Conditions: Chronic Troublesome Sialorrhea Cerebral Palsy Stroke Traumatic Brain Injury Intellectual Disability
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 256
Healthy volunteers: no

Brief summary:
The objective of this study is to investigate the efficacy and safety of NT 201 compared with placebo for the treatment of chronic troublesome sialorrhea associated with neurological disorders (e.g. cerebral palsy, traumatic brain injury) and/or intellectual disability in children and adolescents naïve to Botulinum neurotoxin treatment and aged 2-17 years.

Detailed description:

Arms:
arm 1: Participants will receive placebo via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. Volumes will be matched to the volumes of NT 201 (incobotulinumtoxinA; Xeomin) injected in the experimental arm. arm 2: Participants will receive NT 201 (up to 2.5 Units per kilogram \[U/kg\] body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. arm 3: Participants will receive NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands in one injection session on Day 1 (Visit 2) of the MP, followed by an observation period of 16 weeks. arm 4: Participants will receive NT 201 (up to 2.5 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total). This arm will consist of participants who will participate in MP arms "Double-blind, MP: placebo (age 6 to 17 years)" and "Double-blind, MP: NT 201 (age 6 to 17 years)". arm 5: Participants will receive NT 201 (about 1.5-2 U/kg body weight) via bilateral intraglandular injection into the parotid and submandibular glands on Day 1 of second (Visit 6), third (Visit 10), and fourth (Visit 14) injection cycle of the OLEX, followed by an observation period of 16 weeks each (48 weeks in total).

Interventions: intervention 1: NT 201 Placebo intervention 2: NT 201
Intervention descriptions: intervention 1: NT 201 placebo matching injection. intervention 2: NT 201 injection.

Protocol document:
Prot_001.pdf: 
Merz Phamiaceuticals GmbH 
MRZ60201 3091 1 
NCT02270736, redacted version v1.0, 09Nov2020
SOP/245/EN - CLINICAL STUDY PROTOCOL 
Version 2.0 Version 16-JUN-2016 
Prospective, randomized, double-blind, placebo-controlled, 
parallel-group, multicenter study with an open-label extension 
period to investigate the efficacy and safety of NT 201 in the 
treatment of children and adolescents (2-17 years) with chronic 
troublesome sialorrhea associated with neurological disorders, 
and/or intellectual disability 
Development phase: 
Study identifier 
EudraCT Number 
IND Number 
Acronym 
Date of original clinical study 
protocol and all previous 
amendments: 
Indication: 
Planned study period: 
Investigational product: 
Sponsor: 
Responsible for the clinical 
study protocol content at the 
sponsor: 
Phase 3 
MRZ60201 3091 1 
-
-
2013-004532-30 
112,731 
SIPEXI Sialonhea Pediatl'ic Xeomin Investigation 
Final protocol version 1.0 (17-JUL-2014) 
Previous amendment 1 version 1.0 (24-APR-2015) 
was erroneous and not submitted. 
Previous amendment 1 version 2.0 (04-MA Y-2015) 
approved and executed. 
Chronic troublesome sialonhea associated with 
neurological disorders ( e.g. cerebral palsy, traumatic 
brain injmy), and/or intellectual disability in children 
and adolescents aged 2-17 years 
1st quarter 2015 to 2nd quaiier 2019 
NT 201 100 units, powder for solution for injection 
(active ingredient: NT 101, Botulinum neurotoxin 
type A free from complexing proteins; USAN 
'incobotulinumtoxin A') 
Merz Phaimaceuticals GmbH 
Eckenheimer Landstr. 100 
60318 Frankfurt/Main Ge1many 
Telephone: 
+49 69 1503 0 
Telefax: 
+49 69 1503 200 
Medical expe1i: 
Biostatistician: 
Clinical study manager: 
CONFIDENTIAL AND PROPRIETARY 
The contents of this document are confidential and proprietruy to Merz Phannaceuticals 
Unauthorized use, disclosw-e 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 Phannaceuticals. 
CONFIDENTIAL 
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Statement of Compliance 
Investigational Sites 
I have thoroughly read and reviewed this clinical study protocol. I understand the 
requirements and conditions of the clinical study protocol, I agree to perform the clinical 
study with accuracy and integrity according to this clinical study protocol, the case report 
form, ICH-GCP principles, the Declaration of Helsinki, regulatory authority requirements 
and those listed in the ethics section of this protocol (Section 3.2). 
I have received the current investigator’s brochure. Having been adequately informed 
about the development of the investigational product to date, I also agree to: 
• Sign and date this clinical study protocol before the study formally starts. 
• Wait until I have received written approval from the appropriate IEC/IRB before 
enrolling any subject (child participant) in this study. 
• Obtain written informed consent from the parent(s) / legal guardian(s) before any 
study-related action is performed, and to obtain written and/or oral assent from the 
children wherever possible. (This will depend on their mental capacity to understand 
about the study requirements and whether or not they can clearly express their wish to 
participate or not.) 
• Start the study only after all legal requirements in my country have been fulfilled. 
• Permit study-related monitoring, audits, IEC/IRB review, and regulatory inspections. 
• Provide direct access to all study-related records, source documents, and subject files 
for the monitor, auditor, IEC/IRB, or regulatory authority upon request. 
• Notify study sponsor as soon as possible after notification of potential Food and Drug 
Administration [FDA], European Medicines Agency [EMA] or other audit. 
• Notify the appropriate IEC/IRB on serious adverse events [SAEs] in a timely manner 
according to local requirements (if applicable). 
• Use the investigational product and all study materials only as specified in the clinical 
study protocol. 
• Report to the responsible drug safety officer, within 24 hours, any adverse event [AE] 
that is serious, and of any AE of special interest [AESI], whether considered 
treatment-related or not. 
• Before initiating the study, I will provide the sponsor with a written disclosure of any 
financial interest in accordance with 21 CRF Part 54 and a signed FDA 1572 form 
according to 21 CFR Part 312. 


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Furthermore, I understand that: 
• Changes to the clinical study protocol must be made in the form of an amendment 
that has the prior written approval of Merz and – as applicable – of the 
appropriate IEC/IRB and regulatory authority.  
• The content of the clinical study protocol is strictly confidential, and both the 
protocol and all study-related materials are proprietary to Merz.  
• Any deviation from the clinical study protocol may lead to early termination of 
the study site.  
I confirm that: 
• I have the experience and up-to-date training in ICH/GCP, ethical issues and 
study-related procedures necessary to ensure the safety and well-being of 
vulnerable children and their families.  
 
 
 
 
Principal investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
 
 
 
 
Investigator 
Date 
 
Signature 
 
 
 
 
 
 
 
Print Name 
Stamp of investigation site:  


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Lis t of Abbreviations  and Definitions  of Terms  
AE 
Adverse event 
AESI 
Adverse event of special interest 
ANCOVA 
Analysis of covariance 
BMI 
Body mass index 
BoNT 
Botulinum neurotoxin 
BP 
Blood pressure 
BW 
Body weight 
CP 
Cerebral palsy 
CRO 
Contract research organization 
C-CASA 
Columbia-Classification Algorithm for Suicide Assessment  
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
DSFS 
Drooling Severity and Frequency Scale 
eCRF 
Electronic case report form 
EDTA 
Ethylene diamine tetra-acetic acid 
EMA 
European Medicines Agency 
EudraCT 
European clinical trial database 
FAS 
Full analysis set 
FDA 
Food and Drug Administration, USA 
GCP 
Good Clinical Practice  
GICS 
Global Impression of Change Scale 
FIA 
Fluorescence immunoassay 
FIA-AB 
Fluorescence immunoassay detecting antibodies 
GMFCS 
Gross Motor Function Classification System 
HDA 
Hemidiaphragm assay 
HR 
Heart rate 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonization 
ID 
Intellectual disability 
IEC 
Independent ethics committee  
IND number 
Investigational new drug number (issued by the FDA) 


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IP 
Investigational Product 
IRB 
Institutional review board  
ISF 
Investigator’s site file 
IU 
International unit(s) 
IWRS 
Interactive Web Response System 
LDU/kg 
Lethal dose units per kilogram 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measurement 
MRZ 
Merz 
mTDS 
Modified Teacher’s Drooling Scale 
N 
Number 
OLEX 
Open-label extension 
PIP 
Pediatric Investigation Plan 
PPS 
Per protocol set 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SES 
Safety evaluation set 
SOP 
Standard operating procedure 
TBV 
Total blood volume 
TEAE 
Treatment emergent adverse event 
TEAESI 
Treatment emergent adverse event of special interest 
TESAE 
Treatment emergent serious adverse event 
U 
Unit(s) 
USAN 
United States Adopted Name 
uSFR 
Unstimulated Salivary Flow Rate 
V 
Visit (number) 


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Parent(s) In this protocol, the term parent(s) is used for any legally acceptable 
representative(s) including guardian(s), 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. Note that where both parents have responsibility for the subject, 
both will be required to sign all documents where the parent's/parents' 
signature(s) is/are needed.  
Carer 
In this protocol, the term “carer” designates the person who spends the greatest 
amount of time with the subject and is in a responsible position for attending to 
and caring for the subject.  This will often be a parent, but in some situations it 
may alternatively be a nurse, a day-care attendant or a day-care-center staff 
member with special responsibility for the subject. 


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Table of Contents  
1 
SYNOPSIS .................................................................................................................13 
2 
STUDY ADMINISTRATIVE STRUCTURE ........................................................21 
2.1 
Internal responsibilities ..........................................................................................21 
2.2 
External responsibilities .........................................................................................22 
2.3 
Committees ............................................................................................................24 
3 
ETHICS .....................................................................................................................25 
3.1 
Independent Ethics Committee / Institutional Review Board................................25 
3.2 
Ethical conduct of the study – general issues ........................................................25 
3.3 
Subject information and informed consent, assent and dissent .............................25 
3.3.1 
Subject information ..........................................................................................25 
3.3.2 
Informed consent/assent...................................................................................26 
3.3.3 
Subject card ......................................................................................................27 
3.3.4 
Post-study treatment.........................................................................................28 
3.3.5 
Subject privacy.................................................................................................28 
3.3.6 
Contact point ....................................................................................................28 
3.4 
Insurance ................................................................................................................28 
3.5 
Financing................................................................................................................29 
4 
INTRODUCTION ....................................................................................................30 
4.1 
Study background ..................................................................................................30 
4.1.1 
Disease background .........................................................................................30 
4.1.2 
Botulinum toxin in sialorrhea ..........................................................................31 
4.1.3 
Toxicological information ...............................................................................33 
4.2 
Study rationale .......................................................................................................34 
4.3 
Risk-benefit assessment .........................................................................................36 
5 
STUDY OBJECTIVES ............................................................................................40 
6 
INVESTIGATIONAL PLAN ..................................................................................41 
6.1 
Overall study design ..............................................................................................41 
6.1.1 
Summary of design ..........................................................................................41 
6.1.2 
Number and time points of scheduled visits ....................................................41 
6.1.3 
End of study .....................................................................................................42 
6.1.4 
Study flow chart ...............................................................................................43 
6.2 
Discussion of study design, including choice of control groups ...........................43 
6.3 
Recruitment strategy ..............................................................................................45 
7 
STUDY POPULATION ...........................................................................................48 
7.1 
Selection of study population.................................................................................48 
7.2 
Inclusion criteria ....................................................................................................48 


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7.3 
Exclusion criteria ...................................................................................................49 
7.4 
Eligibility criteria for continued treatment in the extension period .......................52 
7.5 
Removal of subjects from treatment or assessment ...............................................53 
7.5.1 
Discontinuation of subject’s study participation..............................................53 
7.5.2 
Premature termination or suspension of the study or a study site ....................54 
7.5.3 
Provision of care for subjects after leaving the study ......................................55 
8 
TREATMENTS ........................................................................................................56 
8.1 
Investigational products .........................................................................................56 
8.1.1 
Description of investigational products ...........................................................56 
8.1.1.1 
Instructions for preparation .......................................................................56 
8.1.1.2 
Instructions for administration ..................................................................57 
8.1.2 
Packaging and labeling ....................................................................................58 
8.1.3 
Storage of investigational product ...................................................................59 
8.1.4 
Accountability for investigational product ......................................................59 
8.1.5 
Destruction of investigational product .............................................................60 
8.2 
Treatments administered ........................................................................................60 
8.2.1 
Methods of assigning subjects to treatment groups .........................................60 
8.2.2 
Selection of doses in the study .........................................................................61 
8.2.3 
Selection and timing of doses for each subject ................................................62 
8.2.4 
Duration of treatment per subject ....................................................................64 
8.2.5 
Treatment compliance ......................................................................................64 
8.2.6 
Treatment of overdose .....................................................................................64 
8.3 
Previous and concomitant therapies.......................................................................65 
8.4 
Restrictions during the study .................................................................................66 
8.5 
Blinding..................................................................................................................67 
8.5.1 
Emergency envelopes ......................................................................................67 
8.5.2 
Unblinding procedures .....................................................................................67 
9 
STUDY ASSESSMENTS AND VISIT SCHEDULE ............................................69 
9.1 
Assessments ...........................................................................................................69 
9.1.1 
Clinical evaluations ..........................................................................................69 
9.1.1.1 
General assessments and screening...........................................................69 
9.1.1.2 
Efficacy assessments ..................................................................................69 
9.1.1.3 
Safety assessments .....................................................................................70 
9.1.2 
Laboratory evaluations.....................................................................................71 
9.1.2.1 
Clinical and research laboratory evaluations ...........................................71 
9.1.2.2 
Clinical chemistry, hematology and pregnancy tests ................................71 
9.1.2.3 
Antibodies against Botulinum toxin ...........................................................72 
9.1.3 
Pharmacodynamics ..........................................................................................73 
9.1.4 
Pharmacokinetics .............................................................................................73 
9.1.5 
Pharmacogenetics ............................................................................................73 
9.1.6 
Table of blood volume .....................................................................................73 
9.1.7 
Specimen preparation, handling, storage, and shipping ..................................75 
9.2 
Visit schedule .........................................................................................................75 


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10 SAFETY ASSESSMENTS .......................................................................................78 
10.1 
Definition of an adverse event ...............................................................................78 
10.1.1 
Definition of intensity ......................................................................................79 
10.1.2 
Definition of causal relationship with investigational product ........................80 
10.1.3 
Categories of actions taken and outcome .........................................................80 
10.2 
Definition of a serious adverse event .....................................................................80 
10.3 
Adverse events of special interest (alert terms) .....................................................82 
10.4 
Expected adverse events ........................................................................................83 
10.5 
Unexpected adverse events ....................................................................................83 
10.6 
Pregnancy ...............................................................................................................84 
10.7 
Other safety assessments........................................................................................84 
11 DATA QUALITY ASSURANCE ............................................................................86 
11.1 
Standardization procedures ....................................................................................86 
11.2 
Source documentation requirements ......................................................................86 
11.3 
Data management...................................................................................................87 
11.4 
Monitoring .............................................................................................................88 
11.5 
Auditing .................................................................................................................88 
12 STATISTICAL METHODS ....................................................................................90 
12.1 
Determination of sample size .................................................................................90 
12.1.1 
Safety ...............................................................................................................90 
12.1.2 
Efficacy ............................................................................................................91 
12.2 
Analysis sets...........................................................................................................91 
12.3 
Variables for analysis .............................................................................................92 
12.3.1 
Efficacy variables.............................................................................................92 
12.3.1.1 
Primary efficacy variables .........................................................................92 
12.3.1.2 
Secondary efficacy variables .....................................................................92 
12.3.2 
Pharmacodynamic variables ............................................................................94 
12.3.3 
Pharmacokinetic variables ...............................................................................94 
12.3.4 
Pharmacogenetic variables ...............................................................................94 
12.3.5 
Safety variables ................................................................................................94 
12.3.5.1 
Primary safety variable..............................................................................94 
12.3.5.2 
Secondary safety variables ........................................................................94 
12.3.5.3 
Other safety variables ................................................................................95 
12.3.6 
Other variables .................................................................................................95 
12.4 
Statistical analysis methods ...................................................................................95 
12.4.1 
Efficacy variables.............................................................................................95 
12.4.1.1 
Primary efficacy variables .........................................................................96 
12.4.1.2 
Secondary efficacy variables .....................................................................96 
12.4.2 
Pharmacodynamic variables ............................................................................97 
12.4.3 
Pharmacokinetic variables ...............................................................................97 


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12.4.4 
Pharmacogenetic variables ...............................................................................97 
12.4.5 
Safety variables ................................................................................................97 
12.4.6 
Other variables .................................................................................................98 
12.4.7 
Special statistical/analytical issues ..................................................................98 
12.4.7.1 
Discontinuations and missing data ............................................................98 
12.4.7.2 
Interim analyses .........................................................................................99 
12.4.7.3 
Committees .................................................................................................99 
12.4.7.4 
Multiple comparisons/multiplicity ...........................................................100 
12.4.7.5 
Examination of subgroups .......................................................................100 
13 DATA HANDLING AND RECORD-KEEPING ................................................101 
13.1 
Corrections to data ...............................................................................................101 
13.2 
Record-keeping ....................................................................................................101 
13.3 
Destruction of study documents...........................................................................102 
14 PUBLICATION POLICY ......................................................................................103 
15 REFERENCES .......................................................................................................104 
16 APPENDICES .........................................................................................................111 


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List of Figures 
Figure 1: Study Flow Chart................................................................................................43 
List of Tables 
Table 1: 
Overview of age groups and recruitment steps ..........................................45 
Table 2: 
Dosing scheme ...........................................................................................63 
Table 3: 
Dosing scheme with dose reduction in the third or fourth injection 
cycle ...........................................................................................................63 
Table 4: 
Standard safety laboratory values ..............................................................72 
Table 5: 
Blood volumes required .............................................................................74 
Table 6: 
Schedule of study tests, procedures and clinic visits .................................76 
Table 7: 
List of AESIs..............................................................................................83 
 


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1 SYNOPSIS 
Study title 
Prospective, randomized, double-blind, placebo-controlled, parallel-group, multi-center 
study with an open-label extension period to investigate the efficacy and safety of 
NT 201 in the treatment of children and adolescents (2–17 years) with chronic 
troublesome sialorrhea associated with neurological disorders, and/or intellectual 
disability. 
Study phase 
Phase 3 
Indication 
Chronic troublesome sialorrhea associated with neurological disorders (e.g. cerebral 
palsy, traumatic brain injury), and/or intellectual disability in children and adolescents 
aged 2–17 years. 
Study objectives 
The objective of this study is to investigate the efficacy and safety of NT 201 compared 
with placebo for the treatment of chronic troublesome sialorrhea associated with 
neurological disorders (e.g. cerebral palsy, traumatic brain injury) and/or intellectual 
disability in children and adolescents naïve to Botulinum neurotoxin treatment and aged 
2–17 years. The total dose of NT 201 ranges from minimum 20 U to maximum 75 U or 
approximately 2 U/kg body weight depending on body weight classes. Subjects with a 
body weight ≥ 30 kg will receive a fixed total dose of 75 U. In this study, treatment-naïve 
subjects are defined as those who have not received BoNT treatment for this indication 
within the last 12 months. 
Study population, diagnosis, and main criteria for inclusion and exclusion 
Male and female children and adolescents will be recruited who are suffering from 
troublesome sialorrhea due to neurological disorders, and/or intellectual disability. 
Main inclusion criteria: 
• Male or female child/adolescent age 2–17 years. 
• Any neurological disorder (e.g. cerebral palsy or traumatic brain injury) and/or 
intellectual disability associated with chronic troublesome sialorrhea for at least 3 
months up to the screening. In subjects with intellectual disability (ID) without 
neurological disorders, a diagnosis of ID by a specialist, e.g. pediatrician or by a center 
for developmental medicine is required for inclusion. 


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• Severe drooling (modified Teacher´s Drooling Scale [mTDS] ≥ 6; clothing 
occasionally becomes damp) as rated by the investigator. 
• Parental consent and the subject's oral or written assent as the subject is able to 
provide. 
Main exclusion criteria: 
• Chronic troublesome sialorrhea not related to neurological disorders and/or intellectual 
disability. 
• Body weight < 12 kg. 
• Pharmacological treatment for sialorrhea or concomitant medication known to 
influence sialorrhea strongly (e.g. anticholinergics with exception of locally applied or 
short acting drugs used under general anesthesia)  within 45 days before baseline and 
during the entire study period. 
• Any previous known or suspected hypersensitivity to Botulinum toxin. 
• Aspiration pneumonia within 6 month before screening. 
• Any previous treatment with Botulinum toxin for any body region during the year 
before screening or within the screening period 
• Prior, concomitant or planned surgery or irradiation to head and neck to control 
sialorrhea (including salivary gland surgery or salivary gland irradiation) within one 
year before screening or planned for any part of the entire study period. 
• Concurrent diseases, including hematological, hepatic, renal, gastrointestinal, 
endocrine, pulmonary, musculoskeletal, or psychiatric diseases or conditions, which in 
the judgment of the investigator would put the subject at risk while in the study, could 
influence the results of the study, or negatively impact the subject’s ability to 
participate in the study. 
• Extremely poor dental and/or oral condition that might preclude safe study 
participation by the judgment of the investigator.   
• Nursing mother or pregnant female subject. 
Study design 
Main study period: The main period of the study, comprising the screening period and 
one injection cycle (single treatment followed by 16 weeks for assessment in several 
visits to the study site) will take place for subjects aged 6–17 years according to a 
prospective, randomized, double-blind, placebo-controlled, parallel-group design, with 
active or placebo treatment (randomization ratio 2:1). Subjects aged 2–5 years will not be 
treated with placebo, but only with active treatment (NT 201) during the main period. 
The treatment will comprise four injections of NT 201 (parotid and submandibular 
glands, bilaterally); the dose is defined according to body weight (approximately 2 U/kg). 
At the end of the main period, subjects will be assessed for eligibility to enter the 
extension period. 


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Extension period: The main period will be followed by a 48-week, three-cycle extension 
period in which all subjects eligible for extension treatment will receive NT 201 (“open-
label” treatment) according to the same per-body-weight formula. Dose reduction will be 
permitted in the third and fourth cycle if relevant adverse events occur. Treatment and 
observation will be similar to that of the main study period and will be concluded with an 
end-of-study examination at the end of the fourth cycle. 
Data monitoring committee [DMC] and progressive reduction of lower age limit for 
subjects: Data will be subjected to continual review by an unblinded DMC. The first 30 
subjects (age group 10 to 17 years) will be subjected to safety review when four weeks 
elapsed since the randomization of the last subject. This will be repeated after the 
recruitment of the next 30 subjects in this age group and then of the first 30 subjects in 
the age group 6–9 years. If in the above analyses no significant risk is identified by the 
DMC, then a next cohort can be opened and finally 30 children representing the youngest 
age group (2–5 years) will be enrolled. In parallel with this, recruitment and treatment of 
subjects in the age group 10–17 years and 6–9 years will continue. Children in the 
youngest age group will not be treated with placebo, but only with active treatment 
(NT 201) during all four injection cycles. 
Planned study period 
1st quarter 2015 to 2nd quarter 2019 
Duration of treatment per subject 
Each treatment is to be followed by an observation period of 16 weeks ± 2 weeks. 
Therefore, for all subjects, the total duration of all injection cycles will be 64 weeks (with 
permitted variation, 56–72 weeks). 
Variables for analysis 
Primary efficacy variables 
For subjects aged 6–17 years the primary and co-primary variables are: 
• Change in unstimulated salivary flow rate [uSFR] from baseline to Week 4. 
• Global Impression of Change Scale [GICS] at Week 4 representing the functional 
improvement in drooling since baseline as assessed by the carer/parent(s). 
Secondary efficacy variables 
For subjects aged 6–17 years: 
• Change in uSFR from baseline to Week 8 and 12. 
• GICS at Week 8 and 12. 




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Safety variables 
Primary safety variable: 
Occurrence of treatment emergent AEs [TEAEs] overall and by injection cycle. 
Secondary safety variables: 
• Occurrence of treatment emergent AESIs [TEAESIs] overall and by injection cycle. 
• Occurrence of treatment emergent SAEs [TESAEs] overall and by injection cycle. 
• Occurrence of TEAEs related to treatment as assessed by the investigator overall and 
by injection cycle. 
• Occurrence of TEAEs leading to discontinuation overall and by injection cycle. 
Other variables: 
• Vital signs (blood pressure, heart rate, body temperature) at screening, baseline, Visits 
weeks 4 and 16, during the main period and at each injection visit in the extension 
period and at the end-of-study visit Week 64. 
• Body height and weight at screening, final visit of the main period Week 16, and the 
end-of-study visit Week 64. 
• BMI, calculated from body weight and height, at screening, final visit of the main 
period Week 16 and the end-of-study visit Week 64. 
• Clinical chemistry and hematology at screening, final visit of the main period 
Week 16, and the end-of-study visit Week 64. 
• Severity of CP will be assessed by the Gross Motor Function Classification System 
(GMFCS) at baseline  
• Results of dental and oral examination by a dentist at screening (considered as baseline 
value), in Week 4, at the final visit of the main period (week 16), at the final visit of the 
second injection cycle (week 32) and the end-of-study visit (week 64), in terms of 
adverse events: findings indicating a worsening of the subject's condition since 
screening are to be recorded as adverse events. 
• Occurrence of antibodies against Botulinum toxin A in subjects’ ≥30 kg body weight. 
• Number of subjects with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent during treatment 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 at each post-baseline site visit. 
Total number of subjects and number of countries 


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A total of 249 subjects is planned to be enrolled. Of these, at least 219 are planned to be 
enrolled in the age group of 6–17 years, who will form the analysis set for the primary 
efficacy analysis. At least 30 children in the youngest age group of 2–5 years are planned to 
be enrolled and treated on an open-label basis with active treatment only. The group of 
older children will be randomized with a randomization ratio of 2:1, i.e., 146 subjects will 
receive NT 201 and 73 will receive placebo in the main period. (Note that in the extension 
period no placebo will be administered.) 
This international study is planned to be performed in eligible investigational sites in 
European Union (EU) and outside of the EU (e.g. Poland, Hungary, Romania, Georgia, 
Turkey, Serbia, Ukraine and Russia). 
Number of study sites 
This study will be conducted in approximately 8 countries and 40 centers. The selection 
of countries and centers will be performed on the basis of the outcome of a feasibility 
survey. 
 
Number of visits 
Twenty-one study visits are planned. These will comprise: 
Screening 
Baseline (beginning of cycle 1): 7–28 days after screening 
Main period (cycle 1): 
Three assessment visits and end-of-cycle visit (final 
visit of the main period). 
Extension period (cycles 2–4): A total of 15 visits; cycles 2 and 3 to end with an end-
of-cycle visit and cycle 4 with an end-of-study visit. 
The end-of-cycle and the respective subsequent injection visits can be combined where 
appropriate. 
Investigational product, dose, and route of administration 
NT 201 (active ingredient: NT 101, Botulinum neurotoxin type A, free from complexing 
proteins, US Adopted Name incobotulinumtoxin A) or matching placebo will be provided 
in vials as a powder to be dissolved before injection. Quantities in the vials will allow 
randomized treatment with (i) NT 201 approximately 2 U/kg body weight, according to 
body weight class, or (ii) placebo, as described under “Study design” (above), under 
double-blind conditions. Subjects with a body weight ≥ 30 kg will receive a fixed total 
dose of 75 U. Note that in the extension period no placebo will be administered. 
NT 201 will be prepared for administration by mixing with physiological saline solution. 
The vials and the volumes used will be selected in such a way that the blinding is not 
compromised. 


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The investigational product will be injected bilaterally into the parotid and submandibular 
glands. 
The dose to be administered will be decided on a body-weight basis according to a 
pre-determined scheme. A single reduction due to AEs at the third and/or fourth 
administration is allowed, again according to a pre-determined scheme, if adverse events 
make this desirable. 
Statistical analysis methods 
Efficacy variables 
Efficacy analyses will be based primarily on the full analysis set [FAS] and where 
deemed sensible additionally, for sensitivity purposes, on the per-protocol set [PPS]. 
Statistical tests will be two-sided hypothesis tests for between-treatment differences in 
general. Continuous variables (values and changes from baseline) will be summarized by 
N, mean, standard deviation, median, quartiles, minimum, and maximum. For qualitative 
variables, absolute and percent frequencies (N, %) and, if applicable, shift tables will be 
displayed. Confidence limits and descriptive p values will be given where appropriate. 
Primary efficacy variables 
The primary efficacy analysis will be performed on the group of subjects within the FAS 
(age 6–17 years). A mixed model repeated measurement analysis (MMRM, 2-sided, 
significance level alpha=0.05) with comparison of least square means between NT 201 
and placebo will be used for the confirmatory analysis of the co-primary efficacy 
variables. The dependent variables will be the change in uSFR from baseline (V2) to V3 
[Week 4] and the carer's/parent's GICS at V3 [Week 4], respectively. The independent 
variables are defined as treatment group, pooled investigation sites and age groups as 
fixed factors, visit*treatment as interaction term, and visit as repeated factor. To adjust 
for the baseline status, the MMRM of the uSFR change additionally includes the baseline 
score of the uSFR as covariate. Since no baseline assessment of the GICS is available, the 
baseline mTDS rated by the parent(s)/carer is used as covariate in the MMRM model for 
the GICS. Only if both co-primary efficacy variables show a statistically significant 
difference compared to placebo the superiority of NT 201 will be considered to be 
proven. Therefore, no α-adjustment for multiple testing is necessary. Sensitivity analyses 
will be performed using the same approach on the PPS. A non-parametric Wilcoxon rank-
sum test will be performed as sensitivity analysis of the co-primary variables to investigate 
the impact of potential deviations from the assumption of normal distribution. 
Secondary efficacy variables 
Analyses of secondary efficacy variables are also based on the FAS (subjects aged 6–17 
years further specified above). The changes in uSFR from baseline to Week 8 and 12 and 
the GICS at Week 8 and 12 are analyzed analogously to the primary efficacy variables by 
means of MMRM.  








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Name 
Function 
Address 
 
Laboratory for 
Hemidiaphragm assay 
[HDA] detecting of 
neutralizing antibodies 
against BoNT-A 
 
, Germany 
Telephone: 
 
Telefax:               
 
  
 
Contract research 
organization 
(responsibility for IWRS) 
 
 
 Belgium 
Telephone: 
 
Telefax:               
 
E-mail:  
 
(Various) 
Data monitoring 
committee (Section 2.3) 
Members' names and affiliations are 
provided in a separate list (DMC charter). 
 


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2.3 
Committees 
To ensure the well-being of subjects (i.e. child/adolescent participants), safety data from 
the study will be evaluated by an independent Data Monitoring Committee [DMC] at 
predetermined points in time, and also after each recruitment step, as detailed in 
Section 6.3. These reviews will help to ensure: 
• The protection of subjects. 
• The early detection of safety signals. 
• That any safety-related recommendations necessary are made to the sponsor in a 
timely manner, for implementation as appropriate. 
• That the proposed continuation of the study is likely to be safe, ethical and 
appropriate. 
The DMC will consist of permanent members who are not associated with the sponsor or 
with the operative conduct of the study. A description of the scope of work and operating 
procedures for the DMC is provided in Section 12.4.7.3. The composition and charter of 
the DMC are provided separately. 


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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 favorable 
opinion obtained prior to study start: 
• The clinical study protocol. 
• Any amendment to the clinical study protocol that is not solely of an administrative 
nature. 
• The IB and all updates. 
• Subject information and informed consent forms, as well as questionnaires and 
updates (as applicable). 
• All subject recruitment procedures and any advertisement used to recruit subjects (if 
applicable). 
• Any other required documents. 
If applicable, and in accordance with local legal requirements, some of the above 
documents will also be submitted to the respective regulatory authority(ies) for separate 
approval. 
3.2 
Ethical conduct of the study – general issues 
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. 
This pivotal study aims to fulfill the requirements defined in the pediatric investigational 
plan [PIP] for Xeomin in sialorrhea in accordance with pediatric drug regulation 
1901/2006/EC. The currently agreed key binding elements for this protocol can be found 
on the homepage of the European Medicines Agency [EMA]. 
3.3 
Subject information and informed consent, assent and dissent 
3.3.1 
Subject information 
The term “subject” used throughout this document includes child and adolescent research 
subjects (total age span: 2–17 years inclusive). Prior to study enrollment, the subject (if 


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applicable) and/or the legally acceptable representative1 (e.g., parent(s), guardian) will be 
given full verbal and written information on the nature, objective, significance, expected 
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 will have ample opportunity to question the investigator 
(or authorized designee) about the study before giving consent, assent or dissent to study 
participation. Participation of subjects living in children’s homes and/or subjects that 
are under state custody can only be enrolled if acceptable by local legislation and 
after written approval of the respective ethics committee. 
3.3.2 
 Informed consent/assent 
As a rule, a pediatric subject is unable to provide IC. Therefore, pediatric subjects 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 subjects 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 
one 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.  
                                                          
1 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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Assent, like consent, is a continuous process and will be sought during the trial as well. 
Objections raised by a child at any time during a trial will be considered. The child’s will 
should be respected.2 
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 
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 and/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 willingness to continue participation in the study. In case 
of AEs, or poor tolerability to the IP, the subject and/or the parent(s) should inform the 
investigator, who then will make a judgment whether continuing in 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. Therefore, 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). They 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 and 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. 
                                                          
2 Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric 
Population; Recommendations of the ad hoc group for the development of implementing guidelines for 
Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal 
products for human use, February 2008 


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• A 24-hour hotline number for emergency unblinding service. 
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 or his/her parents may consult his/her physician for treatment options, and 
receive medication to reduce sialorrhea, e.g. anticholinergics or any other rehabilitation 
measure, at the investigator’s discretion. This also applies to subjects who discontinue the 
study prematurely. 
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 respective country in which 
the study is performed. 
The subject (if applicable) or parent(s) will be informed by the investigator and through 
the subject’s informed consent form about the existence of this insurance and the 
resulting obligations. The insurance conditions will be handed out to the parent(s), if 
requested 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 parent(s) is not covered by this insurance. 


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The sponsor is usually not liable for injuries/cases of death that occur solely as a 
consequence of the subject’s underlying disease or condition, or from diagnostic or 
therapeutic measures not specifically required by the 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. 
For country-specific requirements, see Section 16.1. 
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 
4.1.1 
Disease background 
Sialorrhea (or drooling) is an excess spillage of saliva over the lip margin. This is 
considered normal in infants but usually stops by 18 months of age. After three years of 
age (according to some authors four years) this is generally considered to be pathological. 
In healthy individuals a mean of 1.0–1.5 liters of saliva are secreted and swallowed each 
day. Children before puberty produce significantly less (750–900 ml per day). It is 
produced continuously, predominantly by the three pairs of major salivary glands: 
parotid, sublingual, and submandibular, and it is conducted by salivary ducts to the oral 
cavity. In an unstimulated, “resting” state, the submandibular gland contributes about 
70% to the overall salivary flow. Upon visual, mechanical or olfactory stimulation 
salivation is increased about fivefold, with the ratio varying between the three gland 
pairs. The parotid produces approximately 70% of the total stimulated salivary volume. 
Dry foods and sour (acidic) juices mechanically induce copious salivary secretion. 
Sialorrhea is usually caused by neuromuscular dysfunction (e.g., Parkinson's disease, 
stroke, cerebral palsy), hypersecretion (e.g., medication side effects, gastro-esophageal 
reflux disease) or anatomic abnormalities (e.g., macroglossia, oral incompetence, dental 
malocclusion).The etiology of sialorrhea is multifactorial. In most individuals who drool, 
intra-oral saliva management is disturbed to some extent. These individuals may 
demonstrate a variety of symptoms because of sensorimotor impairments or there may be 
anatomical abnormalities. Inadequate lip closure, habitual open-mouth posture, 
ineffective or limited tongue movements, poor co-ordination between the oral and the 
pharyngeal states of swallowing, malocclusion, flexed posture, gingivitis and dental 
caries may contribute to the origin of drooling. Additionally sialorrhea may be due to 
excessive saliva production or excessive pooling of saliva in the anterior oral cavity 
secondary to poor swallowing.  
Overall, it is estimated that in the general population up to 0.6% of children show 
clinically relevant chronic drooling [Fairhurst 2011]. 
Pediatric sialorrhea can be associated with general physical disability such as infantile 
cerebral palsy, with other neurodevelopmental disorders and/or intellectual disability 
[ID], metabolic and neurodegenerative diseases. It can also be an unspecific symptom of 
disturbed oral-motor control. The majority of children with severe drooling suffer from 
impaired tongue or bulbar control rather than from insufficient closure of the mouth or 
from hypersalivation. 
Cerebral palsy is one of the most important causes of severe drooling in children. The 
most prevalent disease in pediatric droolers, however, is quadriplegic infantile cerebral 


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palsy [CP]. In previous CP studies about 10% of a Swedish population of children with 
CP showed “embarrassing drooling” [Ekedahl 1974]. In another study moderate to severe 
drooling occurred in 10–37% of pediatric CP individuals [Van De Heyning 1980]. 
Furthermore, the prevalence of drooling was investigated in a population of children with 
CP across dental age and of the total population 33% had severe drooling and 58% some 
degree of drooling. The authors concluded that the degree of drooling decreased as the 
dental age increased [Tahmassebi 2003]. A Spanish research group evaluated 50 
individuals with CP, both children and adults and 58% of those had drooling [Morales 
Chavez 2008]. 
In conclusion, approximately every third or fourth patient with CP develops some kind of 
drooling. On the other hand, for CP as the most relevant cause of sialorrhea in children, 
the overall incidence is estimated to around 2 - 2.5 per 1,000 live births in the developed 
countries [Sätilä 2007]. In Europe, the CP incidence for the period 1980–1990 was found 
to be 2.08 per 1000 live births, ranging from 1.49–2.63 among 11 centers (post-natal 
cases excluded) [Surveillance of Cerebral Palsy in Europe 2000]. There are important 
adverse consequences of sialorrhea. These range from quality-of-life issues (such as 
social isolation) and unintelligible speech to facial skin maceration and even increased 
morbidity and mortality (dehydration, choking, aspiration, and pneumonia). The negative 
impact of sialorrhea e.g. on speaking, eating and social interaction was recently 
confirmed in a survey study with 240 patients [Daniel 2012].  
4.1.2 
Botulinum toxin in sialorrhea 
The flow of saliva is enhanced by both sympathetic and parasympathetic innervation, in 
both cases involving the neurotransmitter acetylcholine. Botulinum toxins in general 
block acetylcholinergic transmission at the neuromuscular junction and cholinergic 
synapses by inhibiting the release of acetylcholine from peripheral cholinergic nerve 
endings, and can thus suppress salivation. 
Numerous studies have demonstrated that BoNT-A and BoNT-B are effective and safe 
for the reduction of sialorrhea in children and adult patients [Alrefai 2009, Costa 2008, 
Intiso 2012, Jackson 2009, Lagalla 2009, Lin 2008, Lipp 2003, Nordgarden 2012, 
Reddihough 2010, Reid 2008, Schroeder 2012, Wilken 2008, Wu 2011]. The treated 
salivary glands (parotid and submandibular glands) and the doses injected into salivary 
glands are variable, depending on the type and the preparation of BoNT used. The mean 
global doses injected into salivary glands in adult patients ranged from 55 U to 200 U 
(Botox®) [Lagalla 2006, Porta 2001] and from 250 U to 450 U (Dysport®) [Mancini 
2003, Nobrega 2007] for BoNT-A and from 2500 U to 4000 U for BoNT-B [Jackson 
2009, Lagalla 2009, Ondo 2004]. A recent research study comparing the two toxins in 
controlling sialorrhea of ALS and Parkinson patients reported that either 250 U BoNT-A 
(Dysport®) or 2500 U BoNT-B (Neurobloc®) have similar effectiveness and safety 
[Guidubaldi 2011]. 
In children with cerebral palsy, seven studies [Alrefai 2009, Lin 2008, Nordgarden 2012, 
Reid 2008, Schroeder 2012, Wilken 2008, Wu 2011]  examined the efficacy and safety of 


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BoNT-A or BoNT-B in a randomized, controlled design. Control groups were treated 
either with placebo [Alrefai 2009, Lin 2008, Nordgarden 2012, Wu 2011] or remained 
untreated [Reid 2008], or received BoNT-B [Schroeder 2012, Wilken 2008]. The mean 
doses injected in children's parotid and submandibular glands ranged from 30 U to 100 U 
with Botox® (on average ranging 2–4 U/kg body weight) and 140 U with Dysport®. In 
two studies BoNT-B was used as comparator with the total dose of 2383 U [Schroeder 
2012] and an average dose of 120 U/kg body weight [Wilken 2008]. 
Several uncontrolled, retrospective, or controlled but open-label studies have also been 
performed [Banerjee 2006, Basciani 2011, Bothwell 2002, Ciftci 2013, Erasmus 2012, 
Erasmus 2010, García Ron 2012, Hassin-Baer 2005, Jeung 2012, Jongerius 2004a, 
Kaufman 1995, Khan 2011, Lee 2011, Ong 2009, Reid 2013, Savarese 2004, Scheffer 
2010, Suskind 2002]. In these, a wider range of total doses was used (10 U to 300 U 
Botox®) than in the controlled studies, making the comparison of efficacy and safety 
results more difficult. 
Across published trials, intraglandular injections were administered using a wide 
spectrum of strategies according to the clinician’s experience: single versus multiple 
injection points, both glands treated versus only one, same dose for both the parotid and 
submandibular glands versus different doses, and anatomic landmarks versus ultrasound 
guidance. 
The efficacy analyses of these studies reflect the various objective measures (e.g. saliva 
collection by a cap, cotton rolls, gauze pads, bibs) and/or subjective measures (e.g. Visual 
analogue scale, Drooling Severity and Frequency Scale, Drooling Impact Scale, 
 
. 
Overall, the majority of children responded positively to BoNT-A. With higher doses 
(above 2.5U /kg body weight) reduction of sialorrhea could be achieved two weeks after 
injection, and maximum response was observed one month after treatment [Reid 2008], 
with a positive effect lasting about three to four months in most children. In one study, 
83% of the children treated showed a good response to BoNT-A after the first injection 
[Wilken 2008]. In subjects treated with moderate doses (1.3–2.5 U/kg body weight) the 
salivary flow rate could be decreased significantly in comparison with control [Wu 
2011], and DQs were substantially reduced [Erasmus 2010]. Others report 53% marked 
improvement – as seen by visual analogue scale [VAS], number of bibs used per day, and 
weight of dental rolls – and in 11% no response [Savarese 2004]. Subjects treated with 
rather lower doses (1.3 U/kg body weight or less) showed either no significant reduction 
or around 40% response rate within one month after treatment [Ciftci 2013, Hassin-Baer 
2005]. 
The long-term effect of BoNT was not tested in the above-mentioned studies, and the 
maximum duration covered only two injection cycles. None of the studies were 
sufficiently powered to show significant and clinically relevant treatment effects or 
measurable difference compared with placebo-treated subjects, and therefore the 
information gathered from these trials did not reach the evidence level necessary for the 
market approval of BoNT-A for the indication sialorrhea in children or adults. 


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4.1.3 
Toxicological information 
Several studies have investigated the potential clinical improvement in drooling after the 
injection of Botulinum toxin type A (BoNT-A). In contrast, only some studies have 
investigated histological changes of the salivary glands caused by BoNT-A injection. In 
one study, BoNT-A was injected into rat submandibular salivary glands and the resulting 
change in structure and function was monitored. Atrophy of glandular cells, decreased 
size of acinar cells, and reduced granules in acinar cells were observed on histological 
examination [Teymoortash 2007]. Another study reported salivary gland shrinkage 
following the injection of BoNT-A into rat salivary glands without histopathological 
changes [Coskun 2007]. Animal studies in rabbits did not reveal any histological changes 
three months after 8 U of BoNT-A administration [Gerlinger 2007]. 
To support the injection of NT 201 into the salivary glands in humans, a chronic toxicity 
study has been performed in the Sprague-Dawley rat to determine the toxicity of NT 201 
following four intra-glandular administrations to the left submandibular salivary gland at 
eight week intervals at doses of 0, 2, 10 and 40 LDU/kg and to evaluate the possible 
regression of any toxic signs during an eight week treatment-free period. 
Treatment-related mortality occurred at the dose level of 40 LDU/kg in ten males and 
five females which were found dead or killed moribund a few days after the second, third 
or fourth injection. Severe clinical signs (noisy/labored breathing, subdued 
behavior/decreased activity, pilo-erection, slight hypersalivation and red-stained fur) 
were noted before death or sacrifice. After the histopathological examination, the cause 
of death or moribund status was considered to be acute bronchopneumonia with presence 
of alveolar foreign materials. This was probably a consequence of muscular dysfunction 
in the region surrounding the pharynx/larynx, resulting in inhalation of material from the 
oral cavity. 
Clinical signs such as noisy breathing and red-stained fur were noted mainly during the 
two weeks following the second to fourth injections in a few surviving animals treated at 
40 LDU/kg by the intraglandular route. No relevant clinical signs were seen in animals 
treated at a level of 2 or 10 LDU/kg. 
A severely reduced food consumption and marked body weight loss were noted in the 
week following each injection in animals at 40 LDU/kg, leading to a reduced body 
weight gain throughout the treatment period, partially reversible at the end of the 
treatment-free period. Similar, but by far less marked, changes in body weight and food 
consumption were noted in animals given 10 LDU/kg; these recovered by the next 
injection. Body weight development at 2 LDU/kg was comparable to that in controls. 
Changes in clinical pathology variables were observed throughout the study period; these 
changes were considered to be associated with the reduced food consumption and low 
body weight of the animals, and the changes resolved by the end of the treatment-free 
period. 


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Mean amylase serum activity was slightly lower than controls at all dose levels from the 
second injection; this was considered to be associated with the pharmacological effect of 
the test item. 
Mean weights of the left (injected) mandibular salivary gland were lower than controls 
and also lower compared with the weights of the respective contralateral gland in all 
treated groups. Histopathologically, a treatment-related multifocal acinar atrophy was 
observed in the left mandibular salivary gland in some animals receiving 40 LDU/kg, 
accounting for the slightly lower weight of the gland. These treatment-related changes in 
mandibular glands were probably related to the pharmacological action of NT 201. At the 
end of the eight week treatment-free period, the mean weight of the left mandibular gland 
was still slightly lower than that of controls and the right mandibular gland. 
Consequently, under the experimental conditions of this study, the ‘no observed adverse 
effect’ level was concluded to be 10 LDU/kg. This is around four times the maximum 
intended clinical dose in the indication with children (2.5 U/kg) or five times the average 
intended dose in children in this study (2.0 U/kg). 
4.2 
Study rationale 
Merz has initiated a clinical development program for bilateral intraglandular injection of 
incobotulinumtoxin A (NT 201; Xeomin®) into the parotid and submandibular salivary 
glands for the treatment of chronic troublesome sialorrhea in adult and pediatric patients. 
This pivotal phase 3 study will serve to investigate the efficacy and safety of NT 201 in 
children and adolescents with chronic troublesome sialorrhea. The study has been 
discussed and acknowledged by the EMA's Pediatric Committee as the pivotal study of 
the Xeomin PIP for sialorrhea and aims to fulfill the requirements of the pediatric drug 
regulation of the EU (see Section 16.1). The results of this study will enlarge the data 
base of clinical studies with BoNT-A treatment for sialorrhea of neurological origin and 
improve the low-level evidence [Vashishta 2013] for efficacy and safety of repeat-dose 
treatment of BoNT-A. This monitored, placebo-controlled, randomized clinical study will 
observe the treated subjects following the PIP and in accordance with a high scientific 
standard, with ICH GCP, and with all local laws and regulations. 
Troublesome sialorrhea can have several different causes, including being a chronic 
symptom of neurological diseases (e.g. cerebral palsy). Sialorrhea may require 
continuous treatment to improve functioning and quality of life for patients. Symptomatic 
therapies for sialorrhea include long-term repeated treatment with BoNT-A or BoNT-B 
as an established off-label therapy [Reddihough 2010]. Therefore, this study is planned to 
investigate repeated treatments over a 12-month period. 
The repeat treatments will be injected at intervals of 16 weeks. This is oriented toward 
the EU-approved interval for NT 201 in spasticity, i.e., every 12 weeks [Merz 
Pharmaceuticals GmbH 2013] and the effect maintained in a recently published study 
with BoNT-B of 12 weeks [Chinnapongse 2012]; however, the interval is extended in the 
present study to minimize any possible overlapping of dose effects. 


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This study will investigate the treatment of sialorrhea with an average per-body-weight 
dose of 2 U per kg (corresponding e.g. to 30 U in a 15-kg child at each injection session. 
(In practice this will be done by using fixed doses determined by weight classes; see 
Section 8.2.3.) Repeated injections with doses in line with the upper dose limit of NT 201 
used in the off-label treatment of sialorrhea are expected to allow a systematic evaluation 
of safety and efficacy within the protected frame of a monitored study. 
Each subject in the age group 6–17 years will receive active treatment at some point (at 
the latest with the second treatment) during the study. Each child aged 2–5 years will 
only receive active treatment. 
Subjects with chronic troublesome sialorrhea who are treatment-naïve will be enrolled. In 
this study, treatment-naïve subjects are defined as those who have not received BoNT 
treatment for this indication within the last 12 months. This regulatory definition aims to 
avoid bias by comparison of treatment effects in subjects’ assessments. 
At present, no data from a controlled clinical study are available regarding treatment of 
chronic troublesome sialorrhea with a per-body-weight dose of 2 U NT 201 administered 
at fixed 16-week intervals. The performance of this study will contribute to the clinical 
development program of NT 201 in the indication chronic troublesome sialorrhea. 
Currently, no pharmacological agents have FDA or EU approval for treatment of 
sialorrhea even in adults. However, many trials have been reported since the first 
description of the treatment of sialorrhea with Botulinum toxin formulations [Bhatia 
1999, Jost 1999] over the years, only some consensus has been established among 
specialists on the treatment of sialorrhea with Botulinum toxins [Miller 2009, Naumann 
2008, Reddihough 2010]. Nevertheless the appropriate dosing and the advantages of 
ultrasound guided injections versus anatomic landmarks guided application are not 
evidence-based recommendations. 
Ultrasound guidance for the intraglandular injections is recommended by current 
consensus papers [Reddihough 2010] although there is no further evidence for better 
efficacy or safety of ultrasound-guided compared with landmark-guided injections. To be 
compliant with the agreed PIP in the EU the use of ultrasound guidance is mandatory in 
this study. 
Periodontal and dental diseases are known adverse reactions caused by iatrogenic 
xerostomia following salivary gland irradiation. Injections with Botulinum toxins into the 
salivary glands result in less severe and only temporary changes of periodontal or dental 
tissues. Thickened saliva resulting from salivary gland injection with Botulinum toxin 
was described for children, as causing worsening of swallowing, breathing or speaking 
[Erasmus 2010]. Human saliva serves multiple functions in the oral cavity, including 
moistening of food, facilitation of mastication and swallowing, and cleaning and 
lubrication of the oral mucosa. 
Additionally, secretory immunoglobulin A (sIgA) content within the saliva protects the 
oral cavity, including dental structures, from bacterial growth and plaque formation (part 


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of the immune system), preventing dental decay and erosion. With reduced salivary flow 
rates resulting from the BoNT treatment, the concentration of sIgA increases in the saliva 
probably as a result of reduced saliva volume [Ellies 2002]. The lack of detrimental effect 
upon dental and oral health with long-term treatment of sialorrhea with BoNT has not 
been demonstrated, and, furthermore, both adults with Parkinson’s disease and children 
with cerebral palsy are known to be at increased risk of dental and periodontal disease 
due to their disabilities in regular oral hygiene. Therefore, the FDA has recommended 
that a qualified dental health provider need to perform several oral examinations on study 
subjects during the trial. 
4.3 
Risk-benefit assessment 
In the main period of this study, approximately 176 subjects will be treated with NT 201 
(all age groups) and 73 with placebo (age groups 10–17 years, 6–9 years). Combined, 
bilateral injections of NT 201 (or placebo) into both the parotid and the submandibular 
glands will be given; because of the minor contribution and anatomical location of the 
sublingual glands, these will not be treated. Provided the proven therapeutic equivalence 
of NT 201 and Botox® [Benecke 2012, Roggenkamper 2012], the chosen average dose 
level of 2 U NT 201 /kg body weight can be expected to be safe and efficacious, as the 
same average dose level of Botox® has been shown to be safe and efficacious in a similar 
trial in CP patients [Banerjee 2006].  Additionally, this dose level is within the dose 
recommendations of a recent consensus paper [Reddihough 2010]. The mean doses 
injected in children's parotid and submandibular glands ranged from 30 U to 100 U with 
Botox® (average dose ranging 2–4 U/kg body weight). 
Further, Rodriguez and Abarca [Rodríguez Abarca 2012] reported on administration of 
total 60 units NT 201 in 9 children (4–15 year of age) suffering from sialorrhea due to CP 
and progressive encephalopathy. One subject reported a transitory nasopharyngeal reflux 
after the administration of NT 201.  
Because previous studies have shown a variability of the effective dose [Reddihough 
2010] and because of treatment limitations due to potential worsening of dysphagia by 
local side effects of Botulinum toxin, the treatment will be investigated in an extension 
period where all subjects will receive active treatment. 
Because of the need to proceed with particular caution in a pediatric population, frequent 
safety reviews will take place and the three age groups 10–17 years, 6–9 years, and 2–5 
years will begin treatment in a staggered manner. The first two age groups are required to 
have safety assessments by a data monitoring committee [DMC] after every 30 subjects 
has been treated, and the results of these analyses will determine the continuation of the 
study. In addition, the DMC will monitor safety data on a regular basis, and any adverse 
events of special interest will be elicited by specific questioning. Thus, the risks of study 
participation are considered to be at least outweighed by its potential benefits. 
As this is the first placebo-controlled, randomized pediatric study with NT 201 in this 
indication, no clear information regarding its expected side effects is available. However, 


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on the basis of the literature [Reddihough 2010] the following risks of intraglandular 
Botulinum toxin injections could be identified: 
Adverse effects relating to trauma at the site of the injection 
• Pain (not severe) at the injection site either during the procedure, or because of gland 
swelling (hours) or hematoma formation (days) following the procedure. 
• Hematoma in the peri-glandular region caused by bleeding from the skin or 
subcutaneous tissue. 
• Intra-oral blood caused by intraglandular/transductal bleeding. 
• Swelling of the gland caused by bleeding or injection of too large a volume of 
solution. 
• Swallowing problems, caused by swelling of the gland, which usually resolves within 
two hours. 
• Infection. 
• Theoretical possibility of trauma to the facial nerve when injecting the parotid gland. 
Adverse effects relating to BoNT-A and BoNT-B 
• Increased dryness of the mouth leading to problems such as manipulation of solid 
food. 
• Thickening of saliva because the water component is influenced by cholinergic 
blockade, leading to an increase in the concentrations of mucins and proteins. 
• Chewing and swallowing problems because of diffusion of BoNT into the surrounding 
muscular tissue. 
• Loss of BoNT because of intravascular injection (without systemic consequences 
because of the low dosages used; however, iatrogenic botulism has been reported in a 
single case). 
When BoNT is injected into the parotid, diffusion of BoNT into the masseter muscle is 
possible, causing weakness in chewing. 
Currently no large, randomized, double-blind, placebo controlled clinical trial has been 
performed on the use of NT 201 in the management of sialorrhea in adult or pediatric 
patients. Only small case series and clinical trials with significant design limitations have 
been performed. 
Kossmehl [Kossmehl 2007] found in a case series (N = 6) of patients suffering from 
Parkinson's disease, multiple system atrophy or stroke a clear reduction in saliva 
production (greater than 50% reduction in saliva production by objective measurement of 
saliva weight collected with dental rolls before and after placement), and drooling 
severity and frequency scale [DSFS] score improvements in all patients after ultrasound-
guided injections of 50 U NT 201 in both parotid glands (total dose 100 U). 
South [South 2011] performed a double-blind, placebo-controlled, cross-over study of 
NT 201 for sialorrhea in eight subjects with Parkinson‘s disease. Participants received in 
total 80 U of NT 201 (40 U each in the right and left parotids, distributed evenly) or 


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saline injected at 0 and 16 weeks. There was a trend toward progressive reduction in 
saliva weight measures after the injection of NT 201. In the placebo arm, there was an 
initial improvement of drooling and then a decline by 12 weeks after injection. This trend 
was also present in the subjective measures [DSFS] and was similar in the active-
treatment and placebo arm of the trial. There was significant variation in results of both 
objective and subjective measures of sialorrhea among individual participants. There was 
a mild increase in impairment in subjective rating of swallowing function at four weeks 
after injection with NT 201; this was not seen in the placebo arm. However, no 
participants reported significant worsening of their swallowing function such that diet 
modification or formal assessment was required. 
Castelnovo [Castelnovo 2013] performed an open-label study of NT 201 for the treatment 
of sialorrhea in subjects with Parkinson’s disease (N = 17), amyotrophic lateral sclerosis 
(N = 7) and cerebral palsy (N = 1). In total, 25 patients were treated. In group A, 
comprising 12 patients, only one injection was given into the parotid glands. In group B, 
comprising 13 patients, single injections were given in both parotid and submandibular 
glands. The amount of neurotoxin injected was 35 U NT 201 in each parotid gland and 
25 U in each submandibular gland. The efficacy of the BoNT treatment was evaluated 4–
12 weeks after the injection, measured with the drooling rating scale [DRS] and the 
clinical global impression scale. Intraglandular injection of NT 201 was safe, well 
tolerated, and effective in treating sialorrhea. Both injection protocols, i.e. in the parotid 
glands only or injection of both the submandibular and parotid glands, showed similar 
effectiveness in controlling sialorrhea. No adverse events were recorded in either of the 
two groups. 
Huß [Huß 2009] published a case report of sialorrhea caused by a swallowing impairment 
in a 24-year-old female patient with CP, who was treated with intraglandular NT 201 
injected at 3.25 U/kg body weight after decreasing responsiveness to BoNT-B. The 
salivary production was reduced noticeably, without adverse systemic or local effects; 
constipation was a distant effect. 
Rodriguez [Rodríguez Abarca 2012] performed a prospective, longitudinal, controlled 
study (N = 9; CP and progressive encephalopathy) of NT 201, testing efficacy in 
sialorrhea in children (4–15 years of age). Efficacy was analyzed after four months. In 
eight patients a decrease in the intensity and frequency of sialorrhea (60–80%) was 
observed. 
With respect to the recommendations of the FDA concerning prospective suicidality 
monitoring [Food and Drug Administration (FDA) 2012] in clinical studies with NT 201 
the risk of suicidality was assessed retrospectively before implementing the C-SSRS. 
Cumulatively, 794,297 patients have been exposed to Xeomin® in the context of post-
marketing experience overall (3,177,186 vials) during the reporting period 31-MAY-
2005 until 31-Dec-2014. Until now, approximately 4,206 subjects received NT 201 
during the clinical development program. Additionally, a literature and internet research 
was performed to identify scientific publications covering the incidence of suicide related 
events in patients treated with any botulinum toxin. Overall, no relevant publications 


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could be identified, which reported about suicide in relation with botulinum toxin 
treatment.  
In summary no evidence of a causal relationship of suicide and suicide related events in 
patients treated with NT 201/Xeomin® could be revealed. 
For further information, see the current investigator's brochure [IB] for NT 201. 


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5 STUDY OBJ ECTIVES 
The objective of this study is to investigate the efficacy and safety of NT 201 compared 
with placebo for the treatment of chronic troublesome sialorrhea associated with 
neurological disorders (e.g. cerebral palsy, traumatic brain injury) and/or intellectual 
disability in children and adolescents aged 2–17 years, naïve to Botulinum neurotoxin 
treatment. The total dose of NT 201 ranges from minimum 20 U to maximum 75 U or 
approximately 2 U/kg body weight depending on body weight classes. Subjects with a 
body weight ≥ 30 kg will receive a fixed total dose of 75 U. In this study, treatment-naïve 
subjects are defined as those who have not received BoNT treatment for this indication 
within the last 12 months. 


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6 INVESTIGATIONAL PLAN 
6.1 
Overall study design 
6.1.1 
Summary of design 
This is a prospective, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study with a screening period, a main period [MP] followed by an open-label 
extension [OLEX] period. 
Subjects (adolescents and children) will be recruited in a staggered manner in consecutive 
age groups: 10–17 years (inclusive), 6–9 years (inclusive) and 2–5 years (inclusive). In 
the main period the subjects in the age groups from 6 to 17 years will be randomized to 
receive double-blind, placebo-controlled treatment. Subjects aged 2–5 years at screening 
will not be randomized, but will be treated with NT 201 in an open-label fashion. In the 
extension period all subjects will be treated with NT 201 in an open-label fashion. 
The study will consist of four injection cycles. The first injection cycle is the main 
period. The total duration of the main period is 15–22 weeks (comprising the screening 
period of up to 4 weeks before the first injection and the main treatment period of 16 ± 2 
weeks). This first injection cycle will be followed by three subsequent open-label 
injection cycles (16 ± 2 weeks each) for all subjects. The total treatment period will thus 
last for 56–72 weeks after the first injection for those completing all four injection cycles. 
For the safety of subjects, a DMC will assess adverse events [AEs], including adverse 
events of special interest [AESIs] and serious adverse events [SAEs] at regular intervals 
and after each group of 30 subjects has been fully recruited. 
It is planned that a total of 249 subjects will be enrolled and that, of these, at least 219 in 
the age group 6–17 years (inclusive) will form the set of subjects for the primary analysis. 
At least 30 children in the youngest age group of 2–5 years inclusive are planned to be 
enrolled; these will be treated with active treatment only. The group of older subjects will 
be randomized at a randomization ratio of 2:1, i.e., 146 subjects will be treated with 
NT 201 and 73 with placebo. 
6.1.2 
Number and time points of scheduled visits 
Screening 
• Screening visit [V1] (Day –28 to –7). 
Placebo-controlled main period (first injection cycle) 
• Baseline injection visit [V2] (Day 1 of first injection cycle; randomization). 
• Assessment visit [V3] (Week 4 ± 3 days). 


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• Assessment visit [V4] (Week 8 ± 7 days). 
• Assessment visit [V5] (Week 12 ± 7 days). 
• Final visit of main period [V6] (Week 16 ± 2 weeks). 
Open-label extension period (second, third and fourth injection cycle) 
Second injection cycle (16 ± 2 weeks after 1st injection): 
• Injection visit [V6a] (Day 1 of second injection cycle). 
• Assessment visits [V7] (4 weeks ± 3 days after the 2nd injection) and [V8, V9] (8, 12 
weeks ± 7 days after the 2nd injection). 
• End of cycle visit [V10] (16 weeks ± 2 weeks after 2nd injection). 
Third injection cycle (16 ± 2 weeks after 2nd injection): 
• Injection visit [V10a] (Day 1 of third injection cycle). 
• Assessment visits [V11] (4 weeks ± 3 days after 3rd injection) and [V12, V13] (8, 12 
weeks ± 7 days after 3rd injection). 
• End of cycle visit [V14] (16 weeks ± 2 weeks after 3rd injection). 
Fourth injection cycle (16 ± 2 weeks after 3rd injection): 
• Injection visit [V14a] (Day 1 of fourth injection cycle). 
• Assessment visits [V15] (4 weeks ± 3 days after 4th injection) and V16, V17] ( 8, 12 
weeks ± 7 days after 4th injection). 
• End of cycle/study visit [V18] (16 weeks ± 2 weeks after 4th injection). 
End-of-study visit 
This will be the same as the end-of-cycle visit for the fourth injection cycle (above). 
Subjects who withdraw, or are withdrawn, prematurely from the study will be requested 
to attend for this final examination. 
6.1.3 
End of study 
The end of the study as a whole will be defined as the date of the last study visit by the 
last subject. 


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6.1.4 
Study flow chart 
 
Figure 1: Study Flow Chart 
Note: For children age 2–5 years only the NT 201 arm is applicable. 
6.2 
Discussion of study design, including choice of control groups 
Important design features of this study are discussed in turn below. 
Randomization and blinding 
The use of 2:1 randomization (NT 201 or placebo) in the main period and the migration 
to all-active treatment in the extension period has been chosen in order to keep the 
number of subjects treated with placebo as small as possible. 
The double-blind, placebo-controlled, randomized, multi-center design of the main period 
has been chosen to allow the acquisition of scientifically robust efficacy and safety data 
on NT 201 in children and adolescents with chronic troublesome sialorrhea due to 
neurological disorders – data that will not be biased by the subject or the investigator. A 
superiority study with a placebo control allows valid conclusions about efficacy and 
safety and represents the state of the art in this kind of clinical research. 
Currently, no pharmacological agents have FDA or EU approval for treatment of 
sialorrhea in adults. For pediatric patients, there is currently only one pharmacological 
agent approved by the FDA for chronic severe sialorrhea (Cuvposa (glycopyrrolate) Oral 
Solution [NDA 022571]). This is an anticholinergic indicated to reduce chronic 
troublesome drooling in patients aged 3–16 years with neurological conditions associated 


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with problem drooling (e.g., cerebral palsy). The use of this agent is compromised by the 
occurrence of dose-limiting constipation and drowsiness, both of which already can be 
problematic in CP. Additionally, Cuvposa has other anticholinergic drug effects which 
may limit its use in patients with coronary heart disease, congestive heart failure, and 
cardiac tachycardia. Cuvposa is administered as an oral solution. Therefore using it as a 
comparator in this study would compromise the blinding and it could only be 
implemented by a double-dummy design, meaning that both the NT 201-treated group 
and the control group would need to receive the oral solution (placebo or active 
treatment) and the injection (active treatment or placebo, respectively) at the same time. 
This would lead to higher risks for subjects than the pure placebo control. 
As no substance has yet received marketing approval for the treatment of chronic 
troublesome sialorrhea for minors in the EU, and to date no appropriately powered 
pivotal study data on Botulinum toxin in this indication are available, therefore placebo 
treatment in about 33% of all enrolled and randomized subjects (age 6–17 years) for one 
single injection cycle during the main period out of a total of four injection cycles is 
justified. All children age 2–5 years will receive NT 201 in the main period. However, it 
was also considered to be important not to withhold treatment from subjects needing it in 
this burdensome indication. Therefore, the placebo group in the main period was kept 
small, and the extension period (required by the need for long-term safety data) was 
designed without placebo treatment. All subjects will receive active treatment during the 
extension period. All subjects are expected to benefit from treatment with NT 201 
(subjects in the placebo group three times, subjects in the active treatment group four 
times). 
Following discussions with the relevant regulatory authorities, it was considered 
necessary to follow at least 100 children treated with clinically relevant doses of NT 201 
continuously for one year. At least 50 of these patients must have received the high dose 
(at least 2 U/kg body weight) consistently for one year (series of four injections). The 
safety database requirement in children for cumulative exposure at six months is also at 
least 100 subjects treated consistently with clinically relevant dosages for two injections. 
Duration of treatment and assessment 
The length of each injection cycle was chosen on the basis of reported observations that 
the effect of Botulinum toxin builds up over approximately two weeks after treatment and 
decays after 8–12 weeks [Chinnapongse 2012, ClinicalTrials.gov 2011]. Therefore, in 
order to avoid any unwanted reinforcement of consecutive doses, a separation of 16 
weeks (at least 14 weeks) between doses was incorporated into the design. 
Sialorrhea manifesting itself as a consequence of neurological disease is a chronic health 
problem and requires long-term treatment. Therefore, the extension period of this study 
investigates the efficacy and safety of repeated administration of NT 201, given at fixed 
intervals. Following the placebo-controlled main period of 16±2 weeks' duration, all 
subjects complying with the eligibility criteria will receive active treatment in the 
extension period. Each subject will receive at least three injections with NT 201 within an 
overall treatment period of 64 weeks. 




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Step 2 
If in the above analysis no significant risk is identified by the DMC, then a second set of 
30 children/adolescents (10–17 years of age) will be recruited, randomized and treated in 
the same manner as the first 30 subjects (cohort 2). 
Safety data acquired from cohorts 1 and 2 will be reviewed by the DMC when 4 weeks 
elapsed after the last subject of cohort 2 was randomized. 
Step 3 
If in the above analyses no significant risk is identified by the DMC, then a further group 
of 30 younger children (6–9 years of age) will be recruited, randomized and treated 
(cohort 3). 
In parallel with this, recruitment and treatment of subjects in the age group 10–17 years 
will continue. 
Safety data acquired from all subjects randomized hitherto (N > 90) will be reviewed by 
the DMC when 4 weeks elapsed after the last subject of cohort 3 was randomized. 
Step 4 
If in the above analyses no significant risk is identified by the DMC, then a further 30 
children representing the youngest age group (2–5 years of age) will be enrolled (cohort 
4). Children in this youngest age group will not be treated with placebo, but only with 
active treatment (NT 201) during all four injection cycles. 
In parallel with this, recruitment and treatment of subjects in the older two age groups 
will continue. 
Termination of recruitment 
Recruitment will continue in the age groups covering the age range from 6 to 17 years 
inclusive until the target number of 219 subjects randomized and treated is reached. 
Recruitment in these age groups will then stop. 
Recruitment will continue in the age group 2–5 years inclusive until the target number of 
30 subjects treated is reached. Recruitment in this age group will then stop. 
If recruitment in one or another group is unexpectedly or disproportionately slow, then 
the sponsor has the right to terminate recruitment before the respective target number is 
reached.  The sponsor also has the right to terminate recruitment, overall or in a given age 
group, by recommendation of the DMC for safety-related reasons. 
With the recruitment strategy described above, and assuming that no premature 
termination of recruitment takes place as outlined above, a total of 249 subjects will be 
enrolled and treated; of these, 30 will have received active treatment without 
randomization, 219 will have been randomized to receive either active treatment (146 
subjects) or placebo (73 subjects) in the main period. All study subjects will have 
received NT 201 in the extension period. 


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Period of recruitment 
It is estimated that recruitment will commence in the first quarter of 2015 and will be 
completed during the first quarter of 2018. The end of the study (final study visit by the 
last subject) would then be in the second quarter of 2019. 


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7 STUDY POPULATION 
7.1 
Selection of study population 
Study subjects (male and female children and adolescents in the respective age groups) 
will be recruited according to criteria determined by having a relevant medical condition 
of chronic troublesome sialorrhea associated with neurological disorders and/or 
intellectual disability requiring study treatment, and by having no medical condition or 
other circumstance that might interfere with the conduct or result of the study or endanger 
a subject's safety. 
Distribution of gender 
As the study indications are not gender-specific, no stratification or selective recruitment 
of male/female subjects will be performed. It is assumed that the accrual of male and 
female subjects without distinction at all investigation sites will in itself lead to a balance 
of the genders that will be adequate for the study analysis. 
7.2 
Inclusion criteria 
Only individuals meeting all of the following inclusion criteria, at screening and/or at 
baseline as indicated, will be considered for study enrollment: 
Inclusion Criteria 
Ratio-
nale 
Scr BL 
1. Written informed consent obtained from the child’s/adolescent’s 
parent(s) and oral or written assent by the child/adolescent 
(following information to the extent compatible with the subject's 
understanding if applicable). 
Adm 
X 
 
2. Male or female child/adolescent aged 2 to 17 years (i.e., second 
birthday reached, and eighteenth birthday not yet reached, on the 
date of first administration of study medication). 
Adm 
X 
X 
3. Understanding of study procedures and willingness to abide by all 
procedures during the course of the study by the parent(s) and/or 
the child/adolescent (if applicable). 
Adm 
X 
 


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Inclusion Criteria 
Ratio-
nale 
Scr BL 
5. Any neurological disorder (e.g. cerebral palsy or traumatic brain 
injury) and/or intellectual disability associated with chronic 
troublesome sialorrhea for at least 3 months up to the screening. 
In subjects with intellectual disability (ID) without neurological 
disorders, a diagnosis of ID by a specialist, e.g. pediatrician or by 
a center for developmental medicine is required for inclusion. 
Ind 
X 
 
6. mTDS of ≥ 6 (= severe drooling to the extent that clothing 
becomes damp occasionally) rated by the investigator. 
Ind 
X 
X 
7. Female subjects of child-bearing potentiala must be using a highly 
effective method of birth controlb. 
Safety 
X 
X 
a Any female who has experienced menarche and is not permanently sterilized (e.g. tubal occlusion, 
hysterectomy, bilateral salpingectomy). 
b Defined as a method that results in a low failure rate (i.e., less than 1% per year) when used consistently 
and correctly, such as implants, injectables, combined oral contraceptives, sexual abstinence, or 
vasectomised partner. 
Screening [Scr]; baseline [BL]; administrative [Adm]; definition of the study indication [Ind]. 
 
Note: The technical prerequisite for inclusion of subjects is the confirmation through the 
IWRS [interactive web response system] that the study is currently recruiting in the age 
group of the child/adolescent. 
7.3 
Exclusion criteria 
Individuals meeting any of the following criteria, at screening or at baseline as indicated, 
will not be included in the study: 
Exclusion Criteria 
Ratio-
nale 
Scr BL 
1. Diagnosis of chronic troublesome sialorrhea not related to a 
neurological disorder and/or intellectual disability, e.g. 
malformation of the salivary ducts or glands. 
Int 
X 
 
2. Subject with body weight < 12 kg. 
Safety 
X 
X 


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Exclusion Criteria 
Ratio-
nale 
Scr BL 
4. Aspiration pneumonia within 6 months before screening. 
Safety 
X 
X 
7. Prior, concomitant or planned surgery or irradiation to head and 
neck to control sialorrhea (including salivary gland surgery or 
salivary gland irradiation) within one year before screening or 
planned for any part of the entire study period. 
Int 
X 
X 
9. Any previous treatment with Botulinum toxin for any body region 
during the year before screening or within the screening period. 
Int 
X 
X 
11. Known or suspected hypersensitivity to either Botulinum toxin 
(any serotype) or any ingredient of the formulation or analgesics 
or sedatives (used for premedication for analgosedation or 
anesthesia). 
Safety 
X 
X 
12. Extremely poor dental and/or oral condition that might preclude 
safe study participation by the judgment of the investigator. 
Int 
X# 
X 


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Exclusion Criteria 
Ratio-
nale 
Scr BL 
16. Pharmacological treatment for sialorrhea or concomitant 
medication known to influence sialorrhea strongly (e.g. 
anticholinergics with exception of locally applied or short acting 
drugs used under general anesthesia) within 45 days before 
baseline and during the entire study period.  
Int 
X 
X 
18. Concurrent diseases, including hematological, hepatic, renal, 
gastrointestinal, endocrine, pulmonary, musculoskeletal, or 
psychiatric diseases or conditions, which in the judgment of the 
investigator would put the subject at risk while in the study, could 
influence the results of the study, or negatively impact the 
subject’s ability to participate in the study 
Safety 
X 
X 
19. Nursing mother or pregnant female subject. 
Safety 
X 
X 


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Exclusion Criteria 
Ratio-
nale 
Scr BL 
Screening [Scr]; baseline [BL]; risk of interference with study objectives [Int]; administrative [Adm]; (*) to 
avoid unnecessary distress to the subject; #dental examination by dentist needs to be performed until 
baseline visit. 
7.4 
Eligibility criteria for continued treatment in the extension period 
Criteria for the transition to the extension period (V6/6a) and for continued treatment 
within the extension period (V10/10a and V14/14a) are listed below. (Note that the pairs 
of visits 6/6a, 10/10a and 14/14a will normally take place on the same respective day.) 
If these eligibility criteria are not fulfilled at the end-of-cycle visit postponement of study 
treatment may take place at the beginning of the following injection cycle of the 
extension period. The re-injection visit can be postponed for up to a maximum of two 
weeks (but no longer than 18 weeks after the preceding treatment visit). For subjects who 
still do not fulfill the eligibility criteria at the revisit, study participation will be ended.  
 
Eligibility Criteria for Extension Treatment 
Ratio-
nale 
Visits 6, 
6a, 10, 
10a, 14, 
14a 
1. Clinical need for re-injection. 
Ind 
X 
2. Absence of medically-relevant severe adverse events of special 
interest that are judged to have a causal relationship to the study 
treatment (indicative of toxin spread in the area of injection), 
especially respiratory arrest/distress/failure and dysphagia 
necessitating diet changes occurred during any period of the study. 
Safety 
X 
3. No concomitant infection or inflammation in the head and neck 
region. 
Safety 
X 


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Eligibility Criteria for Extension Treatment 
Ratio-
nale 
Visits 6, 
6a, 10, 
10a, 14, 
14a 
4. Negative result of pregnancy test (testing only performed for 
female with history of menarche, i.e. the first menstrual bleeding). 
Safety 
X 
5. No significant risk of suicidality since last injection based on  
• 
the Investigator’s judgment, and 
• 
if appropriate, as indicated by a response of “no” to questions 
4 or 5 in the suicidal ideation section of the C-SSRS  
• 
and no non suicidal self-injurious behavior  
• 
and no suicidal behavior. 
Safety 
X 
Definition of indication for continued study treatment [Ind]; administrative [Adm]. 
7.5 
Removal of subjects from treatment or assessment 
7.5.1 
Discontinuation of subject’s study participation 
In accordance with the Declaration of Helsinki and the informed consent form, the 
subject or his/her parent(s) may discontinue the subject's participation in the study at any 
time without any penalty or loss of benefits to which the subject is otherwise entitled (see 
Section 7.5.3). Both the premature withdrawal from the study and the reason(s) for this 
are to be recorded in the subject's file and the eCRF. The date and circumstances of the 
discontinuation should be stated. 
Subjects are to be withdrawn from the study by the investigator at any time if any of the 
following occurs: 
• Withdrawal of informed consent. 
• Pregnancy (no further administration of NT 201, blood sampling, or any other 
interventional or invasive procedure will be performed). 
• Any AE for which treatment continuation would constitute an unacceptably high risk 
for the subject. 
• Any eligibility criteria for reinjection are not met within 18 weeks after the previous 
injection of IP in the respective injection cycle (MP or OLEX). 


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• AESIs of severe intensity that represent respiratory function disorders or swallowing 
disorders will trigger the premature termination of a subject without reexposition to 
IP. The terms for these severe AESIs are: 
• AESI terms related to respiratory function disorders are aspiration, diaphragmatic 
paralysis, dyspnoea, pneumonia aspiration, respiratory arrest, respiratory 
depression, and respiratory failure. 
• AESI terms related to swallowing disorders are bulbar palsy, multiple cranial 
nerve palsies, dysphagia, hypoglossal nerve paresis, cranial nerve paresis, cranial 
nerve paralysis.  
• Positive report on suicidality of subject (C-SSRS answer „yes“ to questions 4 or 5 or 
any suicidal behavior) or non-suicidal self-injurious behavior. 
Deviations from this clinical study protocol, or conditions arising from the exclusion 
criteria as set out in Section 7.3, may (but will not necessarily) lead to the subject's 
withdrawal. All such conditions are to be properly documented. In such cases, the 
decision on whether or not to withdraw the subject will be made by the investigator in 
consultation with the sponsor, taking principally the safety of the subject into account. 
Subjects who are withdrawn from the study because of AEs will be treated by standard 
clinical methods and will be followed up until (and including) the last scheduled visit of 
the injection cycle in which they were withdrawn or until 28 days after the onset of the 
adverse event, whichever date is the later. All pertinent information concerning the AE 
will be documented in the subject's hospital medical file as well as in the eCRF AE report 
form. 
Following a subject's withdrawal, a final examination should be performed for safety 
reasons if parents/carers are willing to bring the child for the visit. The investigator is 
required to make every effort to contact subjects lost to follow-up, and all such efforts are 
to be documented in the subject's hospital medical file (e.g., times and dates of telephone 
contact, copies of letters). 
7.5.2 
Premature termination or suspension of the study or a study 
site 
The study or a study site can be terminated prematurely, or suspended, by the sponsor. 
Reasons for termination of the study or closure of a study site may include, but are not 
limited to, the following: 
• Subject enrollment is unsatisfactory. 
• The risks and benefits of continuing the study have been reassessed, and the risks 
outweigh any potential benefits. 
• The incidence of AEs constitutes a potential health hazard to the subjects. 


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• New scientific data on NT 201 do not justify a continuation of the study. 
• 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 or clinical requirements. 
• The sponsor decides to terminate the study at any time for any other reason (e.g. 
based on the recommendation of the DMC). 
• AESIs of severe intensity that represent respiratory function disorders or swallowing 
disorders, that are deemed to be related to IP administration, and that last >1 week 
will trigger premature termination of the study. The threshold for premature study 
termination is set to at least five of the severe AESIs described above for the first 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. 
• AESI terms related to respiratory function disorders are aspiration, diaphragmatic 
paralysis, dyspnoea, pneumonia aspiration, respiratory arrest, respiratory depression, 
and respiratory failure. 
• AESI terms related to swallowing disorders are bulbar palsy, multiple cranial nerve 
palsies, dysphagia, hypoglossal nerve paresis, cranial nerve paresis, cranial nerve 
paralysis. 
Furthermore, the study (or the participation of a study site) may be ended prematurely if 
the regulatory authority or the IEC/IRB decides 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 and/or their legally acceptable representatives and ensure appropriate 
follow-up treatment. Within the time-frames stipulated in the applicable regulations, the 
sponsor will promptly inform the investigators, study sites, IEC/IRB and regulatory 
authorities of the termination or suspension of the study, and will provide reasons for this 
action. 
7.5.3 
Provision of care for subjects after leaving the study 
After leaving the study (following regular completion or premature 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. 




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Dose regimens in the main period 
For the NT 201 group dosages will be given according to the predefined volumes of fixed 
total doses defined for each of the six body-weight classes (see Table 2 in Section 8.2.3 
below). 
In general for subjects with a body weight of 12–30 kg the total dose is approximately 
2 U/kg. Subjects with a body weight ≥ 30 kg will receive a fixed total dose of 75 U. Due 
to the unitary concentration of the NT 201 solution the dose adjustment will be performed 
by adapting the injection volumes for each dose group (see Table 2). 
In the placebo group, subjects will receive the respective volume of placebo solution 
(0.9% sodium chloride, sucrose and human serum albumin) as in the NT 201 treatment 
group according to their bodyweight classification. 
Dose regimens in the extension period 
There will be no placebo group in the extension period. The regimen for the 
administration of NT 201 will be the same body weight-adjusted dosing scheme as for the 
main period. Dosages will be adapted to actual body weight of subjects at each injection 
visit according to the dosage instructions. 
The subject's body weight will be re-determined at each injection visit, and if the body 
weight has increased (or decreased) over the limit of the class then the subject will be 
treated in the next higher (or lower) dosage group accordingly. 
Dose reduction in the extension period (3rd or 4th injection cycles only) 
In the third or fourth injection cycles, the quantities of NT 201 administered can be 
reduced if there are treatment emergent adverse events that the investigator considers as 
demanding a reduction in dose level in order to avoid a repetition of the adverse event or 
the withdrawal of the subject from the study. This reduction will take place at the 
discretion of the investigator to minimize the risk of further occurrence of such AEs or 
the discontinuation of the study for the subject. The quantities to be administered in the 
reduced-dose treatment are defined in Section 8.2.3. Quantities other than those given in 
Section 8.2.3 (with corresponding adaptation to body weight and possible dose reduction 
following relevant adverse events) are not allowed. 
If the dose has been reduced in the third injection cycle, then in the fourth cycle the 
reduced dose will also be given. 
8.1.1.2 
Instructions for administration 
The technique of injection is described in Appendix 16.5. 
Treatment will be administered via intraparenchymal/intraglandular injections 
(percutaneously) into the parotid and submandibular glands bilaterally with a single 


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injection site per gland per side. To avoid swallowing problems caused by thickened 
saliva and in order to safeguard against excessive reduction of salivary flow during 
mastication and eating, the ratio of toxin dosages injected into the parotid and 
submandibular gland is set to be 3:2. 
Injection of both salivary glands at each side will be performed at each injection visit 
using mandatory ultrasound guidance (see Appendix 16.5 for injection technique). 
Investigators will receive specific training on ultrasound guidance technique and on the 
anatomical localization of the target injection points. 
Quantities to be administered (one injection into each gland, four injections per 
treatment) are shown below in Section 8.2.3. Note especially the normal and reduced 
dose levels in Table 2 and Table 3 respectively; the reduced amounts in Table 3 apply 
only to the third and fourth study treatments if a treatment emergent adverse event occurs 
that the investigator considers as demanding a reduction in dose level. 
Investigators will be trained in the administration of study medication before the 
inception of the study at their respective centers. 
The injections will be performed with ultrasound guidance at each gland and on each 
occasion. The salivary glands are to be examined sonographically by using a 
commercially available ultrasound system equipped with a high-resolution, 7.5-MHz 
small-parts transducer. The transducer is to be positioned in such a way that injection 
with the needle is possible along the longitudinal axis of the transducer, providing a quick 
and easy-to-perform visualization of the needle in the gland. Furthermore, ultrasound is 
to be used to monitor and guide the spreading of the fluid throughout the gland 
accordingly [Jongerius 2004a]. 
General anesthesia, medication for analgesia and analgosedation will be offered to all 
subjects unless contraindicated and in line with international guidelines on sedation in 
children. It is to be administered by (or under direct supervision of) trained and qualified 
anesthesiologists with adequate experience, monitoring equipment and support personnel. 
In case the child has an anaphylactic reaction or unexpected airway problems, easy access 
to a pediatric intensive care bed and extensive monitoring and emergency equipment and 
support personnel is required. 
The investigator will use the NT 201 and placebo vials provided and all other study 
materials only within the framework of this clinical study and in accordance with this 
protocol. 
8.1.2 
Packaging and labeling 
Boxes for each injection visit, containing one vial of investigational product (IP; vials 
containing NT 201 or placebo), will be sent to the study sites. Sites are supported in 
purchasing vials with 10 ml sterile saline for reconstitution, syringes and needles for the 
reconstitution, and syringes and needles for the injections. Boxes and vials will be labeled 


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appropriately; printed labels will contain the information set out below. To maintain the 
blind, medication (NT 201 and placebo) for use in both periods of the study will have the 
same printed label information on the outer packaging (box) and the immediate 
containers (vials). See Section 8.5 for further details on the blinding procedures planned 
for this study. 
The study medication will be labeled according to the regulatory requirements of the 
participating countries. The labels will include, as minimum information, the name and 
address of the sponsor, the study reference number, EudraCT/IND number, expiry date, 
medication kit number, dosage form, route of administration, quantity of dosage units, 
batch number, directions for use, storage conditions, period of use and ‘For clinical trial 
use only’. 
If exchange of IP due to the expiry date becomes necessary, the IP will be replaced in due 
time. 
8.1.3 
Storage of investigational product 
Study medication should be stored at +2 to +25 °C (36–77 °F). It is recommended not to 
freeze the study medication. 
Storage temperature will be monitored once daily on working days, and the 
minimum/maximum temperature for each day (or shorter monitoring interval) will be 
recorded in a temperature log. 
The IP should be reconstituted shortly before use. However, reconstituted IP can be 
stored in the original vial for up to 24 hours at +2 to +8°C (36–46°F) in a drug 
refrigerator if the injection needs to be postponed to the day following that on which the 
reconstitution was performed. Any deviation from this will be documented on the drug 
accountability log. Reconstituted study medication is not to be stored in syringes. 
8.1.4 
Accountability for investigational product 
It is the responsibility of the investigator, or pharmacist according to local law, to ensure 
that a current record of inventory and of drug accountability is maintained. Inventory and 
drug accountability 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, dates, quantities, batch number, expiry date, 
and the code number assigned to the IP. 
Supply and receipt of IP will be managed with the help of the IWRS-system. Upon 
receipt of the IPs, the investigator or pharmacist or other qualified staff according to local 
law will visually inspect the shipment and verify the number and condition of the IPs. 
The investigator or authorized site staff or pharmacist will electronically acknowledge the 


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receipt of IP and also the temperature log (Section 8.1.3). An IP supply and return form 
will be completed and signed by the investigator or authorized site staff or pharmacist 
according to local law. The original signed form is to be filed with the inventory / drug 
accountability records. Prescription and Return of IP will be tracked in the IWRS-system 
according to data input from the investigator or authorized site staff. Drug Accountability 
forms will be signed by the investigator and filed in the investigator site file and trial 
master file. 
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. 
For subject drug accountability and treatment compliance, see Section 8.2.5. 
8.1.5 
Destruction of investigational product 
All used vials including residual fluid content are to be neutralized by adding a 
denaturing solution (i.e. alcohol) to the active substance according to local standard 
practice. The IP inactivation has to be done immediately after each injection session. 
Upon the completion or termination of the study, all unused and used and denaturated 
empty vials of IP(s) have to be shipped to an authorized warehouse for destruction of the 
IP. More detailed information is given in the Trial Medication Handling Manual and in 
the IWRS Manual. 
8.2 
Treatments administered 
Subjects aged 6–17 years will receive NT 201 or placebo in the main period and NT 201 
in the extension period. In the main period the treatment will be randomized and double-
blinded; in the extension period all patients will receive open-label active treatment. 
Subjects aged 2–5 years will receive NT 201 in the main period and in the extension 
period. For details, see Sections 8.2.1 to 8.2.4. 
8.2.1 
Methods of assigning subjects to treatment groups 
Each subject screened will be given a screening number through the IWRS. Rescreened 
subjects will receive a new screening number. Only the subjects who are randomized will 
receive a randomization number at baseline visit (V2). 
Randomization to NT 201 and placebo in a ratio of 2:1 will be applied during the main 
period, for the subjects aged 6–17 years. Subjects aged 2–5 years will not be randomized. 
Randomization will include staggering of the age groups as described in Section 6.3. 
The randomization officer responsible will perform the random allocation of treatments 
to subjects using the computerized randomization program 
 


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, Germany) by preparing a randomization 
list for each age group including – for each subject – a randomization number and the 
allocation to treatment for the main period. The IWRS will allocate the randomization 
number to a subject and will determine a medication kit with a unique medication number 
for each injection visit of the subject. The randomization number and the medication 
numbers for each subject will be recorded in the eCRF. 
Recruitment in each age group will be closed when the requisite number of subjects has 
been recruited; for details see Section 6.3. Slight over-recruitment (up to 10%) may occur 
in consequence of technical factors. After the end of recruitment, subjects leaving the 
study prematurely will not be replaced. 
The randomization list will be sealed and locked in the sponsor's quality management 
department and will not be accessible before database closure. 
8.2.2 
Selection of doses in the study 
The mean doses injected in children's parotid and submandibular glands ranged from 
30 U to 100 U with Botox® (on average ranging 2–4 U/kg body weight) and are within 
the dose recommendations of a recent consensus paper [Reddihough 2010].  
Rodriguez and Abarca [Rodríguez Abarca 2012] reported on administration of total 60 
units NT 201 in 9 children (4–15 years of age) suffering from sialorrhea due to CP and 
progressive encephalopathy. One subject reported a transitory nasopharyngeal reflux after 
the administration of NT 201. 
Two randomized, double-blind, active-controlled, parallel-group Phase 3 studies in the 
indications cervical dystonia and blepharospasm in adults demonstrated that NT 201 and 
Botox® show good and similar efficacy for both primary and secondary endpoints. Not 
only statistical non-inferiority of NT 201 versus Botox® was shown by these studies but 
also therapeutic equivalence of NT 201 and Botox® was proven [Benecke 2012, 
Roggenkamper 2012].  
Based on these facts and that in a similar trial with onabotulinumtoxin A in CP patients 
the average dose level of 2 U/kg body weight has been shown to be safe and efficacious 
[Banerjee 2006] the average dose of 2 U NT 201/kg body weight was chosen. Body 
weight classes and dose ranges were defined accordingly. 
Dose regimens for main period 
All subjects aged 6–17 years inclusive will receive a dose of NT 201 or matching placebo 
(randomization ratio 2:1). 
For subjects with a body weight of 12–30 kg the total dose on each treatment day will be 
approximately 2 U/kg. Subjects with a body weight ≥ 30 kg will receive a fixed total dose 
of 75 U. As NT 201 is supplied at a fixed concentration, the dose adjustment will be 


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performed by adapting the injection volumes for each dose group (see Table 2 in 
Section 8.2.3 below). 
All subjects in the age range 2–5 years inclusive will receive a body-weight-based dose 
of approximately 2 U/kg NT 201, and none will receive placebo. 
Dose regimens for the extension period 
There will be no placebo group in the extension period. The regimen for the 
administration of NT 201 will be the same body weight-adjusted dosing scheme as for the 
main period. Dosages will be adapted to actual body weight of subjects at each injection 
visit according to the dosage instructions. 
The subject's body weight will be re-determined at each injection visit, and if the body 
weight has increased (or decreased) over the limit of the class then the subject will be 
treated in the next higher (or lower) dosage group accordingly. For details see 
Section 8.2.3.  
No dose reduction due to AE is allowed for the second injection cycle (V6). If, in the 
opinion of the investigator, a dose reduction is advised, the dose can be reduced for the 
third injection cycle (V10) at the earliest. Only one dose reduction due to AE is allowed 
during the entire study period. 
8.2.3 
Selection and timing of doses for each subject 
For selection of doses, see Section 8.2.2; for timing of doses see Sections 6.1.2 and 9.2. 
No other dose levels and no other timing will be permitted. 
The principle of by-weight dosing set out in Section 8.2.2 leads to the following table of 
doses for guidance of the investigator (Table 2). 
Table 2 shows the amount of IP to be administered for each subject at each visit, 
according to the subject's body weight as determined at that visit. 
Therefore: 
– The subject's body weight will be determined immediately before each injection 
session, and if the body weight has increased (or decreased) then the subject will be 
treated in the next higher (or lower) dosage group. 
– At each injection session (V2, V6, V10 and V14), a total of four injections will be 
administered, one in each gland (left and right parotid, left and right submandibular). 


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Table 2: 
Dosing scheme 
If a treatment-emergent adverse event occurs that the investigator considers as 
demanding a reduction in dose level, this reduction can only be implemented at the 
following injection visit of the extension period (V10 or V14) if the dose was not reduced 
because of weight loss at the same visit. 
For reduced dose at the third and fourth administration of study medication (following a 
relevant adverse event; see Section 8.1.1.2 for details), each subject will be treated at the 
dose level set out in Table 2.  For subjects in the smallest weight group (12 to 15 kg) dose 
reduction to a reduced level is not allowed; the only option is reduction to zero, i.e., 
discontinuation of the subject’s participation in this study. 
Table 3: 
Dosing scheme with dose reduction in the third or fourth injection 
cycle 
(following an adverse event; see text) 


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If in the third cycle the dose is reduced, then in the fourth cycle the dose will likewise be 
determined by reference to Table 3, using the subject's current body weight. 
In the event of a subject's gaining weight such that he/she would progress from one dose 
level to a higher dose level according to Table 2, while at the same time requiring dose 
reduction because of a relevant adverse event (as described above and in Section 8.1.1.2), 
the subject will remain at the previous dose level. 
In the event of a subject's losing weight and the occurrence of a relevant AE, only one 
dose reduction is allowed at the next injection session. 
8.2.4 
Duration of treatment per subject 
Each subject who completes the study will have received the total of four treatments, 
each comprising four intraglandular injections administered on a single day. The fourth 
treatment day is scheduled to be 48 weeks after the first treatment day, with a permitted 
variation of up to ±6 weeks. For details see Section 6.1.2. 
Each treatment is to be followed by an observation period of 16 weeks ± 2 weeks. 
Therefore, for all subjects, the total duration of all injection cycles will be 64 weeks (with 
the permitted variation as specified in Table 6, 56–72 weeks). 
8.2.5 
Treatment compliance 
At the beginning of the study, the site will receive drug accountability forms to document 
how and when IP is dispensed to subjects or returned unused. These forms will be made 
available to the authorized individuals (e.g. monitor, auditor) and will include the 
following information: study number, dates, quantities, and the code number assigned to 
the IP and study subjects. 
All injections will be administered by study-site staff, so deviations from compliance 
with the treatment schedule (apart from discontinuation) are not anticipated. 
The vials will be checked to ensure that the IP assigned by the IWRS was administered. 
8.2.6 
Treatment of overdose 
As study treatment will be administered exclusively in a clinical setting by study-site 
medical personnel, the risk of overdose (e.g. due to reconstitution or application error) in 
this study is considered to be low. Nevertheless, any deviation from the planned dosing 
scheme (excluding dose adjustment due to body weight changes or AEs) is to be reported 
as an AE and treated accordingly. The investigator is advised to use best clinical 
judgment in the unlikely event of an overdose with the IP. 
There is no significant information regarding overdose from clinical studies in adults in 
upper limb spasticity, cervical dystonia, and blepharospasm. 


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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 hours 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 in four adult patients whose clinical signs were 
consistent with those of naturally occurring botulism [Chertow 2006]. 
Symptoms of overdose are not immediately apparent following injection. By the time 
symptoms of intoxication are observed, treatment with anti-toxin will no longer be 
effective because the neurotoxin has already irreversibly blocked the transmitter release. 
Compounds 
releasing 
acetylcholine 
(e.g., 
physostigmine, 
guanidine, 
3,4-
diaminopyridine) might be helpful. However, there is no experience with a specific 
antidote to BoNT including NT 201 in the clinical management of overdose. A published 
case report describes the successful treatment of dysphagia with intranasal neostigmine 
[Marchini 1997]. 
Subjects (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 
Before enrollment, the subject's medical history is to be recorded. It is to include a 
detailed list of all medications (including rescue medication) that the subject took during 
at least the four weeks (for Botulinum toxin preparations, one year) up to the date of 
screening. The record is to include the drug name (trade or generic), route of 
administration (e.g., intravenous, oral), total daily dose/unit (expressed in mg, mL, or IU), 
indication, the start and stop date (day, month, and year) for each medication, and it must 
later be completed to show whether the medication is ongoing at the end of the study. 
Similar information should be collected and assessed for any non-drug therapies that may 
have an impact on study results, e.g. salivary-gland surgery. 
For details of medications prohibited at/before screening, see the exclusion criteria 
(Section 7.3). 
The following medications are forbidden, or their intake is restricted, during the study: 


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– Botulinum toxin during the screening period and the entire year before screening. 
– Botulinum toxin (other than the study treatment) at (or planned for) any time during 
the entire study period. 
– Concomitant medication known to cause strong hypersalivation (e.g. clozapine). 
– Concomitant use of aminoglycoside antibiotics, curare-like agents, or other agents 
that might interfere with neuromuscular function and of anticoagulants (however 
aspirin and platelet aggregation inhibitors are allowed) 
– Pharmacological treatment for sialorrhea or concomitant medication known to 
influence sialorrhea strongly (e.g. anticholinergics; with exception of locally applied 
or short acting drugs used under general anesthesia) within 45 days before baseline 
and during the entire study period. 
The following non-drug therapies are forbidden to be planned during the study: 
– Salivary gland surgery or irradiation during the entire study period (including the 
screening period). 
– Surgery (except minor surgeries not affecting the head-neck region) in any indication 
in the three months before screening, during the screening period or planned for any 
time during the main study period. 
Hyposalivation or dry mouth – as a possible temporary consequence of the study 
treatment – can be eased by sialogogues such as ice chips or cold water. The use of sugar-
free chewing gums or sour sugar-free sweets is also considered suitable for reducing a 
sensation of dry mouth. Furthermore, for a purely symptomatic treatment of 
hyposalivation a wide range of saliva substitutes are available on market, including 
sprays, gels and mouth rinses. It is recommended to use those agents to diminish 
symptoms 
of 
dry 
mouth 
temporarily. 
Saliva 
substitutes 
mostly 
contain 
carboxymethylcellulose, xanthan gum or mucins. Oxygenated glyceroltriester-based 
saliva substitute sprays seem to be also effective improving symptoms of xerostomia. The 
dental association of Baden-Württemberg, Germany, recommends two saliva substitutes: 
Glandosane® (Cell Pharm GmbH, Bad Vilbel, Germany) for edentulous patients (it is 
based on carboxymethylcellulose) and Dry Mouth Gel® (GC Europe, Leuven, Belgium) 
for dentulous patients (as it has a neutral pH value and is based on diglycerine). Subjects 
with dry mouth should be advised to try some saliva substitutes and should choose one 
agent according to their preference and to avoid the use of such substances before or 
during saliva collection as specified in Appendix 16.3.1. 
Therapy changes (including changes of regimen) during the study are to be documented 
in the subject's file and in the eCRF. All concomitant medications administered in 
connection with adverse events are to be recorded. 
8.4 
Restrictions during the study 
The following life-style behavior patterns are forbidden during the study: 


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– All recreational drugs (i.e., the use of any illegal drugs, or the use of legal drugs for 
recreational purposes). 
– Smoking and the consumption of alcoholic drinks are prohibited during the study. 
For restrictions on concomitant medications and other forms of treatment, see 
Section 8.3. 
8.5 
Blinding 
The main period of the study will be conducted in a double-blind fashion. All vials 
containing study medication (active or placebo) will have the same appearance. The 
identity of individual IP will remain unknown to the investigator, medical staff, all 
subjects, their caregivers and other study staff (excluding the external unblinded 
biostatistician). All other individuals involved in the study (e.g. clinical study manager, 
medical expert, study biostatistician) will remain blinded. 
An independent DMC will assess subject safety data throughout the study (see 
Section 12.4.7.3). Special care will be exercised in the selection of DMC members in 
order to safeguard the study team from unblinding. Procedures for the evaluation of 
safety data and unblinding will be documented in writing. Details of DMC members and 
the committee's charter are provided separately. 
8.5.1 
Emergency envelopes 
The
 computer randomization program (see Section 8.2.1) also will be used to 
prepare a complete set of sealed emergency envelopes. In an emergency, these envelopes 
will allow unblinding of the treatment received by an individual subject while 
maintaining the overall study blind. The set of envelopes will be sent to 
 
, Germany) to be kept there for emergency unblinding if necessary. 
At the end of the study, all emergency envelopes are to be returned to the sponsor's 
quality management department. Any opened emergency envelope must be returned 
bearing the date and reason for opening.  
Any other emergency unblinding will be done through the IWRS. 
8.5.2 
Unblinding procedures 
The blind will not be broken until the blind data review meeting has convened, the 
statistical analysis plan [SAP] has been finalized, and the database has been closed. After 
the blind is broken, the statistical analysis of results will proceed, which will be 
documented according to GCP. 
The DMC will be semi-blinded with respect to treatment group comparisons based on 
frequency tables (“semi-blinded” means here that tables will only contain labeled 
treatment-group information such as “Treatment A” and “Treatment B”). Subject data 


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listings will not contain any treatment-group information; thus, the DMC will remain 
blinded in respect of the treatment administered to individual subjects. To ensure blinding 
of the sponsor's study-team members and of the staff at the sites, these persons will not 
participate in the closed sessions of the DMC meetings and will not have access to the 
semi-blinded data prepared for the DMC. An electronic version of the semi-blinded 
treatment allocation (“Treatment A” and “Treatment B”) will be transferred from the 
randomization officer to the DMC biostatistician, who will be responsible for the 
preparation of the tables and listings for the DMC meetings and will not be part of the 
study team. The DMC may require knowing 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 to give advice. The biostatistician of the DMC will also receive 
IWRS access and a password enabling him/her to break the blinding code of subjects via 
this system. The DMC biostatistician is responsible for the safekeeping of the password. 
If safety concerns arise that require the unblinding of a subject by the DMC, then the 
DMC should confer with Merz before performing unblinding of the subject by IWRS. 
Detailed procedures for unblinding in any case of safety concern are laid down in the 
DMC charter. 
The investigator will remain blinded throughout the study except in cases where 
unblinding is required: In the event of an SAE that requires further therapeutic decisions 
depending on the knowledge of the treatment group, the investigator will use the IWRS 
for unblinding. The sponsor will be notified through the IWRS. Additionally, the 
Corporate Product Safety department will be able to unblind subjects by means of the 
IWRS. 
Furthermore, PharmOlam will also receive IWRS access and a password for regulatory 
unblinding for reporting suspected unexpected serious adverse reactions to regulatory 
authorities and IEC(s)/IRB(s).  
 
 


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9 STUDY ASSESSMENTS AND VISIT SCHEDULE 
9.1 
Assessments 
9.1.1 
Clinical evaluations 
9.1.1.1 
General assessments and screening 
After consent and assent has been obtained, at the screening visit the subject's 
demographic data, medical history and all previous (i.e., administered within the past 
year for BoNT products or 45 days for all other medications), current and concomitant 
medications and treatments planned during the study will be recorded (see Section 8.3). 
A review of this information will aid the investigator in assessing whether the subject 
should be enrolled. Other data will be collected as required, including information 
obtained from a physical examination (which must include the chest, to ensure there is no 
previous evidence of aspiration), a neurological examination and vital signs (see below). 
For children suffering of cerebral palsy (CP) the severity of CP will be assessed by the 
Gross Motor Function Classification System (GMFCS) at baseline. Dental examination 
by a dentist needs to be performed during the screening period (allowing the investigator 
to review the dental examination report and dental exclusion criteria at baseline visit the 
latest). Counseling of parents and subjects may take place according to need and mental 
capacity, at the investigator's discretion. In case if the subject is not eligible (due to any 
temporarily limited condition e.g. short term infection of airways) at the baseline visit 
he/she will be considered to fail screening. Rescreening of this particular subject is 
allowed to be performed subsequently to the resolution of the temporary condition. In this 
case a new screening number needs to be generated and all screening assessments need to 
be he repeated. 
The following vital signs will be examined as scheduled in the overview of study 
activities (Table 6): heart rate and systolic and diastolic blood pressure (after 5 min. in a 
recumbent position); temperature. Body height will be measured with a stadiometer, and 
body weight (with the subject in underwear and not wearing shoes) will also be 
measured. 
9.1.1.2 
Efficacy assessments 
The following efficacy assessments will be used to compare the efficacy of the active 
treatment (NT 201) with that of placebo. Details of these assessments are given in the 
appendices to this protocol Appendix 16.3. 
• Unstimulated salivary flow rate [uSFR] (weighing of two absorptive swabs soaked 
with saliva over five minutes; procedure repeated once after 30 minutes [±5 minutes]) 
for all randomized subjects. 




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To monitor potential spread of toxin, subjects, carer and parent(s) (as appropriate) will be 
actively questioned about the occurrence of AESIs at every visit after every injection 
session of investigational product (for details see Section 10.3). AESIs are to be reported 
to the responsible CRO within 24 hours (see reporting procedure in Section 10.2). Any 
adult responsible for the child’s care will be given (a) contact card(s) with emergency 
instructions for the prompt reporting of adverse events. 
All subjects for whom AEs are reported, whether these are considered related to the use 
of investigational product or not, will be monitored carefully until the AE has resolved or 
stabilized, or until the final visit of this study (i.e. 16 weeks after the last injection of the 
IP). 
9.1.2 
Laboratory evaluations 
9.1.2.1 
Clinical and research laboratory evaluations 
Blood and urine will be sampled for standard laboratory assessments and for antibodies 
against BoNT according to the schedule set out in Table 6. For hematological 
measurements 1.2 mL blood will be drawn into an EDTA tube, for clinico-chemical 
assessments 1.2 mL blood will be drawn into a serum tube and for antibodies against 
BoNT testing 19.9 mL blood will be drawn into 3 serum tubes for subjects ≥30 kg BW. 
The total blood volume required for this study will be 47.0 mL over 72 weeks (details in 
Table 5 and Section 9.1.6). 
In order to minimize distress and bruising, only qualified staff, experienced in pediatric 
venipuncture, will perform the blood draw as follows: 
• All children will be offered local anesthesia (e.g., using lidocaine plaster such as 
EMLA or lidocaine or Ametop cream). 
• Children will always have a loved one present to comfort them (if they want) and be 
distracted during the blood sampling as necessary. 
• Depending on IEC/IRB advice and local rules, we suggest that only two attempts 
should be made for research-only sampling. Should the participant become acutely 
and inconsolably distressed during or before the blood draw the procedure must stop 
immediately and the subject must be withdrawn from the sampling. 
• Blood samples will be kept to a minimum, particularly for the younger children. 
9.1.2.2 
Clinical chemistry, hematology and pregnancy tests 
Safety laboratory assessments will include the values listed in Table 4 below. 


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Table 4: 
Standard safety laboratory values 
Clinical Chemistry: 
Alanine aminotransferase 
Glucose 
Albumin 
γ-Glutamyltransferase 
Alkaline phosphatase 
Lipase 
Amylase, total * 
Potassium 
Aspartate aminotransferase 
Protein total  
Bilirubin, total † 
Sodium 
Calcium 
Triglycerides 
Chloride 
Thyroid-stimulating hormone 
Cholesterol, total 
Urea / Blood urea nitrogen 
Creatine kinase 
Uric acid 
Creatinine 
 
Hematology: 
Hematocrit, hemoglobin, red blood cell count and derived parameter 
(MCH, MCV, MCHC) 
White blood cell count  
Differential count (automated count, percentage and absolute; manual 
count, percentage) 
Platelet count 
Pregnancy test: 
β-HCG Human chorionic gonadotropin, beta form (in females of child-
bearing potential only) in urine (at visits where pregnancy testing is 
specified). 
* If total amylase is elevated, then pancreatic amylase will also be measured 
† If total bilirubin is increased, then indirect bilirubin will also be measured. 
9.1.2.3 
Antibodies against Botulinum toxin  
To detect antibodies against Botulinum toxin in study subjects the fluorescence 
immunoassay [FIA] and the hemidiaphragm assay [HDA] will be used. 
Blood will be sampled for analysis of antibodies against BoNT for subjects with ≥30 kg 
BW. For children with <30 kg BW no blood samples for analysis of antibodies against 
BoNT will be taken. Blood amounts will be taken according to the weight group of the 
subject in context of all blood withdrawals during the study (Section 9.1.7). For subjects 
with ≥30 kg BW first blood samples are taken at baseline (V2). Subsequent antibody tests 
after repeated IP exposure will be performed for subjects with ≥30 kg BW only at the 
end-of-study visit (V18; alternatively, if preferred, at V17). 
The serum amount necessary for FIA-AB is 1.5 mL and 4.5 mL for HDA. To yield the 
required serum amount the estimated blood amount is 4.9 mL for FIA-AB and 15 mL 
(2x7.5 mL) for HDA. Sample work-up at the study site includes 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. 


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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 react with the toxin, but the FIA-AB is not capable to 
discriminate between neutralizing and non-neutralizing antibodies [Goschel 1997]. 
Samples that are positive in the FIA-AB will be tested using the validated mouse ex vivo 
HDA. The HDA is the most sensitive functional assay (sensitivity <0.5 mU/mL) 
currently available [Sesardic 2004]. To spare animals, the assay is performed only if the 
FIA-AB is positive. 
9.1.3 
Pharmacodynamics 
Not applicable. 
9.1.4 
Pharmacokinetics 
Not applicable. 
9.1.5 
Pharmacogenetics 
Not applicable. 
9.1.6 
Table of blood volume 
Blood samples will be taken for general safety testing (hematological and clinico-
chemical assessments) and also for additional measurements of antibodies against BoNT. 
Laboratory evaluations will be performed as possible for the age group of the subject. 
The bulletin of the World Health Organization 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 eight weeks were 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. 
Per individual, the trial-related blood loss (including any losses in the maneuver) should 
not exceed 3% of the total blood volume during a period of four weeks and should not 
exceed 1% at any single time. The total volume of blood is estimated at 80–90 ml/kg 
body weight; 3% is 2.4 ml blood per kg body weight [European Medicines Agency 
(EMA) 2008]. 
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 will be restricted in frequency and 


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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 body weight 
Maximum blood volume in any withdrawal: 1% of TBV 
Maximum blood volume over 12 weeks: 
3% of TBV 
A central laboratory capable of handling properly the relatively smaller volumes of 
samples (as compared to those usually obtained from adult subjects) will perform the 
analyses. 
The following blood volumes are necessary to result in sufficient serum volumes for the 
respective tests: 
• Hematology (EDTA tube): 
 
1.2 mL  
• Clinical chemistry (serum tube): 
1.2 mL  
• Fluorescence immunoassay [FIA]: 
4.9 mL blood (1.5 mL serum) 
• Hemidiaphragm assay [HDA]:  
15.0 mL blood (4.5 mL serum) 
Note that for clinical chemistry the same procedure for blood sampling is always to be 
followed, irrespective of which laboratory values are to be measured at the visit in 
question.  Details of the procedures, including possible local anesthesia, are given in 
Section 9.1.2 
Table 5 shows the maximum amounts of blood that will be required and the calculated 
maximum total amount of blood to be drawn during the study. 
Table 5: 
Blood volumes required 
Visit 
Blood volume withdrawn 
Hematology * 
Clinical chemistry † 
Antibody tests†# 
Screening 
1.2 ml 
1.2 ml 
 
Visit 2 
 
 
19.9 ml 
Visit 6 
1.2 ml 
1.2 ml 
 
Visit 18 
1.2 ml 
1.2 ml 
19.9 ml 
Total volume drawn: 
7.2 ml (47.0 ml#)  
* To be collected in an EDTA tube (Section 9.1.2).  † To be collected in a serum tube (Section 9.1.2).  
# Only for subjects with ≥ 30 kg BW (Section 9.1.2.3). 


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9.1.7 
Specimen preparation, handling, storage, and shipping 
This study does not involve the retention of any biological samples. The only samples 
taken will be blood and urine for safety testing (the latter for on-site pregnancy tests 
only). These will be analyzed at the central laboratory without retention of material. 
9.2 
Visit schedule 
The purpose of the screening visit is to determine the subject's eligibility for study 
participation. The subject will be notified of any new diagnosis of an abnormal medical 
condition during the screening process, and will be referred for appropriate care. The 
screening evaluation must be completed 7–28 days (Table 6) before the baseline visit. 
The baseline visit, at which the final decision on inclusion, the randomization (subjects 
aged 6–17 years only) of the subject and the administration of the first study treatment 
are performed, is defined as Day 1. 
During the study, subjects will receive NT 201 (or, in the main period, matching placebo 
[subjects aged 6–17 years only]) at the beginning of each 16-week injection cycle. The 
visit schedules with study activities are shown in Table 6. For each study visit a time 
window is allowed, as detailed in Table 6 and described in Section 6.1.2. 
The final study visit will take place after a total of 64 ± 8 weeks, at the end of the fourth 
injection cycle. Since this will be as long as 16 ± 2 weeks after the last administration of 
NT 201, no further visit for safety follow-up is planned. 
At the physician's discretion, the final visit of each study injection cycle can be advanced 
by up to two weeks (e.g., if the physician considers earlier repeated treatment/assessment 
to be advisable) or postponed by up to two weeks (in the converse situation). 
Unscheduled visits may be required in the case of premature discontinuation of study 
treatment. In this case, a final assessment (the end-of-study visit) will be performed. If 
additional safety follow-up is necessary after this assessment, subjects may be contacted 
by telephone or assessed in the clinic, depending on the nature of the follow-up required. 


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Table 6: 
Schedule of study tests, procedures and clinic visits 




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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., subject-reported outcome variables [questionnaires 
and scales] during the course of the study) need not be documented as AEs, because these 
changes will be recorded as efficacy variables. Elective treatments planned before 
screening and which are documented in the subject’s source data are usually not regarded 
as AEs. 
The period of observation for AEs extends from the time when the informed consent 
form was signed until the subject's final study visit. Any medical occurrence between the 
time when the informed consent form is signed and the first intake of study medication is 
an AE and has to be documented in the subject's file and in the eCRF AE report form. 
Non-serious AEs will not be followed up after the final study visit (i.e., 16 ± 2 weeks 
after the last administration of NT 201), which will take place after a total of 64 ± 8 
weeks, at the end of the fourth injection cycle. In cases of study participation 
discontinuation the final visit takes place 16 ± 2 weeks after the last administration of NT 
201, after which no further visit for safety follow-up is considered necessary (see 
Section 9.2). 
Pre-existing conditions that do not worsen during the course of the study are not 
reportable as AEs. To determine whether a condition has worsened, it is compared to the 
condition of the subject at screening. Abnormal clinically relevant laboratory values 
obtained during the subject’s screening period will only meet AE criteria if newly 
detected. 
Incidental findings of abnormal laboratory values will be reported to the investigator 
immediately so that the subject can promptly be referred for treatment and care. 
Data pertaining to AEs will be collected during each study visit based on the subject’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 file and on the eCRF AE report page. The following information 
must be recorded: 
• AE diagnosis or main symptom. 


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• Date of onset. 
• Date of worsening. 
• Intensity (maximum observed; see Section 10.1.1). 
• Causal relationship (not related, related). 
• Serious (yes or no). 
• Outcome (see Section 10.1.3). 
• Action taken with IP (see Section 10.1.3). 
• Whether the AE led to discontinuation of the study (yes or no). 
• Date of resolution (and time, if applicable). 
After completion of all scheduled visit assessments the investigator must document any 
AEs arising from these assessments. 
In the case of an SAE or an AESI (alert term, as defined in Section 10.3), the investigator 
is also to complete an SAE report form or AESI report form and report the event to the 
sponsor immediately, as described in Section 10.2. 
Conduct in the unlikely event of overdose with NT 201 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 his/her daily activities. 
The definitions above are difficult to apply for some data (e.g., clinically relevant 
laboratory values that are documented and evaluated on the eCRF AE report page). In 
such situations, the investigator should make a judgment based on personal experience. 


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10.1.2 
Definition of causal relationship with investigational product 
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.” 
10.1.3 
Categories of actions taken and outcome 
Action taken with the IP: 
• Drug withdrawn (no further study injections given). 
• Dose reduced (at the next injection possible i.e. at V10a [injection cycle 3] or V14a 
[injection cycle 4] only, due to weight loss or AEs). 
• Dose increased (at next injection visit i.e. at V10a or V14a only, according to weight 
gain of subject). 
• Dose not changed. 
• Unknown. 
• Not applicable. 
• Drug withdrawn temporarily (further study injections delayed). 
The reportable outcomes and/or sequelae of an AE are as follows: 
• Recovered/resolved. 
• Recovering/resolving. 
• Not recovered / not resolved. 
• Recovered / resolved with sequelae. 
• Fatal. 
• Unknown. 
If there is more than one AE, only the AE leading to death will be attributed with a 
“fatal” outcome. 
10.2 Definition of a serious adverse event 
An SAE is any untoward medical occurrence, at any dose, that: 
• Results in death. 


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• Is life-threatening.3 
• Requires inpatient hospitalization, or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Consists of any other medically important condition.4 
For this study the following may be considered important medical conditions: suicidal 
ideation (a response of “yes” to questions 4 or 5) or any suicidal behavior as indicated by 
the C-SSRS and confirmed by the Investigator or when reported based on other 
information by the Investigator. 
In case of death, an autopsy report should be submitted (if available). The date and cause 
of death should be recorded. 
Hospitalizations for elective treatments planned before screening and which are 
documented in the subject’s source data are usually not regarded as SAEs. 
All SAEs that occur during the study period, whether considered to be related to IP(s) or 
not, must be reported by telefax, 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). 
• 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 report assessing site of the CRO listed below. 
                                                          
3 The term “life-threatening” in the definition of “serious” refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event that hypothetically might have caused death if 
it were more severe. 
4 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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Table 7: 
List of AESIs 
MedDRA Preferred Term (MedDRA version 15.1) 
Accommodation disorder 
Eyelid ptosis 
Peripheral nerve palsy 
Areflexia 
Facial paresis 
Peripheral paralysis 
Aspiration 
Hemiparesis 
Pelvic floor muscle weakness 
Botulism 
Hypoglossal nerve paresis 
Pneumonia aspiration 
Bradycardia 
Hyporeflexia 
Pupillary reflex impaired 
Bulbar palsy 
Hypotonia 
Quadriparesis 
Constipation 
Ileus paralytic 
Respiratory arrest 
Cranial nerve palsies, multiple 
Monoparesis 
Respiratory depression 
Cranial nerve paralysis 
Muscular weakness 
Respiratory failure 
Diaphragmatic paralysis 
IIIrd nerve paresis 
Speech disorder 
Diplopia 
IVth nerve paresis 
Trigeminal nerve paresis 
Dysarthria 
VIIth nerve paralysis 
Urinary retention 
Dysphagia 
Paralysis 
Vision blurred 
Dysphonia 
Paralysis flaccid 
Vocal cord paralysis 
Dyspnea 
Paraparesis 
Vocal cord paresis 
Extraocular muscle paresis 
Paresis 
 
Eyelid function disorder 
Paresis cranial nerve 
 
In addition to the terms listed in Table 7, adverse event ‘dry mouth’ considered to be 
severe, serious or irreversible are also to be reported as AESIs. 
10.4 Expected adverse events 
Expected AEs are those listed in the current version of the Investigator’s Brochure [IB] 
for Xeomin®. It should be noted that intraglandular application of BoNT is not 
necessarily expected to lead to the same adverse events as application at other sites (e.g. 
intramuscular injection). 
10.5 Unexpected adverse events 
An unexpected AE is an experience not previously reported in nature, severity, or 
incidence in the current IB. 


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10.6 Pregnancy 
Any pregnancy that starts during the study must be reported by the investigator to the 
CRO (see contact details in Section 10.2.) within 24 hours of learning of its occurrence. 
The pregnancy plan will include: 
• Ensuring that the young person is treated with respect and confidentiality. 
• Measures taken at site to ensure the physical and mental safety and well-being of the 
mother and baby; the mother will be referred for counseling as appropriate. 
• The subject will be withdrawn from the study immediately (apart from end-of-study 
safety checks and assessments). 
• She will receive no further study drug. 
• Pregnancies and pregnancy follow-up are to be reported on a pregnancy monitoring 
form. 
• With the explicit consent from the subject's parents or legal representative(s), which 
must be documented in the subject's medical records, pregnancy follow-up must 
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 pregnancy is to be reported as a non-serious AE (drug exposure before or during 
pregnancy) within 24 hours of knowledge as well. 
10.7 Other safety assessments 
A dental and oral examination will be performed by a qualified dental health provider 
(minimum qualification: dentist) at screening (V1), V3 and V6 of the main study period, 
at V10 and  at the-end-of-study visit (V18), or at the subject's last study visit if this is 
earlier. Results of dental and oral examination will be reported in terms of adverse 
events: findings indicating a worsening of the subject's condition since screening are to 
be recorded as adverse events. 
Details are given in Appendices 16.4.1. 
As part of the physical examination, particular attention will be paid to lungs in order to 
detect any signs of aspiration, at baseline and every subsequent visit. 
C-SSRS 
Prospective monitoring of suicidality with the Columbia-Suicide Severity Rating Scale 
[C-SSRS] should be considered the most important (but not the only) source of 
information concerning suicidality. 


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Suicidality will be assessed prospectively in subjects at baseline and every scheduled and 
unscheduled post-baseline site visit. 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 newly recruited patients:  
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 electronic 
Case Report Form (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] supported by Columbia-Classification Algorithm for Suicide 
Assessment (C-CASA)  developed by the same group [Posner 2007b]. 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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11 DATA QUALITY ASSURANCE 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any 
time, even after the end of the 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. 
The sponsor is also to be notified immediately of any inspection foreseen at third-party 
vendors (e.g. inspection of investigation sites or a CRO by national authorities). 
11.1 Standardization procedures 
Standardization procedures will be implemented to ensure accurate, consistent, complete, 
and reliable data, including – but not limited to – methods to ensure standardization 
among sites (e.g., training, newsletters, investigator meetings, monitoring, central 
laboratories, centralized evaluations, and validation methods). 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP and ethical 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 are to be entered 
and/or filed in the respective subject file. This includes a copy of the letter sent to the 
subject’s primary physician about the subject’s participation in the study (provided the 
subject has a primary physician and has agreed to the primary physician being informed). 
The subject's file must also contain a descriptive statement on the informed consent 
procedure (see Section 3.3.2). The site will keep a source data location list which will 
outline for the different data categories (e.g. demographics, medical history, and adverse 
events etc.), including electronic data, which document serves as source for this data (e.g. 
subject file, laboratory report). 
If the subject has no medical history on file at the study site, every attempt (e.g. by letter, 
e-mail, phone) should be made to obtain the following data by means of a doctor's letter, 
in order to verify the fulfillment and non-fulfillment of inclusion and exclusion criteria. 
These attempts are to be documented in the subject file. 
Study sites will use a sponsor-validated, web-based electronic case report form [eCRF], 
and study data will be entered on a secure on-line basis by authorized study-site 
personnel. 
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 


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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, such as printing by 
sequential date order. 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 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 corrections of any paper-based data. 
If the site is using a validated computer system including audit trail with a separate access 
for the monitor (i.e., the monitor can only access the data of the study subjects), then no 
such paper print-outs are required. 
11.3 Data management 
Authorized members of the investigator’s staff will enter the information required by the 
protocol into the web-based eCRFs (electronic data-capture [EDC] system 
) 
provided by Merz Pharmaceuticals/
 and developed by the data manager for 
the study. 
All persons who are to enter data into the eCRF will be trained by using an e-learning 
tool and support from a member of the CRO if necessary. After the successful completion 
of the training, all participants will receive a training certificate. Access to the e-learning 
tool and to the eCRF will be password-controlled. Passwords must be kept securely and 
be individual to each member of staff, and must not be shared with or used by anyone 
else. 
Plausibility checks will be performed according to a data validation plan. Inconsistencies 
in the data will be queried to the site via the web-based eCRF; answers to queries or 
changes to the data will be documented in the eCRF directly by an authorized member of 
the investigator’s staff. The audit trail in 
 documents all changes. Edit checks 
trigger automatic queries during data entry when a field is not populated according to the 
specifications set out in the data validation plan. Manual queries (to be answered by site 
staff) can be raised during source data verification or during medical, safety or data 
management review. 
Laboratory data will be received electronically and merged with the eCRF data (but not 
uploaded into the EDC system). Plausibility checks will be performed to ensure 
correctness and completeness of these data. Abnormal results will be reported to the 
investigator in a timely manner for review and treatment if necessary to ensure the 
subject’s well-being during the research. 
The sponsor’s data management function team will be responsible for data-processing, in 
accordance with the sponsor's data management procedures and all applicable laws. No 
identifiable data will be processed. After all data have been entered and all queries 
solved, the data base will be closed. After database closure, unblinding will take place. If 


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there are any changes to the data after data-base closure, these changes will be 
documented according to the relevant SOP. 
The results of the semi-structured interview will be documented by using the paper 
version of the C-SSRS and the data will be entered into the eCRF. Plausibility checks 
will be performed to ensure correctness and completeness of these data. 
11.4 Monitoring 
This study will be monitored regularly by a qualified monitor from the CRO according to 
GCP guidelines and the respective SOPs. 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 all 
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. Risk-based monitoring will not be used for 
this study because of the vulnerable nature of the study participants. 
In addition, the monitor will check whether all AEs and SAEs have been reported 
appropriately within the time periods required. 
The investigator and all staff will be expected to cooperate with the monitor by providing 
any missing information whenever possible. The investigator must be available to answer 
questions arising during regular monitoring visits. In addition, the investigator is required 
to: 
• Have all data properly recorded in the eCRF and subject files before 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 subject 
screening/enrollment log according to local confidentiality requirements – for example by 
initials and date of birth. 
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 team may arrange to 
visit the investigator in order to audit the performance of the study at the study site, as 


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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 authorized contract auditors. In this case, the sponsor’s 
quality assurance function manager 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 accompany the auditor(s). 






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Safety evaluation set MP 
The safety evaluation set [SES] of the main period is the subset of all subjects who 
received study medication (NT 201 or placebo) during the main period of the study. 
Full analysis set 
The full analysis set [FAS] is identical to the subset of subjects in the SES (MP). 
Per protocol set 
The per protocol set [PPS] is the subset of subjects in the FAS aged 6-17 years without 
major deviations from this protocol. Major protocol deviations will be defined during the 
blind data review meeting at the end of this study.  
For the OLEX period, the following analysis set is defined: 
Safety evaluation set OLEX 
The safety evaluation set [SES] of the OLEX period is the subset of all subjects who 
received study medication (NT 201) at least once during the OLEX period of the study. 
12.3 Variables for analysis 
12.3.1 
Efficacy variables 
12.3.1.1 
Primary efficacy variables 
The following variables will be defined as primary and co-primary efficacy variables for 
the subjects aged 6–17 years: 
• Change in mean uSFR from baseline (V2) to V3 [Week 4]. The mean uSFR is 
calculated by averaging the two assessments at each visit. 
• GICS at V3 [Week 4] representing the functional improvement in drooling since 
baseline as assessed by the carer/parent(s). 
12.3.1.2 
Secondary efficacy variables 
The following secondary efficacy variables will be analyzed for the subjects aged 6–17 
years: 
• Change in mean uSFR from baseline (V2) to V4 and V5 [Week 8 and 12, 
respectively]. 
• GICS at V4 and V5 [Week 8 and 12, respectively]. 


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12.3.2 
Pharmacodynamic variables 
Not applicable. 
12.3.3 
Pharmacokinetic variables 
Not applicable. 
12.3.4 
Pharmacogenetic variables 
Not applicable. 
12.3.5 
Safety variables 
12.3.5.1 
Primary safety variable 
Occurrence of treatment emergent AEs [TEAEs] overall and by injection cycle. 
12.3.5.2 
Secondary safety variables 
• Occurrence of treatment emergent AESIs [TEAESIs] overall and by injection cycle. 
• Occurrence of treatment emergent SAEs [TESAEs] overall and by injection cycle. 
• Occurrence of TEAEs related to treatment as assessed by the investigator overall and 
by injection cycle. 
• Occurrence of TEAEs leading to discontinuation overall and by injection cycle. 


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12.3.5.3 
Other safety variables 
• The number of subjects with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent during treatment based on the C-SSRS. 
12.3.6 
Other variables 
The following additional variables will be analyzed: 
• Vital signs (blood pressure, heart rate, body temperature) at screening (V1), baseline 
(V2), V3 [week 4], V6 [week 16], during the main period and at each injection visit in 
the extension period  and at the end-of-study visit (V18) [Week 64]. 
• Body height and weight at screening (V1), final visit of the main period (V6) 
[Week 16], and end-of-study visit (V18) [Week 64]. 
• BMI, calculated from body weight and height, at screening (V1), final visit of the main 
period (V6) [Week 16], and end-of-study visit (V18) [Week 64]. 
• Clinical chemistry (including alkaline phosphatase [AP] and blood glucose [BG]) and 
hematology at screening (V1), final visit of the main period V6 [Week 16], and end-of-
study visit V18 [Week 64]. 
• GMFCS level at baseline (V2) for CP patients. 
• Occurrence of antibodies against BoNT-A in subjects with ≥ 30 kg BW. 
12.4 Statistical analysis methods 
Full details of all analyses will be given in the SAP. 
12.4.1 
Efficacy variables 
All efficacy analyses on data from the main period will be based primarily on the FAS 
and where deemed sensible additionally, for sensitivity purposes, on the PPS. Analyses 
on data from the extension period are based on the SES only. If not stated otherwise, 
analyses are performed by all age groups and treatments. Statistical tests will be two-
sided hypothesis tests for between-treatment differences in general. Continuous variables 
(values and changes from baseline) will be summarized by N, mean, standard deviation, 
median, quartiles, minimum, and maximum. For qualitative variables, absolute and 
percent frequencies (N, %) and, if applicable, shift tables will be displayed. Confidence 
limits and descriptive p-values will be given, where appropriate. 






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All analyses will be performed by age groups and treatment and additionally for the 
group of subjects of all ages (2-17) who received NT 201 in the respective treatment 
period (main or extension period). 
12.4.6 
Other variables 
Subject dispositions, demographic data, and baseline characteristics will be presented by 
using standard descriptive statistics; no homogeneity tests will be performed. 
Demographic data will be summarized for all subjects in the SES, the FAS and the PPS. 
This will be done by age groups and treatment and for the SES additionally for the group 
of subjects of all ages (2-17) who received NT 201 in the respective treatment period 
(main or extension period). The remaining baseline data will be summarized descriptively 
for the FAS and the PPS only. 
Frequencies of concomitant treatments will be given based on different ATC [Anatomic 
Therapeutic Chemical] code levels for the SES. Indications for concomitant therapies will 
not be coded and will only be listed. Medical history and concomitant diseases will be 
described on the basis of MedDRA system organ class and preferred term levels for the 
SES.  
Occurrence of antibodies against BoNT-A in subjects with ≥ 30 kg BW will be analyzed 
descriptively (values and changes from baseline) and screened for individual notable 
values and/or changes. 
12.4.7 
Special statistical/analytical issues 
12.4.7.1 
Discontinuations and missing data 
Reasons for premature discontinuation by a subject will be summarized descriptively and 
listed. Where the discontinuation was due to an adverse event, this will be included in the 
listing of adverse events, and such events will be included as a category in the summary 
of adverse events. 
The analysis of the primary and secondary efficacy variables will be performed using a 
MMRM as well as using an ANCOVA based on observed cases and an ANCOVA with 
missing values replaced by the baseline value or “no change” (‘baseline observation 
carried forward approach’). By using all values of the dependent efficacy variable 
available in the timeframe underlying the MMRM, i.e. the main period, the MMRM 
reduces the influence of single missing values. The use of the ANCOVA model with 
missing values replaced by the baseline value is considered to be a conservative approach 
because if a comparable percentage of missing values is expected in both treatment 
groups (in the placebo group there may be more missing values due to lack of efficacy 
and in the verum group more due to adverse events) the replacement of missing values by 
the baseline value of the uSFR – or by ‘no change’ for the GICS – leads to a decrease in 
the difference of the observed treatment effects (see also Section 12.4.1.1). 


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If a subject is not able to answer (documented in the eCRF) then the result of the subject's 
GICS entry will be replaced by the result of the carer's GICS entry. If it is not 
documented in the eCRF that the subject is not able to answer then the subject's GICS 
entry will not be replaced by the carer's GICS entry. 
12.4.7.2 
Interim analyses 
No interim analysis is planned for this study except from the analyses providing tables 
and listings for the DMC meetings. 
12.4.7.3 
Committees 
An independent DMC will be assigned to monitor subjects’ safety throughout the clinical 
course of the study (see Appendix 2, Section 16.2). It will consist of an odd number (e.g., 
three) of physicians who are suitably qualified and who have experience in analyzing 
pediatric clinical trial data, to allow majority decisions to be made. The primary purpose 
of the DMC is to safeguard subjects by monitoring AESIs, SAEs and AEs on a regular 
basis. 
The DMC will meet at regular intervals, either physically or remotely by secure 
teleconference during the main and extension period to review safety data. They will 
decide upon and prioritize any safety issues and actions for the attention of the sponsor. 
The DMC is semi-blinded (see Section 8.5.2) with respect to treatment group 
comparisons based on frequency tables. Subject data listings will contain no treatment 
group information such that the DMC remains blinded with respect to individual subjects 
unless the treatment codes of individual subjects with AESIs, SAEs and AEs are 
unblinded for the DMC on request, by using the IWRS (see Section 8.5 for information 
on maintaining the study blind). 
If considered necessary, the DMC will make recommendations regarding the timely 
management of subject withdrawals and/or measures for the study if there are relevant 
safety findings. 
The DMC can make recommendations, if necessary, such as the following: 
• Changes in study design (such as lowering the dose, additional telephone contacts etc.). 
• Changes in timing of assessments. 
• Implementation of additional safety measures. 
• Unblinding of subjects if required for safety reasons. 
• Prematurely discontinuing dosing in an age group. 
• Prematurely discontinuing dosing in all age groups. 
• Putting the study on hold. 
• Stopping the study, as defined in Section 7.5.2. 


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For each DMC meeting, minutes will be taken by the responsible DMC 
coordinator/administrator of the CRO and reviewed by the DMC members before 
finalization. 
Details of responsibilities and procedures to be followed by the DMC will be laid down 
in the DMC Charter. 
A list of members of the committee and a copy of the committee's charter are provided 
separately and will be reviewed by the IEC/IRB. 
12.4.7.4 
Multiple comparisons/multiplicity 
The overall hypothesis of no differences between treatment groups is only to be rejected 
if both treatment comparisons – based on the co-primary efficacy variables – yield a 
significant result, i.e. if for both tests the hypothesis of no difference between treatment 
groups can be rejected. Thus, no issue with respect to multiplicity arises and no 
α-adjustment is necessary. 
Results of all other tests or confidence intervals are only descriptive; a confirmatory 
interpretation is not valid in this context. 
12.4.7.5 
Examination of subgroups 
Subgroups analyses by age groups are planned. Further details and the definition of any 
further subgroup analyses will be provided in the SAP. 


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13 DATA HANDLING AND RECORD-KEEPING 
By signing the eCRF (eSignature), the investigator will confirm that all investigations 
have been 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 
If corrections are necessary, an authorized member of the investigator’s staff will enter 
the correct data into the web-based eCRF. The audit trail in 
 documents all 
changes. 
All data required by this clinical study protocol are to be recorded in the eCRF as soon as 
possible. However, except where otherwise specified in Section 11.2, direct entries are 
not allowed; data must be transcribed from the source (e.g., subject file) to the eCRF. 
If corrections in the subject scales are necessary, the subject is to be instructed to make a 
correction by drawing only a single line through the error, leaving the incorrect entry 
legible. The subject is to date the correction but not initial it. The investigator is not to 
make any changes to these documents. 
Entries in paper-based source documents must be made with a blue or black ballpoint pen 
and must be legible. Pencils may not be used. It is not allowed to erase or overwrite 
entries, or to use correction fluid or tape. The monitor is not allowed to make entries. If 
corrections in paper-based source documents are necessary, an authorized member of the 
investigator’s staff will enter them in the following manner: the wrong entry will be 
crossed out, although it must remain legible, and the correct entry will be placed next to 
it. Corrections will be initialed, dated and, if necessary, explained (e.g. for corrections 
concerning adverse events or a co-primary variable). 
The sponsor's data management function team will be responsible for data-processing, in 
accordance with the sponsor's data management procedures. Database close will occur 
only after quality assurance procedures have been completed. 
13.2 Record-keeping 
Essential documents should be retained securely until at least two years after the last 
approval of a marketing application (whether pending or contemplated) in an ICH region, 
or at least two years have elapsed since the formal discontinuation of IP clinical 
development. 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 investigation site include (among other documents): 
• Subject files including records of study specific assessments and of the results of 
dental assessments. 


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• Subject 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. 
• A DVD with eCRF data and any associated subject-related source data (or, where 
applicable, authorized copies of source data). 
• Signed informed consent and assent forms. 
• Copies of site investigators’ and co-workers' curricula vitae. 
• Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies). 
• Copies of laboratory normal ranges and methods and most recent inspection 
accreditation. 
• 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 before the end of the 
retention period specified above without the prior written consent of the sponsor. The 
institution must inform the sponsor in due time if the principal investigator 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 results will be published in an appropriate journal, and publishing details will 
be given in the clinical study agreement. Publications concerning study results must be 
approved in advance by the sponsor in writing. 
The results of this study and any discoveries related to this study, regardless of whether 
they have technical or medical character, are the property of the sponsor. 
The 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 commitments of pharmaceutical industry 
associations. Study registration may include a list of the investigational sites, as 
applicable. 
No publications of results will reveal the identity of any subject. 
Note: A summary of the results may be required to be placed in the public domain, e.g., 
on the web sites of regulatory authorities. 


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15 REFERENCES 
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JJ. Effect of botulinum toxin in the treatment of drooling: a controlled clinical trial. 
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Jost WH. Treatment of drooling in Parkinson's disease with botulinum toxin. Mov 
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Khan WU, Campisi P, Nadarajah S, et al. Botulinum toxin a for treatment of sialorrhea in 
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Kossmehl P, Freudenberg B, Wissel J. Experience with a New Botulinum Toxin Type A 
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SAP_000.pdf: 
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Merz Pharmaceuticals GmbH 
Statistical Analysis Plan 
Prospective, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study with an open-label extension period to investigate the efficacy 
and safety of NT 201 in the treatment of children and adolescents (2–17 years) 
with chronic troublesome sialorrhea associated with neurological disorders, 
and/or intellectual disability 
Phase 3 
MRZ60201_3091_1 
EudraCT Number: 2013-004532-30, IND Number: 112,731 
Version 1.0 Final 
Date: 21-Jun-2019 
Author: 
 (Statistician) 
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. 
NCT02270736, redacted version v1.0, 24Nov20




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TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................... 2 
 
LIST OF ABBREVIATIONS .................................................................................... 5 
1
 
GENERAL AND TECHNICAL ASPECTS ............................................................ 7 
2
 
Clinical Study Design and Objectives ....................................................................... 7 
3
3.1 
Clinical Study Design .............................................................................................. 7 
3.2 
Clinical Study Objectives ........................................................................................ 9 
 
Determination of Sample Size ................................................................................... 9 
4
4.1 
Safety ..................................................................................................................... 10 
4.2 
Efficacy .................................................................................................................. 10 
 
Analysis Sets .............................................................................................................. 11 
5
Safety Evaluation Set MP .................................................................................................. 11 
Full Analysis Set ................................................................................................................ 11 
Per Protocol Set ................................................................................................................. 11 
Safety Evaluation Set OLEX ............................................................................................. 12 
 
Variables for Analysis .............................................................................................. 12 
6
6.1 
Efficacy Variables ................................................................................................. 12 
6.1.1 
Primary efficacy variables ............................................................................... 12 
6.1.2 
Secondary efficacy variables ........................................................................... 13 
6.2 
Pharmacodynamic Variables ................................................................................. 17 
6.3 
Pharmacokinetic Variables .................................................................................... 17 
6.4 
Pharmacogenetic Variables ................................................................................... 17 
6.5 
Safety Variables ..................................................................................................... 17 
6.5.1 
Primary safety variable .................................................................................... 17 
6.5.2 
Secondary safety variables .............................................................................. 17 
6.5.3 
Other safety variables ...................................................................................... 17 
6.6 
Other Variables ...................................................................................................... 19 
 
Statistical Analysis Methods .................................................................................... 20 
7
7.1 
Efficacy Variables ................................................................................................. 20 
7.1.1 
Primary/Co-primary Efficacy Variable ........................................................... 21 
7.1.2 
Secondary Efficacy Variables ......................................................................... 24 
7.2 
Pharmacodynamic Variables ................................................................................. 25 
7.3 
Pharmacokinetic Variables .................................................................................... 25 
7.4 
Pharmacogenetic Variables ................................................................................... 26 


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7.5 
Safety Variables ..................................................................................................... 26 
7.6 
Other Variables ...................................................................................................... 34 
7.7 
Special Statistical/Analytical Issues ...................................................................... 41 
7.7.1 
Discontinuations and Missing Data ................................................................. 41 
7.7.2 
Interim Analyses .............................................................................................. 41 
7.7.3 
Data Monitoring Committee ............................................................................ 42 
7.7.4 
Multiple Comparisons/Multiplicity ................................................................. 43 
7.7.5 
Examination of Subgroups .............................................................................. 43 
7.7.6 
Pooling of Sites ................................................................................................ 44 
7.7.7 
Definition of Study Baseline and Cycle Baseline ........................................... 45 
7.7.8 
Definition of Study End ................................................................................... 45 
 
Changes in the Planned Analyses ........................................................................... 45 
8
 
References ................................................................................................................. 45 
9
Appendix 1: List of Tables, Figures, and Listings ............................................................ 46 
Appendix 2: List of Programmed In-text Tables, Figures, and Listings ........................... 46 


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 LIST OF ABBREVIATIONS 
1
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
AP 
Alkaline Phosphatase 
ATC 
Anatomical Therapeutic Chemical 
BDRM 
Blind Data Review Meeting 
BG 
Blood Glucose 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
BoNT 
Botulinum neurotoxin 
CI 
Confidence interval 
CP 
Cerebral palsy 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
EudraCT 
European Union Drug Regulatoring Authorities Clinical Trials 
FAS 
Full Analysis Set 
GICS 
Global Impression of Change Scale 
GMFCS 
Gross Motor Function Classification System 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board  
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
LS 
Least square 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 


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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measurement  
MP 
Main Period 
mTDS 
Modified Teacher’s Drooling Scale 
OLEX 
Open-Label Extension 
PDF 
Portable Document Format 
PPS 
Per Protocol Set 
PT 
Preferred Term 
PVA 
Polyvinyl Alcohol 
SAE 
Serious Adverse Event 
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 
TFLs 
Tables / Figures / Listings 
TEAE 
Treatment Emergent Adverse Event 
TEAESI 
Treatment Emergent Adverse Event of Special Interest 
TESAE 
Treatment Emergent Serious Adverse Event 
uSFR 
Unstimulated Salivary Flow Rate 
WHO-DD 
World Health Organization Drug Dictionary 


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 GENERAL AND TECHNICAL ASPECTS 
2
The objective of this statistical analysis plan (SAP) is to specify the statistical analyses in 
more detail than stated in the clinical study protocol 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 1.0, dated 17-Jul-
2014 and amendment no. 1 Version 2.0, dated 04-May-2015 which were consolidated in the 
clinical study protocol Version 2.0, dated 16-Jun-2016. 
All programs will be written using SAS version 9.4. A font size of 10 points will be used for 
the tables and figures in section 14, corresponding to a linesize of 111 digits and a pagesize of 
42 lines for an output in A4 format. For listings a standard font size of 10 points with the 
linesize and pagesize as defined above 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 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 for tables, figures and listings (TFLs) will be applied. 
 CLINICAL STUDY DESIGN AND OBJECTIVES 
3
3.1 
Clinical Study Design 
This is a prospective, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study with a screening period, a main period (MP) followed by an open-label 
extension (OLEX) period.  
Subjects (adolescents and children) are recruited in a staggered manner in consecutive age 
groups: 10–17 years (inclusive), 6–9 years (inclusive) and 2–5 years (inclusive). In the main 
period the subjects in the age groups from 6 to 17 years are randomized to receive double-
blind, placebo-controlled treatment. Subjects aged 2–5 years at screening are not randomized, 
but are treated with NT 201 in an open-label fashion. In the extension period all subjects are 
treated with NT 201 in an open-label fashion.  
The study consists of four injection cycles. The first injection cycle is the main period. The 
total duration of the main period is 15–22 weeks (comprising the screening period of up to 4 
weeks before the first injection and the main treatment period of 16 ± 2 weeks). This first 
injection cycle is followed by three subsequent open-label injection cycles (16 ± 2 weeks 
each) for all subjects. The total treatment period thus lasts for 56–72 weeks after the first 
injection for those completing all four injection cycles. For the safety of subjects, a Data 
Monitoring Committee (DMC) assesses adverse events (AEs), including adverse events of 


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special interest (AESIs) and serious adverse events (SAEs) at regular intervals and after each 
group of 30 subjects has been fully recruited.  
The treatment comprises four injections of NT 201 (parotid and submandibular glands, 
bilaterally); the dose is defined according to body weight (approximately 2 U/kg). At the end 
of the main period, subjects are assessed for eligibility to enter the extension period.  
There will be one final analysis at the end of the study including MP and OLEX. 
The study includes the following visits: 
Table 1: Visit Schedule 
Screening Visit (V1): 
Day -28 to -7 
Placebo-controlled main period (first injection cycle): 
Baseline injection visit (V2): 
Day 1 of first injection cycle, randomization 
Assessment visit (V3): 
Week 4 ± 3 days 
Assessment visit (V4): 
Week 8 ± 7 days 
Assessment visit (V5): 
Week 12 ± 7 days 
Final visit of main period (V6): 
Week 16 ± 2 weeks 
Open-label extension period (second, third and fourth injection cycle): 
Second injection cycle (16 ± 2 weeks after 1st injection): 
Injection visit (V6a) 
Day 1 of second injection cycle 
Assessment visit (V7) 
Week 4 ± 3 days after the 2nd injection 
Assessment visit (V8) 
Week 8 ± 7 days after the 2nd injection 
Assessment visit (V9) 
Week 12 ± 7 days after the 2nd injection 
End of cycle visit (V10) 
Week 16 ± 2 weeks after 2nd injection 
Third injection cycle (16 ± 2 weeks after 2nd injection): 
Injection visit (V10a) 
Day 1 of 3rd injection 
Assessment visit (V11) 
Week 4 ± 3 days after 3rd injection 


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Assessment visit (V12) 
Week 8 ± 7 days after 3rd injection 
Assessment visit (V13) 
Week 12 ± 7 days after 3rd injection 
End of cycle visit (V14) 
Week 16 ± 2 weeks after 3rd injection 
Fourth injection cycle (16 ± 2 weeks after 3rd injection): 
Injection visit (V14a) 
Day 1 of 4th injection cycle 
Assessment visit (V15) 
Week 4 ± 3 days after 4th injection 
Assessment visit (V16) 
Week 8 ± 7 days after 4th injection 
Assessment visit (V17) 
Week 12 ± 7 days after 4th injection 
End of cycle/study visit (V18) 
Week 16 ± 2 weeks after 4th injection 
3.2 
Clinical Study Objectives 
The objective of this study is to investigate the efficacy and safety of NT 201 compared with 
placebo for the treatment of chronic troublesome sialorrhea associated with neurological 
disorders (e.g. cerebral palsy (CP), traumatic brain injury) and/or intellectual disability in 
children and adolescents aged 2–17 years, naïve to Botulinum neurotoxin treatment. The total 
dose of NT 201 ranges from minimum 20 U to maximum 75 U or approximately 2 U/kg body 
weight depending on body weight classes. Subjects with a body weight ≥ 30 kg receive a 
fixed total dose of 75 U. In this study, treatment-naïve subjects are defined as those who have 
not received Botulinum neurotoxin (BoNT) treatment for this indication within the last 12 
months. 
 DETERMINATION OF SAMPLE SIZE 
4
A total of 249 subjects was planned to be enrolled. Of these, at least 219 children and 
adolescents were planned to be enrolled in the age group 6–17 years (inclusive), which form 
the population for the primary efficacy analysis. In the main period, this group of 
children/adolescents is randomized with a randomization ratio of 2:1, i.e. 146 subjects should 
receive NT 201 and 73 subjects should receive placebo. At least 30 children in the youngest 
age group 2–5 years were planned to be enrolled and treated with active treatment only.  
 
 
 
  
 


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4.1 
Safety 
Subjects in age group 6–17 years  
To generate a database with long-term safety data large enough to fulfill the requirements set 
out in the International Conference on Harmonization (ICH) E1 guideline (at least 100 
subjects treated over one year) and taking into account an anticipated drop-out rate 
 
 at least 144 subjects have to be included in the NT 201 group. 
Subjects in age group 2–5 years  
A total of 30 subjects in the youngest age group are assumed to be a sufficiently large 
database to generate a safety profile for this subject group.  
4.2 
Efficacy 
Subjects in age group 6–17 years  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
The sample size of 219 subjects is sufficient to provide 95% power to detect a statistically 
significant difference in means of 1.0 point between active treatment-treated and placebo-
treated subjects with a standard deviation of 1.93 points (two-sided t test, significance level α 
= 0.05).  
Subjects in age group 2–5 years  
Since the primary efficacy analysis is based on the population of subjects aged 6–17 years, no 
formal sample size estimation is necessary for the subjects in the youngest age group (2–5 
years) who all receive active treatment. Additionally, only the co-primary efficacy variable 
‘GICS four weeks after injection’ is assessed in this population. Power calculations with 
respect to the GICS four weeks after injection show that the sample size of 30 subjects is 


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sufficient to detect a GICS of ± 2.0 points as a statistically significant difference to a GICS of 
0 points (no change) at Week 4 (V3) with a power of 95% by assuming a standard deviation 
of 2.94 points (two-sided t test, significance level α = 0.05). 
 ANALYSIS SETS 
5
The following analysis sets are defined for the statistical analysis of the main period: 
Safety Evaluation Set MP 
The safety evaluation set (SES) of the main period is the subset of all subjects who received 
study medication (NT 201 or placebo) during the main period of the study.  
Full Analysis Set  
The full analysis set (FAS) is identical to the subset of subjects in the SES (MP). 
Per Protocol Set  
The per protocol set (PPS) is the subset of subjects in the FAS aged 6-17 years without major 
deviations from the protocol. Major protocol deviations will be defined during the blind data 
review meeting at the end of this study.  
If subjects aged 6-17 years have erroneously not been treated according to the randomization 
list in the MP, in MP tables performed on the SES these subjects will be analyzed as treated 
and in MP tables performed on the FAS or PPS they will be analyzed as randomized/ 
assigned for the MP treatment group. 
If subjects aged 2-5 years have erroneously not been treated with an NT 201 medication kit in 
the MP but with a main period medication kit containing placebo, then these subjects will be 
excluded from the MP analysis.  
 
 


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For the OLEX period, the following analysis set is defined:  
Safety Evaluation Set OLEX  
The safety evaluation set (SES) of the OLEX period is the subset of all subjects who received 
study medication (NT 201) at least once during the OLEX period of the study. 
If subjects have erroneously been treated with placebo during single OLEX cycles, no safety 
data in the respective cycle will be displayed. For summaries of safety data of the whole 
OLEX period or tables displaying changes between single cycles, for example shift tables, all 
subjects who received placebo in single OLEX cycles will be excluded. In case the OLEX 
period will be analyzed respective of MP treatment group, the actual treatment in MP will be 
used for safety data. For efficacy data subjects erroneously treated with placebo during single 
OLEX cycles will be included. Furthermore, the randomized/ assigned treatment in MP will 
be used for analysis respective of MP treatment group in chapter 14.1 and 14.2. 
In the subject data listings, the treatment group of MP/OLEX will be listed as randomized/ 
assigned except for the section 16.2.7 and 16.2.8, here the actual treatment group of the 
respective cycle will be listed. All listings will be sorted by site, treatment group, subject and 
cycle. 
 VARIABLES FOR ANALYSIS 
6
6.1 
Efficacy Variables 
6.1.1 
Primary efficacy variables  
The following variables will be defined as primary and co-primary efficacy variables for the 
subjects aged 6–17 years:  
 Change in mean unstimulated salivary flow rate (uSFR) from baseline (V2) to V3 (Week 
4). The mean uSFR is calculated by averaging the two assessments at each visit.  
 Global Impression of Change Scale (GICS) at V3 (Week 4) representing the functional 
improvement in drooling since baseline as assessed by the caregiver/parent(s).  
Unstimulated Salivary Flow Rate (uSFR) 
Unstimulated salivary flow rate (uSFR) is measured by the swab method of direct saliva 
collection.  
The saliva collection method by absorbent swabs with safety threads are used instead of 
cotton rolls to prevent subjects from swallowing the swab. The used swab (made of polyvinyl 
alcohol (PVA)) has a size of 35 x 9 x 12 mm, with 15 cm safety thread, provided in double, 
sterile packaging. It is approved as medical device and used in clinical practice as nasal packs.  


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Two absorbent swabs (1 swab per side) are placed in the mouth, positioned between cheek 
and gums directly at the orifices of the salivary ducts of the glands, for 5 minutes. The flow 
rate can be calculated by the following formula:  
Salivary flow rate [g/min] = Weight increase of rolls [g] 
Time of collection [min]  
The procedure is repeated after 30 minutes (± 5 minutes) and the average of the two results 
for flow rate is calculated. The assessments are performed under standardized conditions. 
Global Impression of Change Scale (GICS) 
The Global Impression of Change Scale (GICS) rating is performed by the caregiver before 
the quantitative measurement of saliva production.  
The question of the GICS for the caregiver is: ‘Compared to how the child was doing just 
before the last injection into his/her salivary gland, what is your overall impression of how 
he/she is functioning now as a result of this treatment?’ 
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: 
Table 2: Possible responses on GICS rating 
 
+3 
 
Very much improved 
 
+2 
 
Much improved 
+1 
 
Minimally improved 
0 
 
No change 
-1 
 
Minimally worse 
-2 
 
Much worse 
-3 
 
Very much worse 
6.1.2 
Secondary efficacy variables  
The following secondary efficacy variables will be analyzed for the subjects aged 6–17 years:  
 Change in mean uSFR from baseline (V2) to V4 and V5 (Week 8 and 12, respectively).  
 GICS at V4 and V5 (Week 8 and 12, respectively).  


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6.2 
Pharmacodynamic Variables 
Not applicable 
6.3 
Pharmacokinetic Variables 
Not applicable  
6.4 
Pharmacogenetic Variables 
Not applicable 
6.5 
Safety Variables 
As the analyses of all variables in this study will be shown separately for the two study 
periods, main period and extension period, the wording “overall and by injection cycle” in the 
following will be interpreted as “overall (MP and OLEX), per period (MP, OLEX) and by 
injection cycle” and analyzed as such. 
6.5.1 
Primary safety variable  
Occurrence of treatment emergent AEs (TEAEs) overall and by injection cycle.  
6.5.2 
Secondary safety variables  
 Occurrence of treatment emergent AESIs (TEAESIs) overall and by injection cycle.  
 Occurrence of treatment emergent SAEs (TESAEs) overall and by injection cycle.  
 Occurrence of TEAEs related to treatment as assessed by the investigator overall and by 
injection cycle.  
 Occurrence of TEAEs leading to discontinuation overall and by injection cycle. 
6.5.3 
Other safety variables  
 Occurrence of non-treatment emergent AEs. 
 Occurrence of non-serious TEAEs per period. 
 Occurrence of TEAEs by worst intensity per period and injection cycle. 
 Occurrence of TEAEs by worst causal relationship per period and injection cycle. 


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 Occurrence of related serious TEAEs per period and injection cycle. 
 Occurrence of TEAEs by worst outcome per period and injection cycle. 
 Listing of all serious TEAEs of subjects who died per period. 
 Listing of TEAEs of standard MedDRA query suicide/self-injury and of TEAEs with 
possibly suicidal events, per period. 
 Vital signs (blood pressure, heart rate, body temperature) at study baseline, V3 (week 4), 
V6 (week 16), during the main period, at injection visits in the extension period, at end of 
cycle visits in the extension period and at the end-of-study visit (V18) (Week 64).  
 Body height and body mass index (BMI), calculated from body weight and height, at 
study baseline, final visit of the main period (V6) (Week 16), and end-of-study visit (V18) 
(Week 64).  
 Body weight at study baseline, final visit of the main period (V6) (Week 16), at injection 
visits in the extension period, at end-of cycle visits in the extension period and end-of-
study visit (V18) (Week 64).  
 Clinical chemistry (including alkaline phosphatase (AP) and blood glucose (BG)) and 
hematology at study baseline, final visit of the main period V6 (Week 16), and end-of-
study visit V18 (Week 64).  
 Occurrence of antibodies against BoNT-A in subjects with ≥ 30 kg body weight. 
 The number of subjects with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent during treatment based on the Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Prospective monitoring of suicidality with the Columbia-Suicide Severity Rating Scale (C-
SSRS) should be considered the most important (but not the only) source of information 
concerning suicidality.  
Suicidality is assessed prospectively in subjects at baseline and every scheduled and 
unscheduled post-baseline site visit. 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 newly recruited subjects:  


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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 electronic Case Report Form (eCRF) that a 
child was not able to assess the C-SSRS at a respective visit.  
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. 
6.6 
Other Variables 
The following additional variables will be analyzed:  
 Subject dispositions (including number of subjects enrolled, number of discontinuations 
and reason for discontinuations) 
 Incidence of protocol deviations 
 Demographic data  
 Gross Motor Function Classification System (GMFCS) level at baseline (V2) for CP 
subjects 
 Medical history 
 Medical history of sialorrhea 
 Concomitant diseases 
 Previous therapies, including medication and non-drug treatment 
 Concomitant therapies, including medication and non-drug treatment 
 Injection cycle length, period length and length of entire study period 
 Extent of exposure 
 Treatment compliance 
 Method of administration of the injection 


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 Use of analgesics and/or sedatives during injection 
Gross Motor Function Classification System (GMFCS) 
The GMFCS is a 5-level classification system that is a standardized observational instrument 
for children with CP developed to measure change in gross motor function over time 
[Rosenbaum 2002]. It describes the gross motor function of children and adolescents with 
cerebral palsy (CP) on the basis of their self-initiated movement with particular emphasis on 
sitting, walking, and mobility. Distinctions between levels are based on functional abilities, 
the need for aids (e.g., walkers, crutches, and canes) or wheeled mobility, and quality of 
movement. The original version was developed in 1997 [Palisano 1997]. As of 2007, the 
expanded and revised version (GMFCS - E&R) further includes an age band for youth 12 to 
18 years. 
The GMFCS level will be determined at the Baseline Visit (V2) 
 STATISTICAL ANALYSIS METHODS 
7
In most cases the end of cycle visit and the injection visit of the following cycle will be 
performed on the same date. In this case only end of cycle will be documented in the CRF and 
respective values will also be used for the analysis of the following injection visit. If the visits 
are not performed on the same date both visits will be documented for most parameters. Only 
the efficacy variable uSFR will be documented once. This value will be used for the analyses 
of the end of cycle visit and for the analyses of the injection visit. 
7.1 
Efficacy Variables 
All efficacy analyses on data from the main period will be based primarily on the FAS and 
where deemed sensible additionally, to estimate another estimand, on the PPS. Analyses on 
data from the extension period are based on the SES only. If not stated otherwise, analyses are 
performed by all age groups and treatments, i.e. the analyses of the MP will be stratified by 
“Placebo (6-17 years)”, “NT 201 (6-17 years)”, “NT 201 (2-5 years)” and “Total NT 201 (2-
17 years)”. For the OLEX, two sets of tables will be produced: one “respective of main period 
treatment” showing “NT 201 (MP=Placebo, 6-17 years)”, “NT 201 (MP=NT 201, 6-17 
years)”, “NT 201 (MP=NT 201, 2-5 years)”, “NT 201 (MP=NT 201, 2-17 years)” and another 
set “irrespective of main period treatment” showing “NT 201 (6-17 years)”, NT 201 (2-5 
years)” and “NT 201 (2-17 years)”. For the tables respective of main period treatment the 
randomized/ assigned treatment will be used. 
For some variables, analyses by additional age groups and further subgroups will be 
performed (see Section 7.7.5). 
Statistical tests will be two-sided hypothesis tests for between-treatment differences in 
general. Continuous variables (values and changes from baseline) will be summarized by the 
number of observed values (n obs), the number of missing or imputed values (n miss/ n imp), 




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The main analytic approach or primary confirmatory analysis of the co-primary estimands 
will be a mixed model repeated measurement analysis (MMRM, 2-sided, significance level 
alpha=0.05) with comparison of least square means between NT 201 and placebo performed 
on the group of subjects within the FAS aged 6-17 years. 
The dependent variables will be the change in uSFR from baseline (V2) to V3 (Week 4) 
(ΔuSFR) and the carer's/parent's GICS at V3 (Week 4), respectively. 
The independent variables are defined as treatment group, pooled investigation sites (see 
section 7.7.6) and age groups (6-9 years, 10-12 years and 13-17 years) as fixed factors, 
visit*treatment as interaction term, and visit as repeated factor. To adjust for the baseline 
status, the MMRM of the uSFR change additionally includes the baseline score of the uSFR 
as covariate. Since no baseline assessment of the GICS is available, the baseline mTDS rated 
by the parent(s)/carer is used as covariate in the MMRM model for the GICS.  
The following SAS code will be used: 
 
proc mixed data = dataset; 
class treatment pooled_site age_group subject visit; 
model ΔuSFR (GICS) = treatment pooled_site age_group uSFR_baseline 
(mTDS) visit visit*treatment /solution ddfm=kr; 
repeated visit / subject = subject type = un grp = treatment 
 
LSMeans visit*treatment pooled_site age_group / pdiff CL alpha = 
0.05; 
run;  
 
where: 
treatment  
= treatment group (NT 201 (6-17 years) and Placebo (6-17 years)) 
  
pooled_site  
= pooled investigation sites 
 
age_group  
= age group (6-9 years, 10-12 years and 13-17 years) 
 
uSFR_baseline = Value of uSFR at Visit 2 (Baseline) 
 
mTDS 
= Value of mTDS at Visit 2 (Baseline) 
Only if both co-primary efficacy variables show a statistically significant difference compared 
to placebo the superiority of NT 201 over placebo will be considered to be proven. Therefore, 
no α-adjustment for multiple testing is necessary. 
Intercurrent events with potential bias on the co-primary endpoints will be identified prior to 
or during the BDRM. In case these events are judged as relevantly biasing the co-primary 
endpoints, conservative sensitivity analyses on the MMRM model will be specified during the 
BDRM. 
In addition to the MMRM, an analysis of covariance (ANCOVA) model will be performed on 
the FAS (age 6-17 years) using observed cases as well as using the baseline observation 
carried forward approach (BOCF, no effect) for uSFR and imputing missing GICS entries as 
“no change”. The ANCOVA models will be performed by use of the following SAS code: 
 
 
 


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proc mixed data = dataset; 
class treatment pooled_site age_group; 
model ΔuSFR (GICS) = treatment pooled_site age_group uSFR_baseline 
(mTDS)/solution ddfm=kr; 
 
LSMeans treatment pooled_site age_group / pdiff CL alpha = 0.05; 
 
where visit = V3; 
run;  
Furthermore, a non-parametric Wilcoxon rank-sum test will be performed as sensitivity 
analysis of the co-primary efficacy variables to investigate the impact of potential deviations 
from the assumption of normal distribution. The test will be performed for FAS (age 6-17 
years) using observed cases as well as using BOCF for uSFR and “no change” for GICS. The 
Wilcoxon rank-sum test will be performed by use of the following SAS code: 
 
proc npar1way data=dataset wilcoxon; 
 class treatment; 
 var ΔuSFR; 
run; 
For the GICS, a logistic regression will be performed as sensitivity analysis to the distribution 
assumption. The responder rate will be determined, i.e. all subjects with GICS entry of at least 
+1 (Minimally improved). 
Treatment arm comparisons with respect to responders based on the GICS entries will be 
performed analogously to the primary efficacy analysis, but based on estimates of logistic 
regression models. The dependent variable of these models will be the response to treatment. 
Treatment group, pooled investigation site and age group will be included as factors into the 
models. Baseline adjustment will be done by including the baseline values of the mTDS as 
covariate. The following SAS code will be used for estimation: 
 
proc logistic data=dataset desc order=formatted; 
    class treatment pooled_site age_group; 
    model resp(GICS) = treatment pooled_site age_group mTDS; 
where visit = V3; 
run; 
The comparison with respect to treatment group will be performed by use of the Odds Ratios 
and their corresponding 95% Wald confidence intervals (CI). 
This analysis will be performed on the FAS (6-17 years) without imputation of missing values 
and by imputing subjects with missing GICS entries as non-responder. In the observed case 
analysis, percentages will be based on subjects with values at the respective visit. When using 
the imputation approach, percentages will be based on all subjects with observed or imputed 
values at the respective visit. For the response rate frequencies, including 95% confidence 
limits and descriptive p-values for NT201 (6-17 years) vs. placebo (6-17 years) (based on 
Fisher’s exact test or or χ2-test as appropriate  as appropriate) will be given.  




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7.2 
Pharmacodynamic Variables 
Not applicable. 
7.3 
Pharmacokinetic Variables 
Not applicable.  


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7.4 
Pharmacogenetic Variables 
Not applicable. 
7.5 
Safety Variables 
The safety variables will be analyzed for the SES of the MP or OLEX by using descriptive 
summary statistics, frequency tables, and shift tables where appropriate.  
All analyses will be performed by age groups and treatment and additionally for the group of 
subjects of all ages (2-17) who received NT 201 in the respective treatment period (main or 
extension period), i.e. all analyses of the MP will be stratified by “Placebo (6-17 years)”, “NT 
201 (6-17 years)”, “NT 201 (2-5 years)”, “Total NT 201 (2-17 years)”. For the OLEX, two 
sets of tables will be produced: one “respective of main period treatment” showing “NT 201 
(MP=Placebo, 6-17 years)”, “NT 201 (MP=NT 201, 6-17 years)”, “NT 201 (MP=NT 201, 2-5 
years”) and another set “irrespective of main period treatment” showing “NT 201 (6-17 
years)”, “NT 201 (2-5 years)” and “NT 201 (2-17 years)”. OLEX tables for non-serious 
TEAEs with incidence ≥ 5%, C-SSRS and Botulinum toxin antibody results will only be 
presented irrespective of main period treatment.  
For all OLEX tables which are stratified by visit/cycle, only subjects with injection in the 
respective cycle are included. For End of Study all subjects from SES (OLEX) will be 
included and the results from V18 will be used. Visit “Cycle 4 Week 16” will not be analyzed. 
Adverse Events 
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
(version in effect when the database is closed). 
TEAEs of MP are defined as AEs with onset or worsening after the first injection of NT 201 
or Placebo up to and before first injection of the extension period or – in case of 
discontinuation before second injection – up to and including 16 weeks after first injection of 
NT 201 or Placebo or date of last study visit, whichever is later. AEs starting in the MP and 
not having resolved at the final visit of MP (V6) will be followed and further documented in 
the extension period.  
TEAEs of OLEX are defined as AEs with onset or worsening after the first injection of OLEX 
up to and including 16 weeks after last injection or the date of last study visit, whichever is 
later.  
A detailed description of the rules to be used for the classification of TEAEs can be found in 
Appendix 1. 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 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: 


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 if start time is missing and date is given and not equal to first exposure date in MP or 
OLEX, set time to 00:00, else if date is equal to first exposure date in MP or OLEX 
set time to time of first exposure in MP or OLEX, if given (else 00:00), respectively 
 if start time is missing and date is given and equal to the subsequent exposure date in 
OLEX (e.g. 2nd injection in OLEX), set time to time of the subsequent exposure, if 
given (else 00:00) 
 if start date/time is completely missing and end date is not after or equal to first 
exposure of MP: no imputation. 
 if start date/time is (partially) missing and end date is after or equal first exposure in 
MP or missing:  
o only start day is missing, but month and year same as first exposure in MP or 
OLEX: set day and time to day and time of first exposure, else set day to 1 and 
time to 00:00 
o Start day and month are missing, but year is the same as year of first exposure in 
the MP (which is ≠ year of first exposure in OLEX): set day, month, time to day, 
month, time of first exposure in the MP 
o Start day and month are missing, but year is the same as year of first exposure in 
the OLEX (which might be the same as year of first exposure in MP): set day, 
month, time to day, month, time of first exposure in OLEX 
o Start day and month are missing and year is not the same as year of first exposure 
in the MP or OLEX: else set day and month to 1 and time to 00:00 
 if start date/time is completely missing and end date/time is at or after date/time of 
first exposure in the MP and before date/time of first exposure in OLEX, set start 
date/time to date/time of first exposure in the MP (e.g. AE start missing, AE end date 
1OCT2014, first injection MP: 1AUG2014). 
 if start date/time is completely missing and end date/time is at or after date/time of 
first exposure in the OLEX, set start date/time to date/time of first exposure in the 
OLEX 
 if AE end date and time are missing and date and time of study end (i.e. last contact or 
last visit of the study) are not missing, set end date/time to study end date/time, else 
set end date to study end date and time to 23:59. 
 if AE end date/time is partially missing and given information on date is not equal to 
study end, set day to last day of the given month or day/month to 31/12 of the given 
year and missing time to 23:59. 
 if AE end date/time is partially missing and year or year and month are equal to year 
or year and month of study end, set analysis end date/time to the date/time study end 
and missing time to 23:59.  
 if AE end time is missing time will be set to 23:59 
 if start date and end date is completely missing, set end date to study end date and time 
to 23:59. Estimate then missing start date as described above 
In the following case a special rule will be applied: 
If it is not clear in which OLEX cycle the AE starts, incomplete AE start dates/times will 
be replaced in such a way that the AE is assigned to the earliest possible cycle: 


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 if start time is missing but date is given and equal to any exposure date in OLEX and 
AE is assigned to the later cycle, time will be set to start of the later cycle. If AE is 
assigned to the previous cycle, time will be set to 0:00. 
 If day and time are missing, but month and year are given and equal to any exposure 
date (month and year) in OLEX and AE is assigned to the later cycle, day and time 
will be set to start day and time of the later cycle. If AE is assigned to the previous 
cycle, day will be set to 1 and time to 00:00. 
 If month, day and time are missing, but year is given and covering several OLEX 
cycles and the earliest possible OLEX cycle for assignment starts in the year before 
the AE start (but ends in the year of the AE start), month and day will be set to 1 and 
time to 00:00. If the earliest possible OLEX cycle for assignment starts in the year of 
the AE start, month/day/time will be set to month/day/time of the respective cycle 
start. 
Calculation of time to duration of AEs [days]: 
 The duration will be calculated as stop date - onset date + 1 for each episode of 
worsening of AE. 
An overview summary table will be created for TEAEs and non-TEAEs displaying the 
frequencies and percentages of the following categories: “Any TEAE”, “Any TEAE related to 
treatment”, “Any TEAE of special interest”, “Any TEAE of special interest related to 
treatment”, “Any serious TEAE”, “Any serious TEAE related to treatment”, “Any TEAE 
leading to discontinuation”,  “Any TEAE leading to discontinuation related to treatment”, 
“Any fatal TEAE” and “Any fatal TEAE related to treatment” for TEAEs and “Any non-
TEAE”, “Any non-TEAE of special interest”, “Any serious non-TEAE”, “Any non-TEAE 
leading to discontinuation” and “Any fatal non-TEAE” for non-TEAEs. 
Incidences will be calculated for TEAEs, treatment-related TEAEs, serious TEAEs,  related 
serious TEAEs, TEAEs leading to discontinuation, TEAEs of special interest at the system 
organ class level and at the preferred term level and will be presented by treatment, by 
injection cycle and overall (i.e. per period). TEAEs will also be presented by preferred term 
level, by treatment, injection cycle and overall. Additionally, TEAEs will be analyzed by 
worst intensity, by worst causal relationship and by worst outcome.  
The number and percentage of subjects with at least one non-serious TEAE with incidence ≥= 
5% will be displayed by system organ class level and preferred term level.  
In general, all safety analyses for OLEX will be performed overall and for the 2nd, 3rd and 4th 
injection cycle. Only the number and percentage of subjects with at least one non-serious 
TEAE with incidence ≥= 5% will be performed overall only.  
Listings displaying incidences for TEAEs leading to discontinuation, serious TEAEs and 
TEAEs of special interest will also be provided.  


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Listings will be created for subjects who died, subjects with TEAEs of standard MedDRA 
query suicide/self-injury and for subjects with possibly suicidal events. 
TEAEs for the 2nd injection cycle are defined as adverse events with onset or worsening at or 
after date of 2nd injection and before date of 3rd injection. TEAEs for the 3rd injection cycle are 
defined as adverse events with onset or worsening at or after date of 3rd injection and before 
date of 4th injection. TEAEs for the 4th injection cycle are defined as TEAEs with onset or 
worsening at or after 4th injection.  
Duration of AEs will be listed only. Imputed values will be flagged as such.  
In case of missing intensity or missing causal relationship of an AE the worst case principle 
will be applied, i.e. a missing intensity will be set to “severe” and a missing causal 
relationship will be set to “related”. 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. 
For any missing data on seriousness a worst case strategy will be applied for all analysis 
tables. The AE will be regarded as ‘serious’. 
TEAESIs are defined as adverse events occurring after treatment that are thought to possibly 
indicate toxin spread. The list of adverse events of special interest possibly indicating toxin 
spread based on MedDRA version 22.0 (version in effect at database closure) is given in 
Table 4.  


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Table 4: List of Adverse Events of Special Interest Possibly Indicating Toxin Spread 
MedDRA Preferred Term (MedDRA version 22.0) 
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: only when severe, serious, or 
outcome is not recovered, fatal or unknown 
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 preferred terms is according to MedDRA version 22.0 
 
To fulfill FDA requirements, TEAE data will be screened for suicidal events. The MedDRA 
Preferred Terms 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 Preferred Terms of the SMQ ‘Suicide/self-injury’ based on MedDRA version 22.0 
is given in Table 5 (version in effect at database closure).  


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Table 5: List of Adverse Events of Standard MedDRA Query ‘Suicide/self-injury’ 
MedDRA Preferred Term: 
MedDRA Preferred Term: 
Assisted suicide 
Self-injurious ideation 
Columbia suicide severity rating scale 
abnormal 
Suicidal behaviour 
Completed suicide 
Suicidal ideation 
Depression suicidal 
Suicide attempt 
Intentional overdose  
Suicide threat 
Intentional self-injury 
Suspected suicide 
Poisoning deliberate 
Suspected suicide attempt 
Wording of preferred terms is according to MedDRA version 22.0 
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 6: 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’).  
Vital signs, body weight, and BMI 
The individual blood pressure, heart rate, body temperature, body weight, height and BMI 
data will be listed. Vital signs, body height and weight and BMI will be summarized (n, mean, 
standard deviation, minimum, 1st quartile, median, 3rd quartile and maximum) at each time 


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point. Descriptive statistics will be given for absolute values and changes from baseline (V2) 
to all post-baseline visits. 
Frequencies of subjects with lowered, normal, or raised values will be displayed as shift tables 
from baseline (V2) to all post-baseline visits. 
High and low values are defined as given in Table 7. 
Table 7: High and Low Values of Vital Signs 
Vital Sign Variable 
Flag 
Observed 
Value1 
Systolic Blood Pressure (mmHg) 
High 
≥ 180 
Low 
≤ 90 
Diastolic Blood Pressure (mmHg) 
High 
≥ 105 
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/m2) 
High 
> 30.0 
Low 
≤ 18.5 
Temperature (°C) 
High 
> 37.5 
Low 
< 36.5 
1 A value is considered as high/low if it meets the criterion for observed values 


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Laboratory data  
Descriptive summary statistics for original values and for the changes from study baseline 
will be displayed for each parameter.  
Furthermore, the number of subjects with lowered, normal, or raised values compared to 
normal range will be displayed as shift tables from Screening to final visit of main period V6 
and end-of-study visit V18. Laboratory parameters will be sorted by predefined categories 
(Hematology and clinical chemistry). 
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 shift tables or descriptive statistics will be 
created.  
The first valid value will be analyzed for all post-baseline visits. In case no exact value is 
given (<x.x, >x.x) the respective higher/ lower value will be used, e.g. >1.24 will be changed 
to 1.241 and <0.5 will be changed to 0.49.  
Antibodies against BoNT-A 
Occurrence of antibodies against BoNT-A in subjects with ≥ 30 kg BW will be analyzed 
descriptively (frequency tables by category and shift tables from baseline (V2) to end-of-
study visit V18) and screened for individual notable values and/or changes. In case blood 
sample is taken at V17 instead of V18 these values are used for analyses. 
C-SSRS 
The number of subjects with suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent during treatment based on the C-SSRS will be calculated and presented 
as proposed in the Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide 
Version 2.0 (Finalized February 2013)[Mary E. Nilsson 2013].  
Questions which were documented between one day after start of MP and up to start of OLEX 
will be assigned to MP. For subjects who discontinued during MP, all questions which were 
documented at least one day after start of MP will be assigned to MP. Questions which were 
documented at least one day after start of OLEX will be assigned to OLEX.   
The following outcomes are C-SSRS categories and have binary responses (yes/no). 
Category 1 – Wish to be Dead   
Category 2 – Non-specific Active Suicidal Thoughts   
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
Category 6 – Preparatory Acts or Behavior  


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Category 7 – Aborted Attempt  
Category 8 – Interrupted Attempt  
Category 9 – Actual Attempt (non-fatal)  
Category 10 – Completed Suicide  
The following composite endpoints will be calculated: 
1. Suicidal ideation (MP): A “yes” answer during MP to any one of the five suicidal ideation 
questions (categories 1-5) on the C-SSRS.  
2. Suicidal behavior (MP): A “yes” answer during MP to any one of the five suicidal 
behavior questions (categories 6-10) on the C-SSRS. 
3. Suicidal ideation or behavior (MP): A “yes” answer during MP to any one of the ten 
suicidal ideation and behavior questions (categories 1-10) on the C-SSRS.  
4. Suicidal ideation (OLEX): A “yes” answer during OLEX to any one of the five suicidal 
ideation questions (Categories 1-5) on the C-SSRS. 
5. Suicidal behavior (OLEX): A “yes” answer during OLEX to any one of the five suicidal 
behavior questions (Categories 6-10) on the C-SSRS. 
6. Suicidal ideation or behavior (OLEX): A “yes” answer during OLEX to any one of the ten 
suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS.  
Frequency tables for the composite endpoints and for the single questions for these time 
periods will be created. All subjects who filled out at least one questionnaire during the 
respective period will be used for the denominator whereby only questions which are referring 
to the time period since last visit are regarded. Furthermore, information on C-SSRS will be 
listed for subjects with at least one post-baseline suicide-finding during MP (including V6) 
and for subjects with at least one post-baseline suicide-finding after V6. In case the 
questionnaire was not filled out on a visit date the previous visit will be assigned in the listing. 
7.6 
Other Variables 
Disposition, demographic and other baseline data 
Subject dispositions, demographic data, and baseline characteristics (including height, weight 
and BMI at screening V1) will be presented using standard descriptive statistics; no 
homogeneity tests will be performed. Demographic data will be summarized for screening 
failures, the SES of MP (actual treatment will be displayed), the FAS (planned treatment will 
be displayed), the PPS and the SES of OLEX. The analyses of the MP will be stratified by 
“Placebo (6-17 years)”, “NT 201 (6-17 years)”, “NT 201 (2-5 years)” and “Total NT 201 (2-
17 years)”. For tables including all enrolled/randomized subjects, the additional “Total” 
column will be displayed. For the OLEX, two sets of tables will be produced: one “respective 
of main period treatment” showing “NT 201 (MP=Placebo, 6-17 years)”, “NT 201 (MP=NT 


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201, 6-17 years)”, “NT 201 (MP=NT 201, 2-5 years)”, “NT 201 (MP=NT 201, 2-17 years)” 
and another set “irrespective of main period treatment” showing “NT 201 (6-17 years)”, “NT 
201 (2-5 years)” and “NT 201 (2-17 years)”. 
A table given the absolute and relative frequencies for the following European Union Drug 
Regulatoring Authorities Clinical Trials (EudraCT) age categories will be generated: 
 2-11 years 
 12-17 years. 
Furthermore, the absolute and relative frequencies for the following age categories will be 
generated: 
 2-5 years 
 6-9 years 
 10-12 years 
 13-17 years. 
The weight at baseline will be classified in the following categories:  
 >= 12 kg and <15 kg 
 >= 15 kg and <19 kg 
 >= 19 kg and <23 kg 
 >= 23 kg and <27 kg 
 >= 27 kg and <30 kg 
 >= 30 kg. 
 A table giving the absolute and relative frequencies for subject’s reason for premature study 
discontinuation will be generated giving all reasons as documented in the CRF. The analysis 
will be based on all randomized/ assigned subjects of MP and on all subjects entered OLEX 
for OLEX. The randomized/ assigned treatment group will be displayed. For the extension 
period the reason will be summarized overall and for each cycle. The following subjects are 
regarded as completers for MP: 
 Subjects who are included in SES OLEX or 
 Subjects who performed last visit at day 95 or later 


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Additionally, the reason will be summarized for the complete study for randomized/ assigned 
subjects. Further, for MP and OLEX, 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 deviation 
8. Lost to follow-up 
9. Other.  
GMFCS level  
A frequency table for GMFCS level at baseline (V2) for CP subjects will be displayed for 
SES and FAS of MP and SES of OLEX. 
Protocol deviations 
Protocol deviations will be classified into minor and major violations during the BDRM. 
Major protocol deviations (deviations leading to exclusion from per protocol set) will be 
summarized for all randomized/ assigned subjects of the MP and all subjects that entered the 
OLEX using a frequency table. 
All protocol deviations will be listed, including their classification. 
Diseases specific and general medical history and concomitant diseases  
Medical history and concomitant diseases will be coded according to the MedDRA and 
displayed with respect to System Organ Class and preferred terms for SES of MP and FAS. 
Concomitant diseases will also be tabulated for the SES of OLEX; medical history will be 
tabulated for the MP only. A detailed description of the rules to be used to classify medical 
history and concomitant diseases can be found in Appendix 1.  
The following data on the medical history of sialorrhea will be analyzed descriptively for MP 
(SES and FAS) and for OLEX (SES): 


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 Primary reason (frequency table). 
 Duration since first diagnosis of sialorrhea in months: (date of baseline injection visit 
in the main period – date of start of sialorrhea + 1)/30.5 (summary statistics). 
 Intellectual disability (frequency table). 
In case of missing days (but month given) for the start of sialorrhea, 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 left as missing.  
Previous and concomitant therapies 
Previous therapies are defined as therapies for which the stop date is before the date of the 
first injection of NT 201 or Placebo.  
For concomitant therapies of MP (and not OLEX) the following conditions have to be 
fulfilled: 
 stop date is at or after start of first injection of MP. 
 start date is not after start of treatment of the OLEX. 
 not ongoing at the end of MP. 
For concomitant therapies of MP and OLEX the following conditions have to be fulfilled: 
 stop date is at or after start of first injection of OLEX or ongoing at MP/ OLEX. 
 start date is not after start of treatment of the OLEX. 
For concomitant therapies of OLEX (and not MP) the following conditions have to be 
fulfilled: 
 stop date is at or after start of first injection of OLEX or ongoing at OLEX. 
 start date is after start of treatment of the OLEX. 
A detailed description of the rules to be used to classify previous therapies and concomitant 
therapies can be found in Appendix 1. Classes of non-drug treatments are derived from the 
observed data before database close in order to display frequencies of non-drug treatments. 
Indications for previous and concomitant therapies will not be coded and will only be listed. 
Frequencies of previous and concomitant treatments will be given based on different 
Anatomical Therapeutic Chemical (ATC) code levels of the World Health Organization 
(WHO) (dictionary version in effect at database closure)  as well as by generic names. 
Previous therapies will not be tabulated for the OLEX, only for the MP. Previous medication 
will be tabulated for SES of MP and FAS and previous non-drug treatment only for SES of 


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MP. Concomitant therapies for the MP will be analyzed for the SES of the MP and FAS. 
Concomitant therapies for the OLEX will be analyzed for SES of the OLEX. 
Duration of exposure  
The injection cycle length will be determined for each injection cycle. 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. 
Furthermore, the period length for OLEX and the length of the entire study period will be 
analyzed. 
The injection cycle length in weeks will be summarized descriptively for each cycle (SES of 
MP, FAS, SES of OLEX):  
 Injection cycle length of 1st injection cycle in weeks: 
if 1st cycle is the last cycle: (date of last visit – date of 1st injection V2 + 1)/7 
else: (date of 2nd injection – date of 1st injection V2)/7 (rounded to one decimal). 
 
 Injection cycle length of2nd injection cycle in weeks: 
if 2nd cycle is the last cycle: (date of last visit – date of 2nd injection V6a + 1)/7 
else: (date of 3rd injection – date of 2nd injection V6a)/7 (rounded to one decimal). 
 
 Injection cycle length of3rd injection cycle in weeks: 
if 3rd cycle is the last cycle: (date of last visit – date of 3rd injection V10a + 1)/7 
else: (date of 4th injection – date of 3rd injection V10a)/7 (rounded to one decimal). 
 
 Injection cycle length of4th injection cycle in weeks: 
(date of last visit – date of 4th injection V14a + 1)/7 (rounded to one decimal). 
 
In case a cycle is omitted, the day before date of next available injection will be used as end 
date for the calculation of the injection cycle length. 
Furthermore, frequency tables for the injection cycle length will be displayed for SES of MP, 
FAS and SES of OLEX) (< 14 weeks, 14-18 weeks and >18 weeks). 
The length of entire study period is defined as the sum of the duration of all injection cycles 
and will be summarized descriptively (SES of MP, FAS). 
The period length of the OLEX period is defined as the sum of the duration of all injection 
cycles of the OLEX and will be summarized descriptively (SES of OLEX). 
Extent of exposure  


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The extent of exposure will be determined for each injection cycle. For each subject and 
injection the total injected NT 201 units per injection (which will be zero for subjects treated 
with placebo) will be divided by the subject’s body weight at the corresponding injection 
visit. This ratio will be classified into the following categories: 0 U/kg, ]0,1.5[ U/kg, [1.5, 1.8[ 
U/kg, [1.8, 2.2[ U/kg, [2.2, 2.5] U/kg and >2.5 U/kg.  
A frequency table will display the number and percentage of subjects per (above given) 
categories of injected NT 201 units/{kg body weight at respective injection} per injection. 
Furthermore, the total injected NT201 units per injection will be analyzed for the following 
classes: <25 U, [15, 50[ U, [50,75[ U, 75 U, >75 U. Numbers will be based on the SES/ FAS 
of the MP for the first injection and on the SES of the OLEX for the injections within the 
OLEX. 
OLEX tables for extent of exposure will only be presented irrespective of main period 
treatment. 
Subjects with dose reduction or with differences in actual/ randomized treatment will be 
listed. 
Treatment compliance, method of administration of injection and use of analgesics 
and/or sedatives during injection 
For the NT 201 group dosages will be given according to the predefined volumes of fixed 
total doses defined for each of the six body-weight classes (see Table 8 below).  
In general for subjects with a body weight of 12–30 kg the total dose is approximately 2 U/kg. 
Subjects with a body weight ≥ 30 kg will receive a fixed total dose of 75 U. Due to the unitary 
concentration of the NT 201 solution the dose adjustment will be performed by adapting the 
injection volumes for each dose group (see Table 8).  
Dosages will be adapted to actual body weight of subjects at each injection visit according to 
the dosage instructions. The subject's body weight will be re-determined at each injection 
visit, and if the body weight has increased (or decreased) over the limit of the class then the 
subject will be treated in the next higher (or lower) dosage group accordingly. 
In the placebo group (only during MP), subjects will receive the respective volume of placebo 
solution (0.9% sodium chloride, sucrose and human serum albumin) as in the NT 201 
treatment group according to their bodyweight classification. 
Table 8: Dosing scheme 


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The treatment compliance will be calculated for each cycle in percentage by (100 * Total 
volume injected [mL]/Total volume planned [mL]). For MP the compliance will be displayed 
using descriptive summary statistics for SES of MP and FAS. For OLEX the total compliance 
(2nd, 3rd and 4th injection cycle together) and the compliance per injection cycle will be 
displayed using descriptive summary statistics for the SES of the OLEX. The total 
compliance is calculated as the mean compliance per subject for all performed injections of 
OLEX.  
If a dose reduction is documented for a subject then the reduced planned dose will be used for 
calculation of the compliance in the next cycle. E.g. if a subject had an adverse event with 
action taken = ‘dose reduced’ in cycle 3 then it will be assumed that for the subject the 
reduced dose was documented in cycle 4.  The dosing scheme with dose reduction is given in 
Table 9. 
Table 9: Dosing scheme with dose reduction in the third or fourth injection 


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If in the third cycle the dose is reduced, then the fourth cycle dose will likewise be determined 
by reference to Table 9, using the subject’s current body weight. 
In the event of a subject’s gaining weight such that he/she would progress from one dose level 
to a higher dose level according to Table 8, while at the same time requiring dose reduction 
because of a relevant adverse event, the subject will remain at the previous dose level. 
In the event of a subject's losing weight and the occurrence of a relevant AE, only one dose 
reduction is allowed at the next injection session. 
A frequency table for the method of administration of the injection per cycle will be displayed 
(ultrasound and other) for SES and FAS of MP and SES of OLEX. 
A frequency table for the use of analgesics and/or sedatives during injection will be displayed 
(yes and no) for SES and FAS of MP and SES of OLEX. 
7.7 
Special Statistical/Analytical Issues 
7.7.1 
Discontinuations and Missing Data 
Reasons for premature discontinuation by a subject will be summarized descriptively and 
listed. Where the discontinuation was due to an adverse event, this will be included in the 
listing of adverse events, and such events will be included as a category in the summary of 
adverse events.  
The analysis of the primary and secondary efficacy variables will be performed using a 
MMRM as well as using an ANCOVA based on observed cases and an ANCOVA with 
missing values replaced by the baseline value or “no change” (‘baseline observation carried 
forward approach’). By using all values of the dependent efficacy variable available in the 
timeframe underlying the MMRM, i.e. the main period, the MMRM reduces the influence of 
single missing values. The use of the ANCOVA model with missing values replaced by the 
baseline value is considered to be a conservative approach because if a comparable percentage 
of missing values is expected in both treatment groups (in the placebo group there may be 
more missing values due to lack of efficacy and in the verum group more due to adverse 
events) the replacement of missing values by the baseline value of the uSFR – or by ‘no 
change’ for the GICS – leads to a decrease in the difference of the observed treatment effects. 
In general, values measured at the baseline injection visit (V2) will be used as study baseline 
value. If data is missing for this visit the last valid value before first injection will be used 
instead. 
7.7.2 
Interim Analyses 
No interim analysis is planned for this study except from the analyses providing tables and 
listings for the DMC meetings. 


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7.7.3 
Data Monitoring Committee 
An independent DMC is assigned to monitor subjects’ safety throughout the clinical course of 
the study. It consists of an odd number (e.g., three) of physicians who are suitably qualified 
and who have experience in analyzing pediatric clinical trial data, to allow majority decisions 
to be made. The primary purpose of the DMC is to safeguard subjects by monitoring AESIs, 
SAEs and AEs on a regular basis.  
The DMC meets at regular intervals, either physically or remotely by secure teleconference 
during the main and extension period to review safety data. They decide upon and prioritize 
any safety issues and actions for the attention of the sponsor. The DMC is semi-blinded with 
respect to treatment group comparisons based on frequency tables. Subject data listings 
contain no treatment group information such that the DMC remains blinded with respect to 
individual subjects unless the treatment codes of individual subjects with AESIs, SAEs and 
AEs are unblinded for the DMC on request, by using the Interactive Web Response System 
(IWRS).  
If considered necessary, the DMC makes recommendations regarding the timely management 
of subject withdrawals and/or measures for the study if there are relevant safety findings.  
The DMC can make recommendations, if necessary, such as the following:  
 Changes in study design (such as lowering the dose, additional telephone contacts 
etc.).  
 Changes in timing of assessments.  
 Implementation of additional safety measures.  
 Unblinding of subjects if required for safety reasons.  
 Prematurely discontinuing dosing in an age group.  
 Prematurely discontinuing dosing in all age groups.  
 Putting the study on hold.  
 Stopping the study  
For each DMC meeting, minutes are taken by the responsible DMC coordinator/administrator 
of the Contract research organization (CRO) and reviewed by the DMC members before 
finalization.  
Details of responsibilities and procedures to be followed by the DMC are laid down in the 
DMC Charter.  


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A list of members of the committee and a copy of the committee's charter are provided 
separately and is reviewed by the Independent Ethics Committee (IEC)/ Institutional Review 
Board (IRB). 
7.7.4 
Multiple Comparisons/Multiplicity 
The overall hypothesis of no differences between treatment groups is only to be rejected if 
both treatment comparisons – based on the co-primary efficacy variables – yield a significant 
result, i.e. if for both tests the hypothesis of no difference between treatment groups can be 
rejected. Thus, no issue with respect to multiplicity arises and no α-adjustment is necessary.  
Results of all other tests or confidence intervals are only descriptive; a confirmatory 
interpretation is not valid in this context. 
7.7.5 
Examination of Subgroups 
All subgroup analyses will be performed on an explorative level. 
Tables with descriptive statistics for uSFR, GICS, GICS response and mTDS will be repeated 
for the following subgroups:  
 Age group:  
o 6-9 years, 
o 10-12 years 
o 13-17 years. 
 Pooled investigational sites (where pooling will be the same as used for the MMRM and 
ANCOVA models). 
 Etiology (cerebral palsy, traumatic brain injury and other) 
 Gender 
 Weight group (rounded to one decimal place): 
o ]0, 30 kg[ and ≥ 37.5kg (corresponds to a planned NT201 exposure of ≤ 2U/kg) 
o [30, 37.5kg[ (corresponds to a planned NT 201 exposure of > 2U/kg) 
 Baseline disease severity: 
o uSFR at baseline ≤ median of uSFR at baseline 
o uSFR at baseline > median of uSFR at baseline 


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These analyses will be performed for FAS, PPS and SES OLEX for uSFR and GICS. Tables 
for mTDS will be created for FAS and SES OLEX. The analysis by age group will be 
performed for FAS (6-17 years) instead of FAS. 
In addition, the following uSFR and GICS MMRM models will be built: 
1. MMRM model with treatment, pooled site and age group included as (fixed) factors and 
uSFR at baseline (or mTDS at baseline) included as covariate, visit*treatment and 
subgroup*visit*treatment as interaction terms and visit as repeated factors. I.e. two 
different models will be calculated (pooled site as interaction term and age group as 
interaction term). 
2. Primary endpoint MMRM model based on subjects with uSFR at baseline ≤ median of 
uSFR at baseline, only. 
3. Primary endpoint MMRM model based on subjects with uSFR at baseline > median of 
uSFR at baseline, only. 
4. MMRM model with treatment, pooled site, age group, etiology, gender, weight group 
included as (fixed) factors and uSFR at baseline (or mTDS at baseline) included as 
covariate, visit*treatment and subgroup*visit*treatment as interaction terms and visit 
as repeated factors. I.e. five different models will be calculated (pooled site as 
interaction term, age group as interaction term, etiology as interaction term, gender as 
interaction term and weight group as interaction term). 
For each subgroup level of age group and pooled site, the LS-Mean for difference between 
NT201 and placebo at week 4 will be selected from Model 1) and presented in a table and 
forest plot. 
For the first (second) subgroup level of baseline disease severity, the LS-Mean for difference 
between NT201 and placebo at week 4 will be selected from Model 2) (3) and presented in 
the same table and forest plot as mentioned above. 
For each subgroup level of etiology, gender and weight group, the LS-Mean for difference 
between NT201 and placebo at week 4 will be selected from Model 4) and also presented in 
the above mentioned table and forest plot. 
These analyses will be performed for FAS (6-17 years). 
7.7.6 
Pooling of Sites 
During the blind data review meeting (BDRM) it will be decided if for the purpose of the 
analyses sites or countries will be pooled.  


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7.7.7 
Definition of Study Baseline and Cycle Baseline 
Study baseline is defined as the last measurement before first injection.  
Cycle baseline is defined as the measurement on the corresponding injection visit. If an 
injection visit is performed on the same day as the end-of-cycle visit of the previous cycle, the 
measurements of the end-of-cycle visit will be used for the cycle baseline. 
7.7.8 
 Definition of Study End 
Study end is defined as the last documented date in the CRF (including AE end date). 
Incomplete dates will not be used for the calculation. 
 
 CHANGES IN THE PLANNED ANALYSES 
8
Additionally to the planned analysis for the GICS a logistic regression of GICS response rates 
(observed and worst cases for FAS only) will be done. 
Vital signs, body height and weight at screening, BMI, clinical chemistry and occurrence of 
antibodies against BoNT-A, which were defined as other variable in the CSP were added to 
other safety variables. Treatment compliance, injection cycle length, period length, length of 
entire study period, method of administration of the injection and use of analgesics and/or 
sedatives for injection visits were added to other variables. 
Tabulation of occurrences of TEAEs by worst intensity, worst causal relationship and by 
worst outcome is a standard analysis. Therefore these other safety variables were added to 
section 6.5.3 and corresponding analysis was added to the section of TEAE analyses (7.5). 
For the same reason, non-TEAEs will also be analyzed. 
For coding of AEs the Medical Dictionary for Regulatory Activities (MedDRA) (version in 
effect when the database is closed) is used instead of (version in effect when the study is 
initiated). 
Unstimulated salivary flow rate was measured in g units instead of mg units. This deviation 
from the CSP description was corrected in the current version of the SAP. 
 REFERENCES 
9
Jongerius PH, van den Hoogen FJ, van Limbeek J, Gabreëls FJ, van Hulst K, Rotteveel JJ. 
Effect of botulinum toxin in the treatment of drooling: a controlled clinical trial. Pediatrics. 
2004;114(3):620-7. 


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Mier RJ, Bachrach SJ, Lakin RC, Barker T, Childs J, Moran M. Treatment of sialorrhea with 
glycopyrrolate: A double-blind, dose-ranging study. Arch Pediatr Adolesc Med. 
2000;154(12):1214-8. 
Mary E. Nilsson, SS, Cristiana Gassmann-Mayer, Sarah Dubrava, Paul McSorley, and 
Kaihong Jiang. Columbia–Suicide Severity Rating Scale Scoring and Data Analysis Guide. 
2013. p. 1-13. 
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. Dev 
Med Child Neurol. 1997;39(4):214-23. 
Reddihough D, Johnson H, Ferguson E. The role of a saliva control clinic in the management 
of drooling. J Paediatr Child Health. 1992;28(5):395-7. 
Reid SM, Johnson HM, Reddihough DS. The Drooling Impact Scale: a measure of the impact 
of drooling in children with developmental disabilities. Dev Med Child Neurol. 
2010;52(2):e23-e8. 
Rosenbaum PL, Walter SD, Hanna SE, et al. Prognosis for gross motor function in cerebral 
palsy: creation of motor development curves. JAMA. 2002;288(11):1357-63. 
Forcella L, Filippi C, Waltimo T, Filippi A, Measurement of unstimulated salivary flow rate 
in healthy children aged 6 to 15 years. SWISS DENTAL JOURNAL SSO VOL 128 12 P 
2018 
Appendix 1: List of Tables, Figures, and Listings 
See MRZ60201_3091_1-sap-appendix-1-final v1.0-2019-06-21.pdf 
Any  changes  that  become  necessary  after  generation  of  SAP  version  ‘Final  Draft’  do  
not necessarily need to be reflected. Changes which are not only editorial but indicate changes 
in analyses should at least be covered in the SAP text part or may also be implemented in the 
mock tables. 
Appendix 2: List of Programmed In-text Tables, Figures, and Listings 
Not applicable.