Clinical trial NCT02002884
Conditions: Cerebral Palsy Spasticity
Keywords: Upper limb spasticity lower limb spasticity combined upper and lower limb spasticity
Sponsor: Merz Pharmaceuticals GmbH
Start date: 2014-03-28; Completion date: 2018-08-28
Enrollment: 351 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both arms alone or in combination with injections into one or both legs are effective and safe in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Detailed description:

Arms: arm 1: 8 Units per kg body weight (maximum of 200 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 300 Units per injection cycle. Overall maximum dose per injection cycle: 500 Units. arm 2: 6 Units per kg body weight (maximum of 150 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 225 Units per injection cycle. Overall maximum dose per injection cycle: 375 Units. arm 3: 2 Units per kg body weight (maximum of 50 Units) will be injected per treated upper limb per injection cycle. Additionally, lower limb treatment may be administered, depending on clinical pattern: up to 75 Units per injection cycle. Overall maximum dose per injection cycle: 125 Units.
Interventions: intervention 1: IncobotulinumtoxinA (8 Units per kg body weight) intervention 2: IncobotulinumtoxinA (6 Units per kg body weight) intervention 3: IncobotulinumtoxinA (2 Units per kg body weight)
Intervention descriptions: intervention 1: Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles. intervention 2: Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles. intervention 3: Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Protocol documents:
Prot_001.pdf: 
Merz Pharmaceuticals GmbH  
Document status 
Clinical Study Protocol MRZ60201_3072_1 
Amended Protocol Version Final 3.0 (07-Apr-2016) 
Confidential 
Page 1 of 273 
TITLE PAGE 
Prospective, multicenter, randomized, double-blind, parallel-
group, dose-response study of three doses Xeomin® 
(incobotulinumtoxinA, NT 201) for the treatment of upper limb 
spasticity alone or combined upper and lower limb spasticity in 
children and adolescents (age 2 - 17 years) with cerebral palsy 
Development phase: 
Phase 3 
Study identifier 
EudraCT Number 
IND Number 
MRZ60201_3072_1 
2012-005496-14 
110,686 
Acronym: 
XARA – IncobotulinumtoXinA in aRm treatment in 
Cerebral PAlsy 
Indication: 
Upper limb spasticity or combined upper and lower limb 
spasticity 
in 
children 
and 
adolescents 
(age 2 - 17 years) with cerebral palsy 
Planned study period: 
Start of recruitment: Jan-2014 
End of study: 
Jan-2019 
Investigational product(s): 
NT 201, 100 Units, powder for solution for injection 
(active ingredient: NT 101, Botulinum neurotoxin type A 
free 
from 
complexing 
proteins, 
USAN: incobotulinumtoxinA)  
Sponsor: 
Merz Pharmaceuticals GmbH 
Eckenheimer Landstr. 100 
60318 Frankfurt/Main Germany 
Telephone: 
+49 69 1503 0 
Telefax: 
+49 69 1503 200
Responsible for the clinical 
study protocol content at 
the sponsor: 
Medical Expert: 
Biostatistician: 
Clinical Project 
Manager: 
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary to Merz Pharmaceuticals. 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not be 
disclosed to parties not associated with the clinical investigation without the prior written consent of Merz 
Pharmaceuticals. 
NCT02002884, redacted version v1.0, 13Jul2020




Merz Pharmaceuticals GmbH  
Document status 
Clinical Study Protocol MRZ60201_3072_1 
Amended Protocol Version Final 3.0 (07-Apr-2016) 
Confidential 
Page 3 of 273 
F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
STATEMENT OF COMPLIANCE 
Investigational Site(s) 
I have thoroughly read and reviewed the clinical study protocol. Having understood the 
requirements and conditions of the clinical study protocol, I agree to perform the clinical 
study according to the clinical study protocol, the case report form, ICH-GCP principles, 
the Declaration of Helsinki, and regulatory authority requirements. 
I have received the current investigator’s brochure [IB]. Having been adequately 
informed about the investigational product [IP] development to date, I also agree to: 
• Sign this clinical study protocol before the study formally starts. 
• Wait until I have received approval from the appropriate independent ethics 
committees/institutional review boards [IEC/IRB] before enrolling any subject in this 
study. 
• Obtain informed consent [IC] for all subjects prior to any study-related action 
performed. 
• Start the study only after all legal requirements have been fulfilled. 
• Permit study-related monitoring, audits, IEC/IRB review, regulatory inspections and 
cooperate with corresponding functions. 
• Notify Study Sponsor as soon as possible after notification of potential Food and 
Drug Administration [FDA] audit. 
• Notify the appropriate IEC/IRB on serious adverse events [SAE]s according to local 
requirements. 
• Provide direct access to all study-related records, source documents, and subject files 
for the monitor, auditor, IEC/IRB, or regulatory authority upon request. 
• Use the IP and all study materials only as specified in the clinical study protocol. 
• Report to the responsible drug safety officer, within 24 hours, any adverse that is 
serious [SAE], whether considered treatment-related or not as well as any adverse 
event of special interest [AESI] (see Section 10.3 for definition). 
• For US sites: Prior to initiating the study, I will provide the sponsor with a written 
disclosure information including a written disclosure of any financial interest in 
accordance with 21 CFR Part 54 and a signed FDA 1572 form according to 21 CFR 
Part 312. 


Merz Pharmaceuticals GmbH  
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Amended Protocol Version Final 3.0 (07-Apr-2016) 
Confidential 
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F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
Furthermore, I understand that: 
• Changes to the clinical study protocol must be made in the form of an amendment 
that has the prior written approval of Merz Pharmaceuticals GmbH and – as 
applicable – of the appropriate IEC/IRB and regulatory authority. 
• The content of the clinical study protocol is confidential and proprietary to Merz 
Pharmaceuticals GmbH.  
• Any deviation from the clinical study protocol may lead to early termination of the 
study site. 
 
 
 
 
Principal investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
 
 
 
 
Investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
 
 
 
 
Investigational site stamp (if applicable): 
 
 


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F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
 
 
AS 
Ashworth Scale 
ATC 
Anatomical Therapeutic Chemical classification system of the World Health Organization 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BDRM 
Blind data review meeting 
BMI 
Body mass index 
BoNT 
Botulinum toxin 
BoNT-A 
Botulinum toxin type A 
BW 
Body weight 
C 
Celsius 
 
 
CP 
Cerebral palsy 
CRF 
Case report form 
CRO 
Contract research organization 
Ctrl. 
Control 
DMC 
Data monitoring committee 
DVP 
Data validation plan 
eCRF 
Electronic case report form 
EDTA 
Ethylenediaminetetraacetic acid 
EEA 
European Economic Area 
eGFR 
Estimated Glomerular Filtration Rate 
EMG 
Electromyography 
EOC 
End of cycle 
EOS 
End of study 
e-stim 
Electrical stimulation 
EudraCT 
European clinical trial database 
F 
Fahrenheit 
FAS 
Full analysis set 
FDA 
Food and Drug Administration, US  
FIA 
Fluorescence immunoassay 


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F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
FIA-AB 
Fluorescence immunoassay detecting antibodies 
GCP 
Good clinical practice  
GICS 
Global Impression of Change Scales 
GMFCS 
Gross Motor Function Classification System 
Guardian 
Person different from parent(s) who legally represents the child/adolescent  
HDA 
Hemidiaphragm assay 
IB 
Investigator’s brochure 
IC 
Informed consent 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee  
i m. 
Intramuscular 
IND  
Investigational new drug  
IP 
Investigational product 
IRB 
Institutional review board  
ISF 
Investigator’s site file 
IV/WRS 
Interactive voice (web) response system 
LD50U 
Lethal Dose 50 (LD50) Units in animal studies 
LL 
Lower limb 
LOCF 
Last observation carried forward principle 
MAS 
modified Ashworth Score 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MMRM 
Mixed model repeated measurement 
MP 
Main period 
MRZ 
Merz 
N 
Number of non-missing observations 
OC 
Observed case 
OLEX 
Open-label-extension period 
PBO 
Placebo 
PI 
Principal investigator 
PMC 
Post Marketing Commitment (US FDA) 
PPS 
Per protocol set 
QPS 
Questionnaire on Pain caused by Spasticity 
s 
Second 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SD 
Standard deviation 
SES 
Safety evaluation set 
SOP 
Standard operating procedure 
SPC 
Summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
SV 
Safety Visit 
TBV 
Total blood volume 
TEAE 
Treatment emergent adverse event 
TEAESI 
Treatment emergent adverse event if special interest 
TESAE 
Treatment emergent serious adverse event 
U 
Unit 
UL 
Upper limb 
UMNS 
Upper motor neuron syndrome 
US 
United States 
USAN 
United States Adopted Name 
V 
Visit 
WHO 
World Health Organization 
Wk 
Week 


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Table of Contents 
 
SIGNATURE PAGE ..........................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................5 
1 
SYNOPSIS .................................................................................................................14 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................31 
2.1 
Internal responsibilities ..........................................................................................31 
2.2 
External responsibilities .........................................................................................31 
2.3 
Committees ............................................................................................................34 
3 
ETHICS .....................................................................................................................35 
3.1 
Independent Ethics Committee/Institutional Review Board..................................35 
3.2 
Ethical conduct of the study ...................................................................................35 
3.3 
Subject information and informed consent ............................................................35 
3.3.1 
Subject information ..........................................................................................35 
3.3.2 
Informed consent/assent...................................................................................36 
3.3.3 
Subject card ......................................................................................................37 
3.3.4 
Post-study treatment.........................................................................................37 
3.3.5 
Subject privacy.................................................................................................38 
3.3.6 
Contact point ....................................................................................................38 
3.4 
Insurance ................................................................................................................38 
3.5 
Financing................................................................................................................38 
4 
INTRODUCTION ....................................................................................................39 
4.1 
Study background ..................................................................................................39 
4.2 
Study rationale .......................................................................................................41 
4.3 
Risk-benefit assessment .........................................................................................42 
5 
STUDY OBJECTIVES ............................................................................................46 
6 
INVESTIGATIONAL PLAN ..................................................................................47 
6.1 
Overall study design ..............................................................................................47 
6.1.1 
End of study .....................................................................................................49 
6.1.2 
Study flow chart ...............................................................................................50 
6.2 
Discussion of Study Design, Including Choice of Control Groups .......................51 
7 
STUDY POPULATION ...........................................................................................53 
7.1 
Selection of study population.................................................................................53 
7.2 
Inclusion criteria ....................................................................................................54 


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7.3 
Exclusion criteria ...................................................................................................59 
7.3.1 
Eligibility criteria for OLEX injections ...........................................................62 
7.4 
Removal of subjects from treatment or assessment ...............................................65 
7.4.1 
Discontinuation of subjects ..............................................................................65 
7.4.2 
Premature termination or suspension of the study or a study site ....................66 
7.4.3 
Provision of care for subjects after study discontinuation ...............................67 
8 
TREATMENTS ........................................................................................................68 
8.1 
Investigational product(s) ......................................................................................68 
8.1.1 
Description of investigational product(s).........................................................68 
8.1.2 
Packaging and labeling ....................................................................................86 
8.1.3 
Storage of investigational product(s) ...............................................................88 
8.1.4 
Accountability for investigational product(s) ..................................................88 
8.1.5 
Destruction of investigational product(s).........................................................89 
8.2 
Treatments administered ........................................................................................89 
8.2.1 
Methods of assigning subjects to treatment groups .........................................89 
8.2.2 
Selection of doses in the study .........................................................................90 
8.2.3 
Selection and timing of doses for each subject ................................................91 
8.2.4 
Duration of treatment per subject ....................................................................92 
8.2.5 
Treatment compliance ......................................................................................92 
8.2.6 
Treatment of overdose .....................................................................................92 
8.3 
Previous and concomitant therapies.......................................................................93 
8.3.1 
Authorized Concomitant Medication/Treatment .............................................94 
8.3.2 
Non-authorized concomitant therapies ............................................................95 
8.4 
Blinding..................................................................................................................96 
8.4.1 
Emergency envelopes ......................................................................................96 
8.4.2 
Unblinding procedures .....................................................................................97 
9 
STUDY ASSESSMENTS AND VISIT SCHEDULE ............................................98 
9.1 
Assessments ...........................................................................................................98 
9.1.1 
Clinical evaluations ..........................................................................................98 
9.1.2 
Laboratory evaluations...................................................................................104 
9.2 
Visit schedule .......................................................................................................107 
10 SAFETY ASSESSMENTS .....................................................................................114 
10.1 
Definition of an adverse event .............................................................................114 
10.1.1 
Definition of intensity ....................................................................................115 
10.1.2 
Definition of causal relationship with investigational product(s) ..................115 
10.1.3 
Categories of actions taken and outcome .......................................................116 
10.2 
Definition of a serious adverse event ...................................................................116 
10.3 
Adverse events of special interest (alert terms) ...................................................118 
10.3.1 
Expected adverse events ................................................................................120 
10.3.2 
Unexpected adverse events ............................................................................120 
10.4 
Pregnancy .............................................................................................................120 
10.5 
Other safety variables ..........................................................................................120 


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F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
11 DATA QUALITY ASSURANCE ..........................................................................122 
11.1 
Standardization procedures ..................................................................................122 
11.2 
Source documentation requirements ....................................................................122 
11.3 
Data management.................................................................................................123 
11.4 
Monitoring ...........................................................................................................124 
11.5 
Auditing ...............................................................................................................124 
12 STATISTICAL METHODS ..................................................................................125 
12.1 
Determination of sample size ...............................................................................125 
12.2 
Analysis sets.........................................................................................................127 
12.3 
Variables for analysis ...........................................................................................127 
12.3.1 
Efficacy variables...........................................................................................127 
12.3.2 
Pharmacodynamic variables ..........................................................................129 
12.3.3 
Pharmacokinetic variables .............................................................................129 
12.3.4 
Pharmacogenetic variables .............................................................................129 
12.3.5 
Safety variables ..............................................................................................130 
12.3.6 
Other variables ...............................................................................................131 
12.4 
Statistical analysis methods .................................................................................131 
12.4.1 
Efficacy variables...........................................................................................131 
12.4.2 
Pharmacodynamic variables ..........................................................................135 
12.4.3 
Pharmacokinetic variables .............................................................................135 
12.4.4 
Pharmacogenetic variables .............................................................................135 
12.4.5 
Safety variables ..............................................................................................135 
12.4.6 
Other variables ...............................................................................................136 
12.4.7 
Special statistical/analytical issues ................................................................136 
13 DATA HANDLING AND RECORDKEEPING..................................................139 
13.1 
Corrections to data ...............................................................................................139 
13.2 
Recordkeeping .....................................................................................................139 
13.3 
Destruction of study documents...........................................................................140 
14 PUBLICATION POLICY ......................................................................................141 
15 REFERENCES .......................................................................................................142 
16 APPENDICES .........................................................................................................148 
16.1 
Country-specific requirements (not applicable) ...................................................149 
16.2 
Committees/External consultants (DMC) ............................................................150 
16.3 
Global Impression of Change Scales (GICS) ......................................................152 
16.4 
Body weight-adjusted dosing ...............................................................................161 
16.5 
Conversion table for doses to injection volumes .................................................206 
16.6 
Questionnaire on Pain caused by Spasticity (QPS) .............................................210 
 
 
16.8 
Gross Motor Function Classification System (GMFCS – E&R) .........................236 


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16.9 
Amended Protocol - Summary of Changes .........................................................242 
16.9.1 
Rationale of Amendment ...............................................................................242 
16.9.2 
Range of Application .....................................................................................243 
16.9.3 
Technical Aspects of Amendment .................................................................243 
16.9.4 
Amended Articles ..........................................................................................243 
 
 


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List of Figures 
Figure 1 
Study Flow Chart .......................................................................................50 
List of Tables 
 
Table 1 
Treatment Combination A: Dose Groups for uni- and bilateral UL 
injections in MP. ........................................................................................25 
Table 2 
Treatment Combination B: Dose Groups for unilateral UL and 
unilateral LL injections in MP. ..................................................................26 
Table 3 
Treatment Combinations C and D: Dose Groups for unilateral UL 
and bilateral LL injections in MP (C: GMFCS I-III, D: GMFCS IV 
and V. .........................................................................................................27 
Table 4 
Treatment Combination E.: Dose Groups for bilateral UL and 
bilateral LL injections in MP. ....................................................................28 
Table 5 
Scenarios for Assignment of Medication Kits depending on 
Treatment Combination and BW ...............................................................69 
Table 6 
Treatment Combination A: Clinical Need for uni- or bilateral UL 
treatment only (GMFCS levels I-V) ..........................................................73 
Table 7 
Treatment Combination A: Dose Groups for uni- and bilateral UL 
injections in MP. ........................................................................................74 
Table 8 
Treatment Combination B: Clinical need for unilateral combined 
UL and unilateral LL treatment (GMFCS levels I-V) ...............................75 
Table 9 
Treatment Combination B: Dose Groups for unilateral UL and 
unilateral LL injections in MP. ..................................................................75 
Table 10 
Treatment Combinations C and D: Clinical need for unilateral UL 
and bilateral LL treatment ..........................................................................76 
Table 11 
Treatment Combinations C and D: Dose Groups for unilateral UL 
and bilateral LL injections in MP (C: GMFCS I-III, D: GMFCS IV 
and V).........................................................................................................77 
Table 12 
Treatment Combination E: Clinical need for bilateral UL and 
bilateral LL treatment GMFCS levels I-III ................................................78 
Table 13 
Treatment Combination E: Dose Groups for bilateral UL and 
bilateral LL injections in MP. ....................................................................79 
Table 14 
Dose ranges for UL clinical patterns and muscles in the High, Mid 
and Low Dose Group of MP ......................................................................82 


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Table 15 
Dose ranges for LL clinical patterns and muscles in the High, Mid 
and Low Dose Group of MP ......................................................................84 
Table 16 
Overview of Study Activities Main Period MP .......................................109 
Table 17 
Overview of Study Activities in Open-Label Extension Period 
OLEX .......................................................................................................112 
Table 18  
List of Adverse Events of Special Interest Possibly Indicating 
Toxin Spread ............................................................................................119 
Table 19 
Treatment Combination A: BW-Adjusted Doses for Unilateral and 
Bilateral UL Treatment in the High, Mid and Low Dose Group .............162 
Table 20 
BW-adjusted Doses per Muscles of Clinical Patterns for Upper 
Limb Treatment, High Dose Group (MP and OLEX). (Doses for 
High Dose Group in MP and for all subjects in OLEX). .........................164 
Table 21 
BW-adjusted Doses per Muscles of Clinical Patterns for Upper 
Limb Treatment, Mid Dose Group ..........................................................170 
Table 22 
BW-adjusted Doses per Muscles of Clinical Patterns for Upper 
Limb Treatment, Low Dose Group ..........................................................176 
Table 23 
Total Injection Doses to Lower Limb(s) in Treatment 
Combinations B.-E. in High, Mid and Low Dose Group ........................182 
Table 24 
BW-adjusted Doses per Muscles of Clinical Patterns for Lower 
Limb Treatment, High Dose Group .........................................................185 
Table 25 
BW-adjusted Doses per Muscles of Clinical Patterns for Lower 
Limb Treatment, Mid Dose Group ..........................................................192 
Table 26 
BW-adjusted Doses per Muscles of Clinical Patterns for Lower 
Limb Treatment, Low Dose Group ..........................................................199 
Table 27 
Conversion table for doses to injection volumes .....................................207 
 


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F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
1 SYNOPSIS 
Study title 
Prospective, multicenter, randomized, double-blind, parallel-group, dose-response study 
of three doses Xeomin® (incobotulinumtoxinA, NT 201) for the treatment of upper limb 
spasticity alone or combined upper and lower limb spasticity in children and adolescents 
(age 2 - 17 years) with cerebral palsy. 
Study phase 
Phase 3 
Indication 
Upper limb [UL] or combined UL and lower limb [LL] spasticity in children and 
adolescents (age 2 - 17 years) with cerebral palsy [CP]. 
Study objectives 
To investigate efficacy and safety of Xeomin® (incobotulinumtoxinA, NT 201) in 
subjects1 with UL spasticity alone or with combined UL and LL spasticity due to CP with 
a 1st double-blind cycle, the main period [MP], and three subsequent treatment cycles, the 
open-label extension period [OLEX]. Injection treatments in MP and OLEX will be 
followed by 12-16 weeks observation each. 
During MP, in a three arm, parallel-group double-blind design subjects will receive one 
of three fixed doses of Xeomin® per treated UL. 
• In the high dose group 8 Units [U] per kg body weight [BW] NT 201 (maximum 
dose per UL: 200 Units for subjects ≥25kg BW). 
• In the mid dose group 6 U/kg BW (maximum of 150 U) per UL. 
• In the low dose group 2 U/kg BW (maximum of 50 U) per UL. 
As clinically needed, UL treatment can be administered uni- or bilaterally with doses as 
outlined above for each treated UL. 
Subjects may receive additional BoNT injections in one out of five predefined treatment 
combinations up to the maximum total dose applicable for their GMFCS level (I-III: 
20 U/kg BW NT 201, maximum of 500 U; IV and V: 16 U/kg BW NT 201, maximum of 
400 U). 
After completion of MP, all eligible subjects will continue treatment in OLEX with 
NT 201 doses as in the high dose group of MP. 
                                                          
1 Subjects eligible for this study are children (age 2-11 years) and adolescents (age 12-17 years inclusive). 


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Study population, diagnosis, and main criteria for inclusion and exclusion 
Subjects who meet the following main inclusion criteria: 
• Female or male subject of 2 to 17 years of age (inclusive). 
• Uni- or bilateral CP with clinical need for injections with NT 201 for the treatment of 
UL spasticity at least unilaterally. 
• Ashworth Scale [AS] score in the main clinical target patterns in this study: 
o Flexed elbow: AS≥2 in elbow flexors (at least unilaterally). 
and/or 
o Flexed Wrist: AS≥2 in wrist flexors (at least unilaterally). 
• Clinical need according to the judgment of the investigator in one out of five 
treatment combinations (A-E, as shown below).  
AS score must be ≥2 for each target pattern chosen for injection at the Baseline 
Injection Visit V2. 
A. UL(s) treatment only (GMFCS I-V): 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) for2: 
1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
or 
Bilateral treatment of UL spasticity with 
Equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL.   
Dose per UL must be distributed between: 
1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW). 
and 
                                                          
2 Maximum total body doses in this study protocol refer to subjects with BW ≥ 25kg. In subjects < 25kg 
doses will be adjusted to BW (see Appendix 16.4). 


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2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
B. Unilateral UL and unilateral LL treatment (GMFCS I-V): 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) for2: 
1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
plus 
Ipsilateral unilateral treatment of LL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U). Dose to LL must be distributed to at least 
one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended 
great toe as clinically needed. 
C. Unilateral UL and bilateral LL treatment (GMFCS I-III) 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) for2: 
1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
plus 
Bilateral treatment of LL spasticity with 
12 U/kg BW (maximum of 300 U). Dose must be distributed into at least one of 
clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great 
toe, on each side. Dose distribution may vary between sides as clinically needed. 


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D. Unilateral UL and bilateral LL treatment (GMFCS IV and V) 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) for2: 
1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
plus 
Bilateral treatment of LL spasticity with 
8 U/kg BW (maximum of 200 U). Dose must be distributed into at least one of 
clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great 
toe, on each side. Dose distribution may vary between sides as clinically needed. 
E. Bilateral UL treatment and bilateral LL treatment (GMFCS I-III) 
Bilateral treatment of UL spasticity with 
Equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL   
Dose per UL must be distributed between  
1. at least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or 
flexed wrist (2 U/kg BW) 
and 
2. additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, 
and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW 
(maximum of 200 U) for treatment of a single UL is reached. 
plus 
Bilateral treatment of LL spasticity with 
4 U/kg BW (maximum of 100 U). Dose must be distributed into at least one of 
clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great 
toe, on each side. Dose distribution may vary between sides as clinically needed. 
Treatment-naïve subjects or pre-treated (non-naïve) subjects may enter the study. 
Treatment-naïve subjects will be defined as individuals who have not received any BoNT 
treatment within the last 12 months before study injections for treatment of limb 
spasticity.  
Main exclusion criterion: 


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Pre-treated (non-naïve) subjects must not have received BoNT treatment within the last 
14 weeks prior to the Screening Visit (V1) in any indication. 
 
 
Study design 
Prospective, multicenter, multi-national phase 3 study including a double-blind, parallel-
group dose-response MP and a subsequent OLEX. 
MP: Randomized, double-blind, parallel-group, three arm, dose-response design. 
Subjects will receive uni- or bilateral UL injections alone or additional uni- or bilateral 
LL injection treatment as clinically needed and as allowed up to the maximum total body 
dose (for details see below). Judgment on clinical need will be based on treatment doses 
in the high dose group. In the mid dose and in the low dose group dose(s) to UL(s) and 
LL(s) will uniformly be reduced to 75% (mid dose) and 25% (low dose) of doses 
administered in the high-dose group. 
OLEX: Open-label, non-controlled, repeated-dose design. 
All subjects will receive doses for uni- or bilateral UL injection treatment alone or 
additional uni- or bilateral LL injection treatment as clinically needed and as allowed up 
to the maximum total body dose of the high dose group of MP (for details see below). 
All subjects in this study will receive at least uni- or bilateral treatment of UL(s) 
spasticity with fixed doses per limb: 
The double-blind treatment period will consist of one injection session in three dose 
groups with a subsequent 14 ± 2 weeks observation period. The treatment dose per UL 
will be fixed per dose group. 
In the high dose group 8 U/kg BW NT 201 (maximum of 200 U) will be injected per 
treated UL. 
In the mid dose group 6 U/kg BW NT 201 (maximum of 150 U) will be injected per 
treated UL. 
In the low dose group 2 U/kg BW NT 201 (maximum of 50 U) will be injected per 
treated UL. 
Treatment of additional limbs up to maximum total body dose: 
Depending on the individual distribution of spasticity, subjects may have an additional 
clinical need for injections to LL(s). Thus, even with fixed doses per UL, the total body 


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dose may vary from 8 U/kg BW NT 201 (maximum of 200 U for subjects ≥ 25kg BW) in 
subjects with unilateral UL injections only to 20 U/kg BW NT 201 (maximum of 500 U 
for subjects with BW ≥ 25 kg), e.g. in subjects with unilateral UL plus bilateral LL 
injections in GMFCS level I-III. For details on the five allowed treatment combinations 
(A-E) in this study and the distribution of total body dose in each of the treatment 
combination see also Section 8.1.1.2). 
Subjects showing clinical need for reinjection with IP between 12 to 16 weeks after the 
baseline injection visit in MP will continue treatment in OLEX with three injection 
sessions with injection intervals of 14±2 weeks in the same treatment combination chosen 
in MP but in injection doses of the high dose group of MP. The maximum total dose per 
injection session in OLEX is 500 U of NT 201 for subjects ≥25kg BW and of 
GMFCS level I-III (see details on dose below and in Section 8.1.1.2). 
A data monitoring committee [DMC] for the safeguard of subjects will monitor and 
assess adverse events [AEs], AEs of special interest [AESIs] and SAEs occurring after 
the injection treatment. 
Planned study period 
Start of recruitment:  
Jan-2014 
End of study (last subject last visit): 
Jan-2019 
Duration of treatment per subject 
The regular duration of study participation for subjects will be 50 to 66 weeks consisting 
of a screening period of 2 weeks followed by an observation period with 4 treatment 
cycles of 12 to 16 weeks each (total treatment period of 48 to 64 weeks).  
Subjects not showing a clinical need for reinjection until 16 weeks after the baseline visit 
will end study participation after the final visit of MP without reinjection. 
Variables for analysis 
Primary efficacy variable (MP only): 
• Change from baseline in AS in the primary clinical target pattern, i.e. elbow flexors or 
wrist flexors, at Day 29 (Week 4) of MP.  
An IV/WRS will be used for selection and randomization to treatment groups in MP, 
if two main clinical target patterns would qualify for primary efficacy analysis based 
on (for further details see Section 8.2.1)  
 
(a) clinical need for IP injection in combination with 
  
 
(b) an AS score of ≥2.  
The other main clinical target pattern (if treated) will be analyzed as key secondary 
variable (see below). For subjects with bilateral UL treatment, the body side for 
analysis will be decided by the investigator at screening (for details see Section 8.2.1). 


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Co-primary efficacy variable (MP only): 
• Investigator’s Global Impression of Change Scale [GICS] at Day 29 (Week 4) of MP. 
Key-secondary efficacy variables (MP only): 
• Change from baseline in AS score of the other treated main clinical target pattern 
(i.e. of elbow flexors or wrist flexors, if treated) at Day 29 (Week 4) of MP. This 
analysis will be performed in case two target patterns would qualify as main clinical 
target pattern for the main clinical target pattern not analyzed as primary efficacy 
variable. For subjects with bilateral UL treatment body side to be analyzed is decided 
by investigator at screening (for details on definition see 8.2.1). 
• Change from baseline in AS score of treated clinical target pattern clenched fist (in 
subjects treated in combination with flexed wrist) at Day 29 (Week 4) of MP. For 
subjects with bilateral UL treatment body side to be analyzed is decided by 
investigator at screening (for details on definition and on selection of variables to 
assess treatment of target patterns flexed wrist and clenched fist see Sections 8.2.1, 
12.4.1.1 and 12.4.1.3). 
Secondary efficacy variables (MP only): 
• Change from baseline in AS score for each treated clinical pattern (e.g., flexed elbow, 
flexed wrist, clenched fist, etc.) of the UL at all other post baseline visits of MP. For 
subjects with bilateral UL treatment body side to be analyzed will be decided by 
investigator at screening. 
• Change from baseline in scores of pain intensity (from subjects) and pain frequency 
(from parent/caregiver) assessed with ‘Questionnaire on Pain caused by Spasticity 
[QPS]’ to all post baseline visits of MP. 
• Child’s/Adolescent’s (if applicable) and Parent’s/Caregiver’s GICS at Day 29 
(Week 4) of MP. 
Safety variables: 
 
Primary safety variables: 
Not applicable 
 
Secondary safety variables: 
• Occurrence of treatment emergent adverse events [TEAEs] overall and per treatment 
cycle. 
• Occurrence of TEAEs of Special Interest [TEAESIs] overall and per treatment cycle. 


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• Occurrence of serious TEAEs [TESAEs] overall and per treatment cycle. 
• Occurrence of TEAEs related to treatment as assessed by the investigator overall and 
per treatment cycle. 
• Occurrence of TEAEs by worst intensity overall and per treatment cycle. 
• Occurrence of TEAEs by worst causal relationship overall and per treatment cycle. 
• Occurrence of TEAEs by final outcome overall and per treatment cycle. 
• Occurrence of TEAEs leading to discontinuation overall and per treatment cycle. 
 
Other safety variables: 
• Investigator’s Global Assessment of Tolerability at Day 99 (Week 14) of MP and all 
OLEX cycles. 
• Vital signs (blood pressure, heart rate) at all visits of MP and all OLEX cycles. 
• BMI, weight, height at Screening V1, Baseline Injection Visit V2, at the Final Visit 
of MP V5, at all Injection Visits of OLEX (V63, V10 and V14) and at the End of 
Study Visit (V17). 
• Clinical chemistry and hematology at Screening (V1), the Injection Visit V6 of 
OLEX and the End of Study Visit (V17). 
• Occurrence of antibodies against BoNT-A in subjects ≥21 kg BW. 
Total number of subjects and number of countries 
At least 344 subjects (ratio 2 : 1 : 1) will be randomized: 
 
 
at least 172 subjects will be randomized to the high dose group, 
 
 
at least 86 subjects to the mid dose group and 
 
 
at least 86 subjects to the low dose group. 
 
Overall and in each of the treatment groups, there will be 50% of subjects with flexed 
wrist and 50% with flexed elbow as primary clinical target pattern. 
This international study is planned to be performed in eligible investigational sites 
worldwide. 
Number of study sites 
                                                          
3 If V5 and V6 will be performed at the same day, BW and height can be transferred from V5 to V6. 


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It is planned to conduct the study in approximately 45 sites. 
Number of visits 
Each subject will participate in a total of 14 regular visits and four telephone contacts. 
The number of visits may increase to a maximum of 17, if the Injection Visits of OLEX 
will be scheduled to revisits. To assess the length of treatment effects one optional 
telephone contact [TC] can be scheduled at week 12 of MP, to inquire the need for 
reinjection with IP before week 16.  
The injection visit of each OLEX cycle may be performed on the same day as the Final 
Visit of MP or the End of Cycle Visits of the preceding treatment cycle.4 If eligibility for 
reinjection is not reached on the day of the Final Visit of MP or on the End of Cycle 
Visits, injection visits can be rescheduled up to 16 weeks after the injection visit of the 
preceding cycle. If possible, all visits should be performed at similar day time. 
Screening: 
Screening Visit (V1): 
Day -14 (Week –2) ± 5 days 
Main Period (MP): 
Baseline Injection Visit (V2): 
Day 1, randomization 
Telephone Contact (TC1): 
Day 8 (Week 1) ± 3 days of MP 
Ctrl. Visit (V3): 
Day 29 (Week 4) ± 3 days of MP 
Ctrl. Visit (V4): 
Day 57 (Week 8) ± 3 days of MP 
Optional Telephone Contact 
Wk12: 
Day 85 (Week 12) ± 3 days of MP 
Final Visit of MP (V5) 
Day 99 (Week 14) ± 14 days of MP 
Open-Label Extension Period (OLEX) 
Injection Visit (V6, V10, V14): 
Day 1 of the 2nd to 4th treatment cycle. 
Telephone Contact 
(TC2, TC3, TC4): 
Day 8 (Week 1) ± 3 days of 2nd to 4th treatment cycle 
                                                          
4 At each injection visit eligibility criteria have to be assessed prior to injection. If all of the eligibility 
criteria are fulfilled, the Injection Visit will be on the same day as the End of Cycle Visit. In case an 
eligibility criterion is not met and the investigator assumes that the respective eligibility criterion is likely 
to be fulfilled within the upper time limit for reinjection of 16 weeks after the last injection, the injection 
visit may be scheduled. Otherwise the subject will be withdrawn from the study. 


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Ctrl. Visit (V7, V11, V15): 
Day 29 (Week 4) ± 3 days of 2nd to 4th treatment cycle 
Ctrl. Visit (V8, V12, V16): 
Day 57 (Week 8) ± 3 days of 2nd to 4th treatment cycle 
End of Cycle Visit (V9, V13) 
Day 99 (Week 14) ± 14 days of 2nd and 3rd treatment 
cycle 
End of Study Visit (V17):  
Day 99 (Week 14) ± 14 days of 4th treatment cycle. 
Investigational product(s), dose, and route of administration 
NT 201, 100 U, powder for solution for injection (active ingredient: NT 101, Botulinum 
neurotoxin type A free from complexing proteins; USAN: incobotulinumtoxinA) and 
placebo [PBO] will be used for reconstitution. PBO will be only used as part of the IP to 
achieve the lower concentrations in the mid and low dose group with an equal injection 
volume for all three dose groups. 
Each medication kit consists of four vials of IP. Each vial will be reconstituted with 2 mL 
sterile physiological (0.9%) sodium chloride solution. Based on the selection of one out 
of five treatment combinations (A-E, for details see section below) in combination with 
the subjects BW either one (for total injection volume up to 8 mL) or two (for total 
injection volume up to 10 mL) medication kits will be assigned to a subject via IV/WRS 
in MP and OLEX. In MP the medication kit (blinded mixture of NT 201 only or NT 201 
and PBO vials) will consist of 4 vials which must be pooled to achieve the target 
concentration of NT 201 in the respective study arm. In OLEX two different medications 
kits are provided. They either contain 4 or 1 vials with 100 U NT 201. 
MP: 
For subjects randomized to the high dose group each medication kit of MP consists of 
four vials with 100 U NT 201 (dilution strength of IP: 5 U per 0.1 mL).  
For subjects randomized to the mid dose group each medication kit of MP consists of 
three vials with 100 U NT 201 and one PBO vial (dilution strength of IP: 3.8 U per 
0.1 mL5). 
For subjects randomized to the low dose group each medication kits of MP consist of 
one vial with 100 U NT 201 and three PBO vials (dilution strength of IP: 1.3 U per 
0.1 mL5). 
OLEX: For subjects in OLEX who will need total injection volumes of NT 201 of up to 
8ml each medication kit consists of four vials with 100 U NT 201 (dilution strength of IP: 
5 U per 0.1 mL).  
                                                          
5 Values rounded to the 1st decimal place. 


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Subjects with a total injection volume from >8ml to 10ml will need an additional 
medication kit (OLEX only) with 1 vial NT 201 (100 U). 
 
The IP will be injected as intramuscular [i.m.] injection into spastic muscles. 
Fixed total doses will be used for the main clinical target patterns flexed elbow (e.g. 
4 U/kg BW NT 201 in the high dose group in MP and for all subjects in OLEX) and 
flexed wrist (e.g. 2 U/kg in the high dose group in MP and for all subjects in OLEX) with 
pre-defined dose ranges and ranges for injection sites per muscle. In the target pattern 
flexed elbow treatment of biceps is mandatory. The investigator has to choose at the 
Baseline Injection Visit V2 to either inject brachialis or brachioradialis, as clinically 
appropriate. 
In the optional clinical target pattern clenched fist fixed dosing (e.g. 2 U/kg BW NT 201 
in the high dose group in MP and in OLEX) will be applied. In the remaining optional 
target patterns thumb in palm and pronated forearm muscles can be chosen by the 
investigator as clinically appropriate within dose ranges specified for individual muscles 
in this study (see also Table 14). 
Selection of clinical patterns for LL treatment is up to the discretion of the investigator 
based on her/his clinical judgment. As in the UL(s), in LL(s) only target patterns with an 
AS score ≥2 at the Baseline Injection Visit of MP are eligible for treatment. The dose 
ranges per muscle and number of injection sites given in Table 15 should be adhered. 
Clinical patterns for treatment are pes equinus, flexed knee, adducted thigh, and extended 
great toe. The specified maximum dose limits per muscle and the total dose limits for LL 
treatment must be respected. 
Investigators must be experienced and/or trained in technically guided BoNT treatment of 
children/adolescents with CP. Technically guided injection is mandatory for all injected 
muscle groups. Ultrasound will be the preferred guidance technique. Alternatively, 
electromyography [EMG] or electrical stimulation [e-stim] may be used. 
Local anesthesia and/or analgosedation may be used as necessary. Physiotherapy (e.g., 
strengthening, stretching, and motor training), orthotic management, and any other 
rehabilitation treatment are allowed, but should be kept preferably stable in MP. Casting 
of the treated UL(s) is not permitted during the MP of this study. 
The maximum dose per injection site should be 25 U NT 201 for subjects of <25 kg BW. 
The maximum dose per injection site for subjects of ≥25 kg BW should be 50 U NT 201. 










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status (pre-treated, treatment naïve) as fixed factors, visit*treatment as interaction term, 
and visit as repeated factor. The covariates are the AS score of the primary clinical target 
pattern at baseline (Day 1 of MP) and the GMFCS level at screening.  
Co-primary efficacy variable: An analysis of covariance (ANCOVA) approach (2-sided, 
significance level alpha=0.05) with comparison of least square means will be used for the 
confirmatory analysis of the co-primary efficacy variable. The dependent variable is 
defined as the ‘Investigator’s GICS at Day 29 (Week 4) of MP’. The independent 
variables are defined as treatment group (high dose, low dose), site (or pooled sites), 
BoNT-A pre-treatment status (pre-treated, treatment naïve) as fixed factors and the 
covariates are the maximum AS score of the two possible primary clinical target clinical 
patterns flexed elbow or flexed wrist at baseline (Day 1 of MP) and the GMFCS level at 
Screening Visit.  
Sites might be pooled for the statistical analysis, e.g., based on geographic criteria. If 
applicable, pooling of sites will be defined in the SAP. 
Both, the primary efficacy variable and the co-primary efficacy variable have to show 
statistically significant treatment differences in order to prove superiority of high dose vs. 
low dose treatment. 
Confirmatory testing will be performed on the full analysis set [FAS] of MP with 
accounting for missing values by using MMRM approach for the primary efficacy 
variable. In case of missing data in the co-primary efficacy variable these will be imputed 
by “0” (no change) (see Section 12.4.7.1). 
If the confirmatory tests of the (co-)primary efficacy variables both yield significant 
results, in a second step using a hierarchical testing approach in the high dose treatment 
group, the key-secondary efficacy variable ‘change from baseline in AS score of the 
other treated main clinical target pattern (i.e. of elbow flexors or wrist flexors, if 
treated) at Day 29 (Week 4) of MP’ and the co-primary efficacy variable ‘GICS at Day 
29 (Week 4) of MP’ for the subpopulation defined by this key-secondary endpoint will be 
compared to low dose treatment group in both efficacy variables. Other than using the 
key-seondary efficacy variable and the co-primary efficacy variable for this 
subpopulation, the analysis models will be identical to the analysis described above for 
the 1st step. Both, the key-secondary efficacy variable and the co-primary efficacy 
variable for the subpopulation have to show statistically significant treatment differences 
in order to prove superiority of high dose vs. low dose treatment in this subpopulation. 
Only if the confirmatory analysis of step 2 yields a statistically significant result, in a 
third step a confirmatory analysis of the key-secondary efficacy variable ‘change from 
baseline in AS score of treated clinical target pattern clenched fist (in subjects treated in 
combination with flexed wrist), at Day 29 (Week 4) of MP will be done. This variable 
has been chosen, since it is anticipated that the vast majority of subjects will have a 
combined clinical presentation of clinical patterns clenched fist and flexed wrist. Subjects 


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with either treatment alone (i.e. clenched fist or flexed wrist) with other clinical target 
patterns will be evaluated separately in a descriptive manner (see also Section 12.3.1.3). 
Only if the confirmatory analysis of step 3 yields a statistically significant result, in a 
fourth step, using a hierarchical testing approach, the mid dose treatment will be 
compared to low dose treatment in both (co-)primary efficacy variables. Other than using 
the mid instead of the high dose group treatment data, the analysis models will be 
identical to the analysis described above for the 1st step. Both, the primary efficacy 
variable and the co-primary efficacy variable have to show statistically significant 
treatment differences in order to prove superiority of mid dose vs. low dose treatment. 
For the confirmatory analyses a two-sided significance level of α=0.05 will be applied. A 
MRMM analysis as described for the primary efficacy variable will be applied for the 
change from baseline in AS score. An ANCOVA model as described for the co-primary 
efficacy variable will be applied for the Investigator’s GICS. The analysis will be 
performed on the FAS of the MP. 
Due to the hierarchical testing strategy of (co-)primary and key-secondary efficacy 
variables and the two dose group comparisons (high versus low and mid versus low), this 
four step hierarchical testing procedure ensures the overall type I level of 5% for the 
confirmatory tests. If one of four hierarchical tests does not yield a statistically significant 
result, the consecutive test(s) will still be performed but will be considered to be only 
descriptive. 
All other test procedures will be explorative. Sensitivity analyses will be performed on 
the per protocol set [PPS] of MP (subset of the FAS of MP without major protocol 
deviations) as well as on the FAS of MP using last observation carried forward [LOCF] 
(for AS score) and, additionally, without missing value replacement (observed case 
analysis). 
Secondary 
 efficacy variables will be analyzed descriptively. Statistical tests 
will be interpreted in an explorative manner. 
Safety Analysis: Analysis of the safety variables will be performed on the Safety 
Evaluation Set [SES] of MP and OLEX using descriptive summary statistics, frequency 
tables, and, if applicable, shift tables/graphs. The SES of MP is the subset of all subjects 
who were treated in the MP with study medication at least once. The SES is the subset of 
all subjects treated in OLEX with study medication at least once. 








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2.3 
Committees 
Safety data will be evaluated by an independent DMC at regular time intervals to 
ascertain protection of subject’s safety (Appendix 16.2). Safety data will be evaluated 
without knowledge of efficacy data. If deemed necessary by the DMC, emergency 
unblinding in individual cases can be performed by the DMC (see Section 12.4.7.3). The 
DMC will advise the sponsor regarding subject withdrawals and/or study measures in 
case of relevant safety findings. The DMC will consist of members who are assigned to 
the DMC of the NT 201 pediatric clinical study program. The members are not associated 
with the sponsor or with the operative conduct of any study sponsored by Merz. Details 
on responsibilities and procedures to be followed by the DMC will be laid down in the 
DMC charter. A summarized description of the scope of work and operating procedures 
for the DMC is provided in Section 12.4.7.3. 


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3 ETHICS 
3.1 
Independent Ethics Committee/Institutional Review Board 
The following documents must be submitted to the responsible IEC/IRB and approval 
obtained: 
• The clinical study protocol.  
• Any amendment to the clinical study protocol that is not solely of an administrative 
nature. 
• The IB and all updates. 
• Study information and IC forms, as well as updates (if applicable). 
• All recruitment procedures and any advertisement used to recruit subjects 
(if applicable). 
• Any other required documents.  
If applicable, and in accordance with local legal requirements, the above documents also 
may be submitted to the respective regulatory authority(ies) for separate approval. 
3.2 
Ethical conduct of the study 
This study will be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, and are consistent with ICH-GCP and applicable 
regulatory requirements. Regulatory authorities will be notified and consulted as required 
prior to, during, and after the conduct of the study. 
3.3 
Subject information and informed consent 
3.3.1 
Subject information 
The term “subject” used throughout this document includes children (age 2-11 years) and 
adolescents (age 12-17 years inclusive). Prior to study enrollment, the subject (if 
applicable) and/or the legally acceptable representative7 (e.g., parent(s), guardian) will be 
given full verbal and written information on the nature, objective, significance, expected 
                                                          
7 The term parent(s) is used for any legally acceptable representative including guardian(s) in this study 
protocol as defined in the ICH guideline E6 (R1) as individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical 
trial. Guardian(s) may replace parent(s) in the performance of study procedures. 


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benefits, potential risks, and expected consequences of the study. This verbal and written 
information will be provided by the investigator (or authorized designee) according to the 
provisions set forth in the Declaration of Helsinki. The obligations of the investigator are 
set forth in the clinical study protocol, the ICH-GCP principles (effective as of 
17-JAN-1997), and the respective national regulations governing medical research and
experimentation on humans.
Each subject and/or the parent(s) will have the opportunity to question the investigator 
(or authorized designee) about the study prior to giving consent. 
3.3.2 
Informed consent/assent 
As a rule, a pediatric subject is legally unable to provide IC. Therefore, the 
children/adolescents are dependent on their parent(s) to assume responsibility for their 
participation in clinical studies. Full IC should be obtained from the parent(s) in 
accordance with regional laws or regulations. 
IC for the subject will be obtained: 
•
In writing from the subject’s parent(s), or
•
Verbally from the parent(s), if the consent is confirmed in writing by an impartial
witness.*
* If the subject’s parent(s) is/are unable to write, the subject can enter the study by verbal
consent of the parent(s). The verbal consent must be documented in writing by at least
1 impartial 3rd party who witnesses the entire consent process, and signs and dates the
consent document. The witness must NOT be a person who is an employee from or a
member of the study site (or its institution), CRO, or Merz.
All subjects should be informed to the fullest extent possible about the study in language 
and terms they are able to understand. Depending on the extent of the subject’s level of 
understanding and decision-making capacity, the subject should assent to the IC given by 
the subject’s parent(s). Participants of appropriate intellectual maturity should personally 
sign and date either a separately designed, age-conform written assent or the written IC if 
the adolescent’s maturity ensures understanding of the wording in the IC. 
The consent must be confirmed and personally signed and dated by the person who 
conducted the IC briefings. This person may be the investigator or an authorized designee 
if in accordance with local legal requirements. In case the IC briefing has been performed 
by a person different from the investigator, the investigator has to countersign the IC. 
The IC process must be traceable from the available documentation, i.e., the subject’s 
medical file (see Section 11.2). At a minimum, this documentation should include 
information about when the subject (if applicable) and the parent(s) were 1st informed 
about the study and who supplied the information. The parent(s) will be given a copy of 


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the signed and dated written IC form as well as all consent form updates (if applicable). 
Subjects will be given a copy of the signed and dated, separately designed and 
age-conform written informed assent form (if applicable).  
During the course of the study, the subject or the parent(s) will be informed in a timely 
manner if information becomes available that may be relevant to the subject’s (if 
applicable) and/or the parent’s (parents’) willingness to continue participation in the 
study. In case of AEs, or poor tolerability to the IP, the subject or the parent(s) should 
inform the investigator, who then will make a judgment whether continuing the study 
serves the subject’s best interests. The subject and/or the parent(s), however, are free to 
withdraw consent at any time and for any reason, whether expressed or not. All subjects 
and/or their parent(s) should be made aware of their rights to decline to participate or to 
withdraw from the study at any time. Attention should be paid to signs of undue distress 
in subjects who are unable to clearly articulate their distress. 
3.3.3 
Subject card  
A subject card will be given to all subjects (if the subject is able to keep the card) and the 
parent(s), who will be instructed to keep it in their possession at all times. The subject 
card will contain the following printed information: 
• The name, address, and telephone number of the investigator or study site’s 
institution, as the main contact for product information and emergency unblinding. 
• Information that the subject is taking part in a clinical study conducted with 
Botulinum toxin type A [BoNT-A] with the randomization number of the assigned 
medication. 
• A 24-hour hotline number for emergencies and for an emergency unblinding service 
of subjects during their participation in the double-blind MP. 
3.3.4 
Post-study treatment 
No specific post-study arrangements are made and no specific post-study care will be 
performed after this study. 
The subject and the parent(s) may consult his/her physician for treatment options, and 
receive antispastic medication including BoNT treatment, alcohol, phenol injections as 
well as physiotherapy, orthotic management, and any other rehabilitation treatment at the 
investigator’s discretion. This also applies to subjects who discontinue the study 
prematurely. 


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3.3.5 
Subject privacy 
The subject (if applicable) and/or the parent(s) will be informed of procedures to protect 
privacy of the subject. Although recorded data will be passed on in a coded version only 
to authorized individuals, re-identification by the investigator (e.g., in case of 
emergencies) will be possible by the study number assigned to the subject (see 
Section 8.2.1). Access to non-coded data will be allowed solely to check validity, and 
such access will be limited strictly to authorized individuals (e.g., the sponsor or 
individuals authorized by the sponsor, auditors, regulatory authorities, or members of 
IECs/IRBs) who have been bound to confidentiality. If the results of the study are 
published, the subject’s identity will remain confidential. 
3.3.6 
Contact point 
If required by local regulations subjects (if applicable), and/or the parent(s) will be 
provided with a contact address where they may obtain further information regarding 
clinical studies. 
3.4 
Insurance 
From the enrolment into the study by signature of the IC until its termination, each 
subject is insured against any health impairment occurring as a result of participation in 
the study in accordance with the laws and regulations of the country in which the study is 
performed. 
The subject (if applicable) and/or parent(s) will be informed by the investigator and 
through the IC form about the existence of this insurance and the resulting obligations. 
The insurance conditions will be handed out to the parent(s), if requested by the parent(s) 
or if required by local law. 
Any medical deviation from the clinical study protocol that is deemed to have occurred 
through the fault of the subject or the parent(s) is not covered by this insurance. 
The sponsor is usually not liable for injuries/cases of death that occur solely as a 
consequence of the underlying disease or condition of the subject, or from diagnostic or 
therapeutic measures not specifically required by the agreed clinical study protocol. The 
sponsor is also usually not liable for events resulting from negligence of the investigator, 
clinical study staff, and/or CRO, including failure to act according to ICH-GCP 
principles or to comply strictly with the agreed clinical study protocol. 
3.5 
Financing 
The financial aspects of the study will be documented in an agreement between the 
sponsor, the CRO, and each investigator or any other involved party, and must be 
confirmed in writing before the study commences. 


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4 INTRODUCTION 
4.1 
Study background 
Medical background 
Cerebral palsy is described as a group of permanent disorders of the development of 
movement and posture, causing activity limitation, which is attributed to non-progressive 
disturbances that occurred in the developing fetal or infant brain. The motor disorders of 
CP are often accompanied by disturbances of sensation, perception, cognition, 
communication, behavior, by epilepsy and by secondary musculoskeletal problems 
[Rosenbaum 2007, Aisen 2011]. 
CP is the most common cause of the upper motor neuron syndrome [UMNS] in children 
[Fehlings 2010, Aisen 2011]. Patients with UMNS show a mixture of negative 
phenomena like muscle weakness, loss of dexterity and fatigability. Positive features of 
UMNS are increased muscle tone, muscle spasms, clonus, exaggerated deep tendon 
reflexes and most important spasticity [Mayer 2001]. The overall incidence of CP is 
estimated at around 2 per 1,000 neonates in developed countries [Aisen 2011]. The 
majority of CP patients (76-87%) suffer from spasticity [Lannin 2006].  
Spasticity is a chronic, not fatal condition. In children/adolescents with UL spasticity, the 
treatment of UL flexor deformity, e.g., flexed elbow and flexed wrist, is crucial [Heinen 
2010]. Most children/adolescents with CP suffer from combined UL/LL spasticity. So in 
addition to functional impairment by UL spasticity, these children present very frequently 
with equinus gait initially. In older children and adolescents, weakness of proximal LL 
muscles may result in various types of flexed knee gait [Mayer 2001, Love 2010]. Goals 
of spasticity treatments include reducing pain and muscle spasms, facilitating brace use, 
improving posture, minimizing contractures and deformity, facilitating mobility and 
dexterity, and improving patient ease of care as well as hygiene/self-care [Ward 2003, 
Hagglund 2005, Chaleat-Valayer 2011]. 
In a non-focal condition such as CP, a number of muscle groups must be targeted using a 
multi-level treatment approach in which overactive muscle groups have to be injected to 
achieve an improvement of limb motion and posture [Heinen 2010]. BoNT-A temporarily 
reduces spasticity in muscles and facilitates the use of other treatments, e.g., physical 
therapy and orthotic management. Early BoNT-A therapy may help maximizing the 
development potential, may delay or reduce the need for corrective orthopedic surgery, 
and may minimize the impact of commonly occurring secondary musculoskeletal 
impairment [Heinen 2006]. 
BoNT-A injections are given to multiple small and large muscles in doses tailored to the 
individual child’s/adolescent’s needs. If necessary, it may be administered in sequential 
injection treatments as long-term spasticity treatment. The efficacy of treatment over one 
or more injection treatments with BoNT-A for spasticity in children has been sufficiently 


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demonstrated in several trials [Sutherland 1999, Wissel 1999, Koman 2000, Ubhi 2000, 
Love 2001, Baker 2002, Polak 2002, Mall 2006, Bjornson 2007]. Currently, there are 
2 BoNT-A preparations Dysport® [USAN: abobotulinumtoxinA, Ipsen] and BOTOX® 
[USAN: onabotulinumtoxinA, Allergan] licensed in e.g., some European countries, 
Australia, Canada, and/or Mexico for treatment of pediatric patients. Both products are 
approved for the treatment of dynamic equinus foot deformity due to spasticity in 
ambulant pediatric CP patients, two years of age or older. The WE MOVE organization 
provided clinicians with BOTOX® dose recommendations for children [Brashear and 
Mayer 2008]. Recent treatment guidelines document the therapeutic role of BoNT-A for 
reduction of muscle tone and improvement of function in current treatment regimens 
[Simpson 2008, Delgado 2010, Esquenazi 2010, Heinen 2010]. BoNT-A is an established 
option for safe and effective spasticity treatment in UL and LL in children/adolescents as 
to international consensus groups [Fehlings 2010, Love 2010]. 
Comparative clinical study results suggest that Xeomin and the comparator product 
containing conventional Botulinum toxin type A complex (900 kD) have a similar 
efficacy and safety profile in patients with blepharospasm or cervical dystonia when used 
in a dosing conversion ratio of 1:1 [Merz Pharmaceuticals (GmbH) 2012]. 
Investigational product 
BoNT-A is produced by fermentation of the anaerobic bacterium strain Clostridium 
botulinum as part of a high molecular weight complex, which is formed by several 
hemagglutinins and other non-toxic non-hemagglutinin proteins. BoNT-A acts selectively 
on peripheral cholinergic nerve endings, inhibiting the release of the neurotransmitter 
acetylcholine, and thus reduces increased muscle tone by partial paralysis. 
Xeomin® (NT 201, USAN: incobotulinumtoxinA) is the only marketed BoNT-A 
preparation that is free from complexing proteins. In animal models, NT 201 did not 
induce neutralizing antibodies [Jost 2007]. None of the adult subjects developed 
neutralizing antibodies when treated with up to 400 U NT 201 in a clinical study 
investigating treatment of adult post-stroke spasticity of the UL up to 89 weeks 
[Kanovsky 2011]. The highly purified nature of NT 201 may be thought to represent a 
clinical advantage compared with other BoNT-A complex preparations. A further 
advantage is that NT 201 can be stored and transported at room temperature (up to 
25°C/77°F) which simplifies handling. 
Up to date NT 201 is approved in Argentina, Brazil, Canada, South Korea, Mexico, 
Russia, Uruguay, USA, and 19 European Economic Area [EEA] countries (including 
Germany). The 1st marketing authorization was granted by the BfArM in Germany 
on 31 May-2005, which is considered the International Birth Date of the product. The 
different national approvals cover a variety of indications such as blepharospasm, 
spasmodic torticollis, post-stroke spasticity of the upper limb, focal spasticity, 
strabismus, tremor, hyperkinetic facial lines, and glabellar frown lines. NT 201 is 
marketed under the brand names Xeomin, Bocouture (EEA only), Xeomin Cosmetic™ 
(Canada only for aesthetic use), and Xeomeen(Mexico only). 


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4.2 
Study rationale 
This pivotal phase 3 study is part of an international pediatric study program for 
Xeomin® agreed with the US FDA. It will serve to collect first efficacy and safety data in 
the treatment of CP caused spasticity with NT 201 in a pediatric population. The study 
will compare NT 201 treatment in three dose arms (high and mid against low) with fixed 
doses for UL injection treatments. The focus of this study is to generate efficacy and 
safety data for the use of NT 201 in pediatric UL spasticity. 
In complete contrast to adult UL post-stroke spasticity, in children/adolescents with CP 
isolated presentation of UL spasticity is rare. Only these children/adolescents would have 
no need for additional spasticity treatment in the LL(s). The main reason for this 
fundamental difference in clinical presentation between the most frequent forms of adult 
and pediatric spasticity is that in CP the brain damage is generally more widespread 
[Aisen 2011]. Even in children with territorial deficits due to cerebral hemorrhage related 
to preterm birth additional white matter abnormalities can be observed [Babcock 2009]. 
Most children/adolescents therefore present at least with unilateral CP with combined UL 
and LL involvement. Due to the scarcity of CP patients with isolated UL spasticity it is 
necessary to design pediatric UL efficacy trials for inclusion of subjects with combined 
UL/LL spasticity also. 
The study will compare NT 201 treatments in the high dose group (8 U/kg BW NT 201 
per treated UL, max. of 200 U) and in the mid dose group (6 U/kg BW NT 201 per 
treated UL, max. of 150 U) to active treatment in the low dose group (2 U/kg BW 
NT 201 per treated UL, max. of 50 U). 
The number of published trials of evidence class II and higher in the indication UL 
spasticity in CP is limited [Simpson 2008]. Most studies have limitations in regard to 
control groups, outcome measures or even more important statistical power due to limited 
sample sizes. However, published studies used doses of onabotulinumtoxinA (Botox®) 
comparable to the Xeomin® doses in the present trial: Fehlings and coworkers applied 2-
6U/kg BW Botox® to at least 3 UL muscles using a single blind design. Similarly, 
Wallen and coworkers used a treatment regimen with 0.5 to 2 U/kg BW 
onabotulinumtoxinA per treated muscle with a maximum dose of 12 U/kg BW (165.1+/-
88.6 U) [Wallen 2007] and Russo et al. applied in a single-blinded controlled trial a mean 
of 8U/kg BW onabotulinumtoxinA (range 5.0-11.6U/kg BW) [Russo 2007]. Overall, 
published doses for UL treatment of CP spasticity are within the range of doses 
administered in the present study. 
Although the main focus of efficacy assessment is treatment of UL(s) with fixed doses 
per dose group, injection doses to LL(s) in the respective treatment combinations allowed 
in this study will also reflect assignment to one of the three dose groups in the double-
blind MP only. After completion of MP, all eligible subjects will continue in OLEX with 
three subsequent treatment cycles with injection doses of the high dose group of MP.  


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For safety reasons, the maximum total body dose in this trial will be 20 U/kg BW NT 201 
(max. of 500 U) for subjects with GMFCS levels I-III and 16 U/kg BW (maximum of 
400 U) for subjects of GMFCS level IV and V (for details see Section 8.1.1).  
The study complements the overall clinical development program of NT 201 in 
indications such as treatment of post-stroke spasticity in the adult population. 
Two BoNT-A preparations (Dysport® and BOTOX®) are licensed in some European 
countries, Australia, Canada, and/or Mexico for treatment of pediatric patients of the 
spastic upper limb deformity and dynamic equinus foot deformity. BoNT-A treatment of 
children/adolescents is often performed for several spasticity patterns. Several clinical 
study data for efficacy and safety of BoNT-A were reported for UL and LL [Fehlings 
2000, Baker 2002, Speth 2005, Lowe 2006, Mall 2006, Russo 2007, Wallen 2007]. 
Currently, no randomized data of NT 201 in the pediatric population exists. This 
randomized parallel-group, dose-response study will observe the participating subjects in 
accordance with a high scientific standard, ICH-GCP, local laws and regulations, and 
international consensus recommendations on pediatric BoNT-A treatment. 
Pediatric CP subjects with uni- and bilateral UL spasticity alone or combined with LL 
spasticity must have a clinical need for NT 201 treatment to be enrolled in this study. 
Distribution of CP spasticity and clinical need for treatment may not be 100% 
overlapping, e.g. a subject with bilateral UL spasticity may only have a need for NT 201 
treatment in one UL. 
Subjects pre-treated with BoNT-A or BoNT-A treatment-naïve children/adolescents will 
be eligible for this study. Treatment-naïve subjects are defined as those who have not 
received BoNT treatment for limb spasticity within the last 12 months. This regulatory 
definition aims to ensure the lack of assessment bias possibly caused by the subject’s 
and/or parent’s remembrance of former treatment effects. Subjects will be randomized to 
one of three treatment groups in MP in a ratio of 2 : 1 : 1 (High : Mid : Low dose of 
NT 201). This ratio attempts to minimize the number of subjects treated with doses less 
than the target dose of 8 U/kg BW per UL. 
4.3 
Risk-benefit assessment 
There is no monitored experience in children/adolescents available for the BoNT-A 
preparation under investigation. NT 201 was subject to extensive toxicological and safety 
pharmacological testing in non-clinical as well as clinical studies, which showed that 
NT 201 is well tolerated and has an acceptable safety profile (see current IB [Merz 
Pharmaceuticals (GmbH) - IB]). In a juvenile toxicity study in rats, decreased mating 
rates and atrophy of the testicular germinal epithelium with subsequent hypospermia 
without functional consequences were observed at 30 Lethal Dose 50 (LD50) Units 
[LD50U]/kg. However, no indications of frank systemic toxicity other than growth 
retardation were seen at 10 LD50U/kg and below. The clinical relevance of the findings 
from this animal study with these extremely high doses and reinjection already at 


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maximal paralysis is unknown. In a clinical setting, subjects are only re-injected upon 
recovery of the muscle function, usually 3 to 6 months after injection of BoNT-A. In this 
study investigators who are informed on preclinical safety data of NT 201 will judge the 
clinical need for an injection in doses of up to a maximum of 20 U/kg BW NT 201 at 
least 12 weeks after the last injection treatment. Two clinical studies with NT 201 in adult 
subjects with UL muscle spasticity after stroke and other etiologies with a maximum dose 
of 400 U NT 201, respectively, showed good efficacy and no safety issues [Barnes 2010, 
Kanovsky 2011]. 
In general, BoNT-A is well tolerated in children/adolescents [Naumann and Jankovic 
2004, Lukban 2009, Heinen 2010]. Common undesirable effects after BoNT-A injection 
include local, generalized, or procedural AEs. Local AEs are usually mild and self-
limiting. The most commonly reported local AEs after BoNT treatment in 
children/adolescents are potential and expectable consequences of overshooting muscle 
relaxation such as excessive localized weakness [Love 2010]. Systemic AEs related to 
BoNT-A include nausea, fatigue, bladder incontinence, flu-like symptoms, and rash 
[Naumann 2006, Howell 2007]. Procedural AEs include complications due to local 
anesthesia or analgosedation before injection. 
A retrospective analysis supports the safety of high BoNT-A doses citing the occurrence 
of AEs in 261 subjects treated with doses of up to 25 U/kg BW [Willis 2007]. 
Occurrences of AEs ranged from 3.9%-8.6% with no trend to higher percentages of AEs 
in the highest dose group (20-25 U/kg BW). No case of iatrogenic botulism could be 
observed. The authors concluded that the safety profile of BoNT injections is comparable 
over all dose groups analyzed. 
Subjects will be closely monitored for AEs occurring in this study. A DMC will be 
established to monitor for safety signals and to note unexpected hazard (see Section 
12.4.7.3). Common AEs (>1/100, <1/10) listed in the current summary of product 
characteristics for Xeomin® regarding adult post-stroke spasticity of the UL are injection 
site pain, injection site hematoma, and muscular weakness [Merz Pharmaceuticals 
(GmbH) 2012]. 
At Baseline Visit V2 of MP and at all subsequent Control (Ctrl.) Visits and telephone 
contacts of MP and OLEX, subjects will be thoroughly monitored for AEs and AESIs. 
The site staff will even actively question the subject (if applicable) and the parent(s) or 
caregivers (if applicable) for signs of potential toxin spread such as swallowing 
difficulties, speech or breathing disorders, botulism, or muscular weakness. 
As this is a clinical study in the 1st pediatric NT 201 development program, the adequate 
dose ranges were defined from international consensus statements with advice by a board 
of experts experienced in BoNT-A treatment of children/adolescents. Recommendations 
of international consensus groups for onabotulinumtoxinA (BOTOX®) are bridged to 
NT 201 on basis of demonstrated comparability of NT 201 for adult efficacy and safety 
in comparison to BOTOX® when investigated in a 1 : 1 ratio [Benecke 2005, 
Roggenkamper 2006, Jost 2007]. The maximum total body dose of 500 U NT 201 for 


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GMFCS levels I-III and 400 U NT 201 for GMFCS levels IV and V in this study is 
within the comparable upper limit of 400 to 600 U onabotulinumtoxinA (BOTOX®) for 
treatment in children/adolescents with CP by international recommendations [Heinen 
2010, Love 2010]. Moreover, the maximum total dose of this study complies with the 
comparable maximum body dose recommendation by WE MOVE [Brashear and Mayer 
2008]. 
Pediatric subjects are expected to benefit from local treatment with NT 201 in addition to 
their current management for spasticity. Subjects will continue any existing 
physiotherapy, orthotic management and antispastic medication (except for medication 
excluded in this study) to treat spasticity during the study. Mid and low dose treatment in 
25% each of all subjects for one treatment cycle in MP are also considered to show 
treatment effects on limb spasticity (for details see Section 4.2). 
Burden and risk level 
The burden for the individual subject caused by this study is kept to a minimum. 
Injections of IP may be done under local anesthesia and/or analgosedation as appropriate 
to minimize discomfort and pain. Analgosedation will be performed by qualified 
anesthesia personnel in accordance to recommendations from the American Society of 
Anesthesiologists [American Society of Anesthesiologists - Anesthesia Care Team 
Committee 2009] (for further details see Section 8.1.1.2). Pre-treated subjects who 
needed general anesthesia for BoNT injections will not be eligible for this study, since 
general anesthesia will not be used in this study. 
During this study, subjects may receive most of their pre-study medication, 
physiotherapy and other measures to treat spasticity (except casting of the UL during the 
MP, since it may bias the primary efficacy analyses). The investigator will check at each 
on-site 
visit 
that 
the 
individual 
subject 
receives 
appropriate 
concomitant 
medication/therapy. 
Subjects in the mid and low dose arm may experience less effect compared to the high 
dose for only one treatment cycle in MP. However, doses especially in the mid dose 
group (6 U/kg BW NT 201 per UL) but also in the low dose group (2 U/kg BW NT 201 
per UL) lie within the dose ranges of published clinical trials showing effects of BoNT-A 
treatments on spasticity [Fehlings 2000, Wallen 2004, Speth 2005, Wallen 2007]. 
The same dose group assigned to a subject for UL injections will be also applied for LL 
treatment (if applicable). This appears to be justified, since treatment errors with different 
dilutions strength for UL and LL treatments (e.g. by mixing up syringes with different 
dilution strength) may be considered a higher risk for a subject as compared to potentially 
smaller effects on LL spasticity compared to the high dose group for only one treatment 
cycle in MP. 
The overall risk level indicated by the number of occurrences impacting the safety of an 
individual subject is moderate due to the good safety profile of NT 201 and the good 


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clinical experience in this indication with other BoNT preparations. The well experienced 
investigator will carefully reflect the clinical need for BoNT injection based on his/her 
experience-based clinical judgment and will use the pre-specified dosing scheme of this 
study protocol. If the dosing schemes specified in this clinical study protocol do not fit 
the subject’s clinical needs for NT 201 injections, eligibility for study participation is not 
given. At each telephone or site contact (starting at V2), the investigator or authorized 
delegate will actively inquire the subject (if applicable) and/or parent(s) about the 
occurrence of AESIs. By regular review of all AEs including AESIs, the DMC will 
ensure additive control over the safety of the pediatric study population as well as over 
the individual. 
In conclusion, the sponsor believes that this clinical study MRZ60201_3072_1 is 
carefully designed to minimize risks and to maximize potential benefits for the subjects. 


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5 STUDY OBJ ECTIVES 
To investigate efficacy and safety of Xeomin® (incobotulinumtoxinA, NT 201) in 
subjects8 with UL spasticity alone or with combined UL and LL spasticity due to CP with 
a 1st double-blind cycle, the MP, and three subsequent treatment cycles, the OLEX. 
Injection treatments in MP and OLEX will be followed by 12-16 weeks observation each. 
During MP, in a three arm, parallel-group double-blind design subjects will receive one 
of three fixed doses of Xeomin® per treated UL. 
• In the high dose group 8 U/kg BW NT 201 (maximum dose per UL: 200 Units for 
subjects ≥25kg BW). 
• In the mid dose group 6 U/kg BW (maximum of 150 U) per UL.  
• In the low dose group 2 U/kg BW (maximum of 50 U) per UL. 
As clinically needed, UL treatment can be administered uni- or bilaterally with doses as 
outlined above for each treated UL. 
Subjects may receive additional BoNT injections in one out five predefined treatment 
combinations up to the maximum total dose applicable for their GMFCS level (I-III: 
20 U/kg BW NT 201, maximum of 500 U; IV and V: 16 U/kg BW NT 201, maximum of 
400 U). 
After completion of MP, all eligible subjects will continue treatment in OLEX with 
NT 201 doses as in the high dose group of MP. 
                                                          
8 Subjects eligible for this study are children (age 2-11 years) and adolescents (age 12-17 years inclusive). 


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6 INVESTIGATIONAL PLAN 
6.1 
Overall study design 
This prospective, multicenter, multi-national, randomized, double-blind, parallel-group, 
dose-response study in phase 3 of three doses Xeomin® will treat subjects with UL 
spasticity alone or with combined UL and LL spasticity due to CP. The study comprises a 
single double-blind treatment cycle (MP) with three dose arms followed by three 
open-label treatment cycles (OLEX) with a single treatment arm using the high dose 
regimen of MP. 
The study consists of a screening period of 2 weeks and a total of four observation 
periods of 12 to 16 weeks, i.e. 14 weeks ± 14 days, after one double-blind injection 
treatment in MP and after three open-label injection treatments in OLEX. The duration of 
study participation for the individual subject is 50 to 66 weeks. 
Treatment of UL(s) in MP will be administered in three parallel dose groups of NT 201 
with fixed doses to UL(s): 
• In the high dose group 8 U/Kg BW NT 201 (maximum dose per UL: 200 Units 
for subjects ≥25kg BW). 
• In the mid dose group 6 U/kg BW (maximum of 150 U) per UL. 
• In the low dose group 2 U/kg BW (maximum of 50 U) per UL. 
As clinically needed, UL treatment can be administered uni- or bilaterally and subjects 
may receive additional BoNT injections in one out of five predefined treatment 
combinations (A-E) (for details on dose distribution to UL(s) and LL(s) see 
Section 8.1.1.2) up to the maximum total dose applicable for their GMFCS level (I-III: 
20 U/kg BW NT 201, maximum of 500 U; IV and V: 16 U/kg BW NT 201, maximum of 
400 U). In MP only, LL(s) treatment will be performed within the same dose groups as 
UL treatment, i.e. subjects in the mid and low dose group will receive 75% or 25%, 
respectively, of the dose in the high dose group to all limbs treated. 
A total of 344 subjects (2 : 1 : 1 ratio) will be enrolled with:  
• At least 172 subjects randomized to the high dose group. 
• At least 86 subjects to the mid dose group. 
• At least 86 subjects to the low dose group.  
For details on the sample size calculation see Section 12.1. 
This international study is planned to be performed in eligible investigational sites 
worldwide. 


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An independent DMC will be established to monitor the safety of subjects (see 
Section 12.4.7.3). 
After all subjects have completed the End of Study Visit, the analysis of efficacy and 
safety data will be performed and reported in an integrated clinical study report. 
The Flow Chart in Section 6.1.2 provides an overview of the study design. The overview 
of the study activities/visit schedule in Section 9.2 displays the procedures per visit. If 
possible, all visits should be performed at similar day time. The study includes the 
following visits: 
Screening: 
Screening Visit (V1): 
Day -14 (Week –2) ± 5 days 
Main Period (MP): 
Baseline Injection Visit (V2): 
Day 1, randomization 
Telephone Contact (TC1): 
Day 8 (Week 1) ± 3 days of MP 
Ctrl. Visit (V3): 
Day 29 (Week 4) ± 3 days of MP 
Ctrl. Visit (V4): 
Day 57 (Week 8) ± 3 days of MP 
Optional Telephone Contact 
Wk12: 
Day 85 (Week 12) ± 3 days of MP 
Final Visit of MP (V5) 
Day 99 (Week 14) ± 14 days of MP  
Open-Label Extension Period (OLEX) 
Injection Visit (V6, V10, V14): 
Day 1 of the 2nd to 4th treatment cycle. 
Telephone Contact 
(TC2, TC3, TC4): 
Day 8 (Week 1) ± 3 days of 2nd to 4th treatment cycle. 
Ctrl. Visit (V7, V11, V15): 
Day 29 (Week 4) ± 3 days of 2nd to 4th treatment cycle 
Ctrl. Visit (V8, V12, V16): 
Day 57 (Week 8) ± 3 days of 2nd to 4th treatment cycle 
End of Cycle Visit (V9, V13) 
Day 99 (Week 14) ± 14 days of 2nd and 3rd treatment 
cycle 
End of Study Visit (V17):  
Day 99 (Week 14) ± 14 days of 4th treatment cycle. 


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Revisit for reinjection 
If any eligibility criterion is not met either at the Final Visit of MP (V5) or at an End of 
Cycle Visit in OLEX (V9 or V13), the injection may be rescheduled within up to 
16 weeks after the last injection treatment. An injection visit may be rescheduled 
(‘revisit’), if the investigator assumes that the respective eligibility criterion is likely to be 
fulfilled within the remaining period of time to complete 16 weeks after the last injection 
treatment. For details on eligibility criteria see Section 7.3.1. 
If the investigator assumes the criterion will not be met within up to 16 weeks after the 
last injection treatment, or if the subject does not fulfill all eligibility criteria at the 
rescheduled injection visit, the subject will be withdrawn from the study (see 
Section 7.4.1). A subject can perform only one revisit, i.e., the revisit cannot be repeated 
even if the limit of 16 weeks after the last injection has not been reached. 
If rescheduling of an injection visit becomes necessary, this additional visit will be 
interposed into the regular visit series without affecting the numbering or time window of 
regular visits, i.e., the day of injection is designated as Day 1 of each cycle. If an End of 
Cycle Visit and an Injection Visit should not be performed on the same day (e.g., if a 
revisit is required), all procedures that would be transferred from the End of Cycle Visit 
to the Injection Visit must be performed again at the revisit. At a rescheduled injection 
visit (after eligibility criteria have been confirmed and before injection), AEs/AESIs, vital 
signs, concomitant medication, and efficacy assessments will be documented. 
AESI monitoring and Safety Visit 
To monitor potential spread of toxin, the subject (if applicable) and/or parent(s) or 
caregivers (if applicable) will be actively questioned for the occurrence of AESIs at each 
visit or Telephone Contact [TC] starting with Baseline Visit of MP (V2). If a TC 
identifies an (S)AE/AESI that needs confirmation or treatment (e.g., respiratory disorder, 
dyspnoea, aspiration, dysphagia, speech disorder, dysphonia, other signs of bulbar palsy 
or botulism), the investigator must schedule a Safety Visit [SV] in addition to scheduled 
visits as soon as possible after the Telephone Contact. SV are unscheduled extra visits for 
assessment of (S)AE/AESIs only. 
If a subject withdraws from participation during the study at any point of time, every 
attempt should be made to conduct the assessments foreseen for the End of Study Visit 
(V17). 
6.1.1 
End of study 
The end of study will be defined as the End of Study Visit of the last subject.


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6.1.2 
Study flow chart 
Figure 1 
Study Flow Chart 
 


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6.2 
Discussion of Study Design, Including Choice of Control Groups 
The multicenter, double-blind, randomized, three dose arms parallel-group dose-
response, design of this study is chosen to obtain scientifically robust data on efficacy 
and safety of NT 201 in treatment of UL spasticity in subjects with need for UL spasticity 
treatment alone or need for combined UL and LL spasticity treatment due to CP. By 
using a double-blind parallel-group design, study assessments will not be biased by 
investigator, subject and parent(s) or caregiver(s).9 A superiority study with an adequate 
low dose group control holds validity for efficacy and safety with evidence based class 1. 
An IV/WRS will be used to achieve an overall equal distribution of primary clinical 
target patterns (i.e. flexed elbow and flexed wrist) for primary efficacy analysis. Clinical 
patterns flexed elbow and flexed wrist only qualify as target patterns for primary efficacy 
analysis with an AS score ≥2 in elbow flexors or wrist flexors at Baseline Visit (Day 1) 
of MP, respectively. A combination of the two main clinical target patterns in this study, 
i.e., of flexed elbow and flexed wrist in subjects with pediatric CP is expected to be very 
frequent. For this reason, since at same AS scores a clinical decision on which of the two 
main clinical target patterns to select for primary efficacy analysis could not be 
operationalized, the clinical target pattern for primary efficacy analysis will be selected 
randomly by the IV/WRS (for details see Section 8.2.1). Accordingly, the respective 
treated pattern not selected for primary efficacy analysis in this subgroup of subjects will 
be analyzed as key secondary efficacy variable. If only one main clinical target pattern 
should present with an AS score ≥2, this pattern will be selected for primary efficacy 
analysis. Overall, a ratio of 1 : 1 between main clinical target patterns flexed elbow and 
flexed wrist will be ensured by stratified randomization using the IV/WRS. 
To be eligible for this study with concealed allocation to treatment groups in MP, 
subjects must have a clinical need for the fixed dose of NT 201 specified for the high 
dose group (8 U/kg BW NT 201, maximum of 200 U per UL). Only pediatric subjects of 
age 2 to 17 years will be enrolled. A clinical benefit of local treatment with BoNT-A 
injections for children below age 2 years has not been established [Molenaers 2010]. 
Treatment allocation to one of three dose groups of NT 201 will be performed in a 
2 : 1 : 1 randomization scheme to treat as few subjects with doses below the target dose 
of 8 U/kg BW per UL as necessary for statistical analysis.  
Treatment with doses below 8 U/kg BW in 50% of enrolled subjects for only one 
treatment cycle in MP seems to be justified since all subjects may continue any existing 
stable antispastic medication, and all other medications that are not expected to interfere 
with BoNT-A and physiotherapy.  
                                                          
9 In subjects, living e.g. in a special-care unit permanently or most of the time with caregivers being his/her 
main social contacts, a caregiver may replace parent(s) for the assessment of the respective scales and 
measures. 


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Since the 6 U/kg BW dose is only 25% less than the target dose of 8 U/kg per UL, 
relevant treatment effects in comparison to the low dose group are also expected in this 
dose group. In addition, clinical studies using onabotulinumtoxinA (BOTOX®) have 
shown a treatment effect even in the dose range injected in the low dose group of the 
present study. By comparing low dose with high and mid dose group in the MP of this 
study, valuable information not only on peak treatment effects but also on duration of 
treatment effects in relation to dose group will be obtained. 
Local anesthesia and/or analgosedation for injection treatment are permitted to reduce 
discomfort for subjects and to facilitate injections for investigators. Subjects are expected 
to benefit from treatment with NT 201 in addition to the current antispastic therapy. 
After Final Visit of MP, if all eligibility criteria are fulfilled subjects automatically pass 
to OLEX with three injections cycles with NT 201 administered in the dose regimen of 
the high dose group of MP. 


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7 STUDY POPULATION 
The study population will consist of at least 344 subjects (age 2 to 17) with UL spasticity 
alone or with combined UL and LL spasticity due to CP. Subjects must have clinical 
need for injection treatment in the UL at least unilaterally. A subject may be enrolled, if 
she/he suffers from uni- or bilateral CP with clinical need for uni- or bilateral UL 
injections with BoNT for the treatment of spasticity regardless of GMFCS level. The 
subject should present an AS score ≥2 at least unilaterally in one or both of the main 
clinical target patterns of this study, flexed elbow and flexed wrist.  
Overall, subjects must have a clinical need for a dose of 8 U/kg NT 201 per UL 
(maximum of 200 U) according to the experience-based clinical judgment of the 
investigator. 
By using an IV/WRS an overall equal distribution of both main clinical target patterns 
(i.e. flexed elbow and flexed wrist) for primary efficacy analysis will be achieved. Of 172 
subjects allocated in MP to the high dose group, 86 will be analyzed for AS score 
changes in the clinical pattern flexed elbow and 86 will be analyzed for flexed wrist as 
primary efficacy variable. Accordingly, 43 of the 86 subjects that will be allocated to the 
mid and to the low dose group will be analyzed primarily for flexed elbow and 43 will be 
analyzed primarily for flexed wrist. 
Treatment-naïve subjects or pre-treated (non-naïve) subjects may enter the study. 
Treatment-naïve subjects will be defined as individuals who have not received BoNT 
treatment within the last 12 months for treatment limb spasticity. Pre-treated (non-naïve) 
subjects must not have received BoNT treatment in any indication within the last 14 weeks 
prior to the Screening Visit (V1). Selection of study population 
Subjects of 2 to 17 years of age will be enrolled since benefit of local treatment with 
BoNT-A of children younger than 2 years of age has not been scientifically established. 
Affected subjects of 2 to 17 years are treated with BoNT-A in medical practice and are 
able to contribute to the chosen efficacy assessments with limitations specified in 
Section 9.1.1. 
Subjects must have a clinical need according to the clinical judgment of the investigator 
for fixed total doses specified in five different treatment combinations (A-E; see also 
Section 7.2 and 8.1.1.2). The most frequent clinical patterns of spasticity in clinical 
practice will be prioritized for treatment in this study. 
The main clinical target patterns of UL spasticity are flexed elbow and flexed wrist. 
Additional clinical patterns that are optional for injection treatment are clenched fist, 
thumb in palm and pronated forearm. Doses in optional clinical patterns have to be 
chosen not to exceed the maximum dose limit per limb, 8 U/kg BW NT 201 (max. of 
200 U). 


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In combined UL and LL spasticity, subjects can present with clinical need for uni- or 
bilateral LL spasticity treatment in one or more of the following clinical patterns: pes 
equinus, flexed knee, adducted thigh, and/or extended great toe. Maximum doses for 
additional LL treatment are defined by number of limbs treated and GMFCS level. These 
specified dose limits must not be exceeded (see Section 8.1.1.2). 
The investigator should consider whether the subject and the parent(s) are able to attend 
all scheduled study visits, e.g., long distance between home town and study site may 
reduce visit compliance. Furthermore, only subjects should be recruited who are not 
expected to have a need for non-authorized medication during the study (see 
Section 8.3.2). Referrals from clinicians and institutions treating possibly eligible 
subjects may support recruitment from the study site’s pediatric subject pool. The 
recruitment strategy may differ according to local settings in the respective country. 
Recruitment advertisements according to local law and approved by the responsible 
IEC/IRB will be published as needed. 
Gender distribution at enrollment will not be controlled in this study. Therefore, the 
gender distribution in this study is supposed to reflect the distribution in the underlying 
population, i.e., all children/adolescents with CP. 
7.1 
Inclusion criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study 
enrollment: 
Inclusion Criteria 
Rationale Screening 
(V1) 
Baseline 
(V2) 
1. 
Written informed consent obtained from the 
parent(s)10 and assent by the subject (if 
applicable). 
Admini-
strative 
X 
 
2. 
Understanding 
of 
study 
procedures 
and 
willingness to abide to all procedures during the 
course of the study by the subject (if applicable) 
and parent(s). 
Admini-
strative 
X 
 
                                                          
10 The term parent(s) is used for any legally acceptable representative including guardian(s) in this study 
protocol as defined in the ICH guideline E6 (R1) as individual or juridical or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical 
trial. 


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Inclusion Criteria 
Rationale Screening 
(V1) 
Baseline 
(V2) 
3. 
Female or male subject 2 to 17 years of age 
(inclusive). 
Admini-
strative 
X 
 
4. 
Uni- or bilateral CP with clinical need for 
injections with NT 201 for the treatment of UL 
spasticity at least unilaterally. 
Efficacy 
X 
X 
5. 
Ashworth Scale [AS] score in the main clinical 
target patterns in this study 
- 
Flexed elbow: AS score ≥2 in elbow flexors 
(at least unilaterally) 
and/or 
- 
Flexed Wrist: AS score ≥2 in wrist flexors (at 
least unilaterally). 
Efficacy 
X 
X 
6. Clinical need according to the judgment of the 
investigator in one out of five treatment 
combinations 
(A-E, 
as 
shown 
below). 
AS score must be ≥2 for each target pattern 
chosen for injection at the Baseline Injection Visit 
V2. 
Efficacy 
X 
X 
A: UL(s) treatment only (GMFCS I-V): 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) for11: 
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
 
 
 
                                                          
11 Up to 25kg BW dosing of NT 201 will be subject to BW-adjustment (see Appendix 16.4). Above 25kg 
fixed doses will be applied. 


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Inclusion Criteria 
Rationale Screening 
(V1) 
Baseline 
(V2) 
or 
Bilateral treatment of UL spasticity with 
Equal doses of 8 U/kg BW NT 201 (maximum of 
200 U) to each UL. 
  
Dose per UL must be distributed between:  
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
B: Unilateral UL and unilateral LL treatment 
(GMFCS I-V): 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U)11 for: 
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
plus 
Ipsilateral unilateral treatment of LL spasticity 
with 
8 U/kg BW NT 201 (maximum of 200 U). Dose to 
LL must be distributed to at least one of clinical 
target patterns pes equinus, flexed knee, adducted 
thigh, and extended great toe as clinically needed. 
 
 
 


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Inclusion Criteria 
Rationale Screening 
(V1) 
Baseline 
(V2) 
C: Unilateral UL and bilateral LL treatment  
(GMFCS I-III) 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U)11 for: 
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
plus 
Bilateral treatment of LL spasticity with 
12 U/kg BW (maximum of 300 U). Dose must be 
distributed into at least one of clinical target 
patterns pes equinus, flexed knee, adducted thigh, 
and extended great toe, on each side. Dose 
distribution may vary between sides as clinically 
needed. 
 
 
 
D: Unilateral UL and bilateral LL treatment 
(GMFCS IV and V) 
Unilateral treatment of UL spasticity with 
8 U/kg BW NT 201 (maximum of 200 U) 11 for: 
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
 
 
 


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Inclusion Criteria 
Rationale Screening 
(V1) 
Baseline 
(V2) 
plus 
Bilateral treatment of LL spasticity with 
8 U/kg BW (maximum of 200 U). Dose must be 
distributed into at least one of clinical target 
patterns pes equinus, flexed knee, adducted thigh, 
and extended great toe, on each side. Dose 
distribution may vary between sides as clinically 
needed. 
 
E: Bilateral UL treatment and bilateral LL treatment 
(GMFCS I-III) 
Bilateral treatment of UL spasticity with 
Equal doses of 8 U/kg BW NT 201 (maximum of 
200 U)11 to each UL. 
  
Dose per UL must be distributed between:  
1. At least one of the main clinical target patterns 
flexed elbow (4 U/kg BW) and/or flexed wrist 
(2 U/kg BW). 
and 
2. Additional clinical patterns in the same limb 
(i.e., clenched fist, thumb in palm, and/or pronated 
forearm) with the remaining units until maximum 
dose of 8 U/kg BW (maximum of 200 U) for 
treatment of a single UL is reached. 
plus 
Bilateral treatment of LL spasticity with 
4 U/kg BW (maximum of 100 U). Dose must be 
distributed into at least one of clinical target 
patterns pes equinus, flexed knee, adducted thigh, 
and extended great toe, on each side. Dose 
distribution may vary between sides as clinically 
needed. 
 
 
 










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To qualify for reinjection in OLEX, per eligibility criterion No.1 all subjects in this study 
must have  
a) a clinical need for injection of the main clinical target patterns of UL(s) chosen at 
the Baseline Injection Visit V2 (i.e. either flexed elbow or flexed wrist alone or 
flexed elbow and flexed wrist) with fixed dose per pattern defined in Table 14 
plus 
b) a clinical need for the total dose of 8 U/kg BW NT 201 per UL (maximum dose of 
200 U) per treated UL.  
For the main clinical target patterns adaptations are only allowed within the dose ranges 
per muscle and number per injection sites given in Table 14 as long as the total fixed 
dose per main clinical target pattern is kept. 
For the remaining dose not used for treatment of main clinical target patterns of the UL(s) 
adaptations in OLEX may also include change of clinical target patterns and change of 
doses per muscles and number of injection sites as long as the ranges of Table 14 are 
kept. 
In subjects with additional treatment of LL(s) in treatment combinations B. – E. the 
clinical need must be for  
a) unilateral or bilateral treatment of LL(s) as chosen at the Baseline Injection Visit 
V2. 
b) The total dose of the treatment combination chosen at V2 (see also eligibility 
criterion No.2 below).  
Only for injection treatment of the LL(s), it will be allowed to change the LL patterns 
chosen at V2 in further treatment cycles. Regulations for doses per muscle, number of 
injection sites of Table 15 and for total dose to the LL(s) must be respected. 
It will not be allowed to change the treatment combination chosen at V2 or to change the 
body side of treatment in unilaterally treated subjects. 
Only subjects meeting the following eligibility criteria will receive an NT 201 injection 
treatment in the 2nd to 4th cycle. 
Eligibility Criteria 
Rationale 
Visits V5/6, V9/10 
V13/14 
1. Clinical need for injection of the main clinical 
patterns of the UL(s) treated in the previous 
treatment cycle with 8 U/kg BW NT 201 per UL 
(maximum dose of 200 U). 
Safety 
concern; 
efficacy 
X 


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Eligibility Criteria 
Rationale 
Visits V5/6, V9/10 
V13/14 
2. For subjects with combined UL and LL treatment 
in the previous treatment cycle (Treatment 
combinations B-E): 
 
Clinical need for LL(s) treatment with dose of 
NT 201 used in the previous treatment cycle. 
In B: Unilateral LL with 8 U/kg BW (maximum 
of 200 U) in subjects with unilateral UL 
treatment (GMFCS I-V). 
In C: Bilateral LL with 12 U/kg BW (maximum 
of 300 U) in subjects with unilateral UL 
treatment (GMFCS I-III). 
In D: Bilateral LL with 8 U/kg BW (maximum of 
200 U) in subjects with unilateral UL 
treatment (GMFCS IV and V). 
In E: Bilateral LL with 4 U/kg BW (maximum of 
100 U) in subjects with bilateral UL 
treatment (GMFCS I-III). 
Safety 
concern; 
efficacy 
X 
3. AS score ≥2 in the treated clinical patterns. For 
subjects with an AS score of 1, the investigator 
will decide on the clinical need for reinjection. 
Efficacy 
X 
4. Agreement of investigator and subject (if 
applicable) and parent(s) on the need for 
reinjection.* 
Admini-
strative 
X 
5. No infection and/or inflammation in the area of 
the planned injection points. 
Safety 
concern 
X 
6. Negative pregnancy test for female with history 
of menarche.** 
Safety 
concern 
X 
* It is at the discretion of the investigator to decide whether reliable statements on the need for a 
reinjection can be obtained from the subject or have to be retrieved from a parent(s) only. 
** Menarche is defined as the 1st menstrual bleeding in female signaling the possibility of fertility (even 
if ovulation usually occurs only within some months after the menarche). 
 
 
 


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7.3 
Removal of subjects from treatment or assessment 
7.3.1 
Discontinuation of subjects 
In accordance with the Declaration of Helsinki and the IC form, the subject or parent(s) 
may discontinue the study at any time without any penalty or loss of benefits to which the 
subjects is otherwise entitled (see Section 7.4.3). Both the discontinuation of study and 
the reason(s) why the study was prematurely discontinued must be recorded in the 
subject’s file and the eCRF. Date and discontinuation circumstances should be stated. 
Further details on discontinuation could be documented in the respective section of the 
“End of Study” form of the eCRF. 
Subjects must be discontinued from the study by the investigator at any time for any of 
the following reasons: 
• Withdrawal of IC. 
• Treatment with any other IP in another clinical study. 
• Treatment with any BoNT other than study medication. 
• Pregnancy (no further administration of IP(s), blood draw, or any other interventional 
procedure will be performed; see Section 10.4). 
• Any AE for which treatment continuation would constitute an unacceptably high risk 
for the subject. 
• AESIs of severe intensity that represent respiratory function disorders or swallowing 
disorders will trigger the premature termination of a subject without re-exposition to 
IP. The terms for these severe AESIs are: 
o AESI terms related to respiratory function disorders are aspiration, diaphragmatic 
paralysis, dyspnoea, pneumonia aspiration, respiratory arrest, respiratory 
depression, and respiratory failure. 
o AESI terms related to swallowing disorders are bulbar palsy, multiple cranial 
nerve palsies, dysphagia, hypoglossal nerve paresis, cranial nerve paresis, cranial 
nerve paralysis. 
• Injection treatment cannot be performed for any reason, not even with local 
anesthesia and/or analgosedation. 
• Eligibility criteria are not met after the previous injection of IP in the respective 
treatment cycle (MP or OLEX) (see Section 7.3.1). 


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The DMC may recommend further criteria for discontinuation. Deviations from this 
study protocol, or conditions comprising exclusion criteria established in  Section 7.3 that 
arise after the subject has been included in the study may (but will not necessarily) lead to 
the discontinuation of subject’s study participation. All such conditions must be properly 
documented. 
Any subject who discontinues from the study due to AEs will be treated according to 
standard clinical strategies. All pertinent information concerning the AE will be 
documented in the subject’s file as well as in the eCRF AE report form (and in addition 
in an SAE or AESI report form, if applicable). 
Following discontinuation, a final examination (End of Study Visit) should be performed 
for safety reasons. However in a pregnant female no invasive assessments, e.g., blood 
sampling should be performed. The pregnancy has to be followed up until the date of 
delivery (see also Section 10.4). The investigator is required to make every effort to 
contact the subject (if applicable) or parent(s) lost to follow-up, and all such efforts 
should be documented in the subject’s file (e.g., times and dates of telephone contact, 
copies of letters). 
7.3.2 
Premature termination or suspension of the study or a study 
site 
The study or a study site can be prematurely terminated or suspended by the sponsor. 
Reasons for termination of the study or a study site may include, but are not limited to, 
the following: 
• Enrollment is unsatisfactory. 
• The risks and benefits of continuing the study have been reassessed, and the risks 
outweigh any potential benefits. 
• The incidence of AEs constitutes a potential health hazard to subjects. 
• AESIs of severe intensity that represent respiratory function disorders or swallowing 
disorders, that are deemed to be related to IP administration, and are lasting >1 week 
will trigger premature termination of the study. The threshold for premature study 
termination is set to at least five subjects experiencing those AESIs for the 1st 
50 subjects injected. Once 50 or more subjects have been treated in this study, the 
threshold is set to at least 10% of all treated subjects. 
o AESI terms related to respiratory function disorders are aspiration, diaphragmatic 
paralysis, dyspnoea, pneumonia aspiration, respiratory arrest, respiratory 
depression, and respiratory failure. 


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o AESI terms related to swallowing disorders are bulbar palsy, multiple cranial 
nerve palsies, dysphagia, hypoglossal nerve paresis, cranial nerve paresis, cranial 
nerve paralysis. 
• New scientific data on the IP(s) do not justify a continuation of the study. 
• Recommendation of the DMC. 
• The investigator or study site exhibit serious and/or persistent non-adherence to the 
clinical study protocol, the Declaration of Helsinki, ICH–GCP, and/or applicable 
regulatory requirements. 
• The sponsor decides to terminate the study or study site at any time for any other 
reason. 
Furthermore, the study may be prematurely ended if the regulatory authority or the 
IEC/IRB has decided to terminate or suspend approval for the study, the study site, or the 
investigator. 
If the study is prematurely terminated or suspended for any reason, the investigator must 
inform the subjects (if applicable) and the parent(s) and assure appropriate follow-up 
treatment. Within the timeframes noted in applicable regulations, the sponsor will 
promptly inform the investigators, study sites, the IEC/IRB, and regulatory authorities of 
the termination or suspension of the study, as well as provide reasons for the action. 
7.3.3 
Provision of care for subjects after study discontinuation 
After study discontinuation, the subjects will be treated by their physician according to 
their medical condition and standard treatments in the country concerned. For further 
information, see Section 3.3.4. 
Subjects who discontinue prematurely may receive treatment at the discretion of the 
investigator (e.g., referral to orthopedic surgery, switch to another BoNT, oral/intrathecal 
antispastic medication, and local alcohol or phenol injections). The investigator and/or 
the subject’s physician are free to apply any approved antispastic treatment, 
physiotherapy, orthotic management, and any other rehabilitation treatment to treat 
spasticity. 








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doses of MP’s high dose group in OLEX. Since the actual dose of IP in MP will be 
blinded, injection volume per muscle and per pattern will be controlled and documented 
in the eCRF. Conversion of NT 201 doses to volumes will be facilitated by a conversion 
table (see Appendix 16.5). 
Dose calculations for injection treatment in an individual subject should also consider the 
GMFCS levels I-III or IV-V, the total dose per kg BW, the maximum dose allowed in 
this study, the selection of clinical patterns for treatment, the dose per muscle, and the 
dose per injection site.  
To be eligible for injection with IP each clinical target pattern in UL(s) and LL(s) must 
show an AS score of ≥2 at the Baseline Injection Visit V2.  
In OLEX, eligibility for reinjection among other criteria is given at an AS ≥2 in the 
respective clinical pattern. At AS=1 the decision for injection is up to the investigator. At 
AS=0 no injection is allowed. For eligibility criteria for reinjection in OLEX see also 
Section 7.3.1. 
The investigator will distribute the fixed dose per UL between selected muscles within 
pre-defined dose ranges and number of injection sites per muscle (see Table 14 and Table 
15). The main clinical target patterns for UL treatment chosen at V2 must be kept 
throughout study participation and must be injected with a fixed total dose (see Table 14). 
For subjects with bilateral UL treatment the main clinical target patterns of both sides 
must be kept. Adaptations for the main clinical target patterns are only allowed within the 
dose ranges per muscle and number per injection sites given in Table 14 as long as the 
total fixed dose per main clinical target pattern is kept. 
Depending on which body side(s) and limb(s) are affected by UL spasticity, uni- or 
bilateral UL will be administered in five treatment combinations (A-E) at Baseline 
Injection Visit V2 (see for details see Table 6 to Table 13). It will not be allowed to 
change the treatment combination chosen at V2 or to change the body side of treatment in 
unilaterally treated subjects. 
In subjects with additional treatment of LL(s) in treatment combinations B. – E. it will be 
allowed to change the LL patterns chosen at V2 in further treatment cycles. Regulations 
for doses per muscle, number of injection sites of Table 15 and for total dose to the LL(s) 
must be respected. 
It is recommended to consider pre-existing medical co-morbidities, muscle size and 
activity, and experience from previous BoNT treatments of the subject (if applicable). No 
more than 20 U/kg BW NT 201 (max. total body dose of 500 U for subjects ≥ 25 kg BW) 
will be injected in this study. For safety reasons, the upper dose limit for subjects with 
GMFCS levels IV-V is restricted to 16 U/kg BW NT 201 (max. total body dose of 400 U 
for subjects ≥ 25 kg BW). 


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Doses for subjects of <25 kg BW are displayed in tables Appendix 16.4. Above 25 kg 
BW fixed doses will be injected. The distribution of the total dose to clinical patterns per 
limb in this study is as follows: 
Treatment Combination A: Uni- or bilateral UL treatment only 
Subjects with clinical need for unilateral UL injection of NT 201 must have a need for a 
total injection dose of 8 U/kg BW (maximum of 200 U) to the one UL chosen for 
treatment only (see Table 6). At least one main clinical target pattern (flexed elbow or 
flexed wrist) must be treated. 
The dose not needed for treatment of main clinical target patterns must be distributed to 
additional optional clinical patterns (for details see Table 14). The maximum total dose 
per limb (based on dose decisions using the high dose group) must not be exceeded. The 
selection of main clinical target patterns must not be changed throughout the entire 
duration of study participation. 
 


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Table 6 Treatment Combination A: Clinical Need for uni- or bilateral UL treatment 
only (GMFCS levels I-V) 
 
Unilateral UL treatment 
Bilateral UL treatment 
UL 
Clinical need for total dose per UL 
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one main 
clinical target pattern (flexed elbow 
and/or flexed wrist). 
+  
Additional clinical patterns chosen 
from clenched fist, thumb in palm, 
and/or pronated forearm. 
 
Clinical need for total dose per UL 
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one main clinical 
target pattern (flexed elbow and/or flexed 
wrist). 
+  
Additional clinical patterns chosen from 
clenched fist, thumb in palm, and/or 
pronated forearm. 
Selection of clinical patterns and dose 
distribution may vary within predefined 
ranges between sides as clinically 
needed. 
LL 
No LL treatment 
No LL treatment 
 
The total dose of NT 201 administered for unilateral UL injections in treatment 
combination A in MP ranges from 2 U/kg BW (maximum of 50 U) to 8 U/kg BW 
(maximum of 200 U) (see also Table 7). In bilateral UL treatment subjects must have a 
clinical need for an equal dose of 8 U/kg BW NT 201 per limb (maximum of 200 U per 
UL). 
For unilateral and for bilateral UL treatment the same regulations for selection of clinical 
patterns for treatment apply (for details see Table 14). Between ULs, selection of clinical 
patterns for treatment and doses per muscles may vary within pre-specified ranges as 
clinically appropriate. The selection of main clinical target patterns must not be changed 
throughout the entire duration of study participation. For primary efficacy analyses one 
UL must be chosen at the Baseline Injection Visit and must be kept throughout the entire 
study participation. 






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Treatment Combination C + D: Unilateral UL and bilateral LL treatment in 
GMFCS level I-III and GMFCS level IV, V 
In subjects with a clinical need for combined unilateral UL and bilateral LL injections, 
treatment combinations C or D can be chosen depending on the subjects GMFCS level. 
Details on the distribution of the clinical need are given in Table 10.  
Table 10 Treatment Combinations C and D: Clinical need for unilateral UL and 
bilateral LL treatment  
 
 
C: GMFCS I-III 
D: GMFCS IV and V 
Uni-
lateral 
UL 
Clinical need per UL for 
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one main clinical 
target pattern (flexed elbow and/or 
flexed wrist). 
+  
Additional clinical patterns chosen 
from clenched fist, thumb in palm, 
and/or pronated forearm. 
Clinical need per UL for  
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one main clinical 
target pattern (flexed elbow and/or flexed 
wrist). 
+  
Additional clinical patterns chosen from 
clenched fist, thumb in palm, and/or 
pronated forearm. 
 
Bilateral 
LL 
Clinical need for total dose for both 
LLs 
12 U/kg BW, max. 300 U NT 201 
Treatment of at least one clinical target 
pattern chosen form pes equinus, 
flexed knee, adducted thigh, extended 
great toe. 
Selection of clinical patterns and dose 
distribution may vary within 
predefined ranges between sides as 
clinically needed. 
Clinical need for total dose for both LLs 
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one clinical target 
pattern chosen form pes equinus, flexed 
knee adducted thigh, extended great toe. 
Selection of clinical patterns and dose 
distribution may vary within predefined 
ranges between sides as clinically needed. 




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side in the NT 201 pediatric spasticity program. For details on LL treatment see also 
Table 15. 
Treatment Combination E: Bilateral UL and bilateral LL treatment in GMFCS 
level I-III 
In the scenario of combined bilateral UL and bilateral LL treatment, treatment of ULs 
will be performed as described in treatment combination A (see above). For details on 
clinical need in treatment combination E see Table 12. In MP subjects will receive 
treatment to UL and LL in three different dose groups of NT 201 (see Table 13). An 
overview of the selection of clinical patterns for UL and LL treatment are given in Table 
14 and Table 15. 
Table 12 Treatment Combination E: Clinical need for bilateral UL and bilateral LL 
treatment GMFCS levels I-III 
 
GMFCS I-III 
Bilateral 
UL 
Clinical need for equal dose per upper limb of 
8 U/kg BW, max. 200 U NT 201 
Treatment of at least one main clinical target pattern (flexed elbow 
and/or flexed wrist). 
+  
Additional clinical patterns chosen from clenched fist, thumb in palm, 
and/or pronated forearm. 
Bilateral 
LL 
Clinical need for additional total dose for both LLs 
of 4 U/kg BW, max. 100 U NT 201 
Treatment of at least one clinical target pattern chosen form pes 
equinus, flexed knee, adducted thigh, extended great toe. 
Selection of clinical patterns and dose distribution may vary within 
predefined ranges between sides as clinically needed. 
 
 
 




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wrist. Injection treatment in at least one of these main clinical target patterns in this study 
is mandatory. The dose in both patterns is fixed. 
For treatment of flexed elbow, injection of biceps brachii is mandatory. The investigator 
can select one of the two other muscles contributing to spasticity of elbow flexion, i.e. 
brachialis and brachioradialis, for injection. 
The selection of 2 out of 3 muscles for treatment of flexed elbow must be fixed at the 
baseline injection visit and kept throughout the entire study. 
Subjects with clinical need for treatment of flexed elbow will receive 4 U/kg BW NT 201 
(maximum of 100 U). In the clinical pattern flexed wrist the fixed dose is 2 U/kg BW 
NT 201 (maximum of 50 U). If this pattern is chosen, both muscles must be injected. 
Another subgroup of children/adolescents is expected to present with spasticity of finger 
flexors (clenched fist). Here, a fixed dose of 2 U/kg BW NT 201 (maximum of 50 U) will 
be administered. If this pattern is chosen, both finger flexors must be injected, i.e. flexor 
digitorum superficialis and profundus. 
In the other optional clinical target patterns thumb in palm and pronated forearm, 
investigators can choose muscles as needed as long as the upper dose limits per UL and 
injection session are respected. At least one muscle per pattern must be injected. 
Detailed tables for injection doses per treatment scheme and BW-adjusted dosing 
displaying respective injection volumes, minimum and maximum dose per pattern and 
muscles by BW are displayed in Appendix 16.4. The transfer of IP doses into injection 
volumes may be supported by Table 27, Appendix 16.5.  
LL treatment in clinical target patterns 
For subjects with a clinical need for LL injection treatment, investigators can choose 
from the following clinical patterns: pes equinus, flexed knee, adducted thigh, and 
extended great toe. For flexed knee or adducted thigh investigators are free to choose 
muscles but have to respect dose ranges per muscle and number of injection sites (see 
Table 15). 
Dosing for subjects with GMFCS level IV and V 
To account for the reduced total body dose of 16 U/kg BW NT 201 (maximum of 400 U 
for subjects ≥ 25kg BW) instead of 20 U/kg BW NT 201 (maximum of 500 U NT 201) 
for GMFCS levels I-III specific dose reductions have been introduced in this study. To 
allow for comparability of efficacy and safety outcomes, the doses to UL(s) are fixed for 
all GMFCS levels. The uniform dose per treated UL is 8 U/kg BW NT 201 (maximum 
dose of 200 U). The maximum dose per LL in this study is also 8 U/kg BW NT 201 
(maximum dose of 200 U). Limitation of the total dose to LLs in subjects with GMFCS 
levels IV and V is only necessary in the scenario of unilateral UL plus bilateral LL 
treatment (treatment combination D. Subjects with GMFCS level IV and V will only 


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receive 8 U/kg BW as total dose to LLs instead of 12 U/kg BW in subjects with GMFCS 
level I-III. 
Because of the limitation of the total body dose, bilateral LL(s) treatment in combination 
with bilateral UL treatment will only be allowed for subjects with GMFCS levels I-III at 
a dose to both LLs of 4 U/kg BW NT 201 (maximum of 100 U). 
Dose reduction will not be achieved by reducing the dose to individual muscles but by 
prioritizing the most important muscles for injection in an individual subject. Therefore, 
the doses for LL injection treatment displayed in tables for BW-adjusted dosing (see 
Appendix 16.4) are uniform for all treatment scenarios in this study (see also same 
section above). 
 


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Table 14 Dose ranges for UL clinical patterns and muscles in the High, Mid and Low Dose Group of MP 


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Injection treatment and post-injection measures 
NT 201 will be injected as intramuscular injection at the Baseline Injection Visit of MP 
and all Injection Visits of OLEX. 
If needed, subjects will receive local anesthesia and/or analgosedation to reduce injection 
related pain and discomfort and to facilitate the injection procedure for the investigator. 
Analgosedation will be performed by qualified anesthesia personnel only. Procedures 
will include information of the subject and parent(s) before the start of analgosedation, 
medication with anesthetics, maintenance and monitoring (e.g., cardiovascular and 
respiratory). If analgosedation is intended to be used in a subject for the first time, fitness 
for analgosedation must be ensured first by a general pediatric examination. Fasting times 
required for some forms of analgosedation (e.g., nitrous oxide) have to be met. 
Localization of the target muscle by palpation and anatomical landmarks alone was 
shown to be inaccurate, except for the gastrosoleus complex [Chin 2005]. To confirm the 
correct placement of the injection needle in this clinical study, all injections must be 
guided by at least one of three forms of technical guidance: ultrasound, electrical 
stimulation [e-stim], and/or electromyography [EMG]. Ultrasound will be the preferred 
guidance technique. All investigators performing injections of IP must be experienced in 
technically guided BoNT treatment of children and adolescents with CP. 
The maximum dose per injection site should be 25 U NT 201 with a maximum volume of 
0.5 mL per injection site for subjects of <25 kg BW. The maximum dose per injection 
site for subjects of ≥25 kg BW should be 50 U NT 201 with a maximum volume of 
1.0 mL per injection site. 
The investigator will use the IP and all study materials only within the framework of the 
clinical study and in accordance with this clinical study protocol. 
Following injection of IP, the subject will be under observation for at least 30 min. The 
subject (if applicable) and parent(s) or caregiver(s) (if applicable) will be asked if any AE 
has occurred within the 30 min since injection. 
8.1.2 
Packaging and labeling  
Boxes of IP containing NT 201 and PBO vials, if applicable, will be sent to the study 
sites. If necessary during the course of the study, study sites will be replenished with all 
study materials. The investigator will administer the IP to the subject during the injection 
visits only. IP will not be handed over to subjects or parents. 
The study medication in MP and OLEX will be labelled according to regulatory 
requirements in the participating countries. The labels will include as minimum 
information name and address of the sponsor, study reference number, EudraCT/IND 
number, medication number, dosage form, route of administration, quantity of dosage 


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units, batch number, directions for use, storage conditions, period of use and ‘For clinical 
study use only’. Parts of the study medication might be subject of a reduced labelling 
according to the applicable regulations.  
If exchange of IP due to the expiry date should become necessary or if the retest date is 
extended, the IP will be replaced or relabeled in due time. 
Main Period: 
For the double-blind MP of this study, the IP for all three dose-groups will have the same 
printed label information on the outer packaging (box) and the glass vials. See 
Section 8.4 for details on the blinding procedures planned for MP. 
For the double-blind MP, medication kits with one outer box labeled with a medication 
(randomization) number will be provided. The outer box contains syringes, needles and 
sterile 0.9% saline for reconstitution purposes, pooling syringes, transfer needles and 
syringe connectors as well as an inner box including four vials of study medication. 
Syringes and needles for injection will be provided separately. An inner box of the high 
dose group contains four vials NT 201. For the mid dose group an inner box contains 
three vials NT 201 and one PBO vial. An inner box of the low dose group contains one 
vial NT 201 and three vials PBO. Each of the four vials will be reconstituted with 2 mL 
sterile 0.9% saline. If a vial should be broken, or a medication inner box should become 
unusable for any reason, vials from the medication inner box must not be used and the 
whole box must be replaced from the site stock of study medication using the IV/WRS. 
As outlined in Section 8.1.1.1 based on the information on chosen treatment combination 
and BW, the IV/WRS will assign either one or two medication kits with four vials of IP 
each in MP and OLEX. 
OLEX: 
In OLEX, two different medication kits will be supplied. A second medication kit will 
only be necessary for treatment combinations C and E and subjects with BW over 20kg. 
In both scenarios the total dose exceeds the dose of 400 U provided with a medication kit 
with 4 vials NT 201. This second medication kit will only contain 1 vial NT 201 with 
100U. 
For each treatment cycle in OLEX either one (treatment combinations A-E, for C and E 
subjects with BW <20kg only) or two different medication kits (treatment combinations 
C and E with subject BW of >20kg) will be assigned via IV/WRS (see also Section 
8.1.1.1). The outer box of the medication kit with 4 vials only contains syringes, needles 
and sterile 0.9% saline for reconstitution purposes as well as an inner box including four 
vials of study medication. The smaller medication kit contains one vial NT 201 only. 
If a vial should be broken, or if a medication inner box should become unusable for any 
reason, vials from the medication box must not be used and the whole box (either  4 vial 
box or 1 vial box, as applicable) must be replaced from the site stock of study medication 
using the IV/WRS. 


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Only in OLEX, the actual number of vials to be reconstituted depends on the total body 
dose to be administered (see also Section 8.1.1.2). In contrast to MP, the vials need not to 
be pooled to achieve the correct final concentration of IP. 
For example, for a total body dose of 200 U NT 201 two vials have to be reconstituted, 
for 400 U four vials from one medication kit, and for 500 U four vials from big and one 
vial from the small medication kits have to be dissolved. In any case, the total body dose 
should be calculated before reconstitution to know the exact number of vials for 
reconstitution and to be able to provide this data to the IV/WRS. For calculations of 
BW-adjusted dosing the BW will be measured at the respective Injection Visit. Up to 0.4 
kg BW will be rounded down. At 0.5 kg and above BW will be rounded up. 
8.1.3 
Storage of investigational product(s) 
The IP will be shipped at ambient temperature. Shipment will be performed under 
temperature control. Unopened vials should be stored within a temperature range from +2 
to +25°C (36-77°F). It is recommended not to freeze the study medication. During 
storage the minimum/maximum temperature will be recorded in a temperature log. 
During storage the temperature log should be maintained every business day. For storage 
of reconstituted IP, see Section 8.1.1. IP must be stored in a locked place during all study 
periods. 
8.1.4 
Accountability for investigational product(s) 
It is the responsibility of the investigator or pharmacist according to local law to ensure 
that a current record of inventory/drug accountability is maintained. Inventory records 
must be readily available for inspection by the study monitor and are open to inspection 
by the FDA or other regulatory authorities at any time. Each shipment of materials for the 
study will contain an IP supply and return form to assist the investigator in maintaining 
current and accurate inventory records. This form includes the following information: 
study number, date of delivery, quantities, batch number, expiration date, and the 
medication number assigned to the IP. The form should be filed with the inventory/drug 
accountability records. 
Upon receipt of IP, the investigator or a pharmacist according to local law will visually 
inspect the shipment and verify the number and condition of IP. Receipt of IP will be 
confirmed via an IV/WRS by the investigator or authorized site staff. An 
acknowledgment of receipt form will be send by IV/WRS which should be filed with the 
inventory/drug accountability records. Use of IV/WRS will be laid down in a user 
manual. 
To ensure proper storage and to verify inventory, a drug supply inspection will be 
conducted at regular intervals by the monitor. The results of the inspection will be made 
available to the authorized individuals (e.g., monitor, auditor, and regulatory authorities) 
on request throughout the study.  


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For drug accountability and treatment compliance, see Section 8.2.5. 
8.1.5 
Destruction of investigational product(s)  
Upon the completion or termination of the study, all unused and/or partially used IP vials 
must be returned to the sponsor. Reconstituted but not used IP has to be inactivated at the 
clinical sites (see Section 8.1.1.1) before used IP vials could be returned to the sponsor. 
The sponsor or an authorized party will destroy the IP after completion of the clinical 
study report taking into account local legislation.  
8.2 
Treatments administered 
The study will randomize subjects into three dose groups of NT 201 in MP. In OLEX all 
subjects will be treated open-label in one dose group with doses equal to the high dose 
group in MP. The treatment scheme and dose per UL(s) and doses for LL(s) will depend 
on an individual subject’s need for treatment of spasticity. For details of administration, 
please refer to Section 8.1.1.2. 
8.2.1 
Methods of assigning subjects to treatment groups 
The study is planned as an international multi-center study. At the Baseline Injection 
Visit (Day 1) of the double-blind MP, subjects will be assigned to one of three dose 
groups of NT 201 (high, mid, and low) according to a 2 : 1: 1 randomization scheme. 
Randomization will be balanced in blocks of appropriate size. The distribution of the IP 
to the investigational sites and the randomization will be controlled by IV/WRS to ensure 
a number of enrolled subjects approximately according to the randomization ratio of 
2 : 1 : 1 in the three treatment groups. Subjects discontinued from the study will not be 
replaced. 
In this study, two main clinical target patterns have been defined, i.e. flexed elbow with 
an assessment of the AS score for elbow flexors and flexed wrist with an assessment of 
the AS score for wrist flexors. Randomization will be stratified by primary clinical 
pattern (elbow flexors/flexed wrist) in a 1:1 ratio within each dose group.  
In practice, a subject may have up to two main clinical target patterns qualifying for 
primary efficacy analysis based (a) on the clinical need for IP injection and (b) on the 
presence of an AS score ≥2 in elbow or wrist flexors. Since no clinical algorithm is 
existent to decide which of both main clinical target patterns to take for primary efficacy 
analysis in such a situation, an IV/WRS will be used to achieve an overall equal 
distribution of primary clinical target patterns flexed elbow and flexed wrist in this study. 
The selection will be performed by the IV/WRS before randomization to treatment 
groups (i.e. to one of three dose groups of NT 201 in MP). In case only one main clinical 
target pattern qualifies for primary efficacy analysis, this pattern will be selected by the 
IV/WRS. If both main clinical target patterns would qualify for primary efficacy analysis, 


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the selection has to be in a way that after randomization the distribution of primary 
clinical target patterns is balanced as much as possible in both treatment groups, or at 
random, if this is not possible. 
For bilateral treatment of UL spasticity both sides must (a) have a clinical need for IP 
injection treatment in the clinical patterns allowed in this study according to the clinical 
judgment of the investigator and (b) an AS score ≥2 on each side. For subjects with 
bilateral UL treatment, the body side for primary efficacy analysis will be decided by the 
investigator at screening based on clinical judgment. 
The responsible randomization officer of the sponsor will allocate treatments to subjects 
using the computerized randomization program RANCODE (Version 3.6, IDV 
Datenanalyse und Versuchsplanung, Gauting, Germany). At the injection visit (Day 1) of 
MP at the investigational site, the IV/WRS will assign to each subject a medication 
(randomization) number for the medication to be used in MP. At each injection visit in 
OLEX a separate medication number will be assigned for the medication to be used at the 
respective visit. The medication (randomization) number(s) of MP will be recorded along 
with the date of randomization in the eCRF. The medication numbers of OLEX will be 
recorded with the reinjection dates in the eCRF.  
The MP randomization schedule will be sealed and locked in the corporate quality 
systems of the sponsor and will not be accessible prior to unblinding of MP. 
As all subjects in OLEX will receive NT 201, no further randomization is required at the 
start of this study period. 
8.2.2 
Selection of doses in the study 
In the MP of this study, subjects will be treated in three dose groups NT 201. Doses for 
each treated UL will be fixed (for details see Section 8.1.1.2). In MP, at least 86 subjects 
will be randomized to each the mid and the low dose group. Depending on the clinical 
need for LL injections in addition to UL treatment, a total dose of up to 500 U NT 201 
can be administered according to pre-defined treatment combinations (B-E) (see 
Section 8.1.1.2). 
BoNT has proven to be safe and efficacious in the pediatric population with CP in 
clinical studies. Recommendations by the US organization WE MOVE™ [Brashear and 
Mayer 2008] and international consensus guidelines state 400 to 600 U BOTOX® as 
upper total dose limit [Fehlings 2010, Heinen 2010, Love 2010]. The updated European 
consensus 2009 paper on the use of BoNT for children with CP [Heinen 2010] 
recommends based on clinical studies a total body dose for BoNT treatment using 
onabotulinumtoxinA (BOTOX®) of up to 20-25 U/kg BW. This recommendation is based 
on two BOTOX® trials with multi-level/multi-muscle treatment using doses of 
20-30 U/kg BW [Heinen 2006, Molenaers 2009]. 


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In the present combined three arm dose-response and open-label extension study, the 
maximum dose for unilateral UL treatment is defined to be 8 U/kg BW NT 201 with a 
maximum dose for subjects ≥ 25kg BW of 200 U per limb. Regardless of combinations 
of limb treatment needed by an individual subject total body dose limits must be met. For 
subjects of GMFCS levels I-III this total body dose limit for NT 201 is 20 U/kg BW 
(maximum 500 U for subjects ≥ 25kg) and for GMFCS levels IV and V 16 U/kg BW 
(maximum 400 U for subjects ≥ 25kg). These regulations for the safety of subjects are 
based on the above mentioned data from children/adolescents treated with 
onabotulinumtoxinA and on the recommendation of the advisory board of six 
international experts in pediatric CP treatment [Merz Pharmaceuticals GmbH 2011]. 
As NT 201 has been shown to be used in a ratio of 1 : 1 (NT 201 : BOTOX®) in non-
clinical and clinical studies [Benecke 2005, Roggenkamper 2006, Jost 2007], the dosing 
recommendations for the NT 201 group are justified to be transferred to NT 201. In the 
MP of this study, the high and the mid dose group of NT 201 treatment will be compared 
to the low dose group for pediatric use for regulatory purposes [US Food and Drug 
Administration 2011]. Furthermore, the study will collect experience with standardized 
dose ranges for NT 201 in uni- and bilateral UL spasticity treatment in pediatric subjects. 
The dosing ranges for muscles displayed in Table 14 and Table 15 were adapted 
according to current expert opinion [Brashear and Mayer 2008] in personal 
communication with an international advisory board. Each investigator will decide, if 
maximum dose per UL (8 U/kg BW, 200 U for subjects ≥ 25 kg) and total body doses of 
16 to 20 U NT 201/kg BW (maximum 400 U to 500 U for subjects ≥ 25kg BW) and the 
clinical patterns specified fit an individual subject’s need for treatment of spasticity (see 
also Section 8.1.1.2). 
In summary, the selected doses in the NT 201 group and the chosen distribution ranges 
per muscle are justified to investigate efficacy and safety of NT 201 in the treatment of 
UL spasticity alone and of combined UL and LL spasticity due to CP in 
children/adolescents (age 2 to 17 years). 
8.2.3 
Selection and timing of doses for each subject 
The investigator will decide with his/her experience-based judgment in botulinum toxin 
treatment of CP in conjunction with considering the AS in the target joints, whether 
treatment of the subject within specified dose limits and treatment patterns in this study is 
appropriate. 
The investigator will assess the current clinical pattern of spasticity of UL(s) and LL(s), if 
applicable, and will decide which muscles require treatment with BoNT. The investigator 
will define one UL at the Screening Visit that will serve for (primary) efficacy analyses 
throughout MP and OLEX. In accordance with inclusion criteria, the AS score of all 
treated clinical patterns of spasticity including the main clinical target patterns (either 
flexed elbow or flexed wrist) must be ≥2 at the Baseline Injection Visit V2. 


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If the contralateral UL is also treated, secondary efficacy analyses in the main clinical 
target pattern(s) of this limb also will be performed. Allowed adjustments will help 
tailoring the NT 201 treatment to the individual condition of a subject by deciding on the 
treated clinical patterns, the dose per selected muscles and the number of injection sites. 
Details of the treatment are described in Section 8.1.1.2. 
After the screening period, IP will be injected once at the Baseline Injection Visit (V2) of 
the double-blind MP and up to three times in OLEX, if eligibility criteria for reinjection 
are met up to 16 weeks after the previous injection (for details on eligibility criteria see 
Section 7.3.1). 
8.2.4 
Duration of treatment per subject 
The screening period before (baseline) injection treatment in MP lasts up to 2 weeks 
± 5 days. In MP, subjects will receive one injection treatment followed by an injection-
free observation period of 14 weeks ± 14 days (12 to 16 weeks, see Study Flow Chart in 
Section 6.1.2). After the Final Visit of MP, the subject will continue treatment in OLEX 
with up to three open-label treatment cycles. Therefore, the total study duration for a 
single subject is 50 to 66 weeks from Screening Visit to the end of the observation period 
(End of Study Visit V17). In OLEX cycles also, subjects should show need for 
reinjection 14 weeks ± 14 days after the previous injection. 
8.2.5 
Treatment compliance 
IP will be administered by i.m. injection performed by the investigator during the 
subject’s visit to the investigational site. Thus, full treatment compliance is assured for 
each individual subject. 
At the beginning of the study, the site will receive drug accountability forms to document 
how and when IP is administered, returned unused or returned as used empty vials from 
the site. IP in used, partially filled vials should be inactivated and discarded before 
returning (methods of inactivation are described in Section 8.1.1.1). Drug accountability 
forms will be made available to the authorized individuals (e.g., monitor, auditor) and 
include the following information: study number, dates, quantities, and the medication 
number assigned to the IP and pediatric study subjects. 
8.2.6 
Treatment of overdose 
An overdose is defined as any deviation from the dose specified in the protocol (doses 
that are higher than recommended). Any overdose must be recorded in the IP section of 
the eCRF. Any case of overdose leading to AE(s), SAE(s) or AESI(s) must be reported to 
the CRO in an expedited manner using the appropriate (SAE) reporting form (see Section 
10.1). 


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A vial with 100 U NT 201 contains less than 1/100 of the estimated adult human lethal 
dose for BoNT-A following intravenous or intramuscular application (see current IB for 
additional details [Merz Pharmaceuticals (GmbH) - IB]). As treatment with IP is 
performed exclusively in a clinical setting under the supervision of trained medical 
personnel, the risk of overdose in this study is estimated to be very low. 
There is no significant information regarding overdose from clinical studies in adults with 
upper limb spasticity, cervical dystonia, and blepharospasm. 
Excessive doses of NT 201 may be expected to produce neuromuscular weakness with a 
variety of symptoms. Signs include acute symmetric, descending flaccid paralysis with 
prominent bulbar palsies such as diplopia, dysphonia, and dysphagia, which would 
typically occur 12 to 72 hrs after exposure [Arnon 2001]. Furthermore, signs and 
symptoms of overdose can result in ptosis, generalized muscle weakness and paralysis of 
respiratory muscle leading to aspiration pneumonia. Clinical cases of iatrogenic botulism 
after BoNT injection were reported for four adult patients whose clinical signs were 
consistent with those of naturally occurring botulism [Chertow 2006].  
Symptoms of overdose are not immediately apparent following injection. By the time 
symptoms of intoxication are observed, treatment with anti-toxin will no longer be 
effective because the neurotoxin has already irreversibly blocked the transmitter release. 
Compounds releasing ACh (e.g., physostigmine, guanidine, 3,4-diaminopyridine) might 
be helpful. However, there is no experience with a specific antidote to BoNT including 
NT 201 in the clinical management of overdose. A published case report describes the 
successful treatment of dysphagia with intranasal neostigmine [Marchini 1997]. 
Subjects (if applicable) and parent(s) should be advised to seek immediate medical care if 
symptoms such as swallowing difficulties, speech or breathing problems occur. Subjects 
(if applicable) and parent(s) will receive a subject card with contact information in case 
of emergency (see Section 3.3.3) should additional information on the scope of the study 
be required. 
In case of an overdose the subject must be medically monitored for several days. If signs 
of intoxication appear, hospitalization with general supportive measures is necessary. 
Intubation and assisted ventilation may become necessary where excessive doses cause 
paralysis of the respiratory muscles. Antitoxin would not reverse any BoNT-induced 
effects already apparent by the time of antitoxin administration. 
8.3 
Previous and concomitant therapies 
The concomitant medication page in the eCRF should include a detailed list of all 
medications the subject had received for a period of at least 4 weeks previous to the 
Screening Visit. Previous phenol and alcohol injections within the last 6 months and 
BoNT treatments to any body region regardless of the time of administration prior to the 
Screening Visit should be documented. The record of previous and concomitant 
medication should include the drug name (trade or generic), route of administration (e.g., 


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intravenous, oral), total daily dose/unit (expressed in mg, mL, or IU), indication, the start 
and stop date (if applicable, date with day, month, and year) for each medication, and if 
the medication is ongoing at the beginning of the study (concomitant medication).  
Similar kind of information should be collected and assessed for any non-drug treatment 
applied during the study that may have an impact on study results, e.g., physiotherapy, 
orthotic management, or other rehabilitation measures to treat spasticity. Changes in non-
drug treatment (including changes of regimen) during the study are to be documented in 
the subject’s file and in the eCRF. No recording of information on non-drug treatment for 
the period before the screening is necessary. It also should be noted whether the non-drug 
treatment is ongoing at the end of the study. 
8.3.1 Authorized Concomitant Medication/Treatment 
The following concomitant medication/treatment is permitted during the study: 
• Drugs acting as central muscle relaxants (e.g., oral baclofen tizanidine) and/or 
benzodiazepine medication (e.g., diazepam) and/or any other medication with effects 
on spasticity (e.g., gabapentin, dronabinol) if administered at a stable dose within 
2 weeks prior to Screening Visit (V1), within the screening period and for the 
duration of MP. Administration of benzodiazepines in addition to stable treatment is 
only allowed as part of an analgosedation procedure on days of injection visits in MP 
and OLEX after completion of all other study assessments (see also below). 
• Antidepressant medication if administered at a stable dose within the 2 weeks prior to 
Screening Visit (V1), within the screening period and until the end of MP. 
• Physical therapy (e.g., strengthening, stretching, and motor training), orthotic 
management other than casting, and any other rehabilitation treatment are allowed but 
should preferably be kept stable during study participation. Removable casts will be 
only allowed in the OLEX of this study. 
• At the day of injection visits in MP and OLEX local anesthesia and analgosedation 
are allowed after completion of all efficacy and safety assessments. 
The following concomitant medication is permitted under certain precautions: 
• Orally administered drugs that interfere with neuromuscular transmission should be 
avoided or used with extreme caution because the effect of BoNT might be affected. 
• Aminoglycoside antibiotics and spectinomycin because the effect of Botulinum toxin 
might be potentiated. Alternative treatment options of intercurrent acute infection 
include 2nd and 3rd generation cephalosporines (e.g., cefazoline, ceftriaxone, 
ceftazidime), carbapenemes (e.g., imipenem), or nitrofuranes (e.g., nitrofurantoin).17 
                                                          
17 For anti-infective treatment, choice of antibiotics should be made according to guidelines for pediatric 
use and recommendations of SmPCs for the respective drug (formulation). 


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• Parenterally administered drugs that interfere with neuromuscular transmission (e.g., 
tubocurarine-type muscle relaxants used in anesthesia) should be used with extreme 
caution because the effect of BoNT might be potentiated. 
• Aminoquinolines (chloroquine, hydroxyl-chloroquine) because they antagonize the 
onset of paralysis of BoNT. 
• Vaccinations necessary during the course of this study should be performed at least 6 
weeks after injections of IP because vaccination side effects (e.g., fatigue) could 
confound efficacy and safety assessments. 
8.3.2 Non-authorized concomitant therapies 
These items exclude subjects at Screening and Baseline Injection Visit (see Section 7.3) 
and are not allowed during the entire study duration: 
• Botulinum toxin of any serotype (other than study medication) in any body region 
within 14 weeks prior to Screening Visit V1 and/or within the screening period. 
• Phenol or alcohol injections into any body region within 6 months prior to Screening 
Visit V1 and/or within the screening period. 
• Administered within 2 weeks prior to Screening Visit V1, within the screening period, 
and/or intended to be administered during the study period: 
o Drugs acting as peripheral muscle relaxants (e.g., dantrolene). 
o Intrathecal baclofen. 
o Oral anticoagulants. 
o Serial casting or functional electrical stimulation of the target joint(s) for 
injection. Casting will be forbidden during MP, but removable casts will 
be allowed in OLEX. 
• Vaccination within 2 weeks prior to study participation (V1) and/or within the 
screening period. 
• Surgery in the target UL(s) intended to treat spasticity within 12 months prior to 
Screening Visit (V1), within the screening period or planned for the time of 
participation in this study. 
• Physiotherapy, occupational therapy, or any other rehabilitation measures to treat 
spasticity (including splinting) is not permitted prior to study assessments on the day 
of any visit as this might influence evaluation of the severity of spasticity. 


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8.4 
Blinding 
The study will be conducted in a double-blind fashion in MP only. In OLEX only open-
label treatment will be administered. The vials of all three dose groups in MP will have 
the same appearance. The identity of individual IP will remain unknown to the 
investigator, medical staff, and subjects. All other individuals involved in the study (e.g., 
clinical project manager, medical expert, biostatistician, monitors and personal at CRO) 
will also remain blinded. 
A DMC will assess the safety of subjects by safety data reviews throughout the study (see 
Section 12.4.7.3). The treatment code of an individual subject may be unblinded within 
the DMC if necessary for the safety evaluation. Detailed procedures for the evaluation of 
safety data and unblinding will be laid down in the DMC charter. All safety aspects with 
lifted blind discussed during DMC meetings will be provided for filing in the trial master 
file only after data base lock and subsequent unblinding of the study. 
8.4.1 
Emergency envelopes 
The RANCODE computer randomization program (see Section 8.2.1) will be used to 
prepare one complete set of sealed emergency envelopes, which contains all 
randomization numbers. In case of an emergency, this set of envelopes will allow 
unblinding of the IP for an individual subject while maintaining the overall study blind. 
Emergency envelopes will be used by “Infraserv GmbH & Co. Hoechst KG” for 
emergency unblinding during out-of-office hours. 
At the end of study all emergency envelopes must be returned to the randomization 
officer at the sponsor. Any opened emergency envelope must be returned bearing the date 
and reason for opening, as well as the initials and signature of the person responsible for 
breaking the blind. 
The principal investigator or authorized staff of each investigational site will receive a 
password for the IV/WRS enabling him/her to break the blinding code of subjects via this 
system. The principal investigator or authorized staff is responsible for the safekeeping of 
the password. He/she will remain blinded throughout the study. If a medical emergency 
occurs and a decision regarding the subject’s condition requires knowledge of the 
treatment assignment, the study blind may be broken by the principal investigator or 
authorized staff. Unless the medical emergency is deemed to be life-threatening, the 
medical monitor of the CRO should be consulted prior to unblinding. Upon breaking the 
blinding code the investigator will indicate in the subject’s file the date and reason. 
Merz Global Drugs Safety will receive IV/WRS access and a password for unblinding. 
The chairperson of the DMC will also receive IV/WRS access and a password enabling 
him/her to break the blinding code of subjects via this system. The DMC chairperson is 
responsible for the safekeeping of the password but may delegate this task to the office 
manager of the DMC. 


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During its monitoring, the DMC may require to know the actual treatment for single 
subjects in order to evaluate the safety information of AESIs and SAEs received from the 
study to early identify signals and give advice. In case of such safety concerns which 
require unblinding of a subject by the DMC, the DMC should confer with Merz prior to 
performing unblinding of the subject via IV/WRS. Detailed procedures for unblinding in 
case of a safety concern are laid down in the DMC charter. All non-blinded safety aspects 
discussed during DMC meetings will be provided for filing in the trial master file only 
after data base lock and subsequent unblinding of MP. 
Further the CRO will also receive IV/WRS access and a password for regulatory 
unblinding and suspected unexpected serious adverse reaction [SUSAR] reporting to 
competent authorities and IEC(s)/IRB(s). Personnel involved in unblinding procedures at 
the CRO will maintain the blinding of all other members of the operational team at Merz 
and at the CRO. 
8.4.2 
Unblinding procedures 
The blind of MP will not be broken except for the circumstance mentioned for emergency 
unblinding described above until the blind data review meeting [BDRM] has convened, 
the statistical analysis plan [SAP] of the MP has been finalized, and the database has been 
closed. After the blind of MP has been broken, the statistical analysis of results of MP 
will proceed, which will be documented according to GCP. 
 


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9 STUDY ASSESSMENTS AND VISIT SCHEDULE 
9.1 
Assessments 
The following efficacy and safety assessments will be performed during this 
double-blind, randomized, parallel-group three arm dose-response study. The 
assessments on the AS used as efficacy variables will be performed by trained 
investigators only (see Sections 9.1.1.1 and 9.1.1.2). The assessment of AS must be 
performed after the assessment of GICSs at week 4 of all treatment cycles of MP and 
OLEX. On days of injection visits, all assessments have to be performed prior to 
injection treatments. For standardization of laboratory test results, a central laboratory 
will analyze blood samples in this multi-center study.  
An overall description of the study plan is provided in Section 6.1 and in the Flow Chart 
in Section 6.1.2. The time schedule of assessments is detailed in Section 9.2. A tabular 
overview of study assessments is given in Table 16 and Table 17. 
9.1.1 
Clinical evaluations 
At the beginning of the study, information such as the subject’s medical history, all past 
and concomitant medications within the last 4 weeks, phenol and alcohol injections 
within the last 6 months and BoNT medication regardless the time of administration prior 
to the Screening Visit will be recorded from the subject’s file or from information given 
by the subject (if applicable) and the parent(s) (Section 8.3). Other data will be collected 
as required, including information obtained from physical and neurological examinations. 
The GMFCS level will be assessed as described in Appendix 16.8. A review of this 
information will allow the investigator to assess whether the subject should be enrolled at 
the Screening Visit. Other screening data will be collected at the Baseline Injection Visit 
before decision for eligibility and randomization. 
Instructions regarding assessments on the scales will be provided in a manual for 
investigators and will be trained at the investigators’ meeting(s) before study start. The 
same investigator must perform the ratings on the AS at Baseline Injection Visit and 
Control Visit at Week 4 in MP. Also at all other site visits this investigator should 
preferably perform the AS ratings to reduce variability of assessments. Preferably the 
same investigator should interview the subject (if applicable) and the parent at all visits. 
Preferably, the same parent(s) or caregiver (if applicable)18 should rate on scales at all 
visits. Preferentially, all study visits are performed at a similar day time throughout the 
study to reduce variability of assessments. 
                                                          
18 In subjects, living e.g. in a special-care unit permanently or most of the time with caregivers being 
his/her main social contacts, a caregiver may replace parent(s) for the assessment of the respective scales 
and measures, 












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If a TC identifies a (S)AE/AESI that needs confirmation or treatment, (e.g., respiratory 
disorder, dyspnoea, aspiration, dysphagia, speech disorder, dysphonia, other signs of 
bulbar palsy or botulism) the investigator must schedule a Safety Visit [SV] in addition to 
the scheduled visits as soon as possible after the TC. 
At injection visits, AE questioning will be done prior to and 30 min after injection 
treatment. (see Section 10.1). 
All AEs observed throughout the course of the study must be documented in the eCRF. 
For definitions and details regarding documentation and reporting of AEs see Sections 
10.1 to 10.3. 
9.1.1.7 Physical and Neurological Examination  
The investigator will perform physical and neurological examinations for subjects at 
Screening Visit, at the Final Visit of MP and at the End of Study Visit (V17) (see Table 
16 and Table 17). The physical and neurological examination will cover standard 
physical and neurological examinations. Any abnormal findings will be documented in 
the subject’s medical file. The investigator will confirm the conduct of these 
investigations in the eCRF. 
9.1.1.8 Vital Signs 
Vital signs (i.e., systolic and diastolic blood pressure, heart rate) will be assessed at each 
visit (see Table 16 and Table 17). Vital signs will be recorded in sitting or lying position 
after the subject has rested for at least 5 minutes. 
9.1.1.9 Body Weight and Height 
Body weight (BW) and height will be assessed at Screening, at the Baseline Injection 
Visit V2, at the Final Visit of MP V5, at all Injection Visits of OLEX (V619, V10 and 
V14) and at the End of Study Visit (V17) (see also Table 16 and Table 17). 
9.1.2 
Laboratory evaluations 
9.1.2.1 
Clinical and research laboratory evaluations 
Laboratory evaluations will be performed as possible for the age group of the subject. 
The bulletin of the World Health Organization [WHO] published a recent literature 
review on the blood sample volumes in child health research [Howie 2011]. The author 
concludes that blood sample volume limits ranging from 1–5% of total blood volume 
[TBV] within 24 hours and up to 10% of total blood volume over 8 weeks were 
                                                          
19 If visits at the end of treatment cycle in MP or OLEX (i.e. V5, V9, and V13) and the Injection Visit of 
the following cycle (i.e. V6, V10, and V14) will be performed on the same day, BW and height can be 
transferred. 


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consistent with minimal risk to healthy children as far as limited evidence available may 
support any risk evaluation. However, lower limits for sick children seem advisable. 
In this study, the lower limits mentioned for relevant age groups and weight classes in 
literature [European Medicines Agency EMA 2008] will be applied. Blood sample 
collection for clinical chemistry and hematology as well as for testing antibodies against 
BoNT will be restricted in frequency and volume. Limits will be set by the following 
assumption on the TBV and restrictions on maximum blood volumes withdrawn per time 
period: 
TBV= 80 mL/kg BW 
Maximum blood volume per withdrawal:  
 
 
1% of TBV 
Maximum blood volume withdrawn per 12 weeks:   
3% of TBV 
A central laboratory capable to properly handle the relatively small samples volumes (as 
compared to those usually obtained from adult subjects) will perform the analyses. The 
following blood (serum) volumes are necessary to result in sufficient samples for the 
respective tests: 
• Clinical chemistry (including glucose, AP):  
 1.2 mL blood  
• Hematology: 
1.2 mL blood  
• Fluorescence immunoassay [FIA]: 
4.0 mL blood (1.5 mL serum) 
• Hemidiaphragm assay [HDA]: 
10.0 mL blood (4.0 mL serum) 
9.1.2.1.1 
Clinical chemistry and hematology  
Blood samples for the determination of clinical chemistry (including blood glucose and 
AP) and hematology will be drawn in volumes appropriate for the BW of the subject at 
Screening Visit (V1), at the Injection visit (V6) and at the End of Study Visit (V17). 
Blood samples will be analyzed at a central laboratory that is capable to handle small 
volumes from pediatric samples. The amount of blood, number, kind and size of tubes, 
sample processing at the site as well as storage conditions will be specified in a separate 
instruction manual provided by the central laboratory. Depending on the involved 
countries and their county specific regulations, local laboratories could be involved as 
needed. 
Clinical chemistry analysis includes the following serum parameters: sodium, potassium, 
creatinine, 
urea/blood 
urea 
nitrogen, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, AP, gamma glutamyl transferase, total bilirubin, glucose, and total 
cholesterol. Based on lab values for creatinine and on the subject’s height on the day of 
the blood draw the glomerular filtration rate [GFR] will be estimated [eGFR]. This 
calculation will be done using the “Schwartz” formula [Schwartz 2009, Schwartz 2009]. 


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Hematology will be assessed at the same visits as clinical chemistry. Hematologic 
analysis of EDTA blood comprises hemoglobin, hematocrit, erythrocytes (red blood 
count), leukocytes (white blood count), lymphocytes (absolute), monocytes (absolute), 
neutrophils (absolute), eosinophils (absolute), basophils (absolute), platelets. 
Any laboratory result outside the normal range must be graded by the investigator or 
delegate as “abnormal, not clinically relevant” or “abnormal, clinically relevant”. 
A laboratory abnormality should be regarded as an AE if the investigator judges the value 
to be significantly worse than prior to study start or if relevant abnormal values are newly 
detected during the study, i.e., from signature of IC onwards. Relevant abnormal 
laboratory values should be recorded on the AE Form of the eCRF.  
9.1.2.1.2 
Pregnancy Testing 
In females with history of menarche (i.e., 1st menstrual bleeding), samples drawn for 
serum clinical chemistry will also be used to determine human chorionic gonadotropin at 
Screening and at the End of Study Visit (V17). On injection days (Injection Visits V6, 
V10 and V14), urinary pregnancy tests will be performed. If required by country-specific 
regulations, urinary pregnancy tests may also be performed at all other personal contacts 
in MP and OLEX (see also Table 16 and Table 17). 
9.1.2.1.3 
Antibodies against Botulinum Toxin  
For analysis of antibodies against BoNT blood amounts appropriate in the context of all 
blood withdrawals during the study for the weight group of the subject will be taken 
(Section 9.1.2.1).  
The serum amount necessary for FIA-AB is 1.5 mL and 4 mL for HDA. The estimated 
blood amount to yield the required serum amount is 4 mL for FIA-AB and 10 mL for 
HDA. For subjects ≥21 kg BW samples will be collected at the start of the study at 
Screening Visit and at the End of Study Visit (V17). For subjects <21 kg BW no blood 
samples for analysis of antibodies against BoNT will be taken to avoid an additional 
blood draw, if blood draw for the sample used for HDA testing would be only performed 
after a positive result of the FIA-AB test. 
Sample work-up at the study site include preparation of serum by centrifugation at room 
temperature and transfer into provided tubes. Serum samples should preferably be stored 
at -20°C (±-5°C) but must be within a range of -5°C to -90°C  until frozen shipment to 
the analyzing laboratory. 
Blood samples will be screened using the FIA-AB that detects antibodies against 
BoNT-A in human serum. FIA-AB detects binding to specific BoNT epitopes and allows 
the identification of sera that reacts with the toxin, but the FIA-AB is not capable to 
discriminate between neutralizing and non-neutralizing antibodies [Göschel 1997]. 




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If any Telephone Contact identifies an (S)AE/AESI that needs confirmation or treatment 
(e.g., respiratory disorder, dyspnoea, aspiration, dysphagia, speech disorder, dysphonia, 
other signs of bulbar palsy or botulism), the investigator will schedule a SV as soon as 
possible after the Telephone Contact. At 28 and 56 days after injection treatment of each 
cycle subjects will have Control Visits at the site (V3, V7, V11 and V15 at Day 29 and 
V4, V8, V12, and V16 at Day 57, respectively). 
In case eligibility criteria for reinjection are not fulfilled at a scheduled visit (Final Visit 
of MP or End of Cycle Visits V9 and V13) at the end of an treatment cycle, the Injection 
Visit of the following treatment cycle can be postponed and rescheduled within up to 16 
weeks after the previous injection treatment (for details see Section 6.1) 
Attempt should be made to arrange all visits at the same day time for an individual 
subject (i.e., morning or afternoon) to standardize treatment and assessment conditions. 20 
The End of Study Visit will be at Week 14 ± 2 weeks (Day 99 ± 14 days) of 4th treatment 
cycle. Study activities and visit schedule are detailed in Table 16 and Table 17. 
 
                                                          
20 If the Final Visit of MP and the 1st Injection Visit of OLEX will be performed on the same day the results of these 
assessments can be transferred from V5 to V6. 


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Table 16 Overview of Study Activities Main Period MP 




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10 SAFETY ASSESSMENTS 
10.1 Definition of an adverse event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product that does not necessarily have a causal relationship with the treatment. Thus, an 
AE can be any unfavorable and unintended sign, symptom, or disease (including 
intercurrent illness); deterioration of a pre-existing illness; accident; any suspected drug 
reaction; or a clinically relevant change of laboratory values whether or not considered 
related to the IP and/or study treatment. 
Changes in efficacy variables (e.g., investigator, subject- and/or parent-reported outcome 
variables during the course of the study) are not intended to be documented as AEs, 
because these changes will be recorded as efficacy variables. Elective treatments planned 
before screening and which are documented in the subject’s source data are usually not 
regarded as AEs. Pre-existing conditions that do not worsen during the course of the 
study are not reportable as AEs. Abnormal clinical relevant laboratory values obtained 
during the screening period will only meet AE criteria if newly detected. However, if 
laboratory values resulting from pre-existing conditions worsen to clinical relevance 
during the course of the study AE criteria are met. 
The period of observation for an AE extends from the time when the IC form was signed 
until the End of Study Visit, i.e., 12 to 16 weeks after last administration of IP in OLEX. 
Any medical occurrence that happens between the time when the IC form is signed and 
the 1st intake of IP is an AE and has to be documented in the subject’s file and in the 
eCRF AE report form. Any ongoing AEs will not be followed up after the End of Study 
Visit, which is scheduled up to 16 weeks after last injection of IP in OLEX. 
Data pertaining to AEs will be collected during each study visit based on the subject’s (if 
applicable) or parent(s)’s spontaneous description, through investigator inquiry, or 
discovered in the course of examinations done during the visit. The investigator will 
assess and record any AE in detail in the subject’s file and on the eCRF AE report form. 
The following information must be recorded:  
• AE diagnosis or main symptom. 
• Date of onset. 
• Date of worsening. 
• Intensity (maximum observed; see Section 10.1.1). 
• Causal relationship (not related, related, see Section 10.1.2). 
• Serious (yes or no, see Section 10.2). 


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• Outcome (see Section 10.1.3). 
• Action taken with IP(s) (see Section 10.1.3). 
• AE leading to discontinuation of the study (yes or no). 
• Stop date. 
After completion of all scheduled visit assessments the investigator must document any 
AEs arising from these assessments.  
In case of an SAE, or AESI (alert term, as defined in Section 10.3), the investigator must 
also complete an SAE report form or AESI report form and report it to the CRO within 
24 hours, as described in Section 10.2 and 10.3. 
Treatment of overdose with IP is described in Section 8.2.6. 
10.1.1 
Definition of intensity 
The clinical intensity of an AE will be classified as: 
Mild: 
Signs and symptoms that can be easily tolerated. Symptoms can be 
ignored and disappear when the subject is distracted. 
Moderate: 
Signs and symptoms that cause discomfort and interfere with normal 
functioning, but are tolerable. They cannot be ignored and do not 
disappear when the subject is distracted. 
Severe: 
Signs and symptoms that affect usual daily activity and incapacitate the 
subject, thereby interrupting the daily activities. 
The definitions above are difficult to apply for some data (e.g., clinically relevant 
laboratory values that are documented and evaluated on the eCRF AE report form). In 
such situations, the investigator should make a judgment based on personal experience. 
10.1.2 
Definition of causal relationship with investigational 
product(s)  
An AE is considered to be ‘related’ to IP if a causal relationship between the IP and an 
AE is at least a reasonable possibility (i.e., the relationship cannot be ruled out).  
The expression ‘reasonable causal relationship’ is meant to convey that there are facts 
(evidence) or arguments to suggest a causal relationship (ICH E2A guideline). Otherwise, 
the relationship should be considered as ‘not related’. 


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10.1.3 
Categories of actions taken and outcome 
Action(s) taken with IP: 
• Drug withdrawn. 
• Dose reduced. 
• Dose increased. 
• Dose not changed. 
• Unknown. 
• Not applicable. 
• Drug withdrawn temporarily 
The reportable outcomes and/or sequelae of an AE are as follows: 
• Recovered/resolved. 
• Recovering/resolving. 
• Not recovered/not resolved. 
• Recovered/resolved with sequelae. 
• Fatal.30 
• Unknown. 
10.2 Definition of a serious adverse event 
An SAE is any untoward medical occurrence, at any dose, that: 
• Results in death. 
• Is life-threatening.31 
• Requires inpatient hospitalization, or prolongation of existing hospitalization. 
                                                          
30 If there is more than 1 AE, only the AE leading to death will be attributed with a ‘fatal’ outcome. 
31 The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the child/adolescent 
was at risk of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 


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• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Consists of any other medically important condition.32 
In case of death, an autopsy report should be submitted (if available). The date and cause 
of death should be recorded. 
Hospitalizations for elective treatments planned before screening and which are 
documented in the subject’s source data are usually not regarded as SAEs. 
Hospitalizations for analgosedation starting one day before or on the day of injection 
treatment (V2 and V7) for organizational reasons only (e.g. to allow for an early start of 
the Injection Visits in the morning in subjects living far from the site) are generally not 
regarded as SAEs. However, if any event during or after analgosedation would trigger an 
overnight stay, this will qualify as SAE. The same applies, if analgosedation was started 
in an outpatient setting at the site and then has be changed to an inpatient setting, e.g. due 
to an unexpetedly long monitoring phase post intervention. 
All SAEs that occur during the study period, whether considered to be related to IP or 
not, must be reported by telefax, telephone or e-mail within 24 hours of knowledge of the 
event. SAE report forms are provided in the ISF.  
Although all information required for completion of an SAE report form may not be 
available within the specified time period, an initial report should be submitted if the 
following minimal information is available:  
• An identifiable subject (number, initials).  
• A suspect product. 
• An identifiable reporting source (investigator/study site identification). 
• An event or outcome that can be identified as serious.  
The report must be delivered to the individual(s) listed below.  
 
 
                                                          
32 According to ICH E2A, CPMP/ICH/377/95: ‘Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient/subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. These should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse.’ 


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If SAE fax fails, use email as back-up for all regions: 
Email: 
 
If the report is sent via email then the completed and signed fax form must be attached to 
the email. A simple notification email of the event is not sufficient.The CRO will 
transmit all SAE reports within 1 business day to Merz drug safety.  
The investigator, Merz Pharmaceuticals GmbH, and the CRO will comply with the 
applicable regulatory requirements related to the reporting of suspected unexpected 
serious adverse reactions [SUSAR]s to the regulatory authorities and the IEC(s)/IRB(s).  
Furthermore the investigator has to report the SAE to the responsible IEC/IRB according 
to local requirements. 
The investigator must supply further supporting information within 3 days of knowledge 
of the SAE, and a detailed SAE description is an integral part of this supporting 
information. Follow-up reports should be sent without delay to the drug safety 
department at the CRO as an SAE report form (marked as a ‘follow-up’ report) and 
accompanied by appropriate supporting documentation (e.g., hospital reports). The SAE 
has to be followed up until a final outcome and date are available. These SAEs will be 
followed-up only in the Global Drug Safety database after final SAE reconciliation is 
completed. 
All SAEs will be reviewed by the DMC. Details will be described in a DMC charter. 
SAEs occurring after the end of the observational period need only be reported if the 
investigator considers the event to be related to IP. These reports generally will not be 
entered into the study database.  
10.3 Adverse events of special interest (alert terms) 
AEs occurring after treatment that are thought to possibly indicate toxin spread are 
defined as AESIs (see Table 18). The subject (if applicable) and parent(s) will be actively 
asked by the investigator or an authorized delegate at each visit starting at V2 as well as 
during the telephone contact (starting at TC1 in MP) if any of the AESI occurred since 
the last contact. The questioning and documentation of answers will be standardized. 
AESI questioning at V2 will facilitate recording of pre-existing conditions and/or 
possibly undetected (S)AEs that could confound AESI questioning post injection of IP. 
The site must report all AESIs that occur during the study period, whether considered to 
be related to IP or not, by telefax to the responsible CRO within 24 hrs of knowledge of 
the event. The CRO will transmit these AESIs to Merz Pharmaceuticals GmbH. Each 


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AESI must be reported by the site on the AESI reporting form. Moreover, AESIs should 
be reported on the general pages of the eCRF as well as in the subject’s file. The AE form 
in the eCRF as well as the eCRF pages for Medical History/Concomitant Diseases and 
for Previous/Concomitant Medication and Non-Drug Treatment shall be faxed/sent along 
with the AESI reporting form. 
Table 18  List of Adverse Events of Special Interest Possibly Indicating Toxin 
Spread 
MedDRA Preferred Term 
MedDRA Preferred Term 
Accommodation disorder 
IIIrd nerve paresis 
Areflexia 
Ileus paralytic 
Aspiration 
IVth nerve paresis 
Botulism 
Monoparesis 
Bradycardia 
Muscular weakness 
Bulbar palsy 
Paralysis 
Constipation 
Paralysis flaccid 
Cranial nerve palsies multiple 
Paraparesis 
Cranial nerve paralysis 
Paresis 
Diaphragmatic paralysis 
Paresis cranial nerve 
Diplopia 
Peripheral nerve palsy 
Dry mouth 
Peripheral paralysis 
Dysarthria 
Pelvic floor muscle weakness 
Dysphagia 
Pneumonia aspiration 
Dysphonia 
Pupillary reflex impaired 
Dyspnoea 
Quadriparesis 
Extraocular muscle paresis 
Respiratory arrest 
Eyelid function disorder 
Respiratory depression 
Eyelid ptosis 
Respiratory failure 
VIIth nerve paralysis 
Speech disorder 
Facial paresis 
Trigeminal nerve paresis 
Hemiparesis 
Urinary retention 
Hypoglossal nerve paresis 
Vision blurred 
Hyporeflexia 
Vocal cord paralysis 
Hypotonia 
Vocal cord paresis 
Wording of preferred terms is according to MedDRA version 15.1 


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All AESIs will be reviewed by the DMC on a regular basis. Details will be described in a 
DMC charter. For this study, the AEs in Table 18 are defined as AEs of special interest. 
10.3.1 
Expected adverse events 
Expected AEs are those listed in the reference safety information of the current IB [Merz 
Pharmaceuticals (GmbH)]. Indication-specific expected AEs are not yet available as 
upper limb spasticity in children and adolescents is a new explorative indication. 
10.3.2 
Unexpected adverse events 
An unexpected AE is an experience not previously reported in nature, severity, or 
incidence in the reference safety information of the current IB [Merz Pharmaceuticals 
(GmbH) ]. 
10.4 Pregnancy 
Each pregnancy that starts during the study must be reported by the investigator to the 
drug safety department of the CRO within 24 hours of learning of its occurrence (see 
Section 10.2 for reporting address). Pregnancies and pregnancy follow-up should be 
reported on a pregnancy monitoring form. Pregnancies should be followed up until 
delivery. Pregnancy follow-up should describe the outcome of the pregnancy, including 
any voluntary or spontaneous discontinuation; details of the birth; the presence or 
absence of any congenital abnormalities, birth defects, maternal or newborn 
complications, and their relation to the IP Each normal pregnancy has to be reported as a 
non-serious AE (drug exposure before or during pregnancy). Any abnormal pregnancy or 
pregnancy outcome has to be reported as SAEs. If pregnancy occurs before injection 
visits, the female will meet exclusion criteria. If pregnancy occurs after the 1st injection 
visit (V2), participation in the study will continue with all applicable visits until the end 
of the respective cycle (except invasive procedures such as blood drawing). A final 
examination (End of Study Visit, also except for invasive procedures such as blood 
drawing) should be performed at the end of the respective cycle. After the End of Study 
Visit the study participation will be terminated. 
10.5 Other safety variables 
In addition to the assessment of AEs, the following safety variables will be observed 
during this study. For additional details see Sections 9.1.1.5 to 9.1.1.9. 
• Investigator’s Global Assessment of Tolerability. 
• Vital signs (blood pressure, heart rate). 
• BW, height. 


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• Clinical chemistry (including AP, blood glucose) and hematology.  
• Occurrence of subjects with antibodies against BoNT-A. 


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11 DATA QUALITY ASSURANCE 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any 
time, even after the end of study. The investigator is to notify the sponsor immediately of 
any such inspection. The investigator and institution will permit study-related 
monitoring, audits, reviews by the IEC/IRB and/or regulatory authorities, and will allow 
direct access to source data and source documents for such monitoring, audits, and 
reviews. 
11.1 Standardization procedures 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data including methods to ensure standardization among sites (e.g., training, 
newsletters, investigators’ meeting, monitoring, and central laboratories). Investigators 
will be trained on the scales, on injection techniques and on IP handling during the 
investigators’ meeting. Any investigator who did not participate at the investigators’ 
meeting will receive training documents for self-study. Injections and assessment of 
scales must only be conducted by trained investigators. 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP guidelines and the respective SOPs (see Section 11.4). 
11.2 Source documentation requirements 
All data collected from a subject during the course of a clinical study should be entered 
and/or filed in the respective subject’s file. This includes a copy of the letter sent to the 
subject’s primary physician about the subject’s participation in the study (provided the 
subject has a primary physician and the subject (if applicable) and the parent(s) have 
agreed to the primary physician being informed). The subject’s file must also contain a 
descriptive statement on the IC procedure (see Section 3.3.2).  
Electronic data capture using eCRF is planned to be used at all study sites. 
All entries have to be entered 1st in the subject file, e.g., details on IP administrations, 
questioning of AESIs
. The participation in this study must be appropriately 
documented in the subject’s file with study number, subject number, and date of subject 
information, date of IC, and date of each visit. 
If a study site is using an electronic system for documenting source data, a member of the 
site staff must print out the source data after each visit. The paper print-outs must be 
overlapping, if possible (i.e., must contain at least the last row of data from the subject’s 
previous visit). If it is not possible to obtain overlapping paper print-outs, the 
completeness of source data must be ensured by other suitable means. The print-out must 
be signed and dated by a member of the site staff who can confirm the accuracy and 
completeness of data in the paper print-out. The monitor should also sign and date after 


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verifying the source data. The paper print-out should be stored in the ISF. If source data 
information is entered retrospectively, this must be done directly on the paper print-out 
and should be initialed and dated. The same applies to any corrections of initial data.  
If the site is using a validated computer system including audit trail with a separate access 
for the monitor (i.e., the monitor can only access the data of the subjects), then no such 
paper print-outs are required.  
11.3 Data management 
Data required according to this protocol is to be recorded in the web-based eCRFs 
(electronic data capture system 
) provided by Merz Pharmaceuticals/
 
. All persons who will enter data into the eCRF will be trained by 
e-learning tool. After the successful completion of the training all participants will 
receive a training certificate. The access to the e-learning and to the eCRF is password 
controlled. 
Plausibility checks will be performed according to a data validation plan. Inconsistencies 
in the data will be queried to the investigators via the electronic data capture system; 
answers to queries or changes to the data will also be documented in this system directly 
by an authorized member of the investigator’s staff. The audit trail in 
 documents 
all changes. Edit checks fire automatic queries during data entry when a field is not 
populated to specifications defined in the data validation plan. Manual queries (to be 
answered by site staff) can be raised during source data verification, medical or safety 
review and data management review. 
Laboratory and antibody data will be received electronically and merged to the eCRF 
data (but not uploaded into the EDC system). Plausibility checks will be performed to 
ensure correctness and completeness of these data. The sponsor’s data management 
function will be responsible for data processing, in accordance with the sponsor’s data 
management procedures.  
Database close will occur only after quality control procedures have been completed. 
After all data of MP are entered and all queries are solved, the database of MP will be 
closed. After database close of MP, unblinding will take place. In case of any changes to 
the data after unblinding, these changes will be documented according to respective SOP. 
After all data of OLEX are entered and all queries are solved, the database of OLEX will 
be closed. In case of any changes to the data after database close, these changes will be 
documented according to respective SOP. 
 
 


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11.4 Monitoring 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP guidelines and the respective SOPs. Monitors will be trained during a monitoring 
training meeting. Monitoring procedures include one or more visits designed to clarify all 
prerequisites before the study commences. Interim monitoring visits will take place on a 
regular basis according to a mutually agreed schedule. During these visits, the monitor 
will check for completion of the entries on the eCRFs; for compliance with the clinical 
study protocol, ICH-GCP principles, the Declaration of Helsinki, and regulatory authority 
requirements; for the integrity of the source data with the eCRF entries; and for subject 
eligibility. Monitoring also will be aimed at detecting any misconduct or fraud. 
In addition, the monitor will check whether all AEs (including pregnancies), AESIs, and 
SAEs have been reported appropriately within the time periods required. 
The investigator and all staff will be expected to cooperate with the monitor by providing 
any missing information whenever possible. The investigator must be available to answer 
questions arising during regular monitoring visits. In addition, the investigator is required 
to: 
• Have all data properly recorded in the eCRF and subject’s files prior to each 
monitoring visit. 
• Have the source documentation available at the monitoring visits. 
• Record all IP dispensed in the eCRF and the drug inventory records. 
All subjects who are screened, but not entered into the study, will be listed on the 
screening/enrollment log. 
Further details of monitoring activities will be set forth in the monitoring manual.  
11.5 Auditing 
Audits will be performed according to the corresponding audit program, including the 
possibility that a member of the sponsor’s quality assurance function may arrange to visit 
the investigator in order to audit the performance of the study at the study site, as well as 
all study documents originating there. Auditors conduct their work independently of the 
clinical study and its performance.  
Audits may also be performed by contract auditors. In this case, the sponsor’s quality 
assurance function will agree with the contract auditor regarding the timing and extent of 
the audit(s). In case of audits at the investigational site, the monitor will usually 
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12.2 Analysis sets 
The following analysis sets will be defined for the statistical analysis of the MP of this 
study: 
Safety Evaluation Set (SES) 
The SES is the subset of all subjects treated in the MP with study medication at least 
once.  
Full Analysis Set (FAS) 
The FAS is the subset in the SES of the MP for whom the primary efficacy variable or 
co-primary efficacy variable is available (i.e., all subjects who have at least an AS score 
in the clinical pattern flexed elbow or flexed wrist at baseline (Day 1) or the 
Investigator’s GICS at Day 29 (Week 4)). 
Per Protocol Set (PPS) 
The PPS is the subset in the FAS of the MP without major protocol deviations. Major 
protocol deviations will be defined during the BDRM for MP. 
The following analysis sets will be defined for the statistical analysis of OLEX of this 
study: 
Safety Evaluation Set (SES) 
The SES is the subset of all subjects treated in OLEX with study medication at least once. 
Full Analysis Set (FAS) 
The FAS is the subset in the SES of OLEX for whom at least one value of the AS score 
in the OLEX for the primary clinical pattern flexed elbow or flexed wrist is available. 
12.3 Variables for analysis 
12.3.1 
Efficacy variables 
12.3.1.1 
Primary efficacy variable 
Primary efficacy variable and the co-primary efficacy variable will be determined for MP 
only. 
• Primary efficacy variable is the change from baseline in AS in the primary clinical 
target pattern, i.e. elbow flexors or wrist flexors, at Day 29 (Week 4) of MP. 
 
An IV/WRS will be used for selection and randomization to treatment groups in MP, 
if two main clinical target patterns would qualify for primary efficacy analysis based 


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on (for further details see Section 8.2.1)  
 
(a) clinical need for IP injection in combination with 
 
 
(b) an AS score of ≥2.  
The other main clinical target pattern (if treated) will be analyzed as key secondary 
variable (see below). For subjects with bilateral UL treatment, the body side for 
analysis will be decided by the investigator at screening (for details see Section 8.2.1). 
• Co-primary efficacy variable is the Investigator’s GICS at Day 29 (Week 4) of MP. 
12.3.1.2 
Key-Secondary and secondary efficacy variables 
Secondary efficacy variables will be determined for MP only. 
Key-secondary efficacy variables are:  
• Change from baseline in AS score of the other treated main clinical target pattern 
(i.e. of elbow flexors or wrist flexors, if treated) at Day 29 (Week 4) of MP. This 
analysis will be performed in case two target patterns would qualify as main clinical 
target pattern for the main clinical target pattern not analyzed as primary efficacy 
variable. For subjects with bilateral UL treatment body side to be analyzed is decided 
by investigator at screening (for details on definition see 8.2.1).  
• Change from baseline in AS score of treated clinical target pattern clenched fist (in 
subjects treated in combination with flexed wrist) at Day 29 (Week 4) of MP. For 
subjects with bilateral UL treatment body side to be analyzed is decided by 
investigator at screening (for details on definition see 8.2.1). 
Secondary efficacy variables are (MP only):  
• Change from baseline in AS score for each treated clinical pattern (e.g., flexed elbow, 
flexed wrist, clenched fist, etc.) of the UL at all other post baseline visits of MP. For 
subjects with bilateral UL treatment body side to be analyzed is decided by 
investigator at screening. 
• Change from baseline in scores of pain intensity (from subjects) and pain frequency 
(from parent/caregiver) assessed with ‘Questionnaire on Pain caused by Spasticity 
[QPS]’ to all post baseline visits of MP. 
• Child’s/Adolescent’s (if applicable) and Parent’s/Caregiver’s GICS at Day 29 
(Week 4) of MP. 
 
 
 
 




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12.3.5 
Safety variables 
12.3.5.1 
Primary safety variables 
Not applicable 
12.3.5.2 
Secondary safety variables 
 
Secondary safety variables will be determined for MP and all OLEX cycles. Safety 
variables comprise: 
• Occurrence of TEAEs overall and per treatment cycle.  
• Occurrence of TEAESIs overall and per treatment cycle.  
• Occurrence of TESAEs overall and per treatment cycle. 
• Occurrence of TEAEs related to treatment as assessed by the investigator overall and 
per treatment cycle. 
• Occurrence of TEAEs by worst intensity overall and per treatment cycle. 
• Occurrence of TEAEs by worst causal relationship overall and per treatment cycle. 
• Occurrence of TEAEs by final outcome overall and per treatment cycle. 
• Occurrence of TEAEs leading to discontinuation overall and per treatment cycle. 
12.3.5.3 
Other safety variables 
Other safety variables will be determined for MP and all OLEX cycles. Safety variables 
comprise: 
• Investigator’s Global Assessment of Tolerability at Day 99 (Week 14) of MP and all 
OLEX cycles. 
• Vital signs (blood pressure, heart rate) at all visits of MP and all OLEX cycles. 
• BMI, weight and height at Screening V1, Baseline Injection Visit V2, at the Final 
Visit of MP V5, at all Injection Visits of OLEX (V633, V10 and V14) and at the End 
of Study Visit (V17). 
                                                          
33 If V5 and V6 will be performed at the same day, BW and height can be transferred from V5 to V6. 


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• Clinical chemistry and hematology at Screening V1, the Injection Visit V6 of OLEX 
and the End of Study Visit (V17). 
• Occurrence of antibodies against BoNT-A in subjects ≥21 kg BW. 
12.3.6 
Other variables 
Other variables of interest are the subject dispositions, demographic data, baseline 
characteristics such as medical history, concomitant diseases, previous and concomitant 
therapies, CP history (e.g., distribution, comorbidities), clinical patterns, GMFCS level, 
BoNT-A pre-treatment status, and use of anesthesia/analgosedation for injection 
treatments. 
12.4 Statistical analysis methods 
12.4.1 
Efficacy variables 
All efficacy analyses will be based primarily on the FAS and additionally, for sensitivity 
purposes, on the PPS. Statistical tests will be two-sided hypothesis tests for between-
treatment differences in general. Treatment differences will be tested for comparison of 
the high versus low dose treatment group and the mid versus low dose treatment group, 
respectively. 
Continuous variables (values and changes from baseline) will be summarized by number 
of non-missing observations (N), mean, SD, median, 1st and 3rd quartile, minimum, and 
maximum or/and as counts and percentages. For qualitative variables, absolute and 
percent frequencies (N, %) and, if applicable, shift tables will be displayed. Two-sided 
95% confidence limits and descriptive p-values will be given, where appropriate.  
Descriptive summary statistics will be performed at all visits of MP and OLEX and if 
applicable for the changes from baseline (Day 1 of each treatment cycle) to all post-
baseline visits of each treatment cycle. 
12.4.1.1 
Primary and key-secondary efficacy variables 
Testing of the primary, co-primary and key-secondary efficacy variables will be 
performed in a 4-step approach using a hierarchical test procedure as described in detail 
below. 
The primary efficacy variable is the change from baseline in AS in the primary clinical 
target pattern, i.e. elbow flexors or wrist flexors, at Day 29 (Week 4) of MP. A mixed 
model repeated measurement analysis (MMRM, two-sided, significance level α=0.05) 
with comparison of least square means will be used for the confirmatory analysis to 
detect differences between the high and low dose treatment groups. The dependent 
variable is the primary efficacy variable. The independent variables are defined as 


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treatment group (high dose, low dose), site (or pooled sites), BoNT-A pre-treatment 
status (pre-treated, treatment naïve) as fixed factors, visit*treatment as interaction term, 
and visit as repeated factor. The covariates are the AS score of the primary clinical target 
pattern at baseline (Day 1 of MP) and the GMFCS level at screening. 
Co-primary efficacy variable: An ANCOVA approach (2-sided, significance level 
alpha=0.05) with comparison of least square means will be used for the confirmatory 
analysis of the co-primary efficacy variable. The dependent variable is defined as the 
‘Investigator’s GICS at Day 29 (Week 4) of MP’. The independent variables are defined 
as treatment group (high dose, low dose), site (or pooled sites), BoNT-A pre-treatment 
status (pre-treated, treatment naïve) as fixed factors and the covariates are the maximum 
AS score of the two possible primary clinical target clinical patterns flexed elbow or 
flexed wrist at baseline (Day 1 of MP) and the GMFCS level at Screening Visit.  
Sites might be pooled for the statistical analysis, e.g., based on geographic criteria. If 
applicable, pooling of sites will be defined in the SAP. 
Both, the primary efficacy variable and the co-primary efficacy variable have to show 
statistically significant treatment differences in order to prove superiority of high dose vs. 
low dose treatment. 
Confirmatory testing will be performed on the FAS of MP with accounting for missing 
values by using MMRM approach for the primary efficacy variable. . In case of missing 
data in the co-primary efficacy variable these will be imputed by “0” (no change) (see 
Section 12.4.7.1). 
If the confirmatory tests of the (co-)primary efficacy variables both yield significant 
results, in a second step using a hierarchical testing approach in the high dose treatment 
group, the key-secondary efficacy variable ‘change from baseline in AS score of the 
other treated main clinical target pattern (i.e. of elbow flexors or wrist flexors, if 
treated) at Day 29 (Week 4) of MP’ and the co-primary efficacy variable ‘GICS at Day 
29 (Week 4) of MP’ for the subpopulation defined by this key-secondary endpoint will be 
compared to low dose treatment group in both efficacy variables. Other than using the 
key-seondary efficacy variable and the co-primary efficacy variable for this 
subpopulation, the analysis models will be identical to the analysis described above for 
the 1st step. Both, the key-secondary efficacy variable and the co-primary efficacy 
variable for the subpopulation have to show statistically significant treatment differences 
in order to prove superiority of high dose vs. low dose treatment in this subpopulation. 
Only if the confirmatory analysis of step 2 yields a statistically significant result, in a 
third step, a confirmatory analysis of the key-secondary efficacy variable ‘change from 
baseline in AS score of clinical target pattern clenched fist (in subjects treated in 
combination with flexed wrist), at Day 29 (Week 4) of MP will be done. This variable 
has been chosen, since it is anticipated that the vast majority of subjects will have a 
combined clinical presentation of clinical patterns clenched fist and flexed wrist. Subjects 


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with either treatment alone (i.e. clenched fist or flexed wrist) with other clinical target 
patterns will be evaluated separately in a descriptive manner (see also Section 12.3.1.3). 
Only if the confirmatory analysis of step 3 yields a statistically significant result, in a 
fourth step, using a hierarchical testing approach, the mid dose treatment will be 
compared to low dose treatment in both (co-)primary efficacy variables. Other than using 
the mid instead of the high dose group treatment data, the analysis models will be 
identical to the analysis described above for the 1st step. Both, the primary efficacy 
variable and the co-primary efficacy variable have to show statistically significant 
treatment differences in order to prove superiority of mid dose vs. low dose treatment. 
 
For the confirmatory analyses a two-sided significance level of α=0.05 will be applied. A 
MRMM analysis as described for the primary efficacy variable will be applied for the 
change from baseline in AS score. An ANCOVA model as described for the co-primary 
efficacy variable will be applied for the Investigator’s GICS. The analysis will be 
performed on the FAS of the MP. 
Due to the hierarchical testing strategy of (co-)primary and key-secondary efficacy 
variables and the two dose group comparisons (high versus low and mid versus low), this 
four step hierarchical testing procedure ensures the overall type I level of 5% for the 
confirmatory tests. If one of four hierarchical tests does not yield a statistically significant 
result, the consecutive test(s) will still be performed but will be considered to be only 
descriptive. 
Further, a non-parametric Wilcoxon rank-sum test will be performed as sensitivity 
analysis of the primary efficacy variable and of the co-primary efficacy variable to 
investigate the impact of potential deviations from the assumption of normal distribution 
(for FAS and PPS subset, using LOCF in case of the primary efficacy variable and 
imputing missing data by “0”, i.e. no change, for the co-primary efficacy variable). 
All other test procedures will be explorative. Sensitivity analyses will be performed on 
the PPS of MP as well as on the FAS of MP using last observation carried forward 
[LOCF] (for AS score) and, additionally, without missing value replacement (observed 
case analysis). 
12.4.1.2 
Secondary efficacy variables (MP only) 
The difference between treatment groups in the change from baseline in AS score for 
each treated clinical patterns (e.g., flexed elbow, flexed wrist, flexed fingers) of the UL at 
all other post baseline visits will be analyzed by a MMRM analysis as described for the 
primary efficacy variable. 




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12.4.2 
Pharmacodynamic variables 
Not applicable. 
12.4.3 
Pharmacokinetic variables 
Not applicable. 
12.4.4 
Pharmacogenetic variables 
Not applicable. 
12.4.5 
Safety variables 
All safety analyses will be performed on the SES of MP and OLEX using descriptive 
summary statistics, frequency tables, and, if applicable, shift tables and shift graphs. 
Analyses will be based on both, total population and by MP treatment group.  
Adverse events 
Analyses of adverse events will be performed for total dose group in addition to total 
population and MP treatment group. AEs will be coded by system organ class and 
preferred term level according to the MedDRA version in effect at the time the respective 
databases of MP and of OLEX Period, respectively, are closed. Only TEAEs will be 
analyzed. Non-TEAEs are defined as baseline complaints and will be listed only. 
For MP, only TEAEs of the MP will be analyzed, which are defined as AEs with onset or 
worsening on or after date and time of the first MP administration and before date and 
time of the first OLEX administration at V6. For subjects who do not receive an OLEX 
administration all AEs with onset or worsening on or after date and time of the first MP 
administration will be considered as TEAEs of MP. 
-AEs starting in MP and not having resolved at the Final Visit V5 of MP will be followed 
and further documented during OLEX.  
For OLEX period, only TEAEs of the OLEX will be analyzed, which are defined as AEs 
with onset or worsening on or after date and time of the first OLEX administration at 
V6.Frequencies will be calculated for TEAEs on the system organ class level and on the 
preferred term level. For all TEAEs the occurrence, worst intensity, final causal 
relationship to treatment assessed by investigator, and final outcome will be summarized 
by counts and percentages for all visits and overall. Listings and, if applicable, tables 
displaying frequencies of TEAEs leading to discontinuation, TESAEs, TEAESIs, and 
deaths will also be provided. 
Additional subgroup analyses (e.g., classes for GMFCS level, age groups, use of 
anesthesia/analgosedation for injection treatment) will be specified in detail in the SAP. 


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Other safety variables 
Laboratory evaluations, vital signs, BMI, weight, height, Investigator’s Global 
Assessment of Tolerability, and incidences of subjects with antibodies against BoNT-A 
will be analyzed descriptively (values and changes from baseline) and screened for 
individual notable values and/or changes. 
12.4.6 
Other variables 
Subject dispositions, demographic data, and other baseline characteristics such as medical 
history and concomitant diseases, previous and concomitant therapies, CP history (e.g., 
distribution, comorbidities), clinical patterns, GMFCS level, BoNT-A pre-treatment 
status at screening and use of anesthesia/analgosedation for injection treatments will be 
presented using standard descriptive statistics. No homogeneity tests will be performed. 
Demographic data will be summarized for the SES (MP and OLEX), the FAS (MP and 
OLEX), and the PPS (MP only). Clinical patterns, AS scores at baseline and GMFCS 
level at Screening will be summarized descriptively for the FAS (MP and – for selected 
baseline clinical patterns only - OLEX) and the PPS (MP only).  
Frequencies of concomitant medication will be given based on different Anatomical 
Therapeutic Chemical classification [ATC] system of the WHO code levels for the SES 
(MP and OLEX), the FAS (MP and OLEX), and the PPS (MP only). Indications for 
concomitant therapies will not be coded and will only be listed. Medical history and 
concomitant diseases as well as non-drug treatment will be described based on MedDRA 
system organ class and preferred term levels for the SES (MP and OLEX). 
12.4.7 
Special statistical/analytical issues 
12.4.7.1 
Discontinuations and missing data 
Discontinued subjects will not be replaced (see Section 8.2.1). 
The primary and secondary efficacy variables AS will be analyzed on the FAS and PPS 
of the MP using MMRM for accounting for missing data. As sensitivity analysis for the 
primary efficacy variable and for the secondary efficacy variables of the AS score an 
ANCOVA model without repeated measures will be applied. The LOCF will be followed 
on the FAS and PPS, i.e., the baseline observation will be carried forward to Day 29 
(Week 4) of MP and the last non-missing value before a missing value will be carried 
forward to all further visits with missing values. In addition, further sensitivity analysis 
for the primary and secondary efficacy variables, the so-called observed case analysis 
without missing data replacement, will be performed on the FAS and PPS of the MP to 
explore the impact of the respective missing imputation principle.  
In case of missing data in the co-primary variable these will be imputed by “0” (no 
change). Assuming a similar percentage of missing data in all three treatment arms this 


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imputation leads to a decreased difference of the treatment effects. For this reason the “no 
change” imputation is considered as conservative approach. Sensitivity analyses for the 
co-primary efficacy variable by using the so called ‘observed case analysis’ without 
missing data replacement will be performed on the FAS and PPS to explore the impact of 
missing values. 
For other secondary 
efficacy variables, missing data of the MP will be replaced 
using an appropriate imputation method specified in detail in the SAP.  
Missing data will not be replaced for OLEX. 
In case further missing value replacement strategies will be applied on any variables 
these will be described in detail in the SAP before unblinding of the MP data. 
12.4.7.2 
Interim analyses  
No formal interim analyses are planned.  
An overall study report will be written after completion of OLEX, giving the efficacy and 
safety results of the entire study. 
12.4.7.3 
Data monitoring committee 
An independent DMC will be assigned to monitor subject’s safety throughout the clinical 
course of the study (see Appendix 16.2). It will consist of an uneven number of 
physicians, e.g., three physicians, to achieve a decision of majority. DMC members must 
be experienced in the indication and population and will not be involved in any study 
conduct sponsored by Merz. An independent biostatistician may complement the DMC. 
The primary purpose of the DMC is to safeguard subject. The DMC provides a mean to 
rapidly note an unexpected hazard that may lead to study termination. 
The DMC will meet at regular intervals during MP and OLEX to discuss and decide upon 
safety issues. The treatment code of individual subjects may be unblinded by the DMC if 
necessary for evaluation purposes (see Section 8.3.2). 
If indicated, the DMC will make recommendations regarding withdrawals, and/or 
measures for the study in case of relevant safety findings. Details on responsibilities and 
procedures to be followed by the DMC will be laid down in the DMC Charter. 
12.4.7.4 
Multiple comparisons/multiplicity 
Due to the hierarchical testing strategy described, no further alpha-adjustment for 
multiple testing is necessary as it ensures the overall type I level of 5% for the 
confirmatory tests. Please see Section 12.4.1.1 for details. 


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12.4.7.5 
Examination of subgroups 
Subgroup analyses will be performed for the AS regarding treatment group, site (or 
pooled sites), BoNT-A pre-treatment status, GMFCS level groups at baseline, and AS 
baseline value. In addition, subgroup analysis for the AS regarding subjects with 
unilateral and bilateral treatment will be performed. If applicable, the influence of these 
subgroups will also be analyzed for the other efficacy variables. Potential effects of the 
use of local anesthetics and/or analgosedation on AS and adverse event/adverse events of 
special interest will be analyzed descriptively. 
Details of subgroup analyses and additional subgroup analyses (e.g., gender, dose group, 
age, group [2-5, 6-11, 12-17 years], weight, height) will be specified in detail in the SAP. 


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13 DATA HANDLING AND RECORDKEEPING 
By signing and dating the eCRF, the investigator will confirm that all investigations have 
been completed and conducted in compliance with the clinical study protocol, and that 
reliable and complete data have been entered into the eCRF. 
13.1 Corrections to data 
All data required by this clinical study protocol are to be recorded on eCRF (electronic 
data capture system 
) as soon as possible. Direct entries are not allowed; data 
must be transcribed from the source (e.g., subject file) to the eCRF. 
If corrections are necessary, an authorized member of the investigator’s staff will enter 
the correct data in the web-based eCRF. The audit trail in 
 documents all changes. 
Edit checks issue automatic queries during data entry when a field is not populated to 
specifications defined in the DVP. Manual queries (to be answered by site staff) can be 
raised during source data verification, medical or safety review, and data management 
review. 
The sponsor’s data management function will be responsible for data processing, in 
accordance with the sponsor’s data management procedures. Database close will occur 
only after quality control procedures have been completed.  
13.2 Recordkeeping 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application (whether pending or contemplated) in an ICH region, or at least 
2 years have elapsed since the formal discontinuation of IP clinical development. These 
documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by agreement with the sponsor.  
Essential documents at the investigational site include (among other documents): 
•
Subject’s files.
•
Subject’s identification code list (i.e., provided by template to the investigator, along
with the ISF, at the beginning of the study), which identifies the subject by number,
name, and date of birth.
•
A signed copy of the final clinical study protocol and any amendment.
•
CD/DVD with eCRF data and any associated subject-related source data (or, where
applicable, authorized copies of source data).
•
Signed IC forms.


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•
Copies of site investigators’ and co-workers' curricula vitae.
•
Copies of all direct correspondence with the IEC/IRB and with the regulatory
authority(ies).
•
Copies of laboratory normal ranges and methods.
•
Copies of study supply receipt forms and drug inventory forms.
•
Copies of all correspondence between the investigator and the monitor, and between
the investigator and the sponsor.
•
Copies of safety information reported during the study and submitted by the sponsor.
13.3 Destruction of study documents 
Study documents may not be destroyed by study site personnel prior to the retention 
period specified above without the prior written consent of the sponsor. The PI must 
inform the sponsor in due time if the PI leaves the institution during the retention period. 
This rule also applies when the institution closes within the retention period. 


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14 PUBLICATION POLICY 
The study will be registered and study results will be disclosed by the sponsor (or 
delegate) in one or more public clinical study registry(ies) according to 
national/international regulations and relevant commitments of pharmaceutical industry 
associations. Study registration may include a list of the investigational sites. 
The study results will be submitted for 1st full publication in an appropriate medical 
journal, and publishing details will be given in the clinical study agreement. The principal 
investigator of each site will be mentioned in the acknowledgement of the publication.  
Further submission for publication (e.g., poster, journal) concerning study results after an 
initial full journal publication must be approved in advance by the sponsor in writing. 
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 


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botulinum toxin type A on the functional ability of the child with spastic hemiplegia a 
randomized controlled trial. Eur J Neurol. 2001;8 Suppl 5:50-58. 
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improves upper limb movement and function in children with hemiplegic cerebral palsy. 
Developmental medicine and child neurology. 2006;48(3):170-175. 
Lukban MB, Rosales RL, Dressler D. Effectiveness of botulinum toxin A for upper and 
lower limb spasticity in children with cerebral palsy: a summary of evidence. J Neural 
Transm. 2009;116(3):319-331. 
Mall V, Heinen F, Siebel A, Bertram C, Hafkemeyer U, Wissel J, et al. Treatment of 
adductor spasticity with BTX-A in children with CP: a randomized, double-blind, 
placebo-controlled study. Developmental medicine and child neurology. 2006;48(1):10-
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Marchini C. Intranasal neostigmine therapy of botulinum toxin (BTX) treatment 
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Mayer NH, Esquenazi A, Keenan MA. Patterns of upper motoneuron dysfunction in the 
lower limb. Advances in neurology. 2001;87:311-319. 
Merz Pharmaceuticals (GmbH) - IB. NT 201 (tradename: Xeomin® ) - Investigator's 
Brochure (IB) - (current version). 
Merz Pharmaceuticals GmbH, Chambers HG, Dabrowski E, Gaebler-Spira DJ, Graham 
K, Heinen F, et al. Botulinum Neurotoxin A (BoNT-A) Free From Complexing Proteins, 
USAN: IncobotulinumtoxinA. Agreed dose finding rules and dose recommendations for 
treatment of muscular spasticity in Cerebral Palsy (CP). 2011. 
Molenaers G, Schorkhuber V, Fagard K, Van Campenhout A, De Cat J, Pauwels P, et al. 
Long-term use of botulinum toxin type A in children with cerebral palsy: treatment 
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botulinum toxin A in children with cerebral palsy, with a focus on the lower limb. Journal 
of children's orthopaedics. 2010;4(3):183-195. 
Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of 
botulinum toxin type A following long-term use. Eur J Neurol. 2006;13 Suppl 4:35-40. 


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Clinical Study Protocol MRZ60201_3072_1 
Amended Protocol Version Final 3.0 (07-Apr-2016) 
Confidential 
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Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and 
meta-analysis. Current medical research and opinion. 2004;20(7):981-990. 
Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and 
reliability of a system to classify gross motor function in children with cerebral palsy. 
Developmental medicine and child neurology. 1997;39(4):214-223. 
Pandyan AD, Johnson GR, Price CI, Curless RH, Barnes MP, Rodgers H. A review of 
the properties and limitations of the Ashworth and modified Ashworth Scales as 
measures of spasticity. Clinical rehabilitation. 1999;13(5):373-383. 
Polak F, Morton R, Ward C, Wallace WA, Doderlein L, Siebel A. Double-blind 
comparison study of two doses of botulinum toxin A injected into calf muscles in 
children with hemiplegic cerebral palsy. Developmental medicine and child neurology. 
2002;44(8):551-555. 
Roggenkamper P, Jost WH, Bihari K, Comes G, Grafe S. Efficacy and safety of a new 
Botulinum Toxin Type A free of complexing proteins in the treatment of blepharospasm. 
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the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol 
Suppl. 2007;109:8-14. 
Rosenbaum PL, Walter SD, Hanna SE, Palisano RJ, Russell DJ, Raina P, et al. Prognosis 
for gross motor function in cerebral palsy: creation of motor development curves. JAMA. 
2002;288(11):1357-1363. 
Russo RN, Crotty M, Miller MD, Murchland S, Flett P, Haan E. Upper-limb botulinum 
toxin A injection and occupational therapy in children with hemiplegic cerebral palsy 
identified from a population register: a single-blind, randomized, controlled trial. 
Pediatrics. 2007;119(5):e1149-1158. 
Sesardic D, Jones RG, Leung T, Alsop T, Tierney R. Detection of antibodies against 
botulinum toxins. Mov Disord. 2004;19(Suppl 8):S85-91. 
Simpson DM, Alexander DN, O'Brien CF, Tagliati M, Aswad AS, Leon JM, et al. 
Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, 
double-blind, placebo-controlled trial. Neurology. 1996;46(5):1306-1310. 
Simpson DM, Gracies JM, Graham HK, Miyasaki JM, Naumann M, Russman B, et al. 
Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based 
review): Report of the Therapeutics and Technology Assessment Subcommittee of the 
American Academy of Neurology. Neurology. 2008;70(19):1691-1698. 


Merz Pharmaceuticals GmbH  
Document status 
Clinical Study Protocol MRZ60201_3072_1 
Amended Protocol Version Final 3.0 (07-Apr-2016) 
Confidential 
Page 147 of 273 
F01/ Study Protocol/Investigational Plan/ 245/ EN/ 05/ valid from: 2010-11-05 
Speth LA, Leffers P, Janssen-Potten YJ, Vles JS. Botulinum toxin A and upper limb 
functional skills in hemiparetic cerebral palsy: a randomized trial in children receiving 
intensive therapy. Developmental medicine and child neurology. 2005;47(7):468-473. 
Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ. Double-blind 
study of botulinum A toxin injections into the gastrocnemius muscle in patients with 
cerebral palsy. Gait & posture. 1999;10(1):1-9. 
Ubhi T, Bhakta BB, Ives HL, Allgar V, Roussounis SH. Randomised double blind 
placebo controlled trial of the effect of botulinum toxin on walking in cerebral palsy. 
Archives of disease in childhood. 2000;83(6):481-487. 
US Food and Drug Administration. Memorandum of Meeting Minutes, Type C. 2011. 
Wallen M, O'Flaherty SJ, Waugh MC. Functional outcomes of intramuscular botulinum 
toxin type a and occupational therapy in the upper limbs of children with cerebral palsy: a 
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2007;88(1):1-10. 
Wallen MA, O'Flaherty S J, Waugh MC. Functional outcomes of intramuscular 
botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial. 
Archives of physical medicine and rehabilitation. 2004;85(2):192-200. 
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Willis AW, Crowner B, Brunstrom JE, Kissel A, Racette BA. High dose botulinum toxin 
A for the treatment of lower extremity hypertonicity in children with cerebral palsy. 
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Wissel J, Heinen F, Schenkel A, Doll B, Ebersbach G, Muller J, et al. Botulinum toxin A 
in the management of spastic gait disorders in children and young adults with cerebral 
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S, et al. Dose response with onabotulinumtoxinA for post-stroke spasticity: A pooled data 
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2011;26(2):209-215. 

SAP_000.pdf: 
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SOP/10334/EN - STATISTICAL ANALYSIS PLAN 
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Prospective, multicenter, randomized, double-blind, parallel-group, dose-
response study of three doses Xeomin® (incobotulinumtoxinA, NT 201) for the 
treatment of upper limb spasticity alone or combined upper and lower limb 
spasticity in children and adolescents (age 2 - 17 years) with cerebral palsy 
Phase 3 
MRZ60201_3072_1 
EudraCT Number: 2012-005496-14/ IND Number: 110,686 
Version 1.0, Final 
Date: 18-OCT-2018 
Author: 
 
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietary to Merz Pharmaceuticals GmbH. 
Unauthorized use, disclosure or reproduction is strictly prohibited. This document or parts thereof may not be 
disclosed to parties not associated with the clinical investigation without the prior written consent of Merz 
Pharmaceuticals GmbH. 
NCT02002884, redacted version v1.0, 13Jul20
Merz Pharmaceuticals GmbH 
Statistical Analysis Plan 


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SIGNATURE PAGE 
I confirm that this Statistical Analysis Plan accurately describes the planned statistical 
analyses to the best of my knowledge and was finalized before breaking the blind. 
 
Author (print name) 
Date (dd-mmm-yyyy) 
Signature 
 
Peer Reviewer (print name) 
Date (dd-mmm-yyyy) 
Signature 
 
Study Medical Expert (print name) 
Date (dd-mmm-yyyy) 
Signature 






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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................... 2 
1 
LIST OF ABBREVIATIONS .................................................................................... 5 
2 
GENERAL AND TECHNICAL ASPECTS ............................................................ 7 
3 
Clinical Study Design and Objectives ....................................................................... 7 
3.1 
Clinical Study Design .............................................................................................. 7 
3.2 
Clinical Study Objectives ........................................................................................ 9 
4 
Determination of Sample Size ................................................................................... 9 
5 
Analysis Set ............................................................................................................... 11 
6 
Variables for Analysis .............................................................................................. 12 
6.1 
Efficacy Variables ................................................................................................. 12 
6.1.1 
Primary Efficacy Variable ............................................................................... 12 
6.1.2 
Co-primary, Key-Secondary and Secondary Efficacy Variables .................... 13 
 
 
6.2 
Pharmacodynamic Variables ................................................................................. 18 
6.3 
Pharmacokinetic Variables .................................................................................... 18 
6.4 
Pharmacogenetic Variables ................................................................................... 18 
6.5 
Safety Variables ..................................................................................................... 18 
6.5.1 
Primary Safety Variable .................................................................................. 18 
6.5.2 
Secondary Safety Variables ............................................................................. 18 
6.5.3 
Other Safety Variables..................................................................................... 19 
6.6 
Other Variables ...................................................................................................... 20 
7 
Statistical Analysis Methods .................................................................................... 22 
7.1 
Efficacy Variables ................................................................................................. 22 
7.1.1 
Primary Efficacy Variable ............................................................................... 23 
7.1.2 
Co-Primary, Key-Secondary and Secondary Efficacy Variables .................... 25 
 
 
7.2 
Pharmacodynamic Variables ................................................................................. 31 
7.3 
Pharmacokinetic Variables .................................................................................... 32 
7.4 
Pharmacogenetic Variables ................................................................................... 32 
7.5 
Safety Variables ..................................................................................................... 32 
7.5.1 
Primary Safety Variable .................................................................................. 32 
7.5.2 
Secondary Safety Variables ............................................................................. 32 
7.5.3 
Other Safety Variables..................................................................................... 36 
7.6 
Other Variables ...................................................................................................... 41 
7.7 
Special Statistical/Analytical Issues ...................................................................... 44 


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7.7.1 
Discontinuations and Missing Data ................................................................. 44 
7.7.2 
Interim Analyses .............................................................................................. 45 
7.7.3 
Data Monitoring Committee ............................................................................ 45 
7.7.4 
Multiple Comparisons/Multiplicity ................................................................. 46 
7.7.5 
Examination of Subgroups .............................................................................. 46 
7.7.6 
Pooling of sites ................................................................................................ 48 
8 
Changes in the Planned Analyses ........................................................................... 48 
9 
References ................................................................................................................. 51 
Appendix 1: List of Tables, Figures, and Listings ............................................................ 52 
Appendix 2: List of Programmed In-text Tables, Figures, and Listings ........................... 78 


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1 LIST OF ABBREVIATIONS 
 
ANCOVA 
Analysis of covariance 
AS 
Ashworth scale 
ATC 
Anatomical therapeutic chemical classification 
BDRM 
Blind data review meeting 
BMI 
Body mass index 
BOCF 
Baseline observation carried forward 
BoNT 
Botulinum Toxin 
 
 
CP 
Cerebral palsy 
CSP 
Clinical study protocol 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
Electronic case report form  
Desc. stat. 
Descriptive statistics 
DMC 
Data monitoring committee 
EMG 
electromyography  
e-stim 
electrical stimulation 
FAS 
Full analysis set 
Freq. 
Frequency table 
GICS 
Global Impression of Change Scales 
GMFCS-E&R 
Gross Motor Function Classification System 
(expanded and revised version) 
IV/WRS 
Interactive voice (web) response system 
LOCF 
Last observation carried forward principle 
LL 
Lower limb 
MAS 
Modified Ashworth scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
MP 
Main Period 
n 
Number of non-missing observations 
Nexp 
Number exposed 
OLEX 
Open-label extension 
PBO 
Placebo 


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PDF 
Portable Document Format 
PPS 
Per protocol set 
QPS 
Questionnaire on Pain caused by Spasticity 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System software 
SD 
Standard deviation 
SE 
Standard error 
SES 
Safety evaluation set 
SMQ 
Standard MedDRA query 
SOC  
System organ class 
TC 
Telephone Contact 
TEAE 
Treatment emergent adverse event 
TEAESI 
Treatment emergent adverse events of special 
interest 
TESAE 
Treatment emergent serious adverse event 
TFLs 
Tables, figures and listings 
UL 
Upper limb 
WHO 
World health organization 


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2 GENERAL AND TECHNICAL ASPECTS 
The objective of this statistical analysis plan is to specify the statistical analyses in more detail 
than stated in the clinical study protocol (CSP) and to be precise enough to serve as a 
guideline for statistical programming and creation of tables, figures and listings. 
This statistical analysis plan is based on the clinical study protocol version 3.0, dated 07-
APR-2016 and the following amendment no. 1, dated 24-APR-2015. 
All programs will be written using Statistical Analysis System Software (SAS®) version 9.2 or 
higher. A font size of 10 points will be used for the tables and figures in section 14, 
corresponding to a line size of 111 digits and a page size of 42 lines for an output in A4 
format. The font size of 10 points will also be used for all listings, if possible. If this is not 
possible, for listings, a minimum font size of 8 points with the line size of 140 points and page 
size of 52 lines will be used to produce the output in A4 format. Single SAS programs will be 
written for all tables and figures, and all listings, respectively. All outputs will be transferred 
into Portable Document Format (PDF)-files using the Merz internal SAS macro LST2PDF. 
These PDF-files will be generated separately for the tables and figures of section 14 and the 
listings of section 16.2 of the appendix of the clinical study report. Each PDF-file will include 
the corresponding table of contents, preceding the content of the file.    
The standard tables, figures and listings (TFLs) will be applied. 
3 CLINICAL STUDY DESIGN AND OBJ ECTIVES 
3.1 
Clinical Study Design 
This is a prospective, multicenter, multi-national, randomized, double-blind, parallel-group, 
dose-response study in phase 3 of three doses NT 201. Subjects with upper limb spasticity 
alone or with combined upper limb (UL) and lower limb (LL) spasticity due to cerebral palsy 
(CP) will be treated. The study comprises a Main Period (MP) with a single double-blind 
treatment cycle with three dose arms (high, mid, low), followed by three open-label extension 
(OLEX) treatment cycles with a single treatment arm using the high dose regimen of MP. 
Each of the four treatment cycles has an observation period of 12 to 16 weeks, i.e. 14 weeks 
± 14 days. 
Treatment of UL(s) in MP will be administered in three parallel dose groups of NT 201 with 
fixed doses to UL(s): 
• In the high dose group 8 U/Kg BW NT 201 (maximum dose per UL: 200 Units (U) for 
subjects ≥25kg BW). 
• In the mid dose group 6 U/kg BW (maximum of 150 U) per UL. 
• In the low dose group 2 U/kg BW (maximum of 50 U) per UL. 


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As clinically needed, UL treatment can be administered unilaterally or bilaterally and subjects 
may receive additional Botulinum Toxin (BoNT) injections in one out of five predefined 
treatment combinations (A-E) up to the maximum total dose applicable for their Gross Motor 
Function Classification System expanded and revised version (GMFCS-E&R) level (I-III: 
20 U/kg BW NT 201, maximum of 500 U; IV and V: 16 U/kg BW NT 201, maximum of 400 
U): 
• Treatment Combination A: Unilateral or bilateral UL treatment only 
• Treatment Combination B: Unilateral UL and unilateral LL treatment 
• Treatment Combination C: Unilateral UL and bilateral LL treatment in GMFCS-E&R 
level I-III 
• Treatment Combination D: Unilateral UL and bilateral LL treatment in GMFCS-E&R 
level IV-V 
• Treatment Combination E: Bilateral UL and bilateral LL treatment in GMFCS-E&R 
level I-III 
In MP only, LL(s) treatment will be performed within the same dose groups as UL treatment, 
i.e. subjects in the mid and low dose group will receive 75% or 25%, respectively, of the dose 
in the high dose group to all limbs treated. 
A total of 344 subjects (2 : 1 : 1 ratio) will be enrolled with:  
• At least 172 subjects randomized to the high dose group. 
• At least 86 subjects to the mid dose group. 
• At least 86 subjects to the low dose group.  
The study includes the following visits: 
Screening: 
Screening Visit (V1): 
Day -14 (Week –2) ± 5 days 
Main Period (MP): 
Baseline Injection Visit (V2): 
Day 1, randomization 
Telephone Contact (TC1): 
Day 8 (Week 1) ± 3 days of MP 
Ctrl. Visit (V3): 
Day 29 (Week 4) ± 3 days of MP 
Ctrl. Visit (V4): 
Day 57 (Week 8) ± 3 days of MP 


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Optional Telephone Contact 
Wk12: 
Day 85 (Week 12) ± 3 days of MP 
Final Visit of MP (V5) 
Day 99 (Week 14) ± 14 days of MP  
Open-Label Extension Period (OLEX) 
Injection Visit (V6, V10, V14): 
Day 1 of the 2nd to 4th treatment cycle. 
Telephone Contact (TC) 
(TC2, TC3, TC4): 
Day 8 (Week 1) ± 3 days of 2nd to 4th treatment cycle. 
Ctrl. Visit (V7, V11, V15): 
Day 29 (Week 4) ± 3 days of 2nd to 4th treatment cycle 
Ctrl. Visit (V8, V12, V16): 
Day 57 (Week 8) ± 3 days of 2nd to 4th treatment cycle 
End of Cycle Visit (V9, V13) 
Day 99 (Week 14) ± 14 days of 2nd and 3rd treatment 
cycle 
End of Study Visit (V17):  
Day 99 (Week 14) ± 14 days of 4th treatment cycle. 
Revisit for reinjection 
If any eligibility criterion is not met either at the Final Visit of MP (V5) or at an End of Cycle 
Visit in OLEX (V9 or V13), the injection may be rescheduled within up to 16 weeks after the 
last injection treatment. 
3.2 
Clinical Study Objectives 
The objectives of the study are to investigate efficacy and safety of NT 201 in children (age 2-
11 years) and adolescents (age 12-17 years inclusive) with UL spasticity alone or with 
combined UL and LL spasticity due to CP. 
4 DETERMINATION OF SAMPLE SIZE 
The sample size estimation for the primary efficacy variable ‘change from baseline in AS in 
the primary clinical target pattern, i.e. elbow flexors or wrist flexors, at Day 29 (Week 4)’ was 
based on data of a study with BoNT-A in the treatment of post-stroke UL spasticity in adults 
[Childers 2004 (1)]. In this trial a modification of the original 5-point AS to a 9-point scale by 
adding 4 half point increments was used. Since this modified Ashworth Scale (MAS) is very 
similar to the original Ashworth Scale (AS) used in the present study, it appeared to be 
justified to base the sample size calculation on the MAS results of the study by Childers et al.. 
In this study, a mean change from baseline in MAS scores at the elbow of -1.01 in the 180 U 
BoNT-A dose group and of -0.7 in the 90 U dose group were observed. It was assumed that 
the changes from baseline in AS for flexed elbow will be comparable to the one for flexed 


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wrist. The 180 U dose lies between the 200 U and the 150 U (for subjects ≥25kg) doses 
planned for the high and mid dose group in this study. Since published trial data for the exact 
doses planned in this trial did not exist, and doses of BoNT-A applied in spasticity show 
complex non-linear correlations to AS scores [Yablon 2011 (2)], it appeared to be justified to 
use the same assumptions for both dose groups. 
Comparable Placebo (PBO)-controlled studies showed a low drop-out rate of 3% at the time 
of assessment of the primary efficacy variable. Therefore, a similarly small number of missing 
data for the primary efficacy endpoint was expected for this study. Consideration of 
assumptions above with a 3% rate of missing values and using last observation carried 
forward (LOCF) as originally planned in the CSP led to the group means μNT201_high= -0.98, 
μNT201_mid= -0.98 and μNT201_low= -0.68. 
The assumption for a pooled common standard deviation (SD) was σ=0.6. 
An estimated total number of 258 (with randomization ratio of 2:1) subjects will provide 
96.5% power to show a statistically significant difference between the NT 201 high dose 
group (172 subjects) and the NT 201 low dose group (86 subjects) at an alpha level of 0.05 
(two-sided t-test, Statistical Analysis System software®). 
An estimated total number of 172 subjects (with randomization ratio of 1:1) will provide 
90.3% power to show a statistically significant difference between the NT 201 mid dose 
group (86 subjects) and the NT 201 low dose group (86 subjects) at an alpha level of 0.05 
(two-sided t-test, Statistical Analysis System software®) in the primary efficacy variable. 
For the co-primary efficacy variable ‘Investigator’s Global Impression of Change Scale 
(GICS) 4 weeks after injection’, data from [Childers 2004 (1)] were used as well. In this 
study, a 9-point global assessment scale ranging from +4 (very marked improvement) to -4 
(very marked worsening) was used to assess the response to treatment. In the group treated 
with 180 U Botulinum Toxin Type A, the mean response to treatment rated by the subject at 
week 3 was 1.4 points with a standard deviation of 1.0 points. Given that only PBO values for 
the global assessment scale were reported and since no global response compared to PBO had 
been detected in the 90 U dose group, data from the PBO group were used here. In the PBO 
group, the corresponding point estimator for the mean value was 0.8 points with a standard 
deviation of 0.8 points. It was assumed that the 9-point scale has a comparable effect size to 
the 7-point scale used in this study. 
When conservatively accounting for missing data of about 3% and considering the required 
N=258 (randomization ratio 2:1) subjects for the treatment comparison of the primary 
efficacy variable, a mean treatment response difference of 0.582 points with a pooled 
common standard deviation of 1 will still provide 99.2% power to show statistically 
significant superiority in the co-primary variable in favor of NT 201 high dose group versus 
low dose group. 
An estimated total number of N=172 subjects (with randomization ratio of 1:1) will provide 
96.7% power to show a statistically significant difference between the NT 201 mid dose 


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group (86 subjects) and the NT 201 low dose group (86 subjects) at an alpha level of 0.05 in 
the co-primary efficacy variable. 
It is estimated that the sample size of N=344 subjects will provide 95.7% power (product of 
the single power calculations for both the primary and the co-primary efficacy variable for the 
high versus low dose treatment comparison) to show a statistically significant difference 
between NT 201 high dose and NT 201 low dose group. A power of 87.3% is provided for the 
treatment comparison of the mid versus the low dose in both primary and co-primary efficacy 
variables. 
Using a randomization ratio of 2:1:1 at least 172 subjects were planned to be randomized to 
the NT 201 high dose treatment group, at least 86 subjects were planned to be randomized to 
the NT 201 mid dose treatment group and at least 86 subjects were planned to be randomized 
to the NT 201 low dose treatment group. 
5 ANALYSIS SET 
The following analysis sets will be defined for the statistical analysis of the Main Period of 
this clinical study: 
Safety Evaluation Set (SES) of the Main Period 
The SES of the Main Period is the subset of all subjects who receive study medication in the 
MP at least once.  
Full Analysis Set (FAS) of the Main Period 
The FAS of the MP is the subset in the SES of the MP for whom the primary efficacy variable 
or co-primary efficacy variable is available, i.e. all subjects who have at least either an AS 
score in the clinical pattern flexed elbow or flexed wrist at baseline (Day 1), or the 
Investigator’s GICS for upper limb at Day 29 (Week 4). 
Per Protocol Set (PPS) of the Main Period 
The PPS is the subset in the FAS of the MP without major protocol deviations. Major protocol 
deviations will be defined during the Blind Data Review Meeting (BDRM). 
The following analysis sets will be defined for the statistical analysis of the OLEX period of 
this clinical study: 
SES of the OLEX Period 
The SES is the subset of all subjects who receive study medication at least once during the 
OLEX period.  


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FAS of the OLEX Period 
The FAS is the subset of subjects in the SES of the OLEX for whom at least one post-baseline 
value of any efficacy variable in the OLEX is available. 
Subjects which have not been treated according to the randomization list in the MP will be 
excluded from PPS of the MP. If subjects have not been treated according to the 
randomization list in the MP, tables performed on the SES will be analyzed as treated for the 
MP treatment group and tables performed on the FAS will be analyzed as randomized for the 
MP treatment group. If subjects have been treated with MP medication in the OLEX they will 
be analyzed regularly according to their planned high dose treatment of the OLEX regardless 
if they actually received low, high or mid dose. In the subject data listings the MP treatment 
group will be listed as randomized except for the section 16.2.7 and 16.2.8, here the actual 
MP treatment group will be listed. 
6 VARIABLES FOR ANALYSIS 
6.1 
Efficacy Variables 
6.1.1 
Primary Efficacy Variable 
The primary efficacy variable will be determined for MP only. 
• Primary efficacy variable is the change from baseline in AS in the primary clinical target 
pattern, i.e. elbow flexors or wrist flexors, at Day 29 (Week 4) of MP.  
For subjects with bilateral UL treatment, the body side for analysis will be decided by the 
investigator at screening. If both main clinical target patterns elbow flexors and wrist flexors 
are qualified for primary efficacy analysis, an interactive voice (web) response system 
(IV/WRS) will select the primary clinical target pattern. The primary clinical target pattern 
will be set to missing for subjects whose primary clinical target pattern was not treated in the 
MP by mistake. As a consequence these subjects will not have the primary efficacy variable 
“change from baseline in AS in the primary clinical target pattern”. 
The AS is a well-known and validated scale to categorize the severity of spasticity by judging 
resistance to passive movement. Spasticity will be assessed separately for elbow flexors, wrist 
flexors, forearm pronators, finger flexors and thumb flexors if chosen for BoNT injection on 
the following 5-point scale: 
0 =  
no increase in tone 
1 =  
slight increase in tone giving a “catch” when the limb was moved in flexion or   
 
extension. 
2 =  
more marked increase in tone, but limb easily flexed. 
3 =  
considerable increase in tone - passive movements difficult. 


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4 =  
limb rigid in flexion or extension 
In order to be enrolled, subjects must have an AS score of ≥2 points for elbow flexors and/or 
wrist flexors in at least one UL. For initiation of treatment in this study, all chosen clinical 
patterns (UL and LL) must have an AS score ≥2 at the Baseline Injection Visit V2 of MP. 
6.1.2 
Co-primary, Key-Secondary and Secondary Efficacy Variables 
The co-primary efficacy variable, the key-secondary efficacy variables and the secondary 
efficacy variables will be determined for MP only. 
• Co-primary efficacy variable is the Investigator’s Global Impression of Change Scales 
(GICS) for upper limb at Day 29 (Week 4) of MP. The definition of this variable was 
changed compared to the CSP (for details see section 8). 
The GICS are subjective global outcomes to assess independently the investigator’s, 
child’s/adolescent’s, and parent’s or caregiver’s (if applicable) impression of change due to 
treatment. Caregiver(s) may substitute parent(s) for the assessment of GICS, if they are main 
social contacts of subjects, e.g. in a special-care home. 
The question of the GICS for the investigator is: ‘Based on your clinical experience, what is 
your overall impression of change of the subject’s upper limb spasticity due to treatment, 
compared to the condition before the last injection? Please check the one option that best fits 
your overall impression of change.’ 
The response option for all GICS versions is a common 7-point Likert scale that ranges from 
-3 = very much worse to +3 = very much improved: 
 
+3 
 
Very much improved 
 
+2 
 
Much improved 
+1 
 
Minimally improved 
0 
 
No change 
-1 
 
Minimally worse 
-2 
 
Much worse 
-3 
 
Very much worse 
 
Key-secondary efficacy variables are:  


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• Change from baseline in AS score of the other treated main clinical target pattern (i.e. 
of elbow flexors or wrist flexors, if treated) at Day 29 (Week 4) of MP. This analysis will 
be performed for the main clinical target pattern not analyzed as primary efficacy variable, 
in case two target patterns would qualify as main clinical target pattern.  
• Change from baseline in AS score of treated clinical target pattern clenched fist (in 
subjects treated in combination with flexed wrist) at Day 29 (Week 4) of MP. 
Secondary efficacy variables are: 
• Change from baseline in AS score for each treated clinical pattern (e.g., flexed elbow, 
flexed wrist, clenched fist, pronated forearm and thumb in palm) of the UL at all other 
post baseline visits of MP (V3, V4, and V5). The definition of this variable was made 
more precise compared to the CSP (for details see section 8). 
• Change from baseline in scores of pain intensity (from subjects) and pain frequency (from 
parent/caregiver) assessed with ‘Questionnaire on Pain caused by Spasticity (QPS)’ to all 
post baseline visits of MP (V3, V4, and V5). In the definition of this variable the visit 
numbers were added. 
The QPS is a patient-reported outcome for children and adolescents (2-17 years) with CP on 
spasticity-related pain. For this study, in addition to the UL versions that will be used for all 
subjects/parents/caregivers, the LL versions will also be used for subjects with treatment 
combinations including UL and LL treatment. While pain intensity is reported by the 
children/adolescents, pain frequency (based on observed pain behaviors) will be documented 
by the parent(s)/caregiver(s). In addition, parent(s)/caregiver(s) report on pain location and 
observed pain behaviors. Thus, the information provided by the children/adolescents 
complements the one of the parents/caregivers. Pain intensity and frequency of the QPS are 
assessed for general pain and for four different activity situations. The situations are described 
in different questions for rest, normal day activities, physical exercise and for an individually 
defined ‘very hard thing to do”. First it is always asked if spasticity-related pain for each 
activity situation occurred (Yes/No) and then how severe the experienced spasticity was (6-
point rating scale) or how frequent pain behavior was observed (5-point rating scale). 
From the self-administered version and from the interviewer-administered version of the QPS 
the QPS child/adolescent score will be calculated as sum of the activity related pain items No. 
5, 7, 9, and 12 divided by 4. In case one or more of the 4 items are missing the corresponding 
QPS score will not be calculated. The item No. 3 of the self-administered version and the 
interviewer-administered version will be not included into this score, but will be assessed 
separately as child/adolescent general pain intensity item. 
From the parent/caregiver version the QPS parent/caregiver score will be calculated as sum of 
the items No. 9b, 10b. 11b, and 13b divided by 4. In case one or more of the 4 items are 
missing the corresponding QPS score will not be calculated. The item No. 8 of the 
parent/caregiver version will be not included into this score, but will be assessed separately as 
parent/caregiver general pain frequency item. 










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Secondary safety variables of the OLEX Period comprise: 
• Occurrence of treatment emergent adverse events (TEAEs) overall and per treatment 
cycle. 
• Occurrence of treatment emergent adverse events of special interest (TEAESIs) overall 
and per treatment cycle. 
• Occurrence of serious TEAEs overall and per treatment cycle. 
• Occurrence of TEAEs related to treatment as assessed by the investigator overall and per 
treatment cycle. 
• Occurrence of TEAEs by worst intensity overall and per treatment cycle. 
• Occurrence of TEAEs by worst causal relationship overall and per treatment cycle. 
• Occurrence of TEAEs by worst outcome overall and per treatment cycle. The definition of 
this variable was changed compared to the CSP (for details see section 8). 
• Occurrence of TEAEs leading to discontinuation overall and per treatment cycle. 
6.5.3 
Other Safety Variables 
Other safety variables of the MP comprise: 
• Investigator’s Global Assessment of Tolerability at the Final Visit of MP V5 (In the 
definition of this variable the visit number was added.) 
• Vital signs (blood pressure, heart rate) at all visits of MP 
• Body Mass Index (BMI), weight and height at Screening V1, Baseline Injection Visit V2, 
at the Final Visit of MP V5 
• Clinical chemistry, differential count and hematology at Screening V1 
• Occurrence of antibodies against BoNT-A in subjects ≥21 kg BW at Screening V1 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent based on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
This scale is used to assess suicidality prospectively in this clinical study at baseline and 
all post-baseline visits of the MP. 
Other safety variables of the OLEX comprise: 


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• Investigator’s Global Assessment of Tolerability at Day 99 (Week 14) of all OLEX cycles, 
i.e. at End of Cycle Visit (V9, V13) and at End of Study Visit (V17). In the definition of 
this variable the visit numbers were added. 
• Vital signs (blood pressure, heart rate) at all visits of OLEX period (V6, V7, …, V17). In 
the definition of this variable the visit numbers were added. 
• BMI, weight and height at all Injection Visits of OLEX (V6, V10 and V14) and at the End 
of Study Visit (V17). If V5 and V6 will be performed at the same day, BMI, weight and 
height can be transferred from V5 to V6. 
• Clinical chemistry, differential count and hematology at the Injection Visit V6 of OLEX 
and the End of Study Visit (V17). 
• Occurrence of antibodies against BoNT-A in subjects ≥21 kg BW at the End of Study 
Visit (V17). In the definition of this variable the visit numbers were added. 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent based on the Columbia-Suicide Severity Rating Scale (C-SSRS) 
This scale is used to assess suicidality prospectively at all OLEX visits. 
6.6 
Other Variables 
Other variables of interest are: 
• Subject 
dispositions 
(including 
number 
of 
subjects 
enrolled, 
number of 
discontinuations and reason for discontinuations) 
• Demographic data 
• Other baseline characteristics such as:  
o Medical history and concomitant diseases 
o Previous and concomitant therapies, including medication and non-drug 
treatment 
o CP history (including main cause for cerebral palsy, affected limbs (UL 
unilateral left, UL unilateral right, ULs bilateral, LL unilateral left, LL 
unilateral right, LLs bilateral), duration since first diagnosis of spasticity, and 
duration since the first diagnosis of cerebral palsy) 
o Primary clinical pattern 
o GMFCS-E&R level: 
1 = Level I: Walks without Limitations 


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2 = Level II: Walks with Limitations 
3 = Level III: Walks Using a Hand-Held Mobility Device 
4 = Level IV: Self-Mobility with Limitations; May Use Powered Mobile 
5 = Level V: Transported in a Manual Wheelchair 
• Planned treatment of spasticity: treatment combinations A, B, C, D, and E, limbs 
planned to be treated (lower limb right, lower limb left, upper limb right, and upper 
limb left), and primary body side for analyses, if bilateral: This variable was added in 
the SAP (for details see section 8). 
• BoNT-A pre-treatment status  
• Use of local anesthesia/analgosedation for injection treatments:  
o Inhalative sedatives (e.g. nitrous oxide, sevoflurane) 
o Oral sedatives (e.g. benzodiazepines, antihistamines) 
o Rectal sedatives (e.g. benzodiazepines) 
o Parenteral sedatives (e.g. benzodiazepines, propofol) 
o Topical/Local anaesthetics (e.g. lidocaine/prilocaine cream) 
o Oral analgesics (e.g. paracetamol, opioids) 
o Rectal analgesics 
o Parenteral opioid analgesics 
o Parenteral non opioid analgesics 
o Topical cooling (e.g. cooling spray) 
o Other 
• Monitoring during sedation (yes/no): This variable was added in the SAP (for details 
see section 8). 
• Injection guidance technique (ultrasound, electromyography (EMG)/ electrical 
stimulation (e-stim), e-stim, EMG): This variable was added in the SAP (for details 
see section 8). 
• Treatment compliance: This variable was added in the SAP (for details see section 8). 
• Extent of exposure (injected volume, injected units, number of injected sites per body 
side, per clinical pattern, and per muscle and in total, and frequency of treated limbs 


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and number (%) of subjects with unilateral and with bilateral treatment by upper and 
lower limbs): This variable was added in the SAP (for details see section 8). 
• Length of injection cycles and the total observation period in weeks over the entire 
study.  This variable was added in the SAP (for details see section 8). 
7 STATISTICAL ANALYSIS METHODS 
7.1 
Efficacy Variables 
All efficacy analyses will be based primarily on the FAS and additionally in the MP, for 
sensitivity purposes, on the PPS. For analysis of the MP the FAS of the MP will be used and 
for analysis of the OLEX Period the FAS of the OLEX Period will be used. Statistical tests 
will be two-sided hypothesis tests for between-treatment differences of the MP and two-sided 
hypothesis tests for before treatment versus after treatment comparisons of the OLEX Period 
data in general. In the MP treatment differences will be tested for comparison of the high 
versus low dose treatment group and the mid versus low dose treatment group, respectively. 
The efficacy analysis of the MP and of the OLEX will be performed by Main Period 
treatment group (high, mid, low) and in total. For this purpose the Main Period treatment 
group as randomized instead of as treated will be used. In the unlikely case that a subject has 
received mid or low dose instead of the planned high dose during the OLEX Period, he/she 
will be analyzed in total group of the OLEX tables together with all other subjects with the 
correct high dose treatment. Continuous variables (values and changes from baseline/cycle 
baseline) will be summarized by number of non-missing observations (n), mean, standard 
deviation, median, 1st and 3rd quartile, minimum, and maximum or/and as counts and 
percentages. For qualitative variables, absolute and percent frequencies (n, %) and, if 
applicable, shift tables will be displayed. The base for percentages will be all subjects treated 
in the respective cycle (Nexp = number exposed), in the respective limb and clinical target 
pattern, if analysis is done per limb and or per clinical target pattern. A missing line will be 
given for subjects treated in the respective cycle but not observed at the respective visit, in 
order to have 100% given for the sum of the single observations. Subjects, who were treated 
in the respective cycle, will not be included in the efficacy analysis of this cycle. Two-sided 
95% confidence limits and descriptive p-values will be given, where appropriate. Descriptive 
summary statistics will be performed at all visits and if applicable for the changes from 
baseline of the MP (Day 1) to all post-baseline visits of the MP and of the OLEX, and from 
Day 1 of each treatment cycle to all post baseline Control Visits of the respective treatment 
cycle. For subjects with bilateral treatment, body sides will be analyzed separately per 
primary and per non-primary body side, where applicable. In case that for any subject end of 
cycle visit of cycle x and injection visit of cycle x+1 are on the same day the respective data 
will be used for the analysis of both visits for parameters which are to be assessed at injection 
visits as well. 
For efficacy variables the last measurement before start of treatment is defined as baseline 
value. 


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Testing of the primary, co-primary and key-secondary efficacy variables of the MP will be 
performed in a 4-step approach using a hierarchical test procedure as described below: 
1. Step: Primary and co-primary efficacy variables for high dose vs. low dose. 
2. Step: First key-secondary efficacy variable and co-primary efficacy on subpopulation 
variables for high dose vs. low dose. 
3. Step: Second key-secondary efficacy variable for high dose vs. low dose. 
4. Step: Primary and co-primary efficacy variables for mid dose vs. low dose. 
Due to the hierarchical testing strategy of (co-)primary and key-secondary efficacy variables 
and the two dose group comparisons (high versus low and mid versus low), this four step 
hierarchical testing procedure ensures the overall type I level of 5% for the confirmatory tests. 
If one of four hierarchical tests does not yield a statistically significant result, the consecutive 
test(s) will still be performed but will be considered to be only descriptive. 
The estimand of interest of this study is the treatment effect measured by the primary and co-
primary efficacy variables in all subjects of FAS of the MP regardless of adherence to 
randomization list. 
7.1.1 
Primary Efficacy Variable 
The primary efficacy variable is the change from baseline in AS in the primary clinical target 
pattern, i.e. elbow flexors or wrist flexors, at Day 29 (Week 4) of MP. A mixed model 
repeated measurement analysis (two-sided, significance level α=0.05) with comparison of 
least square means will be used for the confirmatory analysis to detect differences between 
the high and low dose treatment groups. The following working hypotheses will be tested by 
use of a two sample t-test:  
H0: μNT201_high - μNT201_low = 0  vs. 
H1: μNT201_high - μNT201_low ≠ 0 
with μ denoting the mean change from baseline. Stronger negative differences between least 
square mean estimates as defined by the working hypotheses thereby indicate better results 
(stronger reduction of AS from baseline to V3) in the high dose group compared to the low 
dose group.   
Estimates for least square means will be derived from the mixed model repeated measures 
where the dependent variable in the model is defined as the change from baseline in the AS. 
The independent variables are defined as treatment group (high dose, low dose), pooled sites, 
BoNT-A pre-treatment status (pre-treated, treatment naïve) as fixed factors, visit*treatment as 
interaction term, and visit as repeated factor. Covariates are the AS score of the primary 
clinical target pattern at baseline (Day 1 of MP) and the GMFCS-E&R level at screening. The 
following SAS code will be used: 
 


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proc mixed data = dataset; 
    class treatment site btx subject visit; 
    model AS_change = treatment site btx AS_baseline GMFCS                
visit visit*treatment / solution ddfm=kr; 
    repeated visit / subject= subject TYPE=un; 
    lsmeans visit*treatment / diff cl pdiff; 
run; 
Sites will be pooled for the statistical analysis based on geographic criteria. For definition of 
pooling rules please refer to section 7.7.6. 
Confirmatory testing will be performed on the FAS of MP with accounting for missing values 
using the mixed model repeated measures (MMRM) approach. 
In order to investigate the impact of missing values and different approaches for imputation, 
further sensitivity analyses will be performed on the PPS as well as on the FAS of the MP 
using the LOCF principle and without missing replacement (observed case analysis). For this 
purpose the statistical model as described above but without visit*treatment as interaction and 
without visit as repeated factor will be applied for LOCF analysis and for observed case 
analysis. Since there is no assessment of AS between baseline and V3, the baseline 
observation will be carried forward to Week 4 equals the LOCF analysis. Therefore the LOCF 
method is equivalent to the baseline observation carried forward (BOCF) method in this 
special case. The following SAS code will be used: 
 
proc mixed data = dataset; 
     class treatment site btx; 
model AS_change_wk4 = treatment site btx AS_baseline GMFCS / solution 
ddfm=kr; 
     lsmeans treatment / pdiff CL alpha=0.05; 
run; 
Further, a non-parametric Wilcoxon rank-sum test will be performed as sensitivity analysis of 
the primary efficacy variable to investigate the impact of potential deviations from the 
assumption of normal distribution (for FAS of the MP and PPS subset, using LOCF). The 
following working hypotheses will be tested:  
H0: Prob. distributions for high dose group and low dose group are identical 
vs. 
H1: Prob. distribution for high dose group shifted to right or left of distribution for low dose 
group. 
The Wilcoxon rank-sum test will be performed by use of the following SAS code: 
 
proc npar1way data=dataset wilcoxon; 
    class treatment; 
    var AS_change_wk4; 
    exact; 


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run; 
Furthermore, descriptive summary statistics, shift tables and frequency tables of changes will 
be given for the primary efficacy variable. 
7.1.2 
Co-Primary, Key-Secondary and Secondary Efficacy Variables 
Co-primary efficacy variable:  
1. Step: Both, the primary efficacy variable and the co-primary efficacy variable have to show 
statistically significant treatment differences in order to prove superiority of high dose vs. low 
dose treatment. No α-adjustment for multiplicity is necessary. 
The co-primary efficacy variable is the Investigator’s Global Impression of Change Scales 
(GICS) for upper limb at Day 29 (Week 4) of MP. As for the primary efficacy variable, an 
analysis of covariance (ANCOVA) approach (2-sided, significance level alpha=0.05) with 
comparison of least square means will be used for the confirmatory analysis of the co-primary 
efficacy variable. The dependent variable is defined as the ‘Investigator’s GICS at Day 29 
(Week 4) for upper limb of MP’. The independent variables are defined as treatment group 
(high dose, low dose), pooled sites, BoNT-A pre-treatment status (pre-treated, treatment 
naïve) as fixed factors and the covariates are the maximum AS score of the two possible 
primary target clinical patterns flexed elbow or flexed wrist at baseline (Day 1 of MP) and the 
GMFCS-E&R level at Screening Visit. The following SAS code will be used: 
 
proc mixed data = dataset; 
    class treatment site btx; 
    model I_GICS_wk4 = treatment site btx max_AS_baseline GMFCS / solution; 
    lsmeans treatment / pdiff CL alpha=0.05; 
run; 
Positive values for differences between least square mean estimates as defined by the working 
hypotheses (see primary efficacy variable) thereby indicate better results (higher GICS values 
at Day 29, Week 4) in the high dose group as compared to the low dose group. Confirmatory 
testing will be performed on the FAS of MP with replacement of missing data, setting all 
missing values of the co-primary efficacy variable to “0” (no change).  
Further sensitivity analyses will be performed on the PPS as well as on the FAS of the MP 
and the PPS without missing replacement (observed case analysis).  
Further, a non-parametric Wilcoxon rank-sum test will be performed as sensitivity analysis to 
investigate the impact of potential deviations from the assumption of normal distribution (for 
FAS and PPS subset, imputing missing data by “0”, i.e. no change). The same SAS code as 
for the primary efficacy variable will be used with primary efficacy variable replaced by co-
primary efficacy variable. 
Furthermore, frequency tables and descriptive summary will be performed for the co-primary 
efficacy variable. 


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Key-secondary efficacy variables and co-primary efficacy variable restricted to subpopulation:  
2. Step: If the confirmatory tests of the primary efficacy variables and the co-primary efficacy 
variable both show significant results, then the hierarchical testing approach will be continued 
in a second step. In this second step the following two variables will be tested for high dose 
group versus low dose group: 
• First key secondary efficacy variable: Change from baseline in AS score of the other 
treated main clinical target pattern (i.e. of elbow flexors or wrist flexors, if treated) 
at Day 29 (Week 4) of MP 
• Co-primary efficacy variable: Investigator’s Global Impression of Change Scales 
(GICS) for upper limb at Day 29 (Week 4) for the following subpopulation: 
This analysis will be done for the subpopulation defined by this key-secondary endpoint, that 
means only subjects having two main clinical target patterns will be included into the 
anaylsis. All subjects with only one main target pattern will be excluded from the analysis. 
The analysis models will be identical to the analyses described above for the 1st step using the 
the key-secondary variable instead of the primary variable and the co-primary variable 
restricetd to the subpopulation instead of the co-primary variable of the unrestricted 
population. 
Both, the first key-secondary efficacy variable and the co-primary efficacy variable for the 
subpopulation have to show statistically significant treatment differences in order to prove 
superiority of high dose vs. low dose treatment in this subpopulation. 
3. Step: Only if the confirmatory analysis of step 2 yields a statistically significant result, in a 
third step, a confirmatory analysis of the second key-secondary efficacy variable ‘change 
from baseline in AS score of clinical target pattern clenched fist (in subjects treated in 
combination with flexed wrist), at Day 29 (Week 4) of MP will be done. This variable has 
been chosen, since it is anticipated that the vast majority of subjects will have a combined 
clinical presentation of clinical patterns clenched fist and flexed wrist. Subjects with either 
treatment alone (i.e. clenched fist or flexed wrist) with other clinical target patterns will be 
evaluated separately in a descriptive manner as other efficacy variables (see also section 6.1.3 
and 7.1.3).  
4.  Step: Only if the confirmatory analysis of step 3 yields a statistically significant result, in a 
fourth step, using a hierarchical testing approach, the mid dose treatment will be compared to 
low dose treatment for the primary efficacy variables and the co-primary efficacy variable. 
The analysis models will be identical to the analyses described above for the 1st step replacing 
high dose group with mid dose group. Both, the primary efficacy variable and the co-primary 
efficacy variable have to show statistically significant treatment differences in order to prove 
superiority of mid dose vs. low dose treatment. 
For the confirmatory analyses a two-sided significance level of α=0.05 will be applied and  
analysis models as described for the (co)-primary efficacy variables will be applied. The 


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analysis of the primary efficacy variable and of both key-secondary efficacy variables will be 
performed on the FAS of the MP with an MMRM approach. For the co-primary efficacy 
variable and the co-primary variable restricetd to the subpopulation, missing data will be 
imputed by “0”, i.e. no change. 
All other test procedures will be explorative. Sensitivity analyses will be performed on the 
PPS of MP using the MMRM approach, as well as on the FAS and the PPS of MP using a 
mixed model approach without repeated measures first with the LOCF principle and second 
without replacement of missing values (i.e., observed case analysis). As the GICS is measured 
at Control Visit V3 only it is not possible to apply a model based analysis like mixed model 
repeated measurement.  
Secondary efficacy variables: 
All secondary variables will be analyzed on the FAS of the MP and the PPS. All tests will be 
descriptive and interpreted in an explorative manner. Treatment comparisons will be tested for 
comparison of the high versus low dose treatment group and the mid versus low dose 
treatment group, respectively. 
Ashworth scale of the UL 
The difference between treatment groups in the change from baseline in AS score for each 
treated clinical pattern (e.g., flexed elbow, flexed wrist, flexed fingers) of the UL at all other 
post-baseline visits will be analyzed by a mixed model repeated measurement analysis as 
described for the primary efficacy variable. Furthermore, descriptive summary statistics, shift 
tables and frequency tables of changes will be given. Besides the model based missing value 
imputation approach, a mixed model without repeated measures will be applied with missing 
values imputed by LOCF and observed case analyses.  
Questionnaire on Pain caused by Spasticity 
All analyses regarding the QPS will be performed separately for upper limbs and for lower 
limbs. The QPS child/adolescent score, the child/adolescent general pain intensity item, the 
QPS parent/caregiver score, and the parent/caregiver general pain frequency item will be 
analyzed by using descriptive summary statistics at all visits and for changes from baseline to 
all post-baseline visits. The child/adolescent general pain intensity item and the 
parent/caregiver general pain frequency item will additionally be analyzed by using frequency 
tables. All other single items of the QPS will be listed. 
The QPS child/adolescent score and the QPS parent/caregiver score will be analyzed by an 
ANCOVA. The dependent variable is defined as the change from baseline in the QPS score. 
The independent variables are defined as treatment group (high dose and in 2nd step mid dose 
vs. low dose), pooled sites, BoNT-A pre-treatment status (pre-treated, treatment naïve) as 
fixed factors and the covariates are the QPS score at baseline (Day 1 of MP) and the GMFCS-
E&R level at Screening Visit. LOCF as well as observed case analyses will be performed. 










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7.3 
Pharmacokinetic Variables 
Not applicable. 
7.4 
Pharmacogenetic Variables 
Not applicable. 
7.5 
Safety Variables 
All safety analyses of the MP will be performed on the SES of the MP. All safety analyses of 
the OLEX Period will be performed on the SES of the OLEX period. Analyses will be based 
on both, total population and by Main Period treatment group (high, mid, low). For this 
purpose the Main Period treatment group as treated instead of as randomized will be used. In 
the unlikely case that a subject has received mid or low dose instead of the planned high dose 
during the OLEX Period, he/she will be analyzed in total group of the OLEX tables together 
with all other subjects with the correct high dose treatment.   
For safety variables the last measurement before start of treatment is defined as baseline 
value. 
7.5.1 
Primary Safety Variable 
Not applicable. 
7.5.2 
Secondary Safety Variables 
Adverse events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA, 
version 21.0). For MP, only treatment emergent adverse events (TEAEs) of the MP will be 
analyzed, which are defined as AEs with onset or worsening on or after date and time of the 
first MP administration and before date and time of the first OLEX administration at V6. For 
subjects who do not receive an OLEX administration all AEs with onset or worsening on or 
after date and time of the first MP administration will be considered as TEAEs of MP. TEAEs 
of the OLEX are defined as AEs with onset or worsening at or after date and time of the first 
OLEX administration at V6. TEAEs will be allocated to an injection cycle x in the OLEX 
Period, if adverse events has onset or worsening on or after injection x and before injection 
x+1 (if applicable). TEAEs of the OLEX will be analyzed in total and per treatment cycle. 
Additionally TEAEs of the MP and the OLEX period will be displayed together in total.  
Only TEAEs will be analyzed. Non-TEAEs will only be listed. 
If an AE worsens between start and end of this AE it will be considered as new AE starting 
with the date of the worsening. In this case the imputation of end dates within episodes of the 


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same AE will be done by setting the end date/end time to start date/start time of the 
consecutive worsening record. 
In detail missing or partially missing start and stop dates of an AE will be imputed as follows 
for the calculation of the duration of an AE: 
• if start time is missing and start date is given and not equal to date of an injection visit, 
set start time to 00:00, else if start date is equal to date of an injection visit set start 
time to time of injection, if given (else 00:00) 
• if start date/time is completely missing and end date is before first exposure in the MP: 
no imputation 
• if start date/time is (partially) missing and end date after or equal first exposure in the 
MP or missing:  
o only start day is missing, but start month and start year same as an injection visit: 
set start day and start time to day and time of this injection visit, else set start day 
to 1 and start time to 00:00 
o start day and start month are missing, but start year is the same as year of first 
exposure in the MP: set start day, start month, start time to day, month, time of 
first exposure in the MP, else set start day and start month to 1 and start time to 
00:00 
o start date/time completely missing and end date/time not before date/time of first 
exposure in the MP, set start date/time to date/time of first exposure in the MP 
o if AE end date and time are missing set end date to study end date (i.e. last contact 
or last visit of the study) and end time to 23:59 
o if AE end date/time is partially missing, set end day to last day of the given month 
or end day/month to 31/12 of the given end year and missing end time to 23:59 
o if AE end time is missing set time to 23:59. 
 
Imputation rules for multiple records in case of AE worsening: 
• For missing AE start date/time the imputation strategies as defined above will be 
applied to all records of the same AE. 
• For missing TEAE end date/time the imputation strategies as defined above will be 
applied to the last record of the same TEAE. 
 
Calculation of time to onset/duration of AEs [days]: 
• Time to onset of an AE is defined as start date of AE - date of most recent 
administration of study drug [+ 1 for AE starting after start of treatment] 
• The duration will be calculated as stop date - onset date + 1 for each episode of 
worsening.  
Incidences will be calculated for TEAEs overall (MP+OLEX), overall OLEX and by injection 
cycle on the system organ class (SOC) level and on the preferred term (PT) level (i.e., total, 
by worst intensity, by worst relationship, and by worst outcome). Listings and, if applicable, 
tables displaying incidences for TEAEs leading to discontinuation, serious TEAEs, related 
serious TEAEs, TEAEs of special interest, and deaths will also be provided. Additionally the 
number and percentage of subjects with at least one non-serious TEAE with incidence ≥ 5% 


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in any MP treatment group or in the OLEX Period and number of non-serious TEAE will be 
displayed by SOC level and PT level. Time to onset and duration of AEs will be listed. Time 
to onset and duration of AEs will be listed. 
For any missing data of adverse events, a worst case strategy will be applied for all analysis 
tables. The intensity will be imputed by the worst intensity “severe”, the causal relationship 
will be imputed by the worst relationship “drug related”. Missing data of the worst outcome 
will be imputed by “unknown”. If a subject has more than one outcome within a preferred 
term (PT) only the worst outcome will be used in the frequency tables. Also on subject level 
only the worst outcome category per subject will be counted in the frequency table. The worst 
outcome is defined in the following order: 
• recovered/resolved  
• recovered/resolved with sequelae  
• recovering/resolving  
• not recovered/not resolved  
• unknown  
• fatal 
TEAESIs are defined as TEAEs that are thought to possibly indicate toxin spread. A list of 
adverse events of special interest possibly indicating toxin spread is given in Table 1:   
List 
of Adverse Events of Special Interest Possibly Indicating Toxin Spread. 


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Table 1:   List of Adverse Events of Special Interest Possibly Indicating Toxin Spread 
MedDRA PT 
MedDRA PT 
Accommodation disorder 
IIIrd nerve paresis 
Areflexia 
Ileus paralytic 
Aspiration 
IVth nerve paresis 
Botulism 
Monoparesis 
Bradycardia 
Muscular weakness 
Bulbar palsy 
Paralysis 
Constipation 
Paraparesis 
Cranial nerve palsies multiple 
Paresis 
Cranial nerve paralysis 
Paresis cranial nerve 
Diaphragmatic paralysis 
Peripheral nerve palsy 
Diplopia 
Peripheral paralysis 
Dry mouth 
Pelvic floor muscle weakness 
Dysarthria 
Pneumonia aspiration 
Dysphagia 
Pupillary reflex impaired 
Dysphonia 
Quadriparesis 
Dyspnoea 
Respiratory arrest 
Extraocular muscle paresis 
Respiratory depression 
Eyelid function disorder 
Respiratory failure 
Eyelid ptosis 
Speech disorder 
Facial paralysis 
Trigeminal nerve paresis 
Facial paresis 
Urinary retention 
Hemiparesis 
Vision blurred 
Hypoglossal nerve paresis 
Vocal cord paralysis 
Hyporeflexia 
Vocal cord paresis 
Hypotonia 
 
Wording of PTs is according to MedDRA version 21.0 
To fulfill FDA requirements, TEAE data will be screened for suicidal events. The MedDRA 
PTs of all TEAEs will be checked using standard MedDRA query (SMQ) „Suicide/self-
injury“.  Resulting TEAE findings will be listed in a separate listing. A list of the MedDRA 
PTs of the SMQ „Suicide/self-injury is given in Table 2. 


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Table 2: List of Adverse Events of Standard MedDRA Query „Suicide/self-injury“ 
MedDRA PT: 
MedDRA PT: 
Columbia suicide severity rating scale 
abnormal 
Self injurious behaviour 
Completed suicide 
Self-injurious ideation 
Depression suicidal 
Suicidal behaviour 
Intentional overdose  
Suicidal ideation 
Intentional self-injury 
Suicide attempt 
Poisoning deliberate 
Suicide threat 
In addition all comment fields of the case report form (CRF) and all investigator reported 
terms of TEAEs will be screened for the following terms or term elements (‘strings’) and 
listed in a separate listing: 
Table 3: List of Search Terms and Search Strings of Possibly Suicidal Events 
Term: 
Term: 
attempt 
self inflict 
cut 
self injur 
gas 
self-damage 
hang 
self-harm 
hung 
self-inflict 
jump 
self-injur 
mutilate 
shoot 
overdos 
slash 
self damage 
suic  
self harm 
 
Obvious false positive findings will be excluded from the listing (e.g., “gas” in 
“gastrointestinal” or “cut” in “acute” or in “cutaneous”). 
7.5.3 
Other Safety Variables 
Laboratory evaluations, vital signs, BMI, body weight, height, Investigator’s Global 
Assessment of Tolerability, and incidences of subjects with antibodies against BoNT-A will 
be analyzed descriptively (values and changes from baseline) and screened for individual 
notable values and/or changes. Results of the C-SSRS will be summarized descriptively. 
The following analyses will be performed for the MP data: 


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C-SSRS 
Additionally, to fulfill FDA requirements, prospective monitoring of suicidality with the C-
SSRS should be considered the most important (but not the only) source of information 
concerning suicidality. 
These C-SSRS assessments will be done in the subpopulation of subjects enrolled after 
amendment 1.0 approval only. 
Suicidality will be assessed prospectively in subjects at baseline and all post-baseline visits. 
The appropriate version of this scale ensures the consistent application of this important 
measure regardless of indication or investigator experience with the subject matter. With C-
SSRS in place, administration of this semi-structured clinician-based assessment scale is 
standardized. The C-SSRS quickly and efficiently identifies those subjects that require 
additional clinician follow up. 
Following versions of the C-SSRS are to be applied only for subjects enrolled after 
amendment approval:  
1. Children’s baseline / screening version   
2. Children’s since last visit version. 
The C-SSRS interview should only be assessed with children of respective age and cognitive 
state. Clear age cut-offs for the C-SSRS were not defined by the authors, but it has been found 
that administration is possible in general for children with a developmental age of about 7 
years. Otherwise it should be documented in the eCRF that a child was not able to assess the 
C-SSRS at a respective visit. 
The C-SSRS is based on the research and development at the Columbia University by Posner 
et al. [Posner 2007a (3)] supported by Columbia-Classification Algorithm for Suicide 
Assessment (C-CASA) developed by the same group [Posner 2007b (4)]. It is a semi-
structured clinical interview consisting of domains of suicidal ideation, suicidal behavior and 
non-suicidal self-injurious behavior, and details of actual and potential lethality. It is designed 
for personal interview administration. Subjects or Parents/Caregivers are asked directly by a 
trained clinical assessor. Clinical assessment questions are presented, and subjects provide 
their responses. These responses enable the interviewer to branch to the appropriate follow up 
questions, faithfully adhering to C-SSRS probing specifications and potential positive 
responses. This approach provides consistent assessment and documentation.  
At the end of the assessment the subject should not be released from the study center until the 
results of the C-SSRS (positive or negative) are reviewed and the subject is not considered to 
be at risk. If there is doubt about whether a subject is at risk, the Investigator should obtain 
appropriate psychiatric consultation.  


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For the sub-population of subjects enrolled after amendment approval and of respective age 
and cognitive state the following analysis will be performed. Descriptive frequency tables will 
be displayed for total sub-population and by treatment group. The number of subjects who 
experience any suicidal ideation, suicidal behavior, or self-injurious behavior without suicidal 
intent at least once at any post-baseline visit of the Main Period will be tabulated. Statistical 
evaluation of the data will be performed according to Table 1 of the Columbia–Suicide 
Severity Rating Scale Scoring and Data Analysis Guide Version 2.0 (Finalized February 
2013) [Nilsson 2013 (5)]. Baseline data and further C-SSRS data such as intensity of ideation 
and lethality data will only be listed. 
Laboratory data 
Descriptive statistics for absolute values at Screening V1 will be given for continuous 
variables. No categorical laboratory variables will be collected. Laboratory parameters will be 
sorted by predefined categories (e.g., hematology, differential count, and chemistry).  
Laboratory data, unscheduled and doubly performed laboratory data will be listed 
individually. For additionally performed laboratory measurements of certain subjects on other 
visit dates or of other laboratory parameters than planned no descriptive statistics will be 
created.  
If subjects have additional laboratory examinations during screening examination, only the 
last sample before application of study medication will be used for final analysis tables. No 
post-baseline laboratory data is planned for the MP. 
Vital signs, body weight, height, and BMI 
The individual blood pressure, heart rate, body weight, height, and BMI data will be listed and 
summarised (n, mean, standard deviation, minimum, 1st quartile, median, 3rd quartile and 
maximum) at each time point. Descriptive statistics will be given for absolute values and 
changes from baseline V2.  
Frequencies of subjects with lowered, normal, or raised values will be displayed as shift tables 
from Baseline V2 vs. Control Visits V3, V4, and Final Visit V5. 
High and low values are defined as given in Table 4. 
Table 4:  High and Low Values of Vital Signs 
Vital Sign Variable 
Flag 
Observed Value 
Systolic Blood Pressure (mmHg) 
High 
≥ 180 
Low 
≤ 90 
Diastolic Blood Pressure (mmHg) High 
≥ 105 


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Vital Sign Variable 
Flag 
Observed Value 
Low 
≤ 55 
Heart rate (bpm) 
High 
≥ 110 
Low 
≤ 50 
Height (cm) 
High 
Not applicable 
Low 
Not applicable 
Weight (kg) 
High 
Not applicable 
Low 
Not applicable 
BMI (kg/cm2) 
High 
≥ 30 
Low 
≤ 18.5 
A value is considered as high/low if it meets the criterion for observed values 
Botulinum Toxin Antibodies 
For the subset of subjects with body weight greater or equal to 21 kg, frequency tables will be 
presented for Screening V1 by category (Fluorescence Immuno Assay for antibodies (FIA-
AB)/Hemi diaphragm assay (HDA)), treatment group, pre-treatment status (treatment-
naïve/pre-treated, i.e. pre-treatment with any BTX for any indication).  
Investigator’s Global Assessment of Tolerability 
Frequency tables and descriptive statistics will be generated for the data collected at Final 
Visit V5 of the Main Period. 
The following analyses will be performed for the OLEX data: 
C-SSRS 
For the sub-population of subjects enrolled after amendment 1.0 approval and of respective 
age and cognitive state the following analysis will be performed. Descriptive frequency tables 
will be displayed for total sub-population and by MP treatment group. The number of subjects 
who experience any suicidal ideation, suicidal behavior, or self-injurious behavior without 
suicidal intent at least once at any visit of the OLEX will be tabulated. Statistical evaluation of 
the data will be performed according to Table 1 of the Columbia–Suicide Severity Rating 
Scale Scoring and Data Analysis Guide Version 2.0 (Finalized February 2013) [Nilsson 2013 
(5)]. Further C-SSRS data such as intensity of ideation and lethality data will only be listed. 


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Laboratory data 
Descriptive statistics for absolute values at the Injection Visit V6 and the End of Study Visit 
(V17) and changes from Screening V1 to V6 and to V17 will be given for continuous 
variables.  
The number of subjects with lowered, normal, or raised values compared to normal range as 
shift tables from Screening V1 vs. V6 and V1 vs. V17. Laboratory parameters will be sorted 
by predefined categories (e.g., hematology, differential count, and chemistry).  
Laboratory data, unscheduled and doubly performed laboratory data will be listed 
individually. For additionally performed laboratory measurements of certain subjects on other 
visit dates or of other laboratory parameters than planned no descriptive statistics will be 
created. If subjects have additional laboratory examinations during screening examination, 
only the last sample before treatment start will be used. The first valid value for a post-
baseline visit is analyzed. 
Vital signs, body weight, height, and BMI 
The individual blood pressure, heart rate, body weight, height, and BMI data will be listed and 
summarised (n, mean, standard deviation, minimum, 1st quartile, median, 3rd quartile and 
maximum) at each time point. Descriptive statistics will be given for absolute values and 
changes from baseline V2.  
Frequencies of subjects with lowered, normal, or raised values will be displayed as shift tables 
from Baseline V2 vs. all available OLEX period visits. 
Botulinum Toxin Antibodies 
For the subset of subjects with body weight greater or equal to 21 kg, frequency tables and 
shift tables for Screening vs. End of Study Visit (V17) will be presented by category 
(Fluorescence Immuno Assay for antibodies (FIA-AB)/Hemi diaphragm assay (HDA)), 
treatment group, pre-treatment status (treatment-naïve/pre-treated, i.e. pre-treatment with any 
BTX for any indication).  
Investigator’s Global Assessment of Tolerability 
Frequency tables and descriptive statistics will be generated for the data collected at Day 99 
(Week 14) of all OLEX cycles. 


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7.6 
Other Variables 
The analysis will be performed by MP treatment group (high, mid, low) and in total. Tables 
for the SES will be created according to the actual treatment group and tables for the FAS will 
be created for the MP treatment group as randomized. Subject dispositions, demographic data, 
GMFCS-E&R level at Screening, and baseline characteristics will be presented using standard 
descriptive statistics; no homogeneity tests will be performed. Demographic data, GMFCS-
E&R level at Screening and treatment compliance will be summarized for the SES of the MP, 
the FAS of the MP, the PPS of the MP, the SES of the OLEX, and the FAS of the OLEX. 
Demographic data and GMFCS-E&R level at Screening will be given for all randomized 
subjects in addition. The remaining baseline data such as CP history (including main cause for 
cerebral palsy, affected limbs, duration since first diagnosis of spasticity, and duration since 
the first diagnosis of cerebral palsy), primary clinical pattern,  planned treatment of spasticity, 
BoNT-A pre-treatment status at screening and use of local anesthesia/analgosedation for 
injection treatments will be summarized descriptively only for the FAS of the MP, the PPS of 
the MP, and the FAS of the OLEX (AS scores at baseline will be displayed in the efficacy 
section 14.2.). The information, if monitoring was done during sedation of subjects will be 
listed. Injection guidance technique will be listed for each treated clinical pattern.  
The absolute and relative frequencies for subject’s reason for premature study discontinuation 
will be tabulated. Further, the main reason will be tabulated by using the following approach 
for identification: chose from the reasons that are documented for a subject that one that 
occurs first in the list as main reason. The list is as follows: 
1. Death 
2. Pregnancy  
3. Adverse Event(s) 
4. Lack of efficacy 
5. Withdrawal by subject 
6. Physician decision  
7. Protocol violation  
8. Lost to follow-up 
9. Other  
 
The analysis of BoNT-A pre-treatment status includes frequency tables for:  
• number pre-treated/naïve subjects 
• Botulinum Toxin preparations used since first treatment 
• Botulinum Toxin preparation used at most recent injection session 
• specification of limbs and body side of the most recent pre-treatment  
 
and descriptive summary statistics for: 
• number of pre-treatments 


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• duration since first treatment with Botulinum Toxin 
• duration since most recent injection session prior to study entry 
• total body dose of Botulinum Toxin at most recent injection session 
With respect to pre-treatment with Botulinum Toxin the following durations will be 
calculated:  
• Duration since first treatment with Botulinum Toxin [months] = (date of first injection 
(V2) – date of first treatment with Botulinum Toxin) + 1 / 30.5 
• Duration since most recent injection session prior to study entry [months] = (date of 
first injection (V2) – date of most recent injection session prior to study entry) + 1 / 
30.5 
In case of missing days, the date will be set to the first day of the respective month. In case 
the month is also missing, no imputation will be done and the duration will be defined as 
missing.  
The duration since the first diagnosis of spasticity and the duration since the first diagnosis of 
cerebral palsy in months will be calculated as follows:  
• Duration since diagnosis [months] = (data of first injection (V2) - date of first 
diagnosis) + 1/ 30.5 
In case of missing days, the date will be set to the first day of the respective month. In case 
the month is also missing, no imputation will be done and the duration will be defined as 
missing.  
Regarding planned treatment of spasticity frequency tables will be created for treatment 
combinations A, B, C, D, and E, limbs planned to be treated (lower limb right, lower limb 
left, upper limb right, and upper limb left), and primary body side chosen for analyses.  
Treatment compliance for each injection visit (V2, V6, V10, and V14) will be calculated as 
follows: 
• Total Compliance per injection cycle [%] = 100 * Total volume injected in all 4 limbs 
[mL]/ Total planned volume for all 4 limbs according to treatment combinations A, B, 
C, D, and E and body weight. 
• Compliance per injection cycle and per limb [%] = 100 * Total volume injected in 
limb [mL]/ Total planned volume for limb according to treatment combinations A, B, 
C, D, and E and body weight.# 
For the overall OLEX Period the following is calculated in addition: 


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• Total compliance of the OLEX Period is calculated as mean compliance per subject 
for all performed injection cycles of this subject in the OLEX Period. 
Treatment compliance will be displayed using descriptive summary statistics and frequency 
table for classified compliance per injection visit, primary body/non-primary body side, 
upper/lower limb(s) in total for these categories. Separate listings will be given for all subjects 
with total treatment compliance per cycle >100% for the SES of the MP and for the SES of 
the OLEX period. 
Frequencies of previous and concomitant treatments of the MP will be given based on 
different Anatomical Therapeutic Chemical classification (ATC) code levels of the World 
Health Organization (WHO) dictionary version MAR 2018 as well as by generic name for the 
SES of the MP, the FAS of the MP, and the PPS of the MP. Frequencies of concomitant 
treatments of the OLEX period will be given based on different ATC code levels as well as by 
generic name for the SES of the OLEX and the FAS of the OLEX. Indications for previous 
and concomitant therapies will not be coded and will only be listed. Medical history and 
concomitant diseases well as non-drug treatment of the MP will be described based on 
MedDRA SOC and PT levels for the SES of the MP. Concomitant diseases well as non-drug 
treatment of the OLEX period will be described based on MedDRA SOC and PT levels for 
the SES of the OLEX. 
The analysis of extent of exposure, length of injection cycles and total observation period as 
described below will be performed for the SES of the MP or the SES of the OLEX period, 
respectively. 
Descriptive statistics will be generated for injected volume and injected units, number of 
injected sites. The analysis will be done per body side, clinical pattern, primary clinical target 
pattern, and per muscle including ‘total’ for each of these categories. 
Frequency tables will be given for treated limbs at each injection visit V2, V6, V10 and V14  
(lower limb right, lower limb left, upper limb right, and upper limb left). The number and 
percentage of subjects with unilateral treatment and with bilateral treatment for upper limbs 
and for lower limbs will be tabulated.  
Descriptive statistics will be generated for length of injection cycle, and the total observation 
period in weeks over the entire study, for MP and for OLEX period. Frequency tables will be 
given for classified injection cycle length by injection cycle. The following classes will be 
used: 
• < 12 weeks 
• 12 – 16 weeks 
• > 16 weeks 


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The injection visit will be regarded as start of a cycle and the day before the next injection (or 
the last available visit in case of a discontinued cycle or the last cycle) will be regarded as end 
of cycle. Length of injection cycle and observation period in weeks will be calculated as 
follows: 
• Total observation period in weeks over the entire study will be calculated as date of 
last available study visit (e.g. V17 for completers) - date of baseline visit V2 +1 day. 
• Observational period of the MP in weeks will be calculated as:  
Date of first injection in the OLEX V6 - date of baseline visit V2, if V6 is available. 
Date of last available visit of the MP (e.g. V5 for completers of the MP) - date of 
baseline visit V2 +1 day, if V6 is not available. 
• Observational period of the OLEX in weeks will be calculated as date of last available 
visit of the OLEX (e.g. V17 for completers) - date of first injection in the OLEX V6 
+1 day. 
• The injection cycle length of injection cycle (x) in weeks will be calculated as  
   - Date of injection cycle (x+1) - date of injection (x)  or 
   - Date of last available visit – date of injection (x) +1 day in case of last or 
discontinued cycle 
If injection cycle was not performed length of injection cycle will be missing. 
7.7 
Special Statistical/Analytical Issues 
7.7.1 
Discontinuations and Missing Data 
Discontinued subjects will not be replaced. 
The primary and secondary efficacy variables of the Ashworth scale score will be analyzed on 
the FAS and PPS of the MP using MMRM for accounting for missing data. The model will be 
based on the observed cases data without imputing missing values. As sensitivity analysis for 
the primary efficacy variable and for the secondary efficacy variables of the AS score an 
ANCOVA model without repeated measures will be applied. The LOCF principle will be 
followed on the FAS and PPS of the MP, i.e., the last observation (including baseline) will be 
carried forward to Week 4 and all further visits with missing values. In addition, further 
sensitivity analysis for the primary and secondary efficacy variables, the so called observed 
case analysis without missing data replacement, will be performed on the FAS and PPS of the 
MP to explore the impact of the respective missing imputation principle.  
In case of missing data in the co-primary variable these will be imputed by “0” (no change). 
Assuming a similar percentage of missing data in all three treatment arms this imputation 




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On a regular basis the DMC will evaluate safety data of this study to ascertain protection of 
subject’s safety. The DMC will be kept informed by a DMC office manager who is not 
involved in this study and located at a contract research organization. The DMC will convene 
at regular intervals to discuss and decide upon safety issues.  
Safety data will be evaluated without knowledge of efficacy data. The treatment code of an 
individual subject may be unblinded within the DMC if necessary for the safety evaluation. 
Detailed procedures for the evaluation of safety data and unblinding will be laid down in the 
DMC charter. All safety aspects with lifted blind discussed during DMC meetings will be 
provided for filing in the trial master file only after data base lock and subsequent unblinding 
of the study. 
If indicated, the DMC will advise Merz and make recommendations regarding e.g., subject’s 
withdrawals and/or study measures. Details on responsibilities and procedures to be followed 
by the DMC will be laid down in the DMC Charter. 
7.7.4 
Multiple Comparisons/Multiplicity 
Testing of the primary, co-primary and key-secondary efficacy variables will be performed in 
a 4-step approach using a hierarchical test procedure as described in section 7.1.1 and 7.1.2. If 
one of the four hierarchical tests does not yield a statistically significant result, the 
consecutive test(s) will still be performed but will be considered to be only descriptive. 
Whenever two variables are tested in one step (step 1, 2, and 4), both variables have to show 
statistically significant treatment differences in order to prove superiority over low dose 
treatment in this step. For this reason no α-adjustment for multiplicity is necessary in these 
combined tests of two variables. This four step hierarchical testing procedure ensures the 
overall type I level of 5% for the confirmatory tests.  
7.7.5 
Examination of Subgroups 
Subgroup analyses will be performed for the AS regarding treatment group, pooled sites, 
BoNT-A pre-treatment status, GMFCS-E&R level groups at Screening, AS baseline value, 
age (2-5, 6-11, 12-17 years), weight group at baseline (<25 kg, ≥ 25 kg), use of local 
anesthetics and/or analgosedation and  unilateral versus bilateral treatment. Shift tables and 
frequency tables of changes will not be presented for subgroup analyses. 
Subgroup analysis for TEAEs, related TEAEs, serious TEAEs and TEAEs of special interest 
by SOC and PT will be perform for the following subgroups: GMFCS-E&R level groups, age 
(2-5, 6-11, 12-17 years), weight group at baseline (<25 kg, ≥ 25 kg), and use of local 
anesthesia/analgosedation for injection treatment. 
The following TEAESIs will be analyzed by UL treated, LL treated, not applicable (not 
located at any treated limb): 
• Muscular weakness 


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• Monoparesis 
• Hemiparesis 
• Paralysis 
• Paralysis flaccid 
• Paraparesis 
• Paresis 
• Peripheral nerve palsy 
• Peripheral paralysis 
• Quadriparesis 
For this analysis “UL treated” means that the AE is located at an upper limb, which was 
treated. “LL treated” means that the AE is located at a lower limb, which was treated. “Not 
applicable” means that the AE is not located at any treated limb. 
For the subgroup analysis ‘use of local anesthetics and/or analgosedation’ the two following 
subgroups will be analyzed: 
• Subjects with use analgesics and/or sedatives been used during corresponding  
injection 
• Subjects without use analgesics and/or sedatives been used during corresponding  
injection 
For the subgroup analysis regarding ‘unilateral versus bilateral treatment’ the following 
subgroups will be defined for analysis of the AS score of the ULs:  
• Unilateral treatment of the upper limbs (Treatment combination A if unilateral, B, C 
and D) 
• Bilateral treatment of the upper limbs (Treatment combination A if bilateral and E) 
For analysis of the AS score of the LLs the following subgroups will be analyzed: 
• Unilateral treatment of the lower limbs (Treatment combination B) 
• Bilateral treatment of the lower limbs (Treatment combination C, D and E) 


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7.7.6 
Pooling of sites 
For the purpose of the analyses sites will be pooled according to the country the site is 
located. 
8 CHANGES IN THE PLANNED ANALYSES 
The definition of the FAS of the MP and of the OLEX was changed from the CSP in the SAP. 
In the CSP the FAS of the MP is the subset in the SES of the MP for whom the primary efficacy 
variable or co-primary efficacy variable is available (i.e., all subjects who have at least an AS 
score in the clinical pattern flexed elbow or flexed wrist at baseline (Day 1) or the Investigator’s 
GICS at Day 29 (Week 4)). “for upper limb” was forgotten in the CSP, so the definition was 
changed to: The FAS of the MP is the subset in the SES of the MP for whom the primary 
efficacy variable or co-primary efficacy variable is available, i.e. all subjects who have at least 
either an AS score in the clinical pattern flexed elbow or flexed wrist at baseline (Day 1), or 
the Investigator’s GICS for upper limb at Day 29 (Week 4). This means who have only an 
Investigator’s GICS for lower limb at Day 29  and no Investigator’s GICS for upper limb at 
Day 29 and no AS score in the primary clinical pattern at baseline will be excluded from the 
FAS, since Investigator’s GICS for lower limb is no co-primary efficacy variable. 
The definition of the FAS of the OLEX was in the CSP the subset in the SES of OLEX for whom 
at least one value of the AS score in the OLEX for the primary clinical pattern flexed elbow or 
flexed wrist is available. This was changed to: The FAS is the subset of subjects in the SES of 
the OLEX for whom at least one post-baseline value of any efficacy variable in the OLEX 
is available. These means subjects without a value of the AS score in the OLEX for the primary 
clinical pattern, but who have other efficacy data in the OLEX will be included in the FAS of the 
OLEX. 
In the SAP it was added how subjects will be analyzed who were not treated according to the 
randomization list or who have been treated with MP medication in the OLEX (see section 5). 
AS: 
The definition of the secondary efficacy variable change from baseline in AS score for each 
treated clinical pattern (e.g., flexed elbow, flexed wrist, clenched fist, etc.) of the UL at all 
other post baseline visits of MP was made more precise in the SAP. “etc.” was changed to 
“pronated forearm and thumb in palm” to make it more clear that all treated upper limb 
patterns are meant. 
AS score of each treated LL pattern will be analysis using descriptive summary statistics for 
absolute values and changes from baseline only, since the LL patterns will be treated with a 
different dose for all subjects. One-sample t-test and one-sample Wilcoxon signed-rank test 
have been added to the planned analysis of the AS score of the OLEX Period.  




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Other efficacy variables: 
For other efficacy variables in the SAP the visit numbers were added and the variables were 
given in more detail than in the protocol.  
Further other variables: 
Planned treatment of spasticity, treatment compliance, monitoring during sedation, injection 
guidance technique, length of injection cycle, and extent of exposure were added to other 
variables.  
Safety variables: 
The secondary efficacy variable occurrence of TEAEs by final outcome in the CSP was 
changed to occurrence of TEAEs by worst outcome in the SAP. Usually final outcome is the 
same was worst outcome. But it may occur that a subject has two different TEAE at two 
different time points, which are coded with the same PT (e.g. left leg broken and right leg 
broken). Then it is more important to know the worst outcome of both TEAEs than only the 
outcome of the second TEAE. 
TEAE data and all CRF comments will be screened for possibly suicidal events.  For this 
purpose to additional listing will be generated (see section 7.5.2). 
Additionally, to fulfill FDA requirements, only for subjects of respective age and cognitive 
state enrolled after amendment 1 approval, prospective assessments for suicidality using the 
C-SSRS assessments have to be applied.  
 
 
 


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9 REFERENCES 
1. Childers MK, Brashear A, Jozefczyk P, Reding M, Alexander D, Good D, et al. Dose-
dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in
patients after a stroke. Archives of physical medicine and rehabilitation. 2004;85(7):1063-
1069.
2. Yablon SA, Brin MF, Vandenburgh AM, Zhou J, Garabedian-Ruffalo SM, Abu-Shakra S,
et al. Dose response with onabotulinumtoxinA for post-stroke spasticity: A pooled data
analysis. Movement disorders : official journal of the Movement Disorder Society.
2011;26(2):209-215.
3. Posner, K, Brent D, Lucas C, et al. Columbia-Suicide Severity Rating Scale (C-SSRS)
Baseline, Vers. 1/14/09. 2007a.
4. Posner, K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007b;164(7):1035-43.
5. Nilsson, ME, Suryawanshi, S, Gassmann-Mayer, C, Dubrava, S, McSorley, P, and Jiang,
K. Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide. 2013. p. 1-13.