data changes and clarifications can be viewed in the audit trail function of the eCRF. 
10.1.8.1 Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor is responsible for monitoring these data to verify that the rights and wellbeing of 
participants are protected, that study data are accurate (complete and verifiable to source data) 
and that the study is conducted in compliance with the protocol, GCP guidelines and regulatory 
requirements. 

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Sponsor assigned monitors will conduct regular site visits. The investigator will allow direct 
access to all relevant files (for all participants) and clinical study supplies (dispensing and 
storage areas) for the purpose of verifying entries made in the eCRF and will assist with the 
monitor’s activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. The investigator or an approved representative (e.g. pharmacist) 
will ensure that all IMP is reconstituted and dispensed by unblinded qualified staff member who 
will document the participant allocated treatment number. Participants and investigators will 
remain blinded to treatment assignment during the study.  
The site must complete the eCRFs on an ongoing basis in 5 working days to allow regular 
review by the study monitor, both remotely by the internet and during site visits. 
Whenever a participant name is revealed on a document required by the sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the initials 
visible and annotated with the participant number as identification. 
10.1.8.2 Information to Study Personnel 
To ensure accurate, complete and reliable data, the sponsor or its representatives will provide 
instructional material to the study sites, as appropriate. A study initiation visit will be conducted 
prior to screening start to instruct the investigators and study coordinators. This session will 
give instruction on the protocol, the completion of the eCRF and all study procedures. The 
investigator is responsible for giving information about the study to all staff members involved 
in the study or in any element of participant management, both before starting any study 
procedures and during the course of the study (e.g. when new staff become involved). The 
investigator must assure that all study staff members are qualified by education, experience and 
training to perform their specific responsibilities. These study staff members must be listed on 
the study centre authorisation form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
10.1.8.3 Investigator’s Regulatory Obligations 
All clinical work under this protocol will be conducted according to GCP guidelines. This 
includes that the study may be audited at any time by a quality assurance personnel designated 
by the sponsor or inspected by regulatory bodies. The investigator must adhere to ICH GCP 
guidelines in addition to any applicable local regulations. 
If requested, the investigator will provide the sponsor, applicable regulatory agencies and 
applicable EC with direct access to any original source documents. 
The investigator should demonstrate due diligence in recruitment and screening of potential 
study participants. The enrolment rate should be sufficient to complete the study as agreed with 
the sponsor. The sponsor should be notified of any projected delays, which may impact the 
completion of the study. 
This clinical trial will be conducted in compliance with all international laws and regulations 
and national laws and regulations of the country(ies) in which the clinical trial is performed, as 
well as any applicable guidelines. 
10.1.9 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 

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Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
The investigator must maintain accurate documentation that supports the information entered 
in the eCRF. Source data must be attributable, legible, contemporaneous, original, accurate and 
complete. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9.1 Recording of Study Data 
In compliance with GCP guidelines, the medical records/medical notes, etc., should be clearly 
marked and permit easy identification of a participant’s participation in the specified clinical 
study. 
The investigator must record all data relating to protocol procedures, IMP administration, 
laboratory data, safety data and efficacy ratings on the eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff (having certified user access to the eCRF). 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each case 
report book to attest to the accuracy and completeness of all the data. If any changes are made 
to the eCRF after a form has been locked and electronically signed, the investigator will be 
required to perform an additional e-signature authorising agreement with any new information 
or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
10.1.9.2 Data Management 
Electronic Data Capture will be utilised for collecting participant data. Each site is required to 
have a computer and internet connection available for site entry of clinical data. All entries in 
the eCRF will be made under the e-signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of the handwritten signature. 
Only sponsor authorised users will have access to the eCRF as appropriate to their study 
responsibilities. Users must have successfully undergone software application training prior to 
entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s data management 
department. All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, they 
will be monitored at the investigator site, (for further details see Section 10.1.8.1). The eCRF 
and other data documentation removed from the investigator site(s) will be tracked by the CRO 
and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator will 
receive their data, from the clinical study, in an electronic format (PDF files) which will be an 

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exact copy of the eCRF and will include the full audit trail, for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the 
contracted CRO. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history, surgical procedures and concomitant medication terms 
will be performed by the contracted CRO, directed by the sponsor’s data management 
department and reviewed and approved by the sponsor. Concomitant medications will be coded 
using WHODRUG and AEs/medical history terms will be coded using MedDRA. 
Only data from enrolled participants will be reported in the eCRFs and collected in the sponsor’s 
database. 
For screen failure participants, at least the Unique Participant Identifier, the date of informed 
consent signature, the reason why the participant failed screening and the potential AEs which 
occurred during the screening phase will be reported in the eCRFs and collected in the sponsor’s 
database. Rescreened participants will sign a new ICF and a new participant identification 
number will be allocated. 
10.1.9.3 Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the site. The sponsor will inform the investigator, in writing, 
as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 
10.1.10 Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 

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For study termination: 
• 
Discontinuation of further study intervention development 
For site termination: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.11 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 

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10.2 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 4 will be performed by the local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Table 4 
Protocol-Required Safety Laboratory Tests 
Parameters 
Screening 
Intervention Period 
EoS 
Haematology 
Platelet count 
X 
 
 
Red blood cell count 
X 
 
 
Haemoglobin 
X 
 
 
Haematocrit 
X 
 
 
Red blood cell indices: 
MCV 
MCH 
%Reticulocytes 
X 
 
 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
X 
 
 
Coagulation 
International normalised ratio 
X 
 
 
Clinical Chemistry 
Urea 
X 
 
 
Creatinine 
X 
 
 
Glucose (non-fasted)  
X 
 
 
Potassium 
X 
 
 
Sodium 
X 
 
 
Calcium 
X 
 
 
Aspartate aminotransferase / Serum glutamic-
oxaloacetic transaminase 
X 
 
 
Alanine aminotransferase / Serum glutamic-pyruvic 
transaminase 
X 
 
 
Alkaline phosphatase 
X 
 
 
Total and direct bilirubin 
X 
 
 
Total protein 
X 
 
 
Other Screening Tests 
Urine drug screen 
X 
 
 
SARS-CoV-2 
X 
X [a] 
 
Serology (HIV antibody, hepatitis B surface antigen, 
and hepatitis C virus antibody) 
X 
 
 
COVID-19=coronavirus disease 2019; EoS=end of study; HIV=human immunodeficiency virus; MCH=mean corpuscular 
haemoglobin; MCV=mean corpuscular volume 
a 
To be performed predose on Day 1 and at any other timepoint during the intervention period as required or in the 
 
event of suspected COVID-19 infection during the study. 
 
Investigators must document their review of each laboratory safety report. 

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10.4 
Appendix 4: Adverse Events of Special Interest by Function Suggestive of 
Possible Remote Spread of Effect of Toxin 
Function 
AESI 
Related to eye function 
Accommodation 
disorder, 
vision 
blurred, 
diplopia, extraocular muscle paresis, IIIrd nerve 
paresis, IVth nerve paresis, pupillary reflex 
impaired, eyelid function disorder, eyelid ptosis 
Related to chewing/tongue 
 
Bulbar 
palsy, 
hypoglossal 
nerve 
paresis, 
trigeminal nerve paresis 
Related to voice 
Dysphonia, bulbar palsy, dysarthria, hypoglossal 
nerve paresis, speech disorder, vocal cord 
paralysis, vocal cord paresis 
Related to mouth/throat/bowel 
Dysphagia, dry mouth, constipation, paralytic 
ileus, bulbar palsy 
Related to heart function 
Bradycardia 
Related to lung function 
Dyspnoea, diaphragmatic paralysis, respiratory 
arrest, 
aspiration, 
pneumonia 
aspiration, 
respiratory depression, respiratory failure 
Related to bladder function 
Pelvic floor muscle weakness, urinary retention 
Related to muscle function/strength 
Cranial nerve palsies multiple, cranial nerve 
paralysis, paresis cranial nerve, trigeminal nerve 
paresis, 
monoparesis, 
muscular 
weakness, 
paralysis, paralysis flaccid, paresis, peripheral 
nerve palsy, peripheral paralysis, facial palsy, 
facial paresis, areflexia, botulism, hyporeflexia, 
hypotonia, 
quadriparesis, 
hemiparesis, 
paraparesis 
 

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11 
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