A Phase III, Multicentre, Double Blind, Prospective, Randomised, Controlled, Multiple Treatment Study Assessing Efficacy And Safety Of DYSPORT® Used In The Treatment Of Upper Limb Spasticity In Children
Phase: PHASE3
Conditions: Upper Limb Spasticity (Altered Skeletal Muscle Performance) in Children
Sponsor: Ipsen

IPSEN GROUP 
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A PHASE III, MULTICENTRE, DOUBLE BLIND, PROSPECTIVE, RANDOMISED, 
CONTROLLED, MULTIPLE TREATMENT STUDY ASSESSING EFFICACY AND 
SAFETY OF DYSPORT USED IN THE TREATMENT OF UPPER LIMB SPASTICITY IN 
CHILDREN 
 
STUDY PROTOCOL 
Study number: Y-52-52120-153 
DYSPORT 
EudraCT number: 2010-021817-22 
Final 5.0: 24 July 2017 
 
Sponsor’s Medically Responsible Person: 
Sponsor’s Co-ordinating and Monitoring 
Office: 
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Sponsor Details: 
Co-ordinating Investigator:  
Ipsen Innovation 
Z.I. de Courtaboeuf,  
5 Avenue du Canada,  
91940 Les Ulis,  
Cedex France 
 
 
 
 
 
  
 
  
 
Tel: 
+33 (0)1 60 92 20 00 
Fax: 
+33 (0)1 69 07 38 02 
 
 
 
 
 
 
Pharmacovigilance/Emergency Contact: 
  
 
 
 
 
 
 
For serious adverse events (SAE) reporting: Fax:  
  
USA and Latin America: 
Tel: 
 
Fax: 
 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the Sponsor’s prior written 
authorisation. 
PPD
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PROTOCOL SIGNATURES 
Investigator Signature: 
I have read and agree to the protocol Y-52-52120-153, a phase III, multicentre, double blind, 
prospective, randomised, controlled, multiple treatment study assessing efficacy and safety of 
Dysport used in the treatment of upper limb spasticity in children. I am aware of my 
responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP)1, local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study.  
 
 
 
NAME: 
 
 
 
TITLE: 
PRINCIPAL INVESTIGATOR: 
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 
Full investigational site contact details, including telephone numbers, will be documented in 
the Trial Master File. 
 
On behalf of the Sponsor: 
NAME: 
 
 
 
 
TITLE: 
  
SIGNATURE: 
 
 
DATE: 
 
 
OFFICE: 
 
 
 
 
 
 
 
 
 
 
Note: For IND studies, a Form 1572 will also be completed. 
                                                 
1 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996.  
 
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SYNOPSIS 
Study Title: 
 
A phase III, multicentre, double blind, prospective, randomised, 
controlled, multiple treatment study assessing efficacy and safety of 
Dysport used in the treatment of upper limb spasticity in children. 
 
STUDY NUMBER: Y-52-52120-153 
Study Objectives: 
 
The primary study objective is to assess the efficacy of two doses of 
Dysport (8 units (U)/kg and 16 U/kg) compared to Dysport 2 U/kg 
used in the treatment of upper limb spasticity in children with cerebral 
palsy (CP) following a single treatment. 
The secondary study objective is to assess the long term safety of 
multiple treatments of Dysport used in this study population. 
The tertiary study objectives 
 
 quality of life (QoL) 
 
Study Design: 
This is a phase III, multicentre, double blind, prospective, 
randomised, controlled, multiple treatment study. Subjects will 
receive a maximum of four treatments over the course of a minimum 
of one year’s study participation. 
At study entry, subjects will be randomised into one of the following 
three treatment groups for Treatment 1: 
• 
Group A: Dysport 16 U/kg in one upper extremity (the study 
limb). 
• 
Group B: Dysport 8 U/kg in the study limb. 
• 
Group C: Dysport 2 U/kg in the study limb. 
Randomisation will be done with an Interactive Response 
System (IRS) and will be in a 1:1:1 ratio. The IRS will be used to 
allocate packs and envelope numbers (to be considered to reconstitute 
the treatment) and then study treatment reconstitution will be 
performed by an independent reconstitutor who will not be involved 
in any other study related activities in order to maintain the blinding. 
For Treatments 2, 3 and 4, subjects are planned to receive Dysport 
8 U/kg or 16 U/kg according to the treatment allocation by the IRS 
and will remain double blind throughout the study. 
 
 
 
 
 The total dose for the study limb must not exceed 
320 U in the 8 U/kg group and 640 U in the 16 U/kg group. 
The planned retreatment interval is 16 weeks and a maximum of four 
treatments will be administered.  
At study entry, a primary targeted muscle group (PTMG), either the 
elbow flexors or wrist flexors, will be nominated by the Investigator. 
The PTMG can be changed for subsequent treatments, from elbow to 
wrist flexors or wrist to elbow flexors, provided that the following 
criteria are fulfilled: 
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• 
The Modified Ashworth Scale (MAS) score of the other 
muscle group not selected for the last treatment (new PTMG) 
must be higher than the last treatment PTMG, and 
• 
The new PTMG must have a modified MAS score of greater or 
equal to 1+.  
For 
Treatments 2, 
3 
and 
4, 
injection 
into 
the 
lower 
extremity/extremities and the non-study upper limb will be allowed 
at the same time as the study limb is injected (see Study Treatment 
Section).  
The overall duration of the study is anticipated to be approximately 
4 years and 9 months and will include subject recruitment 
(approximately 3 years) and last subject follow up (approximately 
1 year and 9 months). Individual subject participation will be 
approximately 1 year to 1 year and 9 months.  
Stratification will be performed according to age range (2 to 9 years 
and 10 to 17 years) and BTX naïve or non-naïve status assessed at 
baseline. 
Prestudy physiotherapy, occupational therapy, or use of splints and/or 
orthoses must have been initiated at least 30 days prior to the baseline 
visit and agreed to continue the therapy throughout the study and at 
the minimum, up to Week 16 following the first treatment 
administration. In addition, instructions for home exercises will be 
provided to the parents/guardians/caregivers and/or subjects to 
encourage use of the muscle groups injected in the study. School 
therapy will also be allowed during term time. 
After each treatment administration, the follow up visit schedule is as 
follows: 
• 
Week 2 (telephone call, safety follow up). 
• 
Week 4 (telephone call, safety follow up). 
• 
Week 6. 
• 
Week 12 (telephone call, safety follow up). 
• 
Week 16. 
At Week 16, subjects will be assessed for their eligibility to receive 
the next treatment. Subjects who are eligible for retreatment will be 
given the next treatment. Any subjects not eligible for retreatment will 
be evaluated every 6 weeks ±2 weeks in additional visits until they 
are eligible for retreatment. 
Each subject will participate in the study for approximately 1 year to 
1 year and 9 months, depending on the number of treatments 
administered and the treatment intervals. The duration of the 
follow up period will be dependent upon the treatment interval as 
follows: 
• 
All subjects whose first three treatment intervals fall between 
≥16 and ≤22 weeks will receive four treatments and will exit 
the study as soon as a new injection is required and no later 
than 22 weeks after last injection (up to a maximum of 1 year 
and 9 months’ study duration).  

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• 
All other subjects will not be given any further study treatment 
after Week 52 and will exit the study after 16 weeks of follow 
up of the last treatment. 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population: 
Approximately 210 male and female subjects will be randomised into 
the study.  
Subjects must satisfy all of the following inclusion criteria to be 
eligible for the study: 
(1) Signed 
informed 
consent 
obtained 
from 
the 
child’s 
parent(s)/guardian(s) and, if applicable, a signed assent from the 
child.  
(2) Be from 2 to 17 years of age, inclusive.  
(3) Body weight of 10 kg or more at the baseline visit. 
(4) Have a diagnosis of CP, as defined by Rosenbaum.  
(5) Have increased muscle tone/spasticity in at least one upper limb. 
(6) Have a MAS score ≥2 in the upper limb PTMG (elbow flexors or 
wrist flexors) of the study limb (the limb to be injected in the first 
treatment) at the baseline visit. 
(7) Be classified as Gross Motor Function Classification System 
Level 1 to 4.  
(8) 
 
 
 
 
 
Subjects are to be excluded if any of the following applies: 
(1) Fixed myocontracture in the PTMG (elbow flexors or wrist 
flexors) of the study limb 
 
 
 
 
 
 
 
 
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(8) Treatment with any drug that interferes either directly or 
indirectly with neuromuscular function (e.g. aminoglycoside 
antibiotics) or neuroblocking agents used during surgery 
(e.g. curare) within the last 30 days prior to study treatment. 
 
 
 
 
 
(12) Subjects with any clinical (or sub-clinical) evidence of marked 
defective neuromuscular transmission (e.g. Lambert-Eaton 
syndrome or myasthenia gravis) or persistent clinically 
significant neuromuscular disorders. 
(13) Known sensitivity to BTX or to any of the components in the 
formulation or allergy to cow’s milk protein. 
 
(15) Previous rhizotomy less than 6 months prior to the baseline visit 
or rhizotomy planned/anticipated during the course of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(20) Any known medical condition, laboratory or diagnostic 
procedure finding, which might compromise compliance with the 
objectives and procedures of this protocol or preclude 
administration of botulinum toxin type A (BTX-A), as judged by 
the Investigator.  
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(21) Any uncontrolled clinically significant medical condition other 
than CP. 
 
Study Treatment: 
 
Dysport will be supplied as a white, lyophilised powder in a vial 
containing 500 U of BTX-A-haemagglutinin complex. Before 
administration, the powder will be reconstituted at the investigational 
site with preservative free 0.9% sodium chloride for injection. All 
subjects will receive Dysport administered intramuscularly.  
The total volume for injection will be administered into one upper 
extremity (the study limb), divided between injections into the PTMG 
(elbow flexors or wrist flexors) and a number of other muscles 
selected by the Investigator, as specified in the protocol.  
Planned Doses: 
Subjects will receive Dysport 2 U/kg, 8 U/kg or 16 U/kg in the study 
limb in Treatment 1 and are planned to receive Dysport 8 U/kg or 
16 U/kg in subsequent treatments according to the treatment 
allocation by the IRS, illustrated below, and both Investigators and 
subjects will remain blinded throughout the study. 
 
 
 
 
 
 
 
 
 
Group 
Number of 
Subjects 
Treatment 1(a) 
Treatments  
2, 3 and 4 (a) 
 
 
A 
70 
Dysport 16 U/kg 
Dysport 16 U/kg 
 
 
B 
70 
Dysport 8 U/kg 
Dysport 8 U/kg 
 
 
C(b) 
70 
Dysport 2 U/kg 
Dysport 8 U/kg or  
Dysport 16 U/kg 
 
 
 
(a) The total dose for the study limb must not exceed 320 U in the 8 U/kg group and 
640 U in the 16 U/kg group. 
(b) In this group, dynamic dose dispensing will be done by IRS at Treatment 2 to 
maintain a balance between subjects receiving 8 U/kg and 16 U/kg. 
 

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The dose for each subject will be calculated according to the 
subject’s body weight, up to a maximum body weight of 40 kg (even 
if the subject weighs more than 40 kg and therefore a maximum total 
dose of 320 U in the 8 U/kg group and 640 U in the 16 U/kg group). 
The allocated dose will be reconstituted to a fixed volume of 1.6 mL 
for injection. 
 
 
 
 
Dose/Volume: 
For treatments 2, 3 and 4, the investigator may modify the nature and 
number of injected muscles. The volume by muscle may be 
decreased (to allow more muscles to be injected) or increased 
providing that: 
• 
the volume per muscle never exceeds the maximum 
volume/dose indicated in table. 
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• 
the total injection volume in the study upper limb is always 
1.6 mL. 
For Treatments 2, 3 and 4, and according to subject response, if any 
given total dose is not tolerated, the Investigator will request a dose 
reduction of 50% in the IRS. 
 
 
 
 
 
 
 
For Treatments 3 and 4, if any given total dose is not adequate for the 
treatment of the subject’s upper limb spasticity, the Investigator can 
request a dose increase in the IRS. 
  
  
 No dose increase is possible for those subjects who were 
given Dysport 16 U/kg as the subject was already given the highest  
dose allowed in the study. 
  
 
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Concomitant Treatment of Lower Limb Spasticity and the Non-
study Upper Limb: 
For 
Treatments 2, 
3 
and 
4, 
injection 
into 
the 
lower 
extremity/extremities and the non-study upper limb will be allowed 
at the same time as the study limb is injected. Muscle(s) for injection 
will be selected according to the Investigator’s judgement. If there is 
no need to inject the lower limbs, and only the non-study upper limb 
is to be injected (on top of the study upper limb), the dose in the non-
study upper limb should not exceed the dose detailed in table. 
 
Body Weight (kg) 
Maximum Dose 
10 to 40 
5 U/kg, calculated up to 40 kg 
40 and over 
200 U 
 For dose by muscle, please refer to table below 
If there is no need to inject the non-study upper limb and only one or 
two lower limb(s) are to be injected (on top of the study upper limb), 
the dose in the lower limb(s) should not exceed the dose detailed in 
table. 
 
   Body Weight (kg) 
Maximum Dose 
  10 to 36 
10 U/kg, calculated up to 36 kg 
  36 and over 
360 U 
 
Electrical stimulation (ES) and/or ultrasound will be used to localise 
the targeted injection sites. Complementary techniques, such as 
electromyography will be allowed in addition to ES and/or 
ultrasound.  
 
 
 
 
 
 
 
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• 
Modified Ashworth Scale in the injected muscles (elbow, wrist 
and finger flexors) in the study limb other than the ones of the 
PTMG. 
• 
Modified Ashworth Scale in the injected muscles (elbow, wrist 
and finger flexors) in the non-study upper limb. 
• 
 
 
• 
 
 
 
• 
 
 
• 
 
• 
Paediatric Quality of Life (PedsQL™) child and parent 
inventory and CP module. 
Safety Evaluations: 
A Data and Safety Monitoring Board (DSMB) composed of 
independent experts will review safety data including AEs and serious 
AEs. 
Safety will be assessed through collection of AEs, physical 
examination, body weight and height, vital signs (heart rate (HR) and 
blood pressure (BP)), clinical chemistry (including serum alkaline 
phosphatase (ALP) - total and bone isoenzyme, and glycosylated 
haemoglobin (HbA1c)), the presence of antibodies against BTX-A 
(BTX-A-Abs) and electrocardiograms (ECGs). Prior and concomitant 
medications will also be recorded. 
Study Endpoints: 
 
Efficacy Endpoints: 
Efficacy variables will be assessed at the following schedule:  
• 
 Muscle Tone examination, GAS, 
and 
 at baseline (Treatment 1, Day 1) and at each 
post-treatment visit to the study centre. 
• 
Physician’s Global Assessment at each post-treatment visit to 
the study centre. 
• 
 
 
  
• 
Paediatric Quality of Life at baseline (Treatment 1, Day 1), 
Treatment 1, Week 16 and at the end of study visit or early 
withdrawal. 
Primary Efficacy Endpoint:  
• 
Mean change from Baseline to Treatment 1, Week 6 in MAS 
score in the Treatment 1 PTMG (elbow flexors or wrist 
flexors).  
Secondary Efficacy Endpoints: 
• 
Mean PGA score at Treatment 1, Week 6. 
• 
Mean GAS score at Treatment 1, Week 6. 
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Tertiary Efficacy Endpoints: 
• 
Mean change from Baseline to all post-treatment visits of 
treatment 1 (except Week 6) in MAS score in the Treatment 1 
PTMG. 
• 
 
 
 
• 
Mean change from Baseline to all post-treatment visits in MAS 
score in each injected muscle group (elbow, wrist and finger 
flexors) of the study limb. 
• 
 
 
 
• 
 
 
 
 
• 
Mean PGA score at all post-treatment visits (except 
Treatment 1, Week 6). 
• 
 
 
• 
Mean GAS score at all post-treatment visits (except 
Treatment 1, Week 6). 
• 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
 
• 
 
 
 
• 
 
 
 
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• 
 
 
  
• 
 
 
• 
Mean change from Baseline to both post-treatment PedsQL 
scores. 
 
 
Safety Endpoints: 
• 
Treatment emergent adverse events. 
• 
Vital signs (systolic and diastolic BP and HR): absolute values 
and change from Baseline at each visit to the study centre. 
• 
Body weight and height: absolute values and change from 
baseline at Week 16 of each treatment and at the end of study 
visit or early withdrawal. 
• 
Clinical chemistry (including serum ALP - total and bone 
isoenzyme, and HbA1c): absolute values and change from 
Baseline at Treatment 1, Week 16 (serum ALP - total and bone 
isoenzyme, and HbA1c only) and at the end of study visit or 
early withdrawal. 
• 
Presence of BTX-A-Abs at baseline and at the end of study 
visit or early withdrawal.  
• 
A 12-lead ECG: absolute values and change from Baseline in 
ECG parameters and morphology at Treatment 1, Week 6 and 
at the end of study visit or early withdrawal. 
Statistical 
Methods: 
For the efficacy analyses, the primary population will be the modified 
intent to treat (mITT) population, which will consist of all randomised 
subjects who received at least one injection of the study treatment and 
had a MAS score in the PTMG assessed both at baseline and at 
Treatment 1, Week 6. 
For the efficacy analyses, a secondary population of interest will be 
the per protocol population (PP), which will consist of all subjects 
from the mITT population who are not major protocol violators 
between baseline and the Treatment 1, Week 6 visit (inclusive).  
The population for safety analyses will consist of all the randomised 
subjects who received at least one injection of the study treatment.  
 
 
 
 
 
 
 
 
 
 
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Sample Size Calculation: 
The sample size required for this study has been determined on the 
basis of the sample size estimate for each of the three criteria to be 
considered (superiority of any of the two tested Dysport doses to 
Dysport 2 U/kg on the primary efficacy endpoint, superiority of any 
of the two tested Dysport doses to Dysport 2 U/kg on the first 
secondary efficacy endpoint, and proper assessment of the long term 
safety of the two tested Dysport doses); the largest of these three 
estimates is used as the sample size of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Sample Size of the Study: 
Given the above sample size estimates, a targeted study sample size 
of 210 randomised subjects (i.e. 70 randomised subjects per treatment 
group) is considered sufficient to meet both the primary efficacy 
objective and the long term safety objectives. 
Using a sample size of 210 as the largest of the three required figures 
means the actual power for the testing on the primary efficacy 
endpoint and the testing on the first secondary efficacy endpoint rises 
to 99% and 99%, respectively. As a result, the actual power of the 
study to detect a significant effect of any tested Dysport dose for both 
efficacy endpoints (US-targeted methodology) is 98% (= 99% x 
99 %). 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................. 24 
2 
INTRODUCTION ........................................................................................................ 26 
2.1 
Disease Review .............................................................................................................. 26 
2.2 
Compound Review ........................................................................................................ 27 
2.3 
Clinical Study Rationale ............................................................................................... 27 
3 
STUDY OBJECTIVES ................................................................................................. 29 
3.1 
Primary Study Objective .............................................................................................. 29 
3.2 
Secondary Study Objectives ........................................................................................ 29 
3.3 
Tertiary Study Objectives ............................................................................................ 29 
3.4 
Ancillary Study Objectives .......................................................................................... 29 
4 
STUDY DESIGN ........................................................................................................... 29 
4.1 
Overview ........................................................................................................................ 29 
4.1.1 
Population Characteristics ......................................................................... 29 
4.1.2 
Design .......................................................................................................... 29 
4.1.3 
Study Structure ............................................................................................ 29 
4.1.4 
Stopping Rules and Discontinuation Criteria ............................................ 31 
4.1.5 
Early Study Termination ............................................................................ 31 
4.2 
Endpoints ....................................................................................................................... 32 
4.2.1 
Efficacy Endpoints ...................................................................................... 32 
4.2.1.1 
Primary Efficacy Endpoint .......................................................................... 32 
4.2.1.2 
Secondary Efficacy Endpoints ..................................................................... 32 
4.2.1.3 
Tertiary Efficacy Endpoints ......................................................................... 32 
4.2.2 
Safety Endpoints ......................................................................................... 33 
4.3 
Justification of Design .................................................................................................. 33 
4.3.1 
Study Population for Analysis .................................................................... 34 
4.3.2 
Study Duration ............................................................................................ 34 
5 
COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICE, 
ETHICAL 
CONSIDERATIONS AND INFORMED CONSENT ............................................... 35 
5.1 
Compliance with Good Clinical Practice and Ethical Considerations .................... 35 
5.2 
Informed Consent ......................................................................................................... 35 
6 
STUDY POPULATION ............................................................................................... 36 
6.1 
Screening Log and Number of Subjects ..................................................................... 36 
6.2 
Inclusion Criteria .......................................................................................................... 36 
6.3 
Exclusion Criteria ......................................................................................................... 36 
6.4 
Subject Withdrawal Criteria ....................................................................................... 37 
6.5 
Discontinuation/Withdrawal Procedures ................................................................... 38 
7 
METHODOLOGY ....................................................................................................... 38 
7.1 
Study Schedule .............................................................................................................. 38 
7.2 
Study Visits .................................................................................................................... 38 

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7.2.1 
Screening (Day -7 to Day 1, Visit 1) ........................................................... 38 
7.2.2 
Baseline (Treatment 1, Day 1, Visit 2) ....................................................... 39 
7.2.3 
Treatment 1 – Follow Up Visits .................................................................. 39 
7.2.3.1 
Week 2 ±1 week Visit 3 - Telephone Contact ............................................... 39 
7.2.3.2 
Week 4 ±1 week Visit 4 - Telephone Contact ............................................... 40 
7.2.3.3 
Week 6 ±4 days, Visit 5 ................................................................................ 40 
7.2.3.4 
Week 12 ±1 week, Visit 6 - Telephone Contact ............................................ 40 
7.2.3.5 
Week 16 ±2 weeks, Visit 7 ............................................................................ 40 
7.2.4 
Treatments 2, 3 and 4, Day 1, Visits 8, 14 and 20 ...................................... 41 
7.2.5 
Treatments 2, 3 and 4 – Follow Up Visits .................................................. 42 
7.2.5.1 
Week 2 ±1 week, Visits 9, 15 and 21 - Telephone Contact .......................... 42 
7.2.5.2 
Week 4 ±1 week, Visits 10, 16 and 22 - Telephone Contact ........................ 42 
7.2.5.3 
Week 6 ±4 days, Visits 11, 17 and 23 .......................................................... 42 
7.2.5.4 
Week 12 ±1 week, Visits 12, 18 and 24 - Telephone Contact ...................... 42 
7.2.5.5 
Week 16 ±2 weeks, Visits 13, 19 and 25 ...................................................... 43 
7.2.6 
Additional Visits .......................................................................................... 43 
7.2.7 
End of Study or Early Withdrawal Follow up Visit ................................... 43 
8 
STUDY EVALUATIONS ............................................................................................. 44 
8.1 
Efficacy Endpoints and Evaluations ........................................................................... 45 
8.1.1 
Modified Ashworth Scale ............................................................................ 45 
8.1.2 
Physician’s Global Assessment of the Treatment Response ..................... 45 
8.1.3 
Goal Attainment Scale ................................................................................ 46 
 
 
 
 
 
 
 
 
8.1.8 
Paediatric Quality of Life Inventory .......................................................... 46 
8.2 
Safety Endpoints and Evaluations ............................................................................... 47 
8.2.1 
Adverse Events ............................................................................................ 47 
8.2.2 
Physical Examination ................................................................................. 47 
8.2.3 
Vital Signs ................................................................................................... 47 
8.2.4 
Electrocardiogram Analysis ....................................................................... 47 
8.2.5 
Clinical Laboratory Tests ............................................................................ 48 
8.2.6 
Prior and Concomitant Medications .......................................................... 48 
8.2.7 
Body Weight and Height ............................................................................. 48 
8.3 
Total Blood Volume ...................................................................................................... 49 
8.4 
Blood Samples for Putative Antibodies ...................................................................... 49 
9 
STUDY TREATMENTS .............................................................................................. 49 
9.1 
Treatments Administered ............................................................................................ 49 
9.1.1 
Dysport ......................................................................................................... 50 
9.1.2 
Administration Procedures ......................................................................... 50 
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9.1.3 
Treatment of the Study Upper Limb ........................................................... 50 
9.1.3.1 
Total Dose/Volume in the Study Upper Limb .............................................. 50 
9.1.3.2 
Primary Target Muscle Group ..................................................................... 51 
9.1.3.3 
Dose/Volume by Muscle ............................................................................... 51 
9.1.3.4 
Dose/Volume at Treatment 2, 3 and 4 ......................................................... 53 
 
 
9.1.3.6 
Dosing Interval (Applicable to all Treatments) and reinjection criteria ..... 54 
9.1.4 
Concomitant Treatment of Lower Limb Spasticity and the Non-
study Upper Limb ........................................................................................ 55 
9.2 
Subject Identification and Allocation to Study Treatment ....................................... 56 
9.2.1 
Randomisation ............................................................................................ 57 
9.2.2 
Blinding, Emergency Envelopes and Breaking the Blind ......................... 58 
9.3 
Study Treatment Supply, Packaging and Labelling .................................................. 58 
9.4 
Compliance .................................................................................................................... 59 
9.5 
Study Treatment Storage and Accountability ............................................................ 59 
9.6 
Concomitant Medication/Therapy .............................................................................. 59 
9.7 
Treatment of Overdose of Investigational Medicinal Product ................................. 60 
10 
ADVERSE EVENT REPORTING ............................................................................. 60 
10.1 Categorisation of Adverse Events ............................................................................... 61 
10.1.1 
Intensity/Severity Classification ................................................................. 61 
10.1.2 
Causality Classification .............................................................................. 61 
10.1.3 
Assessment of Expectedness ....................................................................... 61 
10.1.4 
Adverse Events of Special Interest ............................................................. 61 
10.1.5 
Laboratory Test Abnormalities ................................................................... 62 
10.1.6 
Abnormal Physical Examination Findings ............................................... 62 
10.1.7 
Other Investigation Abnormal Findings .................................................... 62 
10.2 Recording and Follow up of Adverse Events ............................................................. 62 
10.3 Serious Adverse Events ................................................................................................ 62 
10.3.1 
Definitions ................................................................................................... 62 
10.3.2 
Reporting Requirements ............................................................................. 63 
10.3.3 
Mandatory Information for Reporting a Serious Adverse Event .............. 63 
10.3.4 
Reporting Exemptions ................................................................................. 64 
10.4 Pregnancy ...................................................................................................................... 64 
10.5 Deaths ............................................................................................................................. 64 
10.6 Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events ....... 64 
10.7 Reporting 
to 
Competent 
Authorities/Independent 
Ethics 
Committees/ 
Institutional Review Boards/Other Investigators ...................................................... 65 
11 
STATISTICAL CONSIDERATIONS ........................................................................ 65 
11.1 Subject Classification and Definitions ........................................................................ 65 
11.2 Analyses Populations Definitions ................................................................................ 66 
11.2.1 
Populations Analysed .................................................................................. 66 
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11.2.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 66 
11.3 Sample Size Determination .......................................................................................... 66 
11.3.1 
Significance Testing and Estimations ........................................................ 67 
11.4 Statistical/Analytical Methods ..................................................................................... 68 
11.4.1 
Demographic and Other Baseline Characteristics .................................... 68 
11.4.1.1 
Homogeneity of Treatment Groups .............................................................. 68 
11.4.1.2 
Subject Disposition and Withdrawals .......................................................... 68 
11.4.2 
Pharmacokinetic Data ................................................................................ 68 
11.4.3 
Efficacy Evaluation ..................................................................................... 68 
 
 
 
 
 
 
11.4.3.3 
Similarities Between the Two Statistical Methodologies Planned for the 
Efficacy Analyses ......................................................................................... 70 
11.4.3.4 
Adjustment for Country/Centre Effect ......................................................... 71 
11.4.4 
Safety Evaluation ........................................................................................ 71 
11.5 Subgroup Analyses ....................................................................................................... 73 
11.6 Final Analysis ................................................................................................................ 73 
12 
MONITORING PROCEDURES ................................................................................ 73 
12.1 Routine Monitoring ...................................................................................................... 73 
13 
STUDY MANAGEMENT ............................................................................................ 74 
13.1 Inspections and Auditing Procedures ......................................................................... 74 
13.2 Data Recording of Study Data ..................................................................................... 74 
13.3 Source Data Verification .............................................................................................. 74 
13.4 Data Quality .................................................................................................................. 75 
13.5 Data Management ......................................................................................................... 75 
13.6 Study Management Committees .................................................................................. 76 
13.6.1 
Data and Safety Monitoring Board ............................................................ 76 
13.7 Record Archiving and Retention ................................................................................. 76 
14 
ADMINISTRATION PROCEDURES ....................................................................... 76 
14.1 Regulatory Approval .................................................................................................... 76 
14.2 Publication Policy ......................................................................................................... 77 
14.3 Clinical Study Report ................................................................................................... 77 
14.4 Contractual and Financial Details ............................................................................... 77 
14.5 Insurance, Indemnity and Compensation .................................................................. 77 
15 
PROTOCOL AMENDMENTS ................................................................................... 77 
16 
REFERENCES .............................................................................................................. 79 
17 
LIST OF APPENDICES .............................................................................................. 82 
 
 
 
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LIST OF TABLES 
Table 1 
Planned Dysport Dose Administered per Treatment Group .......................... 51 
Table 2 
 Injection Volumes, Dose per Muscle and Number of Injection Sites in the 
Primary Targeted Muscle Group ...................................................................... 52 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 13 
Domains / Subdomains of GAS Goals ............................................................... 96 
Table 14 
Tanner Grading Scale for Breast Development ............................................. 110 
 
LIST OF FIGURES 
Figure 1 
Planned Study Structure ..................................................................................... 30 
Figure 2 
Dose Modifications Available During the Study .............................................. 54 
Figure 3 
Study Flow Chart ................................................................................................ 90 
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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ABBREVIATION 
Wording Definition  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
 
 
ALP 
Alkaline Phosphatase 
ANCOVA 
Analysis of Covariance 
BP 
Blood Pressure 
BTX 
Botulinum Toxin  
BTX-A 
Botulinum Toxin type A 
BTX-A-Abs 
Antibodies Against BTX-A  
BTX-A-HAC 
BTX-A-Hemagglutinin Complex 
CAs 
Competent Authorities 
CP 
Cerebral Palsy 
CRO 
Contract Research Organisation 
CSR 
Clinical Study Report 
CTSU 
Clinical Trial Supplies Unit 
Da 
Daltons (Unit of Atomic Mass) 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ES 
Electrical Stimulation 
e-signature 
Electronic Signature 
EU 
European Union 
FDA 
Food and Drug Administration 
 
 
GAS 
Goal Attainment Scale 
GCP 
Good Clinical Practice 
GMFCS 
Gross Motor Function Classification Scale 
HbA1c 
Glycosylated Haemoglobin 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
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ID 
Identification  
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
MACS 
Manual Ability Classification System 
MAS 
Modified Ashworth Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent To Treat 
PDD 
Protocol Deviations Document 
PedsQL™ 
Paediatric Quality of Life™ 
PGA 
Physician’s Global Assessment 
POM 
Proportional Odds Model 
PP 
Per Protocol 
 
 
PTMG 
Primary Targeted Muscle Group 
QoL 
Quality of Life 
RIPA 
Radioimmunoprecipitation Assay 
SAE 
Serious Adverse Event 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
 
 
U 
Units 
US 
United States 
 
 
 
 
 
 
 
 
 
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2 
INTRODUCTION 
Dysport® is a neurotoxin complex derived from the bacterium Clostridium botulinum. It 
prevents the release of acetylcholine at neuromuscular junctions, which in turn results in 
weakness of the injected muscle. Over a period of months new nerve endings sprout which 
allows nerve function to return, thus treatment may need to be repeated as required. Dysport 
has been found to be of significant value in the treatment of a variety of ophthalmological and 
neurological disorders, particularly blepharospasm, hemifacial spasm, spasticity and cervical 
dystonia [1, 2, 3, 4, 5, 6, 7, 8]. 
2.1 
Disease Review 
Cerebral palsy (CP) describes a group of permanent disorders of the development of movement 
and posture, causing activity limitation, that are attributed to nonprogressive disturbances that 
occurred in the developing foetal or infant brain. The motor disorders of CP are often 
accompanied by disturbances of sensation, perception, cognition, communication, and 
behaviour, by epilepsy, and by secondary musculoskeletal problems leading to posture and gait 
impairment, and limb deformities [9]. The reported prevalence of CP is between 1.5 and 3 cases 
per 1000 live births [10, 11]. The bilateral form of CP (which includes diplegia, triplegia and 
quadriplegia) predominates, followed by unilateral (hemiplegia), which accounts for about one 
quarter to one third of all spastic cases [9, 11]. 
Cerebral palsy is an upper motor neuron disorder, which can present clinically with different 
combinations of positive and negative phenomena. The positive phenomena of the syndrome 
include among others spasticity, increased tendon reflexes, clonus and muscle co-contraction. 
The negative phenomena are muscle weakness, impaired motor control, loss of skilled 
movements and easy fatigability. In children, the positive phenomena of CP are a major cause 
of disability and considered more amenable to treatment [12]. 
Ninety percent (90%) of subjects with CP suffer from spastic hypertonia. Spasticity is a motor 
disorder, characterised by an increase in velocity dependant stretch reflexes, with exaggerated 
tendon reflexes, resulting from hyper-excitability of the stretch reflex, as one of the 
manifestations of the upper motor neuron syndrome [13]. The increased muscle tone in 
spasticity leads to muscle contractures, initially dynamic and later fixed, followed by shortening 
of ligaments, fascias and joint capsules, and eventually joint deformities and instabilities.  
The Gross Motor Function Classification System (GMFCS) [14, 15, 16] classifies the severity 
of CP and establishes a prognosis of motor development in affected children by describing the 
child’s ability in self-initiated movements, such as sitting and walking. Severity of motor 
impairment depends on the type of CP and children with hemiplegia often have less severe 
disease than children with di- or quadriplegia, with the majority of hemiplegic children being 
classified as GMFCS Level 1 and 2 [17]. However, in children with CP, manual ability and 
gross motor function do not always correlate, thus a different classification is required to assess 
the level of impairment of hand function. The Manual Ability Classification System (MACS) 
focuses on the upper limbs of children with CP and describes how well the children use their 
hands for handling objects in daily activities [18]. The severity of upper limb functional 
impairment as described by MACS varies, ranging from very minor (Level 1) to severe 
limitation of activities and complete dependence (Level 5). In contrast to children with diplegia, 
children with spastic hemiplegia have a lower degree of manual ability despite having less 
severely impaired gross motor function [19]. This could be explained by the fact that children 
with spastic hemiplegia who have one unaffected upper limb, develop various compensatory 
strategies for coping with their disability. Those children tend to use their unaffected upper limb 
for all activities, partially or fully neglecting the affected arm [20]. If left untreated, spasticity 
of the one affected upper limb and associated functional impairment do not allow the children 
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In the upper limbs in particular, the increased muscle tone impairs the reach, grasp, 
manipulation and release, leading to restriction in everyday life and educational activities. The 
inability to fully use the affected arm(s) for bimanual activities prohibits the development of 
independent functioning in daily life. Although the children often have normal intellectual 
capacity to attend school, their impaired arm function prevents them from fully engaging in 
social, educational and leisure roles. Consequently, reduction of the increased muscle tone and 
spasticity is important for the improvement of the motor ability and functional skills of children 
with CP, and for prevention of fixed muscle contractures and deformities. 
The choice of appropriate treatment for spasticity in children with CP depends on the 
topographic distribution of the disorder and any associated co-morbidities. In spastic 
hemiplegia and monoplegia with upper limb involvement, localised treatment of spasticity with 
botulinum toxin (BTX) with or without complementary techniques, such as regular 
physiotherapy, occupational therapy and various therapeutic modalities aimed at improving 
upper limb muscle strength, movement control and manual dexterity, is often used [21, 22]. 
The intramuscular injection of botulinum toxin type A (BTX-A) in targeted muscles reduces 
muscle spasticity which would translate into improved functional ability and pain relief. More 
specifically, the muscles of children to be injected will depend on the specific disease 
presentation for each subject, age, number of muscles affected, disability, presence or absence 
of fixed contractures and the treatment goals. As a result, there is increasing evidence for the 
use of BTX as an adjunct for treatment of upper limb spasticity in children with CP [23]. 
There are a number of systemic antispasticity drugs available, such as baclofen, tizanidine and 
diazepam, but the associated systemic side effects often limit their use in the paediatric 
population. In a limited number of cases intrathecal baclofen has been used for improving upper 
limb spasticity [12]. Orthopaedic surgery is generally reserved for children with already 
developed fixed contractures and deformities. 
2.2 
Compound Review 
Botulinum toxin type A is a potent neurotoxin isolated from the bacterium Clostridium 
botulinum, a gram positive, spore forming anaerobe. Botulinum toxin type A, a single chain 
protein with a molecular weight of approximately 150,000 Daltons (Da), is one of seven 
different serotypes (classed A through G) of BTX produced by this organism. Proteins 
endogenous to the bacterium cleave the single chain protein, resulting in a di-chain neurotoxin 
containing a light chain (molecular weight ~50,000 Da) and a heavy chain (molecular weight 
~100,000 Da) that remain linked by an inter chain disulphide and noncovalent bonds. 
Dysport 500 units (U) is a freeze-dried preparation of Clostridium BTX-A-hemagglutinin 
complex (BTX-A-HAC) formulated with lactose (bulking agent) and human serum albumin. A 
more detailed description of the product is provided in Section 9.1.1. 
For the treatment of spasticity, Dysport is injected directly into target muscles where it acts 
selectively on peripheral cholinergic nerve endings, inhibiting acetylcholine release, effectively 
blocking signal transmission from nerve to muscle and inducing a temporary, partial 
chemodenervation of the injected muscle. 
Typically, Dysport is reconstituted with 1.0 mL or 2.5 mL of preservative free 0.9% sodium 
chloride for injection to yield a solution containing 500 U or 200 U of Dysport per mL, 
respectively, depending on the indication. 
Further details can be found in the Investigator’s brochure [24]. 
2.3 
Clinical Study Rationale 
Previous studies have investigated the use of BTX for the treatment of upper limb spasticity in 
children with hemiplegia due to CP [25, 26, 27, 28, 29, 30]. The effect of a single injection of 
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increased muscle tone, and on the level of functional ability has been compared to control 
groups. In the majority of these studies temporary improvements in spasticity and muscle tone 
were observed in the targeted muscles, providing clear evidence for the beneficial effect of 
BTX. However, the assessment of functional improvement following a single treatment has 
shown variable results in these studies. Functional improvement in upper limb is expected to 
manifest after a sufficiently long period of reduced muscle tone of the upper limb following 
multiple treatments, during which children would have the opportunity to have adequate 
occupational therapy, and to learn new motor skills, necessary for the achievement of their 
individual goals [31]. 
The use of BTX for the treatment of upper limb spasticity in children is well recognised [23, 
32, 33]. The choice of control group in studies is usually occupational therapy, physiotherapy 
and/or no treatment (no placebo injection). However, for the purpose of a phase III study, these 
methods of control are not adequate enough to provide sufficient scientific robustness. Only 
one published placebo controlled study [26] has been identified in this indication. The use of 
placebo as a control group is considered ethically unacceptable since injection into the upper 
limb muscles to this paediatric population often requires anaesthesia or heavy sedation. 
Therefore, a low dose control group has been chosen for this study to maintain the study 
blinding. The dose chosen (2 U/kg) is in line with the lowest upper limb dose used in a previous 
Ipsen sponsored, retrospective study 
 
[34]). 
Dysport is licensed in over 75 countries for various indications. It has been approved for the 
treatment of spasticity of the lower limbs in children (aged 2 to 17 years) with CP at doses up 
to 15 U/kg (with a maximum total dose of 1000 U). In some countries Dysport has also been 
approved for the treatment of adult upper limb spasticity at doses up to 1000 U. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 The Sponsor has not conducted any 
prospective clinical study specifically for the evaluation of safety and efficacy in the treatment 
of upper limb spasticity in children with CP. 
The present phase III, multicentre, double blind, prospective, randomised, controlled multiple 
treatment study has been designed to assess the efficacy of a single treatment of Dysport at the 
doses of 8 U/kg and 16 U/kg compared to Dysport 2 U/kg used in the treatment of upper limb 
spasticity in children with CP. A primary targeted muscle group (PTMG), either the elbow 
flexors or wrist flexors, will be nominated by the Investigator (see Section 9.1.3). Effects of 
muscle tone on the PTMG (using the Modified Ashworth Scale (MAS)) will be assessed as 
primary criterion. The Physician’s Global Assessment (PGA) of the treatment response and 
individual goal attainment are secondary criteria. Furthermore, the study has also been designed 
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to evaluate the long term safety and efficacy following multiple Dysport treatments over the 
course of a minimum of one year’s study participation. 
3 
STUDY OBJECTIVES 
3.1 
Primary Study Objective 
The primary study objective is to assess the efficacy of two doses of Dysport (8 U/kg and 
16 U/kg) compared to Dysport 2 U/kg used in the treatment of upper limb spasticity in children 
with CP following a single treatment. 
3.2 
Secondary Study Objectives 
The secondary study objective is to assess the long term safety of multiple treatments of Dysport 
used in this study population. 
3.3 
Tertiary Study Objectives 
The tertiary study objectives 
 
 quality of life (QoL) 
  
3.4 
Ancillary Study Objectives  
There are no ancillary study objectives.  
4 
STUDY DESIGN 
4.1 
Overview  
4.1.1 
Population Characteristics 
The study will include approximately 210 male and female subjects between 2 and 17 years of 
age, with a body weight ≥10 kg, with a diagnosis of CP and who have increased muscle 
tone/spasticity in at least one upper limb. Additionally, subjects must have a MAS score ≥2 in 
the upper limb PTMG of the study limb (the limb to be injected in the first treatment) at the 
baseline visit and be classified as GMFCS Level 1 to 4. 
 
 
 
 
4.1.2 
Design 
This is a phase III, multicentre, double blind, prospective, randomised, controlled multiple 
treatment study. Subjects will receive a maximum of four treatments over the course of a 
minimum of one year’s study participation.  
4.1.3 
Study Structure 
At study entry, subjects will be randomised into one of the following three treatment groups for 
Treatment 1: 
• 
Group A: Dysport 16 U/kg in one upper extremity (the study limb). 
• 
Group B: Dysport 8 U/kg in the study limb. 
• 
Group C: Dysport 2 U/kg in the study limb. 
Randomisation will be done with an Interactive Response System (IRS) and will be in a 1:1:1 
ratio. The IRS will be used to allocate packs and envelope numbers (to be considered to 
reconstitute the treatment) and then study treatment reconstitution will be performed by an 
independent reconstitutor who will not be involved in any other study related activities in order 
to maintain the blinding. 
For Treatments 2, 3 and 4, subjects are planned to receive Dysport 8 U/kg or 16 U/kg according 
to the treatment allocation by the IRS and will remain double blind throughout the study. 
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 The total dose for the study limb must not exceed 320 U 
in the 8 U/kg group and 640 U in the 16 U/kg group. 
The planned retreatment interval is 16 weeks and a maximum of four treatments will be 
administered. 
At study entry, a PTMG, either the elbow flexors or wrist flexors, will be nominated by the 
Investigator. The PTMG can be changed for subsequent treatments, from elbow to wrist flexors 
or wrist to elbow flexors, provided that the following criteria are fulfilled: 
• 
The Modified Ashworth Scale (MAS) score of the other muscle group not selected for 
the last treatment (new PTMG) must be higher than the last treatment PTMG, and 
• 
The new PTMG must have a modified MAS score of greater or equal to 1+. 
For Treatments 2, 3 and 4, injection into the lower extremity/extremities and the non-study 
upper limb will be allowed at the same time as the study limb is injected (see Section 9.1.4). 
The stages of the study and the planned doses for the study are provided in Figure 1. 
Figure 1 Planned Study Structure 
 
Stratification will be performed according to age range (2 to 9 years and 10 to 17 years) and 
BTX naïve or non-naïve status assessed at baseline. 
 
 
 
 
 
 
A maximum of four treatments will be administered in this study. After each treatment 
administration, the follow up visit schedule is as follows: 
• 
Week 2 (telephone call, safety follow up). 
• 
Week 4 (telephone call, safety follow up). 
• 
Week 6. 
• 
Week 12 (telephone call, safety follow up). 
• 
Week 16. 
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• 
Recommendation by the DSMB. 
4.2 
Endpoints 
4.2.1 
Efficacy Endpoints 
Efficacy variables will be assessed at the following schedule: 
• 
Modified Ashworth Scale, GAS, 
 
 at baseline (Treatment 1, Day 1) and at each post-treatment 
visit to the study centre. 
• 
Physician’s Global Assessment at each post-treatment visit to the study centre. 
• 
 
 
• 
Paediatric Quality of Life (PedsQL™) at baseline (Treatment 1, Day 1), Treatment 1, 
Week 16 and at the end of study visit or early withdrawal. 
4.2.1.1 
Primary Efficacy Endpoint 
• 
Mean change from Baseline to Treatment 1, Week 6 in MAS score in the Treatment 1 
PTMG (elbow flexors or wrist flexors).  
4.2.1.2 
Secondary Efficacy Endpoints 
• 
Mean PGA score at Treatment 1, Week 6. 
• 
Mean GAS score at Treatment 1, Week 6. 
4.2.1.3 
Tertiary Efficacy Endpoints 
• 
Mean change from Baseline to all post-treatment visits of treatment 1 (except Week 6) 
in MAS score in the Treatment 1 PTMG. 
• 
 
 
 
• 
Mean change from Baseline to all post-treatment visits in MAS score in each injected 
muscle group (elbow, wrist and finger flexors) of the study limb. 
• 
 
 
• 
 
 
 
• 
Mean PGA score at all post-treatment visits (except Treatment 1, Week 6). 
• 
 
 
 
• 
Mean GAS score at all post-treatment visits (except Treatment 1, Week 6). 
• 
 
 
 
• 
 
 
 
 
• 
 
 
 
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• 
 
 
 
• 
 
 
 
• 
 
  
• 
 
 
• 
 
• 
Mean change from Baseline to both post-treatment PedsQL scores. 
4.2.2 
Safety Endpoints 
The safety endpoints of this study are:  
• 
Treatment emergent adverse events (TEAEs). 
• 
Vital signs (systolic and diastolic blood pressure (BP) and heart rate (HR)): absolute 
values and change from Baseline at each visit to the study centre. 
• 
Body weight and height: absolute values and change from baseline at Week 16 of each 
treatment and at the end of study visit or early withdrawal. 
• 
Clinical chemistry (including serum ALP - total and bone isoenzyme, and HbA1c): 
absolute values and change from Baseline at Treatment 1, Week 16 (serum ALP - total 
and bone isoenzyme, and HbA1c only) and at the end of study visit or early withdrawal. 
• 
Presence of antibodies against BTX-A (BTX-A-Abs) at baseline and at the end of study 
visit or early withdrawal. 
• 
A 12-lead electrocardiogram (ECG): absolute values and change from Baseline in ECG 
parameters and morphology at Treatment 1, Week 6 and at the end of study visit or early 
withdrawal.  
 
4.3 
Justification of Design 
The present study will be conducted as a phase III, multicentre, double blind, prospective, 
randomised, controlled, multiple treatment study comparing efficacy and safety of Dysport at 
the doses of 8 U/kg and 16 U/kg to Dysport 2 U/kg used in the treatment of upper limb spasticity 
in children with CP. 
Reduction of the increased muscle tone and spasticity is important for the improvement of the 
motor ability and functional skills of children with CP, and for prevention of fixed muscle 
contractures and deformities and to delay the need for surgery. Therefore, the assessment of 
reduction of increased muscle tone of the upper limb has been specified as a primary efficacy 
endpoint of interest for this study. This assessment of muscle tone will be performed using 
MAS, which is the sole validated scale to date, widely used to measure muscle tone [35, 36]. 
The other assessment scales used in this study have been chosen to demonstrate physician’s 
global impression of the treatment effect (PGA), functional outcomes (GAS and 
), 
, QoL, and 
. The 
optimal time to demonstrate the primary and secondary measures is thought to be 6 weeks 
following injection and therefore Week 6 of Treatment 1 has been selected for the primary 
endpoint.  
The clinical presentation of spasticity differs from one subject to another. The Investigator 
should consider the clinical condition, the specific upper limb spasticity pattern (i.e. elbow 
flexion, forearm pronation, wrist and finger flexion, and thumb adduction and flexion) and any 
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associated functional impairment when providing treatment [37]. The design of this study 
allows the Investigator to select the study limb and the PTMG (elbow flexors or wrist flexors) 
and a number of other muscles, as specified in the dosing paradigm (see Section 9.1.2). 
The three Dysport doses chosen for this study are 2 U/kg, 8 U/kg and 16 U/kg. The two higher 
doses of Dysport (8 U/kg and 16 U/kg) will be compared to the lowest dose group (Dysport 
2 U/kg). The choice of each individual muscle dose is based on in house efficacy and safety 
data with Dysport
 [34]), other published data on BTX-A products in this indication, 
and on recommendations from leading clinical experts. 
 
 
 
 The study is designed to 
allow injections into multiple muscle groups in the study limb and since the elbow and the wrist 
flexors were the most commonly injected upper limb muscles in 
, the total dose in 
each treatment group is set to allow concurrent treatment of these two muscle groups. 
Furthermore, the chosen doses are well within the maximum total dose of 30 U/kg of Dysport 
(with a maximum total dose of 1000 U) per treatment session for use in lower limb spasticity 
in children, recommended in the international consensus paper in 2010 [29]. 
A fixed dosing volume was chosen for the study to eliminate the confounding effect of dilution. 
The injection volume of 1.6 mL will be sufficient to inject multiple muscles of the upper limb, 
as required according to clinical need. Proximal and distal muscle groups of the upper limb 
have different sizes of the muscle bulk and may require different doses and volumes of injection 
[33]. For Treatments 2, 3 and 4, Investigators will be allowed to adjust the dose, according to 
treatment response, at the level of individual muscles by changing the injection volume, or total 
dose by requesting a dose change in the IRS without having to break the blind. Furthermore, 
for Treatments 2, 3 and 4, injection into the lower extremity/extremities and the non-study 
upper limb will be allowed at the same time as the study limb is injected. In order to stay within 
the total body dose of 30 U/kg, maximum 1000 U, 
 
 
 
 
 
 
 
  
The planned retreatment interval in this study is 16 weeks, as previously conducted paediatric 
lower limb studies suggest that the effect of Dysport can still be observed 16 weeks after 
treatment [38,39]. In another study, the treatment interval was 4 months [40]. 
4.3.1 
Study Population for Analysis 
The primary analysis will be performed on the mITT population (see Section 11.2). 
4.3.2 
Study Duration 
The overall duration of the study is anticipated to be approximately 4 years and 9 months and 
will include subject recruitment (approximately 3 years) and last subject follow up 
(approximately 1 year and 9 months). The study will be considered to have started when the 
first subject has provided signed informed consent. The study will be considered to have 
finished after the last subject has completed the end of study visit. 
Individual subject participation will be approximately 1 year to 1 year and 9 months, depending 
on the number of treatments administered and the treatment intervals. The 1 year and 9 month 
follow up period will enable subjects whose first three treatment intervals fall between >16 and 
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≤22 weeks to receive four treatments, therefore providing efficacy data for a minimum of 
1 year.  
5 
COMPLIANCE 
WITH 
GOOD 
CLINICAL 
PRACTICE, 
ETHICAL 
CONSIDERATIONS AND INFORMED CONSENT 
5.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study must be conducted in compliance with independent ethics committees/institutional 
review boards (IECs/IRBs), informed consent regulations, the Declaration of Helsinki and 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines 
[41].  
For electronic data capture (EDC) studies the following regulations must be adhered to: Food 
and Drug Administration (FDA), 21 CFR Part 11: Electronic Records, Electronic 
Signatures (e-signature); and FDA, Guidance for Industry: Computerised Systems Used in 
Clinical Trials [42, 43]. In addition, this study will adhere to all local regulatory requirements. 
Before initiating a study, the Investigator/institution must have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form (ICF), any consent form updates, paediatric assent form and any 
updates, subject emergency study contact cards, subject recruitment procedures 
(e.g. advertisements), any written information to be provided to subjects and a statement from 
the IEC/IRB that they comply with GCP requirements. The IEC/IRB approval must identify 
the protocol version as well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should be made only in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
5.2 
Informed Consent 
Prior to study entry, the Investigator, or a person designated by the Investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject and subject’s 
legally acceptable representative and impartial witness, as applicable. Written informed consent 
must be obtained from the child’s parent(s)/guardian(s) (either one or both parent(s)/guardian(s) 
according to local legislation) and a signed assent from the child when and where applicable, 
prior to the subject entering the study (before initiation of any study related procedure and 
administration of study treatment). Sufficient time will be allowed to discuss any questions 
raised by the subject/subject’s representative. If applicable, when a subject becomes an adult 
during study participation, they may be required to sign an adult consent form according to 
local legislation. 
The Sponsor will provide a sample ICF. The final version controlled form must be agreed to by 
the Sponsor, and the IEC/IRB and must contain all elements included in the sample form, in a 
language readily understood by the child’s parent(s)/guardian(s). Each subject’s original ICF 
(and assent form where appropriate), signed and dated by the parent(s)/guardian(s) (and subject 
where appropriate) and by the person who conducted the informed consent discussion, will be 
retained by the Investigator. The Investigator will supply all enrolled child’s 
parent(s)/guardian(s) with a copy of the signed ICF. 
The ICF may need to be revised during the course of the study should important new 
information become available that may be relevant to the safety of the subjects or as a result of 
protocol amendments. In this instance, approval should always be given by the IEC/IRB. It is 
the Investigator’s responsibility to ensure that all parent(s)/guardian(s) of subjects subsequently 

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entered into the study and those currently in the study sign the amended form. This is 
documented in the same way as previously described. Parent(s)/guardian(s) of subjects who 
have completed the study should be informed of any new information that may impact on the 
subjects’ welfare/wellbeing. 
The Investigator should, with the consent of the child’s parent(s)/guardian(s), inform the 
subject’s primary physician about their participation in the clinical study. 
6 
STUDY POPULATION 
6.1 
Screening Log and Number of Subjects 
Each Investigator will maintain a record of all subjects who were considered potentially eligible 
for entry into the study but who were not enrolled. For each subject, the primary reason for 
exclusion will be recorded. 
Each Investigator will also maintain a record of all subjects enrolled into the study (i.e. whose 
parent(s)/guardian(s) signed the ICF). In the event that the subject was not receiving study 
treatment, the primary reason will be recorded. 
It is planned to recruit approximately 210 subjects in this multinational study. Section 11.3 
provides a discussion of sample size. 
6.2 
Inclusion Criteria 
Subjects must satisfy all of the following inclusion criteria to be eligible for the study: 
(1) 
Signed informed consent obtained from the child’s parent(s)/guardian(s) and, if 
applicable, a signed assent from the child. 
(2) 
Be from 2 to 17 years of age, inclusive.  
(3) 
Body weight of 10 kg or more at the baseline visit. 
(4) 
Have a diagnosis of CP, as defined by Rosenbaum [9].  
(5) 
Have increased muscle tone/spasticity in at least one upper limb. 
(6) 
Have a MAS score ≥2 in the upper limb PTMG (elbow flexors or wrist flexors) of the 
study limb (the limb to be injected in the first treatment) at the baseline visit. 
(7) 
Be classified as GMFCS Level 1 to 4.  
(8) 
 
 
 
 
6.3 
Exclusion Criteria 
Subjects are to be excluded if any of the following applies: 
(1) 
Fixed myocontracture in the PTMG (elbow flexors or wrist flexors) of the study limb 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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(7) 
  
 
 
(9) 
Previous injection of alcohol and/or phenol within 1 year prior to the baseline visit 
affecting the study limb wrist flexors and/or elbow flexors selected for injection in 
Treatment 1. 
(10) Treatment with any drug that interferes either directly or indirectly with neuromuscular 
function (e.g. aminoglycoside antibiotics) or neuroblocking agents used during surgery 
(e.g. curare) within the last 30 days prior to study treatment. 
 
 
 
 
 
 
 
(14) Subjects with any clinical (or sub-clinical) evidence of marked defective neuromuscular 
transmission (e.g. Lambert-Eaton syndrome or myasthenia gravis) or persistent clinically 
significant neuromuscular disorders. 
(15) Known sensitivity to BTX or to any of the components in the formulation or allergy to 
cow’s milk protein. 
 
 
(17) Previous rhizotomy less than 6 months prior to the baseline visit or rhizotomy 
planned/anticipated during the course of the study. 
(18) Subjects treated or likely to be treated with intrathecal baclofen within 30 days prior to 
the baseline visit or during the course of the study. 
 
 
 
 
 
 
 
 
 
(22) Any known medical condition, laboratory or diagnostic procedure finding, which might 
compromise compliance with the objectives and procedures of this protocol or preclude 
administration of BTX-A, as judged by the Investigator.  
(23) Any uncontrolled clinically significant medical condition other than CP. 
6.4 
Subject Withdrawal Criteria 
Under no circumstances will subjects be randomised into this study more than once. If one or 
more of the following occurs, the subject will be withdrawn from the study: 
(1) 
Withdrawal of informed consent. 
(2) 
Requirement for administration of concomitant medications and/or treatments that are 
not allowed under the study protocol. 
(3) 
Occurrence of an AE or other nonmedical event, that in the opinion of the Investigator, 
would not be in the subject’s best interest were they to continue in the study.  
(4) 
Pregnancy. 
(5) 
Investigator’s and/or Sponsor’s decision to withdraw the subject if it is considered to be 
in the subject’s best interest. 
(6) 
Continuous failure to comply with the provisions of the study protocol which is likely to 
have an adverse impact on the safety or wellbeing of the subject or subjects, or to 
jeopardise the scientific value of the study. 
(7) 
Any subjects who met any of the stopping rules in Section 4.1.4. 
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6.5 
Discontinuation/Withdrawal Procedures 
If a subject withdraws from the study (i.e. ceases participation in the study prior to completion 
of the assessments planned in the protocol), the primary reason should be recorded in the 
electronic case report form (eCRF). Withdrawal due to AEs should be distinguished from 
withdrawal due to insufficient response.  
The Investigator will provide or arrange for appropriate follow up (if required) for subjects 
withdrawing from the study, and will document the course of the subject’s condition. Where 
the subject has withdrawn due to an AE the Investigator should follow the procedures 
documented in Section 10 in order to assess the safety of the study treatment. 
7 
METHODOLOGY 
7.1 
Study Schedule  
The schedule of observations and assessments is presented in Appendix 1; Treatment 1 is 
presented in Table 8, Treatments 2, 3 and 4 are presented in Table 11, and the additional visits 
and the end of study/early withdrawal visit are presented in Table 12. 
7.2 
Study Visits 
Details of the timing of each visit, together with the tests and procedures to be performed are 
summarised in Appendix 2. Every effort should be made to ensure that visits take place at the 
visit timepoint, or within the visit window where applicable. 
7.2.1 
Screening (Day -7 to Day 1, Visit 1) 
Written informed consent must be signed by the parent(s)/guardian(s) of all subjects, and assent 
obtained from the child, when and where applicable, prior to entry into this study. 
This visit may occur on the same day as the baseline visit (Visit 2 (see Section 7.2.2)) at the 
discretion of the Investigator. Subjects have to undergo the following assessments in order to 
be randomised into the study: 
• 
Eligibility checks (inclusion/exclusion criteria). 
• 
Demographics (date of birth/age, sex, ethnicity and race)2. 
• 
Medical/surgical history, including ongoing medical history. 
• 
Cerebral palsy history and status.  
• 
Botulinum toxin treatment history. 
• 
Prior and concomitant medications. Prior medications will be all medications 
administered within 30 days before the screening visit and stopped either before or at 
study entry. 
• 
Prior and concomitant nondrug therapies. Prior nondrug therapies will be all nondrug 
therapies administered within 30 days before the screening visit and stopped either before 
or at study entry. 
• 
Physiotherapy and occupational therapy (frequency and intensity). Prior physiotherapy 
and occupational therapy will be all therapy within 90 days before the screening visit and 
stopped either before or at study entry. 
• 
Use of splints and/or orthoses. 
• 
Gross Motor Function Classification System level [44].  
• 
Physical and neurological examinations. 
• 
Vital signs (BP and HR) and body weight. 
• 
A 12-lead ECG.  
• 
Collection of AEs. 
                                                 
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7.2.2 
Baseline (Treatment 1, Day 1, Visit 2) 
The screening visit (Visit 1) and the baseline visit (Visit 2) may occur on the same day at the 
discretion of the Investigator. 
All baseline assessments should be performed at this visit prior to randomisation and 
administration of study treatment. If the subject is scheduled to receive study treatment during 
a morning operating theatre session, performance of baseline assessment within 24 hours prior 
to study treatment administration will be acceptable. 
• 
Eligibility checks (inclusion/exclusion criteria). 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy, occupational therapy (frequency and intensity).  
• 
Home exercise instructions 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR) and body weight and height. 
• 
Blood sampling for BTX-A-Ab testing. 
• 
Blood sampling for clinical chemistry (including serum ALP - total and bone isoenzyme, 
and HbA1c). 
• 
Tanner Grading Scale for all female subjects. 
• 
Urine pregnancy test for all female subjects of childbearing potential and for those 
subjects reaching Tanner Grading Scale for breast development Stage II or more will be 
performed at the investigational site. If urine cannot be collected, then alternatively, the 
urine can be taken at home 1 day prior to the visit (only if the ICF has been signed prior 
to urine collection). If the urine pregnancy test is found to be positive, it will be followed 
up with a serum pregnancy test conducted at the central laboratory. 
• 
Hypertonia Assessment Tool will be used for all subjects entering the study (exploratory 
scale) [46]. 
• 
Manual Ability Classification System (MACS) for subjects older than 4 years of age       
(4 years included) and mini-MACS for subjects between 2 and 4 years of age (4 years 
excluded) [18, 19]. 
• 
 
 
• 
Goal Attainment Scale. Individual treatment goals are set at this visit. 
• 
 
• 
 
• 
The PedsQL. 
• 
Collection of AEs. 
• 
Randomisation. If the subject is being anaesthetised prior to treatment injection, 
randomisation must occur before the anaesthetic is given.  
• 
Study treatment administration in the study limb. 
7.2.3 
Treatment 1 – Follow Up Visits 
7.2.3.1 
Week 2 ±1 week Visit 3 - Telephone Contact 
The following assessments will be collected by telephone at Week 2 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity).  
• 
Home exercises (frequency). 
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• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
7.2.3.2 
Week 4 ±1 week Visit 4 - Telephone Contact 
The following assessments will be collected by telephone at Week 4 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
7.2.3.3 
Week 6 ±4 days, Visit 5 
The following assessments will be performed at Week 6 post-treatment for all subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies. 
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR). 
• 
A 12-lead ECG. 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
• 
 
This can be scheduled separately provided it is performed within the visit window. 
• 
 
• 
Collection of AEs. 
7.2.3.4 
Week 12 ±1 week, Visit 6 - Telephone Contact 
The following assessments will be collected by telephone at Week 12 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
7.2.3.5 
Week 16 ±2 weeks, Visit 7 
The following assessments will be performed at Week 16 post-treatment for all subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies. 
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR) and body weight and height. 
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• 
Blood sampling for clinical chemistry (serum ALP - total and bone isoenzyme and 
HbA1c only). 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
• 
 
• 
The PedsQL. 
• 
Collection of AEs. 
• 
Eligibility for retreatment. Any subjects not eligible for retreatment will be evaluated 
every 6 weeks ±2 weeks in additional visits until they are eligible for retreatment (see 
Section 7.2.6). 
7.2.4 
Treatments 2, 3 and 4, Day 1, Visits 8, 14 and 20 
This visit should occur on the same day as the last visit of the previous treatment.  
The following assessments will be performed at this visit: 
• 
Tanner Grading Scale for all female subjects. 
• 
Urine pregnancy test for all female subjects of childbearing potential and for those 
subjects reaching Tanner Grading Scale for breast development Stage II or more will be 
performed at the investigational site. If urine cannot be collected, then alternatively, the 
urine can be taken at home 1 day prior to the visit. If the urine pregnancy test is found to 
be positive, it will be followed up with a serum pregnancy test conducted at the central 
laboratory. 
• 
Goal Attainment Scale. Individual treatment goals are set at this visit. 
• 
Study treatment administration in the study limb. Investigators will be allowed to adjust 
the dose according to treatment response, at the level of individual muscles by changing 
the injection volume or total dose, by requesting a dose change in the IRS without having 
to break the blind (see Section 9.1.3). 
• 
Concomitant treatment of lower limb and/or the non-study upper limb (for subjects who 
require such treatment) (see Section 9.1.4). 
• 
If Day 1 of Treatment 2, 3 or 4 occurs on the same day as the last visit of the previous 
treatment the following assessments will, if conducted, be referenced from that visit. If 
not conducted at that visit, the following assessments will need to be performed prior to 
study treatment administration and recorded in the eCRF: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies. 
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR) and body weight. 
• 
Physician’s Global Assessment Scale. 
• 
 
 
• 
 
• 
Collection of AEs. 
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7.2.5 
Treatments 2, 3 and 4 – Follow Up Visits 
7.2.5.1 
Week 2 ±1 week, Visits 9, 15 and 21 - Telephone Contact 
The following assessments will be collected by telephone at Week 2 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity).  
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
7.2.5.2 
Week 4 ±1 week, Visits 10, 16 and 22 - Telephone Contact 
The following assessments will be collected by telephone at Week 4 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
7.2.5.3 
Week 6 ±4 days, Visits 11, 17 and 23 
The following assessments will be performed at Week 6 post-treatment for all subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR). 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
 
• 
 
• 
Collection of AEs. 
7.2.5.4 
Week 12 ±1 week, Visits 12, 18 and 24 - Telephone Contact 
The following assessments will be collected by telephone at Week 12 post-treatment for all 
subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity).  
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Collection of AEs. 
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7.2.5.5 
Week 16 ±2 weeks, Visits 13, 19 and 25 
The following assessments will be performed at Week 16 post-treatment for all subjects: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR) and body weight and height. 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
 
• 
 
• 
Collection of AEs. 
• 
Eligibility for retreatment. Any subjects not eligible for retreatment will be evaluated 
every 6 weeks ±2 weeks in additional visits until they are eligible for retreatment (see 
Section 7.2.6).  
7.2.6 
Additional Visits 
Any subjects not eligible for retreatment, at Week 16 of any treatment, will be evaluated every 
6 weeks ±2 weeks in additional visits until they are eligible for retreatment. All subjects whose 
first three treatment intervals fall between ≥16 and ≤22 weeks will receive four treatments and 
will exit the study as soon as a new injection is required and no later than 22 weeks after last 
injection (up to a maximum of 1 year and 9 months study duration). All other subjects will not 
be given any further study treatment after Week 52 and will exit the study after 16 weeks of 
follow up of the last treatment. 
The following assessments will be performed at each additional visit: 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
• 
Use of splints and/or orthoses. 
• 
Vital signs (BP and HR). 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
 
• 
 
• 
Collection of AEs. 
• 
Eligibility for retreatment. Any subjects not eligible for retreatment will be evaluated 
every 6 weeks ±2 weeks in additional visits until they are eligible for retreatment. 
7.2.7 
End of Study or Early Withdrawal Follow up Visit 
At the end of study visit or early withdrawal the following assessments will be performed 
(±2 weeks): 
• 
Concomitant medications. 
• 
Concomitant nondrug therapies.  
• 
Physiotherapy and occupational therapy (frequency and intensity). 
• 
Home exercises (frequency). 
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• 
Use of splints and/or orthoses. 
• 
Physical examination. 
• 
Vital signs (BP and HR) and body weight and height. 
• 
A 12-lead ECG. 
• 
Blood sampling for BTX-A-Ab testing. 
• 
Blood sampling for clinical chemistry (including serum ALP - total and bone isoenzyme, 
and HbA1c). 
• 
Physician’s Global Assessment Scale. 
• 
Goal Attainment Scale.  
• 
 
 
• 
 
This can be scheduled separately provided it is performed within 2 weeks before study 
exit. 
• 
 
• 
The PedsQL. 
• 
Collection of AEs. 
8 
STUDY EVALUATIONS 
For the timing of assessments during the study, refer to the study schedules in Appendix 1. 
 
The following examinations will be performed at screening or baseline only. 
Evaluation of Cerebral Palsy 
At baseline, the subjects CP will be evaluated by: 
• 
A diagnosis of CP as defined by Rosenbaum [9]. 
• 
The presence of spastic hemiparesis, paraparesis, diparesis, or tetraparesis.  
• 
Presence and intensity of severe athetoid or dystonic movements in the targeted upper 
limb. 
• 
Evaluation of hypertonia to capture baseline dystonic/spastic characteristic using the 
Hypertonia Assessment Tool [45, 46]. 
• 
Planned or completed surgery of the upper limbs. 
• 
History of injection of alcohol and/or phenol. 
Neurological Examination 
A neurological examination will be performed by the Investigator at screening. The 
neurological examination will include: 
• 
Strength. 
• 
Deep tendon reflexes (biceps and triceps only). 
Gross Motor Function Classification System 
The GMFCS is a five-level classification that differentiates children with CP based on the 
child’s current gross motor abilities, limitations in gross motor function, and need for assistive 
technology and wheeled mobility [44]. Further details will be provided in the study manual. 
Manual Ability Classification System 
The MACS is a five-level classification that assesses how children with CP use their upper limb 
for handling objects in their daily life [18, 19]. Further details are provided in Appendix 7. 
Mini-MACS is the same scale adapted to children between 2 and 4 years of age (4 years 
excluded). For subjects already recruited in the study at the time of protocol amendment 
approval, the MACS (or mini-MACS) will be assessed retrospectively, based on source data 
obtained over 2 months prior to randomization into the study. The investigator will document 
the assessment at the date it is assessed both in the subjects file and in the eCRF (appendix 
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pages). In case it is not possible to assess MACS (or mini-MACS) the data will be noted as not 
applicable in the eCRF. 
 
8.1 
Efficacy Endpoints and Evaluations 
Every effort should be made in each centre to ensure that the evaluating Investigators are the 
same individuals for the duration of the study for a given subject. The assessor who conducts 
the global assessment of the treatment response must be different from the evaluator performing 
the 
and Muscle Tone examination. None of the assessors will have knowledge of the 
scores obtained by the other assessor at the time of his/her assessment.  
 
 
and Muscle Tone Examination 
Modified Ashworth Scale, 
 will be performed as an entire set of examinations 
called 
 and Muscle Tone examination’. It will be performed on the study limb at 
baseline (Treatment 1, Day 1) and at all post-treatment visits, and in the non-study upper limb 
at each visit when the non-study upper limb is injected. The examination will include all of the 
following evaluations: 
• 
 
• 
Elbow flexors MAS and 
. 
• 
Wrist flexors MAS and 
. 
• 
Finger flexors MAS. 
• 
 
This examination must be performed by a different evaluator to the person performing the PGA. 
 
Efficacy Evaluations 
The efficacy evaluations described in the following sections will be evaluated at the following 
schedule: 
• 
 
 
 
 
 
 
 
 GAS, and 
at 
baseline (Treatment 1, Day 1) and at each post-treatment visit to the study centre. 
• 
Physician’s Global Assessment at each post-treatment visit to the study centre. 
• 
 
 
• 
Paediatric Quality of Life at baseline (Treatment 1, Day 1), Treatment 1, Week 16 and at 
the end of study visit or early withdrawal. 
 
8.1.1 
Modified Ashworth Scale  
The MAS is a six-point scale which measures the amount of muscle tone by measuring the 
resistance of the muscle to passive lengthening or stretching [35]. The Investigator will grade 
muscle tone in the PTMG from 0 (no increase in tone) to 4 (affected part(s) rigid in flexion or 
extension). Further details are provided in Appendix 3. 
8.1.2 
Physician’s Global Assessment of the Treatment Response  
The PGA of treatment response will be assessed by asking the Investigator the following 
question: ‘how would you rate the response to treatment in the subject’s upper limb since the 
start of the study?’ Answers will be made on a nine-point rating scale (-4: markedly worse, -3: 
much worse -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, 
+3: much improved and +4: markedly improved). 
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8.1.3 
Goal Attainment Scale 
The GAS is a functional scale used to measure progress towards individual therapy goals. 
Individual goals will be defined for each subject by the Investigator and the child’s 
parents/guardians/caregivers prior to treatment. The GAS will be rated using a defined scale. 
Further details are provided in Appendix 4. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.1.8 
Paediatric Quality of Life Inventory 
Parents/guardians will be asked to complete questionnaires on their child’s QoL [52] at each 
post-treatment visit to the study centre except Week 6. The PedsQL parent inventory measures 
healthcare concepts for children/adolescents of ages 2 to 18 years of age [53]. The Generic Core 
Scales cover four multidimensional scales including physical, emotional, social and school 
aspects with three summary scales of total scale score, physical health summary score and 
psychosocial health summary score.  
Parents/guardians will also complete the Condition-specific Module in CP (in countries where 
translation is available) [53], which is a complement to the Generic Core Scale of the PedsQL. 
It is designed to provide greater measurement sensitivity for circumscribed populations. 
 
Efficacy endpoints are defined in Section 4.2.1. 
 
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8.2 
Safety Endpoints and Evaluations 
8.2.1 
Adverse Events 
Adverse events will be monitored from the signing of informed consent up until the end of the 
study (as defined in Section 4.3.2). All AEs will be elicited by direct, nonleading questioning 
or by spontaneous reports. Further details for AE reporting can be found in Section 10.  
8.2.2 
Physical Examination 
A physical examination will be carried out by a physician, or by another qualified staff member 
designated by the Investigator, at the screening visit and at the end of study visit or early 
withdrawal. The physical examination should include (but is not restricted to) the following 
body systems: cardiovascular, respiratory, abdominal, eyes, ears, nose and throat, skin and 
musculoskeletal. If in the opinion of the Investigator there are any clinically significant changes 
in the physical examination findings (abnormalities) they will be recorded as AEs. 
8.2.3 
Vital Signs 
Vital signs (systolic and diastolic BP and HR) will be measured at each visit to the study centre. 
Blood pressure will be measured with the subject in a sitting position. Absolute values and 
change from Baseline will be analysed. 
8.2.4 
Electrocardiogram Analysis 
An ECG analysis will be included as a safety evaluation/endpoint in this study. 
Subjects will have a set of three 12-lead ECG recordings taken at the screening visit (considered 
as baseline assessment), then subsequently one 12-lead ECG at Treatment 1, Week 6 and at the 
end of study visit or early withdrawal. The 12-lead ECG recordings will be performed at a paper 
speed of 25 mm/sec, recorded with the subject supine. Analysis of the ECG results will be 
performed in a central laboratory. 
All ECGs that are performed post-treatment will be compared to baseline. Any clinically 
significant difference in the ECG parameters or morphology will be noted.  
If at any time point the QTc exceeds 500 msec or the change from Baseline exceeds 60 msec, 
the ECG will be repeated until the parameters fall below these limits or the Investigator is 
satisfied that the subject is not at any significant risk. 
Analysis of the duration of the QT/QTc interval, the HR and the presence of any of the 
following ECG abnormalities: new morphologies, arrhythmias, second degree AV block, third 
degree AV block, ST segment abnormalities, T-wave abnormalities, U-wave abnormalities, 
myocardial infarction, right bundle branch block, left bundle branch block, will be performed. 
These and any other clinically relevant abnormality will also be reported by the central provider 
to the Investigator and recorded as an AE. 
The QT interval is defined as the time (in msec) from the beginning of the QRS complex to the 
end of the T-wave on the ECG. The QTc is defined as the corrected QT interval using the 
Fridericia and the Bazett formula. The duration of the QT/QTc interval in the ECGs taken for 
each subject and at each time point will be used for the analysis. 
In summary, the ECG safety endpoints will include: 
• 
Duration of the QT/QTc interval (in msec) at each ECG time point.  
• 
Mean change from Baseline in the duration of the QT/QTc interval at each ECG time 
point. 
• 
Proportion of subjects at each ECG time point with a duration of QT/QTc interval of: 
>450 to 480 msec, >480 to 500 msec and >500 msec. 
• 
Proportion of subjects at each ECG time point with an increase from baseline in the 
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• 
Proportion of subjects with any of the above listed ECG abnormalities at each ECG time 
point. 
Electrocardiogram test results will be recorded by the central laboratory and provided to the 
study Sponsor, and to the study sites for evaluation of clinically significant changes. See 
Section 10.1.7 for recording clinically significant abnormal ECG findings that should be 
recorded as AEs in the eCRF. 
8.2.5 
Clinical Laboratory Tests 
Blood samples for clinical chemistry (including serum ALP - total and bone isoenzyme, and 
HbA1c) will be collected at Treatment 1, Day 1 (baseline) and at the end of study visit or early 
withdrawal. In addition, a blood sample for serum ALP - total and bone isoenzyme, and HbA1c 
only will be collected at Treatment 1, Week 16. Absolute values and change from Baseline will 
be analysed. 
The following will be assessed: 
Clinical Chemistry (3.5 mL blood): urea, creatinine, total bilirubin, conjugated bilirubin, 
chloride, bicarbonate, sodium, potassium, calcium, phosphate, serum ALP - total and bone 
isoenzyme, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, 
albumin, total protein, total cholesterol, triglycerides and HbA1c. 
Pregnancy: At Day 1 of each treatment, the Tanner Grading Scale for breast development will 
be performed for all female subjects (further details are provided in Appendix 8) [54]. For all 
female subjects of childbearing potential and for those subjects reaching Tanner Stage II or 
more breast development, a urine sample will be collected for a pregnancy test. The test will be 
performed on site using a urine pregnancy test provided by the Sponsor.  
If it is anticipated that urine collection may not be possible on site, parents will be instructed to 
collect a urine sample (at least 15 mL) at home in a clean dry vial on the day preceding the visit. 
The urine sample will be stored in the fridge (between 2°C and 8°C). Parents will take the urine 
sample to the investigational site where the test will be performed.  
If the urine pregnancy test is found to be positive, it will be followed up with a serum pregnancy 
test (1 mL blood) conducted at the central laboratory.  
Clinical laboratory tests will be performed by a central laboratory. Details of the methodology 
and reference ranges will be provided in the Trial Master File. 
Laboratory test results will be recorded by the central laboratory and provided to the study 
Sponsor, and to the study sites for evaluation of clinically significant changes. All clinically 
relevant abnormal laboratory tests occurring during the study will be repeated at appropriate 
intervals until they return to baseline or to a level deemed acceptable by the Investigator and 
the Sponsor’s medical monitor (or his/her designated representative), or until the abnormality 
is explained by an appropriate diagnosis. See Section 10.1.5 for abnormal laboratory tests that 
should be recorded as AEs in the eCRF. 
8.2.6 
Prior and Concomitant Medications 
Prior and concomitant medications will be included as a safety evaluation in this study and will 
be monitored from the time that the child’s parent(s)/guardian(s) give informed consent to the 
end of the study (as defined in Section 4.3.2).  
8.2.7 
Body Weight and Height 
Body weight will be measured at screening, at Day 1 of each treatment, at Week 16 of each 
treatment and at the end of study visit or early withdrawal. 
Height will be measured at Day 1 of Treatment 1, at Week 16 of each treatment and at the end 
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8.3 
Total Blood Volume  
The volume of blood to be taken for clinical chemistry and putative antibodies is described 
below: 
For subjects’ weighing ≥20 kg, the total scheduled volume of blood taken per subject during 
the course of the study will not exceed 39 mL. For subjects’ weighing <20 kg, the total 
scheduled volume of blood taken per subject during the course of the study will not exceed 
29 mL. This is a safe and standard blood volume, appropriate to this study, and should cause 
no safety concerns. 
8.4 
Blood Samples for Putative Antibodies 
Subjects will have blood samples collected prior to study treatment administration at baseline 
and at the end of study or early withdrawal, to test for the presence of BTX-A-Abs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Refer to Appendix 9 for a detailed description of sample collection. 
9 
STUDY TREATMENTS 
9.1 
Treatments Administered 
It is forbidden to use the study treatment for purposes other than as defined in this protocol. 
Administration of the study treatment will be supervised by the Investigator, or designee.  
At study entry, subjects will be randomised into one of the following three treatment groups for 
Treatment 1: 
• 
Group A: Dysport 16 U/kg in one upper extremity (the study limb). 
• 
Group B: Dysport 8 U/kg in the study limb. 
• 
Group C: Dysport 2 U/kg in the study limb. 
For Treatments 2, 3 and 4, subjects are planned to receive Dysport 8 U/kg or 16 U/kg according 
to the treatment allocation by the IRS and will remain double blind throughout the study. 
 
 
 The total dose for the study limb must not exceed 320 
U in the 8 U/kg group and 640 U in the 16 U/kg group. 
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9.1.1 
Dysport 
Dysport will be provided in a 3.0 mL glass vial containing 500 U (nominal) of BTX-A-HAC 
as a white lyophilised powder for reconstitution. Details of the drug composition and excipients 
are provided in the current Investigator’s brochure for Dysport [24]. 
Dysport drug product should be stored at the recommended temperature (between 2ºC and 8ºC). 
The product does not contain any antimicrobial agent. It is therefore recommended that the 
product be used immediately after reconstitution. Dysport should not be frozen and should be 
protected from light.  
9.1.2 
Administration Procedures 
Dysport will be reconstituted at the investigational site with preservative free 0.9% sodium 
chloride for injection. Detailed instructions will be provided for the volume which needs to be 
withdrawn from the reconstituted Dysport vials according to each subject’s body weight and 
the group. The study treatment will be prepared by an independent reconstitutor (see 
Section 9.2.2) according to the instruction leaflet allocated for that treatment. The treatment 
allocation will be kept by the independent reconstitutor and must not be made available to any 
other members of the study team. A total of 1.6 mL of the reconstituted study treatment will be 
provided in syringes to the Investigators (or designee) performing the injection. This syringe 
will be labelled with the subject’s study number without any dose information. Thus, the 
Investigator and subject will be completely blinded to the identity of the study treatment in the 
syringe and the dose. Regardless of the treatment group to which the subject is allocated, the 
volume of 1.6 mL will be constant across all dose groups. 
All subjects will receive Dysport administered intramuscularly (see Section 9.1.3 for dosage). 
Electrical stimulation (ES) and/or ultrasound will be used to localise the targeted injection sites. 
Complementary techniques such as electromyography will be allowed in addition to ES and/or 
ultrasound. Description of the use of ES will be provided in the Study Manual. 
For the injection, each participating centre should maintain their usual injection environment 
and procedures for their pain management strategies (e.g. use of general anaesthesia, topical 
anaesthesia, or oral, intranasal or rectal medication). The injection techniques and pain 
management strategies used will be recorded in the eCRF. 
The study limb (left or right), the PTMG, muscles injected and volume injected (total and per 
muscle) will be documented in the eCRF. 
9.1.3 
Treatment of the Study Upper Limb 
9.1.3.1 
Total Dose/Volume in the Study Upper Limb 
Subjects will receive Dysport 2 U/kg, 8 U/kg or 16 U/kg in the study limb in Treatment 1 and 
are planned to receive Dysport 8 U/kg or 16 U/kg in subsequent treatments according to the 
treatment allocation by the IRS (Table 1) and both Investigators and subjects will remain 
blinded to study treatment throughout the study.  
 
 
 
 
  
 
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Table 1 
Planned Dysport Dose Administered per Treatment Group  
Group 
Number of Subjects 
Treatment 1(a) 
Treatments 2, 3 and 4(a) 
A 
70 
Dysport 16 U/kg 
Dysport 16 U/kg 
B 
70 
Dysport 8 U/kg 
Dysport 8 U/kg 
C(b) 
70 
Dysport 2 U/kg 
Dysport 8 U/kg or 
Dysport 16 U/kg 
(a) The total dose for the study limb must not exceed 320 U in the 8 U/kg group and 640 U in the 
16 U/kg group.  
(b) In this group, dynamic dose dispensing will be done by IRS at Treatment 2 to maintain a balance 
between subjects receiving 8 U/kg and 16 U/kg. 
The dose for each subject will be calculated according to the subject’s body weight, up to a 
maximum body weight of 40 kg (even if the subject weighs more than 40 kg and therefore a 
maximum total dose of 320 U in the 8 U/kg group and 640 U in the 16 U/kg group, Table 2). 
The allocated dose will be reconstituted with preservative free 0.9% sodium chloride for 
injection to a fixed volume of 1.6 mL for injection. 
The IRS will be used to allocate packs and envelope numbers (to be considered to reconstitute 
the treatment) and then study treatment reconstitution will be performed by an independent 
reconstitutor who will not be involved in any other study related activities in order to maintain 
the blinding. 
Study treatment will be supplied to the study centre in individual packs. Each pack will contain 
two vials of 500 U Dysport. The appropriate instruction leaflet, with detailed instructions for 
reconstitution will be provided outside of the treatment packs: one instruction leaflet for each 
of the possible doses 2 U/kg, 4 U/kg, 8 U/kg and 16 U/kg. The Sponsor will provide the 
injection materials (syringes and needles) for paediatric use to sites. 
 
9.1.3.2 
Primary Target Muscle Group 
In Treatment 1, before performing the injection, the Investigator will select the study limb and 
the PTMG (either the elbow flexors or wrist flexors). The PTMG must have a baseline MAS 
score of greater or equal to 2 and must be the muscle group with the highest MAS score. The 
muscle group with the highest score will be the PTMG. If the baseline MAS score is the same 
for the elbow flexors and wrist flexors, the choice of PTMG will be left to the Investigator’s 
judgement. 
 
For Treatments 2, 3 and 4, the PTMG can be changed from elbow to wrist flexors or from wrist 
to elbow flexors, provided that the following criteria are fulfilled: 
• 
The MAS score of the new PTMG must be higher than the MAS score of the previous 
PTMG, and 
• 
The new PTMG must have a modified MAS score of greater or equal to 1+. 
• 
The volume to be injected in the new PTMG should be equal to the volume presented in 
Table 2 if clinically indicated. 
 
9.1.3.3 
Dose/Volume by Muscle 
The entire volume for injection (1.6 mL) will be injected and will be divided between the 
PTMG (elbow flexors or wrist flexors) and a number of additional muscles selected by the 
Investigator according to the disease presentation.  
The volume injected into the additional muscles must not exceed that specified in the dosing 
paradigm in Table 3. No more than 0.5 ml will be injected per injection site. 
 

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The injection volume, number of injection sites and dose by muscles in the PTMG are provided 
in Table 2. Those are mandatory for the PTMG at treatment 1 and should be applied at other 
treatment cycles if clinically indicated. 
 If elbow flexors are chosen as the PTMG, both brachialis and brachioradialis have to be 
injected at the injection volume specified in Table 2.  
 If wrist flexors are chosen as the PTMG, both flexor carpi radialis and flexor carpi ulnaris 
have to be injected at the injection volume specified in Table 2. 
 
Table 2 
 
Injection Volumes, Dose per Muscle and Number of Injection Sites in the Primary Targeted 
Muscle Group 
 
For Primary Targeted 
Muscle Group 
(PTMG)  
Injection  
Number  
Dose per Muscle in U/kg / Maximum U 
Volume 
(mL) 
of Injection 
Sites 
Low 
2 U/kg 
Medium 
8 U/kg(a) 
High 
16 U/kg(a) 
Elbow flexors 
Brachialis 
0.6 
2 
0.75 U/kg/30 U 
3 U/kg/120 U 
6 U/kg/240 U 
Brachioradialis 
0.3 
1 
0.375 U/kg /15 U 
1.5 U/kg/60 U 
3 U/kg/120 U 
Wrist flexors 
Flexor carpi radialis 
0.4 
1 - 2 
0.5 U/kg /20 U 
2 U/kg/80 U 
4 U/kg/160 U 
Flexor carpi ulnaris 
0.3 
1 
0.375 U/kg /15 U 
1.5 U/kg/60 U 
3 U/kg/120 U 
a 
The total dose for the study limb must not exceed 320 U in the 8 U/kg group and 640 U in the 16 U/kg group. 
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9.1.3.4 
Dose/Volume at Treatment 2, 3 and 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
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9.1.4 
Concomitant Treatment of Lower Limb Spasticity and the Non-study Upper Limb 
For Treatments 2, 3 and 4, injection into the lower extremity/extremities and the non-study 
upper limb will be allowed at the same time as the study limb is injected. Muscle(s) for injection 
will be selected according to the Investigator’s judgement.  
 
If there is no need to inject the lower limbs, and only the non-study upper limb is to be injected 
(on top of the study upper limb), the dose in the non-study upper limb should not exceed the 
dose detailed in Table 5 below: 
 
Table 5 
Maximum Dose for Non-study Upper Limb  
Body Weight (kg) 
Maximum Dose 
10 to 40 
5 U/kg, calculated up to 40 kg 
40 and over 
200 U 
 For dose by muscle, please refer to table 8 
 
If there is no need to inject the non-study upper limb and only one or two lower limb(s) are to 
be injected (on top of the study upper limb), the dose in the lower limb(s) should not exceed the 
dose detailed in Table 6 below:  
 
Table 6 
Maximum Dose for the Lower Limb(s) 
Body Weight (kg) 
Maximum Dose 
10 to 36 
10 U/kg, calculated up to 36 kg 
36 and over 
360 U 
For dose by muscle, please refer to table 9 
 
 
 
 
 
 
 
 
 
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No more than 0.5 ml will be injected per injection site. 
 
9.2 
Subject Identification and Allocation to Study Treatment 
All subjects enrolled must be identifiable throughout the study. The Investigator will maintain 
a list of subject numbers and names to enable records to be found at a later date if required. 
At screening, potential subjects will be allocated a subject number. Following confirmation of 
eligibility for the study, subjects will be given a randomisation number and allocated to one of 
the treatment groups specified in Section 9.1. 
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9.2.1 
Randomisation 
Randomisation will be done with an IRS and will be in a 1:1:1 ratio. Stratification will be 
performed according to age range (2 to 9 years and 10 to 17 years) and BTX naïve or non-naïve 
status assessed at baseline. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Any subject meeting the randomisation criteria will be assigned a randomisation number in 
his/her stratum and allocated to the associated treatment arm. At the randomisation and at each 
next dispensation, a treatment number and an envelope number will be then allocated to the 
subject and the corresponding treatment will be administered to the subject after the drug is 
reconstituted according to the subject’s body weight and assigned leaflet. 
This IRS service provides Investigators, site co-ordinators and project team members with a 
24 hour per day, 7 day per week service. In case of medical or technical randomisation queries, 
a 24 hour helpline is available (see supporting information in the Investigator Site File). 
Additional details can be found in the IRS reference manual provided to each site. 
Randomised subjects who terminate their study participation for any reason before 
administration of the drug assigned by IRS will retain their randomisation, envelope and 
treatment numbers, i.e. the envelope and treatment numbers will not be reused. The next subject 
is given another randomisation number, another envelope number and another treatment 
number even if he/she should receive the same treatment. Subjects who leave the study early 
will not be replaced. 
The Sponsor’s Randomisation Manager will keep the master lists. A copy of the list of 
randomisation and envelope numbers (Lists A and B) will be confidentially supplied to the 
independent statistician in the DSMB and the Contract Research Organisation (CRO) in charge 
of the central randomisation allocation. The master lists and the copies supplied to the CRO in 
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charge of the IRS will be kept confidential in a secure location. Access to the randomisation 
lists must be restricted until authorisation is given to unblind for final analysis. 
9.2.2 
Blinding, Emergency Envelopes and Breaking the Blind 
All of the study treatment kits will contain two vials of Dysport 500 U. But, there will be four 
instruction leaflets (2 U/kg, 4 U/kg, 8 U/kg and 16 U/kg). Consequently, to maintain the 
blinding of study treatment, a nurse or a pharmacist, independent of the project team, will be in 
charge of the preparation of each individual subject’s study treatment according to the assigned 
envelope number. This person will be fully trained in the method of preparing the syringes, and 
will be instructed not to convey the dose allocation to anyone else, including other members of 
the study team and Investigator. They will also be made aware of the importance of their role 
in maintaining the blind for the subject, the Investigator and the remainder of the project team. 
The randomisation manager will produce a treatment allocation envelope for each envelope 
number. So, an assigned envelope will have to be opened by the person in charge of the drug 
reconstitution to know the dose leaflet to be considered. The assigned enveloped is strictly to 
be opened by the independent reconstitutor and annotated with the opener identification and the 
date in order to allow identification of the correct reconstitution leaflet to be used. Then after 
the drug preparation, it will be re-sealed by the independent reconstitutor. The unblinded 
monitor will open and check these envelopes for verification, then date, sign and reseal them. 
The independent reconstitutor will play no other part in any other study activities. 
Whenever a situation arises necessitating knowledge of a subject’s study treatment, the 
Investigator should first contact the Pharmacovigilance/Emergency contact, as outlined in the 
front of the protocol, prior to code-break to review the status of all pertinent information. The 
Pharmacovigilance/Emergency contact will discuss all pertinent information surrounding the 
case with the Investigator, to determine if the situation justifies knowledge of the dose 
allocation. 
Where necessary the Investigator and the Central Department of Pharmacovigilance at Ipsen 
may break the blind by logging onto the IRS centre/system to obtain the subjects treatment dose 
identification. In addition, hard copy sealed code-break envelopes will be held by the Central 
Department of Pharmacovigilance at Ipsen, in case of IRS failure. This set of envelopes based 
on the envelope numbers, will be produced by the randomisation manager. 
If code-break was performed using the IRS, the Investigator must store the email notification 
revealing unblinded treatment in a sealed envelope. The Investigator will then sign, date and 
provide reason for the code-break on the Emergency Code-break form, and on the sealed 
envelope. The date and reason for identifying the treatment group will be recorded in the eCRF. 
9.3 
Study Treatment Supply, Packaging and Labelling 
The study treatment will be packaged and released by the CTSU, Beaufour Ipsen Industrie and 
delivered to the investigational sites or interim storage facility. A sufficient quantity of study 
treatment will be supplied as well as an acknowledgement of receipt form.  
The Sponsor’s representative will receive a Certificate of Analysis for which batch of study 
treatment has been used under their study, and the Certificate of Compliance which reflects the 
product release statement.  
The core label texts for all treatment packs will be translated or adjusted, to be in compliance 
with applicable regulatory requirements, national laws in force and in accordance with the local 
languages. A description of the core text of the treatment pack labels is displayed below: 
• 
Sponsor name, address and telephone number. 
• 
Study number. 
• 
Name of study treatment with strength and potency. 
• 
Pharmaceutical dosage form and quantity of dosage unit. 

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• 
Route of administration. 
• 
Batch number. 
• 
Treatment number. 
• 
Specific blank spaces to enter the subject number and envelope number (completed by 
the Investigator).  
• 
For clinical study use only. In the US: ‘Caution: New Drug Limited by Federal (United 
States) Law to Investigational Use.’ 
• 
Investigator name/site (completed by the Investigator). 
• 
Storage conditions. 
• 
Expiry date. 
• 
Directions for use. 
The Investigator, or designee, will only dispense study treatment to subjects included in this 
study. Each subject will only be given the study treatment carrying his/her number. The 
dispensing for each subject will be documented in the eCRF. 
9.4 
Compliance 
Study treatment will be administered intramuscularly at the clinic by the Investigator, thus, 
subject compliance with treatment is not expected to be an issue. Drug accountability records 
will be maintained by the independent reconstitutor documenting that subject received allocated 
drug. 
9.5 
Study Treatment Storage and Accountability 
The Investigator, or an approved representative (e.g. pharmacist), will ensure that all study 
treatment is stored in a secured area, under recommended temperature monitored storage 
conditions, in accordance with applicable regulatory requirements and will be reconstituted and 
dispensed by qualified staff members. 
All study treatments are to be accounted for on the study treatment accountability log provided 
by the Sponsor. It is essential that all used and unused supplies are retained for verification (by 
the Sponsor or Sponsor’s representative). The Investigator should ensure adequate records are 
maintained via the study treatment accountability log. 
The destruction of unused study treatments should be carried out on site only after any 
discrepancies have been investigated and satisfactorily explained and the reconciliation has 
been accepted. The study treatments will be destroyed preferably on site or at the interim storage 
facility or returned to CTSU 
 
 
9.6 
Concomitant Medication/Therapy 
The following concomitant medications/therapies are not permitted during this study (see also 
Section 6.3): 
• 
Botulinum toxin for administration into any site of the body other than Dysport in the 
study limb (or in the non-study upper limb and/or in the lower limbs for Treatments 2, 3 
and 4). 
• 
Any investigational new drug or device or off label use of any drug. 
• 
Treatment with any drug that interferes either directly or indirectly with neuromuscular 
function (e.g. aminoglycoside antibiotics) or neuroblocking agents used during surgery 
(e.g. curare) within ±30 days of any study treatment. 
• 
Intrathecal baclofen therapy. 
• 
Phenol or alcohol injection affecting the study limb. 
The following concomitant medications are permitted during this study but they must be 
monitored closely and every effort should be made to keep concomitant spasticity treatment 
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constant throughout the course of the study. However, changes in pain medication are 
acceptable if absolutely necessary and according to clinical judgement (see also Section 6.3): 
• 
Concomitant use of anticholinergic drugs (which may potentiate systemic anticholinergic 
effects) is permitted if the dosage has been stable for the 4 weeks prior to study treatment 
and is expected to remain at this stable dose throughout the study.  
• 
Concomitant treatment with dantrolene, tizanidine, gabaergic drugs, opioid, oral 
baclofen or other antispasticity agents like benzodiazepines should be kept at the same 
dose throughout the study. 
The following conditions apply for physiotherapy, occupational therapy or use of splints and/or 
orthoses: 
• 
If undergoing pre-study therapy, such physiotherapy, occupational therapy or use of 
splints and/or orthoses, therapy must have been initiated at least 30 days prior to the 
baseline visit and agreed to continue the therapy throughout the study and at the 
minimum, up to Week 16 following the first treatment administration. 
• 
No physiotherapy, occupational therapy or use of splints and/or orthoses should be 
initiated less than 30 days prior to the baseline visit or during the course of the study up 
to Week 16 following the first treatment administration. 
• 
Initiation of physiotherapy, occupational therapy or use of splints and/or orthoses after 
Week 16 following the first treatment administration will be allowed.  
• 
Physiotherapy and occupational therapy sessions, or use of splints and/or orthoses will 
be documented in the subject diary and eCRF. 
• 
Instructions for home exercises will be provided to the parents/guardians/caregivers 
and/or subjects to encourage use of the muscle groups injected in the study. These 
instructions will be given at the baseline visit and the instructions will be adapted based 
on the subject’s need through the study. The use of home exercises will be documented 
in the eCRF. School therapy will also be allowed during term time. 
9.7 
Treatment of Overdose of Investigational Medicinal Product 
Excessive doses of BTX-A may produce distant and profound neuromuscular paralysis. 
Overdose may lead to an increased risk of the neurotoxin entering the bloodstream and may 
cause complications associated with the effects of oral BTX poisoning (e.g. deglutition disorder 
and dysphonia). Respiratory support may be required where excessive doses cause paralysis of 
the respiratory muscles. There is no specific antidote (antitoxin should not be expected to be 
beneficial) so general supportive care is advised. In the event of overdose, the subject should 
be medically monitored for any signs and/or symptoms of excessive muscle weakness and/or 
muscle paralysis. Symptomatic treatment should be instigated if necessary. The signs and/or 
symptoms of overdose may not present immediately following treatment. Should accidental 
treatment or oral ingestion occur, the person should be medically supervised for several weeks 
for any signs and symptoms of excessive muscle weakness or muscle paralysis. 
Any appropriate treatment of overdose of study treatment will be determined by the Investigator 
according to the characteristics of the events and will be recorded in the subject’s eCRF. An 
event resulting from an overdose of the study treatment is not considered as serious unless it 
meets the definition of a serious adverse event (SAE) and consequently should be reported on 
the SAE form (see Section 10.3). 
10 
ADVERSE EVENT REPORTING 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 

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be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g. laboratory findings, ECG). In clinical studies, an AE can include 
an undesirable medical condition occurring at any time, including run in or washout periods, 
even if no study treatment has been administered.  
This definition includes events occurring from the time of the child’s parent(s)/guardian(s) 
giving informed consent until the end of the study (as defined in Section 4.3.2). 
10.1 
Categorisation of Adverse Events 
10.1.1 
Intensity/Severity Classification 
Adverse events will be classified as mild, moderate or severe according to the following criteria: 
• 
Mild: 
Symptoms do not alter the subject’s normal functioning. 
• 
Moderate: Symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject. 
• 
Severe: 
Symptoms definitely hazardous to wellbeing, significant impairment of 
function or incapacitation. 
10.1.2 
Causality Classification 
The relationship of an AE to the study treatment will be classified according to the following: 
• 
Related: 
Where there is good reason(s) and sufficient evidence (e.g. plausible time 
sequence, dose response relationship, known pharmacology of study treatment) to 
assume a causal relationship with the study treatment in the sense that it is plausible, 
conceivable or likely. 
• 
Not related: 
Where there is good reason(s) and sufficient evidence (e.g. implausible 
time sequence and/or event could be attributable to a concurrent disease or concomitant 
drug) to rule out a causal relationship with the study treatment. 
10.1.3 
Assessment of Expectedness  
The reference safety document to be used for assessing the expectedness of AEs in this study 
will be the Investigator’s brochure [24]. 
10.1.4 
Adverse Events of Special Interest 
The effects of Dysport and all BTX products may spread from the area of injection to produce 
symptoms consistent with BTX effects. These symptoms have been reported hours to weeks 
after injection. Remote spread of toxin that affects swallowing and breathing can be life 
threatening, and there have been reports of death. The risk of symptoms is increased in subjects 
who have underlying conditions (e.g. disorders of the neuromuscular junction) that would 
predispose them to these symptoms. Dysport is contraindicated in individuals with known 
hypersensitivity to any BTX preparation or to any of the components in the formulation. 
Adverse events of special interest (AESIs) for Dysport are AEs that suggest a possible remote 
spread of effect of the toxin or hypersensitivity. A list of preferred terms of AESIs is provided 
in the Statistical Analysis Plan. All AEs will be monitored by the sponsor to determine if they 
meet the criteria of AESIs. These AESIs will be further analysed to determine if there is a 
plausible possibility that they represent distant spread of toxin or hypersensitivity. In order to 
perform the analysis, variables including alternate aetiology (medical history, concomitant 
medication, or diagnosis which could account for the symptoms), location of Dysport 
administration, and temporal relationship to Dysport administration will be considered by the 
sponsor. 

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10.1.5 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
• 
They result in a change in the schedule of administration (change in dosage, delay in 
administration, study treatment discontinuation). 
• 
They require intervention or a diagnosis evaluation to assess the risk to the subject. 
• 
They are considered as clinically significant by the Investigator. 
10.1.6 
Abnormal Physical Examination Findings 
Clinically significant changes, in the judgement of the Investigator, in physical examination 
findings (abnormalities) will be recorded as AEs. 
10.1.7 
Other Investigation Abnormal Findings 
Abnormal objective test findings considered by the Investigator as clinically significant (e.g. 
ECG or vital signs changes) and that result in a change in study treatment dosage or 
administration schedule, or in discontinuation of the study treatment, or require intervention or 
diagnostic evaluation to assess the risk to the subject, should be recorded as AEs.  
10.2 
Recording and Follow up of Adverse Events 
At each study visit the subject should be asked a nonleading question such as: ‘do you feel 
different in any way since starting the new treatment/the last assessment?’ 
All observed (or volunteered by subject or parent/guardian) AEs, regardless of treatment group 
or suspected causal relationship to study treatment, will be recorded on the AE page(s) of the 
eCRF.  
Any AEs already recorded in the eCRF and designated as ‘continuing’ should be reviewed at 
each subsequent visit and the AE log of the eCRF updated as appropriate to reflect the clinical 
evolution of the event (e.g. outcome changed from ongoing to recovered and event end date 
added). 
For all AEs, the Investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to the Sponsor or its designated representative. For all AEs, 
sufficient information should be obtained by the Investigator to determine the causality of the 
AE (i.e. study treatment or other cause).  
For each AE recorded, the Investigator must provide their opinion on causal association (i.e. 
whether they consider the AE related/not related to study treatment). Follow up is required until 
the event and/or its sequelae either resolves completely or stabilises to a level acceptable to the 
Investigator and the Sponsor’s clinical monitor or his/her designated representative. 
10.3 
Serious Adverse Events 
10.3.1 
Definitions  
All SAEs (as defined below) regardless of treatment group or suspected causal relationship to 
the study treatment must be reported immediately (within 24 hours of the Investigator’s 
knowledge of the event) to the Sponsors Pharmacovigilance department. If the immediate report 
is submitted by telephone, this must be followed up by a detailed written report using the SAE 
report form provided. 
An SAE is any AE occurring that at any dose: 
(1) 
Results in death. 

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(2) 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the reaction as it occurred. It does not include a reaction that, had it occurred in a 
more severe form, might have caused death. 
(3) 
Results in inpatient hospitalisation or prolongation of an existing hospitalisation, 
excluding admission for social or administrative reasons (see further). 
(4) 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person’s ability to conduct normal daily life functions. 
(5) 
Results in a congenital anomaly/birth defect in the offspring of a subject who received 
the study treatment. 
(6) 
Is an important medical event that may not result in death, be life threatening, or require 
inpatient hospitalisation but where, based upon appropriate medical judgement, may 
jeopardise the subject and may require medical and/or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in hospitalisation, or the development of drug 
dependency or drug abuse. 
• 
Hospitalisation is defined as any formal inpatient admission. For any subjects 
already hospitalised, hospitalisation also includes any transfer within the hospital 
(or to another hospital) to an acute/intensive care unit. 
• 
Prolongation of hospitalisation is defined as any extension of an inpatient 
hospitalisation beyond the stay anticipated/required in relation to the original 
reason for admission, as determined by the Investigator or treating physician.  
• 
Prolongation in the absence of a precipitating, treatment emergent, clinical 
AE (i.e. not associated with the development of a new AE or worsening of a 
pre-existing condition) may meet criteria for ‘seriousness’ but is not an AE and 
thus is not subject to immediate reporting to the Sponsor.  
• 
Pre-planned or elective treatments/surgical procedures should be noted in the 
subject’s screening documentation. Hospitalisation for a pre-planned or elective 
treatment/surgical procedure should not be reported as an SAE unless there are 
complications or sequelae which meet the criteria for seriousness described above. 
10.3.2 
Reporting Requirements 
All SAEs must be reported immediately (within 24 hours), irrespective of the circumstances or 
suspected cause, if it occurs or comes to the attention of the Investigator at any time during the 
study period. 
All SAEs that occur during the study period or within 90 days following the administration of 
study treatment (whichever is the greater), including those events occurring in drop outs, must 
be reported within 24 hours of the Investigator’s knowledge of the event regardless of causality. 
10.3.3 
Mandatory Information for Reporting a Serious Adverse Event 
For every SAE, the following information is the minimum that must be provided to the 
Sponsors’ Pharmacovigilance department: 
• 
Study number. 
• 
Centre number. 
• 
Subject number. 
• 
The AE that met the seriousness criterion/criteria. 
• 
Seriousness criteria. 

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• 
Causality assessment (if there is not enough information for the Investigator to provide 
definitive causality opinion, the Investigator must assign provisional causality based on 
the available information. The causality will be reassessed if more information becomes 
available). 
The additional information included in the SAE form must be provided to the Sponsor or 
representative as soon as it is available. Upon receipt of the initial report, the Sponsor will ask 
for the Investigator’s causality assessment if it was not provided with the initial report. 
The Investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The Investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications. 
10.3.4 
Reporting Exemptions 
There are no applicable exemptions for this study. 
10.4 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
may have interfered with the effectiveness of a contraceptive medication. 
The outcome of any pregnancy will then need to be collected even if this occurs after the end 
of the study. Information regarding pregnancies must be collected on the AE page of the eCRF 
and on the Standard Pregnancy Report Form, including pregnancies with normal progress and 
outcome. A Standard Pregnancy Report Form must be completed by the Investigator and 
provided to the Sponsor’s Pharmacovigilance department within 24 hours of the knowledge of 
the pregnancy in any study subject. 
Investigators must instruct all female subjects to inform them immediately should they become 
pregnant during the treatment phase of this study. The Investigator should counsel the subject; 
discuss the risks of continuing with the pregnancy and the possible effects on the foetus. 
Monitoring of the subject should continue until the outcome of the pregnancy becomes known, 
which may involve follow up after the subject’s involvement in the study has ended. 
Pregnancies with a conception date within the study period or 90 days of the subject being 
dosed with study treatment including those occurring in drop outs must also be reported to the 
Investigator for onward reporting to the Sponsor. 
10.5 
Deaths 
All AEs resulting in death that occur either during the study period or within 90 days following 
the administration of study treatment (whichever is greater), must be reported as an SAE within 
24 hours of the Investigator’s knowledge of the event.  
The convention for recording death is as follows:  
• 
Adverse event term/verbatim: should be the primary cause of death (e.g. pneumonia, 
myocardial infarction). 
• 
Outcome: fatal. 
The only exception is where the cause of death is unknown at the time of reporting. In this case 
and pending confirmation on the actual cause of death a verbatim of ‘sudden death’ or 
‘unexplained death’ is appropriate. When the actual cause of death becomes known then the 
eCRF and the SAE report form should be updated to reflect the cause of death. 
10.6 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
an 
AE 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to insufficient response to the study treatment (see Section 6.4 
and Section 6.5). Every effort should be made to try to attribute withdrawal to a single episode 
of a particular AE and not AEs in general. 

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If the study treatment is discontinued due to an SAE it must be reported immediately to the 
Sponsor (see Section 10.3). 
In all cases, the Investigator must ensure the subject receives appropriate medical follow up 
(see Section 10.2). 
10.7 
Reporting 
to 
Competent 
Authorities/Independent 
Ethics 
Committees/ 
Institutional Review Boards/Other Investigators 
The Sponsor will ensure that processes are in place for the submission of reports of 
Suspected Unexpected Serious Adverse Reactions occurring during the study to the Competent 
Authorities (CAs), IECs, IRBs and all other Investigators concerned with the study treatment. 
Reporting will be done in accordance with the applicable regulatory requirements. 
For study centres in the United States of America, Investigational New Drug Safety Reports 
will be submitted directly to the Investigators. It is the Investigators’ responsibility to notify 
their IRB in a timely manner. 
11 
STATISTICAL CONSIDERATIONS 
11.1 
Subject Classification and Definitions 
Enrolled subject: 
Subject fully informed about the study whose 
parent(s)/guardian(s) have given written informed 
consent to participate (before any occurrence of study 
related procedure).  
Screened failure 
subject: 
Enrolled subject who fails to fulfil one or more entry 
criteria and thus does not proceed to the treatment 
phase of the study. Although not exposed to study 
treatment, they may have been exposed to some study 
related procedures. Records up to the time of 
premature termination should be completed including 
the reason for termination. 
Treated subject: 
Enrolled subject who is treated with at least one dose 
of study treatment. 
Randomised subject: 
Enrolled subject who is allocated to a treatment group 
at random. 
Study completed 
subject: 
Randomised/treated subject who has completed at 
least 52 weeks of follow up 
Drop out: 
Randomised/treated subject who did not complete the 
study and/or treatment.  

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11.2 
Analyses Populations Definitions 
Screened population: 
All subjects enrolled.  
Randomised population: 
All subjects randomised.  
Safety population: 
All randomised subjects who received at least one 
injection of the study treatment.  
modified Intent to treat 
population (mITT): 
All randomised subjects who received at least one 
injection of the study treatment and had a MAS score 
in the PTMG assessed both at baseline and at 
Treatment 1, Week 6. 
Per protocol (PP) 
population: 
All subjects from the mITT population who are not 
major protocol violators between baseline and the 
Treatment 1, Week 6 visit (inclusive). 
11.2.1 
Populations Analysed 
For the efficacy analyses, the primary population will be the mITT population, a secondary 
population of interest will be the PP population.  
The safety analyses will be performed based on the safety population.  
11.2.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviations Document (PDD) 
and its impact on the membership to each analysis population (i.e. mITT, PP and safety 
populations) for any subject having experienced it will be specified. 
The list of major protocol deviations impacting the PP population membership in the latest 
version of the PDD will be reviewed during the blind data review meeting held prior to database 
lock, before any unblinding of treatment groups. If necessary, that list will be updated to include 
any additional major protocol deviation impacting the PP population membership. 
11.3 
Sample Size Determination 
The sample size required for this study has been determined on the basis of the sample size 
estimate for each of the three criteria to be considered (superiority of any of the two tested 
Dysport doses to Dysport 2 U/kg on the primary efficacy endpoint, superiority of any of the 
two tested Dysport doses to Dysport 2 U/kg on the first secondary efficacy endpoint, and proper 
assessment of the long term safety of the two tested Dysport doses); the largest of these three 
estimates is used as the sample size of the study. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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Sample Size of the Study 
Given the above sample size estimates, a targeted study sample size of 210 randomised subjects 
(i.e. 70 randomised subjects per treatment group) is considered sufficient to meet both the 
primary efficacy objective and the long term safety objectives. 
Using a sample size of 210 as the largest of the three required figures means the actual power 
for the testing on the primary efficacy endpoint and the testing on the first secondary efficacy 
endpoint rises to 99% and 99%, respectively. As a result, the actual power of the study to detect 
a significant effect of any tested Dysport dose for both efficacy endpoints (US-targeted 
methodology) is 98% (= 99% x 99%). 
11.3.1 
Significance Testing and Estimations 
The statistical testing of the primary efficacy endpoint is fully described in Section 11.4.3. 
Unless otherwise specified, all statistical tests performed on Treatment 1 efficacy endpoints 
will be conducted at a two-tailed α level of 0.05 and each tested Dysport dose group (8 U/kg 
and 16 U/kg) will be compared to Dysport 2 U/kg separately. 
Descriptive statistics will include n, n missing, and: 
• 
Mean, standard deviation, minimum, median, maximum and 95% confidence for means 
for interval-type variables. 
• 
Counts and percents of each category for categorical nominal variables. 
• 
Both for categorical ordinal variables. 
No statistical tests will be performed on the efficacy endpoints for Treatments 2, 3 or 4. 
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11.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the Sponsor’s 
Statistics Department. 
A Statistical and Analysis Plan describing the planned statistical analysis in detail with table, 
figure and listing templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS®). 
Unless otherwise specified, all summary efficacy tables will be presented by treatment group 
and overall. Unless otherwise specified, all summary safety tables will be presented by 
treatment group, total dose group and overall. 
For the efficacy and safety parameters the Baseline (Treatment 1, Day 1) assessments will be 
considered for the analyses of the changes. 
11.4.1 
Demographic and Other Baseline Characteristics 
All demographic and baseline characteristics will be listed by treatment group and subject 
identification (ID). 
Summary statistics for demographic and baseline characteristics will be presented by treatment 
group for the mITT population. 
11.4.1.1 Homogeneity of Treatment Groups 
Demographic and baseline characteristics will be summarised, but not compared between 
treatment groups by formal statistical testing. 
11.4.1.2 Subject Disposition and Withdrawals 
A listing of all visit assessment dates (relative days) will be presented by treatment group and 
subject ID. 
For each subject’s population of interest, a summary table and a flow chart will present by 
treatment group the number of subjects assessed at each scheduled visit. Reasons for study 
withdrawal will be summarised at each visit. 
A summary table will present the study duration, both overall and by treatment group. 
Counts and percents of subjects with any major protocol violations will be tabulated by 
treatment group. Similarly, reasons for exclusion from the PP population will be presented by 
treatment group. 
11.4.2 
Pharmacokinetic Data  
There are no pharmacokinetic analyses planned for this study. 
11.4.3 
Efficacy Evaluation 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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11.4.3.3 Similarities Between the Two Statistical Methodologies Planned for the Efficacy 
Analyses 
The following will be applied in the same way for the two statistical methodologies planned for 
the efficacy analyses: 
Statistical Analyses 
The primary efficacy endpoint will be analysed using an ANCOVA on the rank. This model 
will include treatment group, the baseline value, the two stratification factors (age range and 
BTX treatment naive status at baseline) and the pooled centre as fixed covariates. A sensitivity 
analysis will be performed using the Proportional Odds Model (POM). 
The first secondary efficacy endpoints will be analysed using an ANCOVA on the rank. This 
model will include treatment group, the two stratification factors and the pooled centre as fixed 
covariates. A sensitivity analysis will be performed using the POM. 
Other efficacy endpoints will be analysed according to their scale (categorical or continuous), 
using ANCOVA on the rank, ANCOVA or Logistic regression for Treatment 1. For Treatment 
2 to treatment 4, only descriptive statistics will be performed. 
Centre Effect 
In order to assure that the centre effect will be properly estimated in both types of model, it is 
necessary to only consider the centres with a sufficient number of recruited subjects. 
Therefore, it has been decided to apply the following approach:  
• 
the centres having recruited at least six subjects will be taken into account for the estimate 
of the centre effect. 
• 
the centres having recruited less than six subjects will be pooled with one (or several) 
centre(s) within the same country (or across countries within the same region) until the 
number of subjects in the resulting pooled centre(s) is at least equal to six. Then, only 
the pooled centre(s) will be taken into account for the estimate of the centre effect. 
With such an approach, all the centres (original or pooled) considered for the estimate of the 
centre effect will account for at least six recruited subjects.  
Missing Values  
In order to assess the impact of the missing values of the primary efficacy endpoint for the 
withdrawals between the baseline visit and the Treatment 1, Week 6 visit, the primary analysis 
performed on the assessed values of the primary efficacy endpoint will be completed with a 
sensitivity analysis performed on the population of all randomised subjects who received at 
least one injection of study treatment. Within that population, any missing assessment on the 
MAS at Treatment 1, Week 6 visit will be imputed with the assessment on the MAS at the 
baseline visit (conservative approach).  
The results of the sensitivity analysis will be taken into account to assess the robustness of the 
results of the primary analysis.  
• 
In view of registration in the US only 
In order to assess the impact of the missing values of the first secondary efficacy endpoint 
for the withdrawals between the baseline visit and the Treatment 1, Week 6 visit as well 
as for subjects not assessed in the mITT population, the primary analysis performed on 
the assessed values of the first secondary efficacy endpoint will be completed with the 
following two sensitivity analyses performed on the population of all randomised 
subjects who received at least one injection of study treatment:  
• 
First sensitivity analysis: any missing assessment on the PGA at Treatment 1, 
Week 6 visit will be imputed with the assessment ‘markedly worse’ (intermediate 
conservative approach).  

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• 
Second sensitivity analysis: any missing assessment on the PGA at Treatment 1, 
Week 6 visit for a subject in a higher dose Dysport group will be imputed with the 
assessment ‘markedly worse’ and any missing assessment on the PGA at 
Treatment 1, Week 6 visit for a subject in the low dose Dysport group will be 
imputed with the assessment ‘markedly improved’ (most conservative approach).  
The results of the two sensitivity analyses will be taken into account to assess the robustness of 
the results of the primary analysis.  
11.4.3.4 Adjustment for Country/Centre Effect 
For the primary efficacy endpoint only, a sensitivity analysis will be conducted in order to 
investigate homogeneity of treatment response across centres: the ANCOVA on the rank will 
be re-run, adding the treatment by centre interaction term. If the p-value from the interaction 
term in the model is lower than 0.1 then the treatment by centre interaction will be deemed 
statistically significant and it will be concluded that the treatment effect is not constant from 
centre to centre. If this is the case then the influence of centre on the treatment effect will be 
investigated by estimating and plotting the treatment groups differences (for any of the two 
higher doses of Dysport, least square means difference Dysport higher dose  Dysport low dose) 
separately for each centre. 
11.4.4 
Safety Evaluation 
The safety endpoints of the study are: 
• 
Treatment emergent adverse events. 
• 
Vital signs (systolic and diastolic BP and HR): absolute values and change from Baseline 
at each visit to the study centre. 
• 
Body weight and height: absolute values and change from baseline at Week 16 of each 
treatment and at the end of study visit or early withdrawal. 
• 
Clinical chemistry (including serum ALP - total and bone isoenzyme, and glycosylated 
HbA1c): absolute values and change from Baseline at Treatment 1, Week 16 (serum 
ALP - total and bone isoenzyme, and HbA1c only) and at the end of study visit or early 
withdrawal. 
• 
Presence of BTX-A-Abs at baseline and at the end of study visit or early withdrawal. 
• 
A 12-lead ECG: absolute values and change from Baseline in ECG parameters and 
morphology at Treatment 1, Week 6 and at the end of study visit or early withdrawal. 
All safety data will be included in the safety data listings and summary tables will be produced 
on the safety population. Descriptive statistics will be provided for the safety endpoints. 
Adverse Events 
Adverse events 
will be coded using the Medical 
Dictionary 
for Regulatory 
Activities (MedDRA, version in force at the time of database freeze). 
All AEs reported during the study will be presented in a listing which will be sorted by treatment 
group, subject ID, primary system organ class (SOC), preferred term, verbatim text and start 
date.  
Listings of all SAEs, AEs leading to withdrawal and deaths reported during the study will also 
be presented by treatment group and subject ID. 
A TEAE is defined as any AE that occurs during the treatment phase of this study if: 
(1) 
It was not present prior to the first of intake of study treatment, or 
(2) 
It was present prior to the first intake of study treatment but the intensity increases during 
the treatment phase of this study. 
(3) 
It was present prior to receiving the first dose of study treatment, the intensity is the same 
but the drug relationship became related during the active phase of the study. 

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An overall summary table of all AEs will be presented. In summaries of intensity, causality, 
and causality combined with intensity, subjects may be reported in more than one category in 
these tables according to how many different levels of intensity and causality are associated to 
the AEs they experience. 
All TEAEs will be summarised overall and by treatment group with the number and percentage 
of subjects with TEAEs presented by primary SOC and preferred term. If a subject experiences 
more than one TEAE within a category (preferred term or primary SOC), the subject will be 
counted only once in that category. 
In addition, TEAEs will be tabulated by decreasing overall preferred term frequency, intensity, 
causality, and causality combined with intensity. 
In the event of multiple reports of the same preferred term for a subject, the maximum intensity 
(severe>missing>moderate>mild) and the most serious causality (related>not related) will be 
counted in the summary of TEAEs by intensity and causality. 
The number of occurrences of TEAEs coded with the same preferred term will also be presented 
by treatment group. 
All TEAEs will be flagged in the AE listing. 
All SAEs and AEs leading to withdrawals will be summarised overall and by treatment group 
with the number and percentage of subjects with SAEs and AEs leading to withdrawals 
presented by primary SOC and preferred term. 
Vital Signs 
Vital signs data will be presented in a listing which will be sorted by treatment group, subject 
ID, and assessment visit. Any unscheduled assessments will be flagged in the listing.  
Baseline values for each treatment group will be defined as the last measurements collected 
prior to administration of the study treatment.  
For each treatment group, descriptive statistics on raw assessments and changes from baseline 
at each assessed study visit will be provided. 
Laboratory Parameters 
For clinical laboratory safety tests (clinical chemistry including serum ALP - total and bone 
isoenzyme, and HbA1c), all the abnormal values will be flagged in the data listings and a list 
of clinically significant abnormal values will be presented by treatment group and by subject 
ID for evaluations at baseline and at the end of study visit or early withdrawal. 
Shift tables from baseline of the number and percentage of subjects with low, normal or high 
values will also be presented by treatment group. 
The Presence of BTX-A-Abs 
The number and percentage of subjects with the presence of BTX-A-Abs (both binding and 
neutralising) at baseline and at the end of study visit or early withdrawal will be compared 
between treatment groups. 
Electrocardiograms 
Summary statistics on the duration of QT/QTc interval and HR will be presented overall and 
by treatment group for each scheduled assessment visit and for both actual values and changes 
from baseline. Baseline values for each treatment group will be defined as the measurements 
collected at screening.  
The number and percentage of subjects with duration of QT/QTc interval within the following 
three ranges of interest will also be presented overall and by treatment group for each scheduled 
assessment visit: 
• 
>450 to 480 msec.  
• 
>480 to 500 msec. 
• 
>500 msec. 

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The number and percentage of subjects with an increase from baseline in the QT/QTc interval 
of >30 msec and >60 msec will also be presented overall and by treatment group for each 
scheduled post baseline assessment visit. 
The number and percentage of subjects with any of the following ECG abnormalities will be 
provided overall and by treatment group for each scheduled assessment visit: 
• 
Arrhythmias.  
• 
Second degree AV block 
• 
Third degree AV block.  
• 
ST segment abnormalities.  
• 
T-wave abnormalities.  
• 
U-wave abnormalities.  
• 
Myocardial infarction. 
• 
Right bundle branch block 
• 
Left bundle branch block. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to the World Health Organisation 
Drug Dictionary (version in force at the time of database freeze).  
The date of Day 1 will be used as the cut off date for the definition of a prior and a concomitant 
medication. A medication that started before the cut off date and is continuing will be 
considered as both prior and concomitant medications. 
The number and percentages of subjects will be provided overall and by treatment group for 
prior and concomitant medications sorted by drug class and preferred drug name. 
A listing will present by treatment group the prior and concomitant medications sorted by drug 
class and preferred drug name. Prior and concomitant medications will be flagged in the listing. 
11.5 
Subgroup Analyses 
 Analysis on the primary and first secondary efficacy endpoints will be performed on the 
randomisation stratification factors i.e. age range and BTX status at baseline (naïve versus 
non-naïve) and on gender. 
 Analysis on the MAS and PGA at Treatment 1Week 6 and 16 will be performed according 
to physiotherapy/occupational therapy status at Treatment 1 Week 16 (subjects without 
physiotherapy nor occupational therapy before week 16 of treatment 1 versus subjects with 
physiotherapy and/or Occupational therapy without any change in the frequency between 
baseline and Week 16 of treatment 1). 
Additional subgroup analyses may be performed according to clinical interest. 
11.6 
Final Analysis 
A final analysis will be performed after the end of the study. 
12 
MONITORING PROCEDURES 
The Investigator is responsible for the validity of all data collected at the site. The Sponsor is 
responsible for monitoring this data to verify that the rights and wellbeing of subjects are 
protected, that study data are accurate (complete and verifiable to source data) and that the study 
is conducted in compliance with the protocol, GCP and regulatory requirements. 
12.1 
Routine Monitoring 
Sponsor assigned monitors will conduct regular site visits. The Investigator will allow direct 
access to all relevant files (for all subjects) and clinical study supplies (dispensing and storage 
areas) for the purpose of verifying entries made in the eCRF, and assist with the monitor’s 

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activities, if requested. Adequate time and space for monitoring visits should be made available 
by the Investigator. 
The site must complete the eCRFs in a timely manner after the subject visit is performed and 
on an ongoing basis to allow regular review by the study monitor, both remotely via the internet 
and during site visits. This time period may be reduced at some specific stages of the study (e.g. 
end of study). The study monitors will use functions of the EDC system to address any queries 
raised while reviewing the data entered by the study site personnel in a timely manner. 
Whenever a subject name is revealed on a document required by the Sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel, leaving the initials 
visible, and annotated with the subject number as ID. 
13 
STUDY MANAGEMENT  
13.1 
Inspections and Auditing Procedures 
Authorised personnel from external CAs and Sponsor authorised Quality Assurance personnel 
may carry out inspections and audits. The purpose of an audit is to ensure that ethical, regulatory 
and quality requirements are fulfilled in all studies performed by the Sponsor. 
Auditors and inspectors must have direct access to study documents and site facilities as 
specified in Section 12.1, and to any other locations used for the purpose of the study in question 
(e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the Investigator must 
notify the Sponsor representative as soon as possible, to assist with preparations for the 
inspection. 
13.2 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, should be clearly marked and 
permit easy ID of a subject’s participation in the specified clinical study. 
The Investigator must record all data relating to protocol procedures, study treatment 
administration, laboratory data, safety data and efficacy ratings on the eCRFs provided for the 
study. The Investigator, by completing the signature log, may formally designate authority to 
complete eCRFs to appropriately qualified staff having certified user access to the eCRF. 
Subject completed questionnaires will be printed. 
All corrections on an eCRF and on source documents must be made in a way, which does not 
obscure the original entry. The correct data must be inserted, dated and initialled/authorised by 
study site personnel. If it is not obvious why a change has been made, a reason must be provided. 
The Investigator must, as a minimum, provide an e-signature to each eCRF casebook to attest 
to the accuracy and completeness of all the data. If any changes are made to the eCRF, after a 
casebook has been electronically signed, the Investigator will be required to perform an 
additional e-signature authorising agreement with any new information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on each 
item entered. 
13.3 
Source Data Verification 
As required by GCP, the Sponsor assigned monitor must verify, by direct reference to the source 
documents, that the data required by the protocol are accurately reported on the eCRF.  
The FDA 21 CFR Part 11 [42] is a regulation which provides criteria for acceptance by the 
FDA, under certain circumstances, of electronic records, e-signatures and hand written 
signatures executed to electronic records as equivalent to paper records and hand written 
signatures on paper. 

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The source documents must, as a minimum, contain the following: a statement that the subject 
is included in a clinical study, the date that informed consent was obtained prior to participation 
in the study, the identity of the study, diagnosis and eligibility criteria, visit dates (with subject 
status), study treatment administration, and any AEs and associated concomitant medication. 
As required by ICH GCP Section 6.4.9, if some items are recorded directly on the eCRF and 
are considered as source data, the identification of these data must be documented and agreed 
between the Investigator and the Sponsor. 
Definitions for source data and source documents are given below: 
• 
Source Data: 
All original records and certified copies of original 
records of clinical findings, observations, or other 
activities necessary for the reconstruction and 
evaluation of the study. Source data are contained in 
source documents (original records or certified copies).  
• 
Source Documents: 
Original documents, data and records (e.g. hospital 
records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from 
automated 
instruments, 
copies 
or 
transcriptions 
certified after verification as being accurate copies, 
microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, and records kept 
at the pharmacy, at the laboratories and at medico 
technical departments involved in the clinical study).  
The parent(s)/guardian(s) must have consented to the child’s medical records being viewed by 
Sponsor authorised personnel, and by local, and possibly foreign, CAs. This information is 
included in the ICF. 
13.4 
Data Quality 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
Group will be reviewed (secondary monitoring) for completeness, consistency and protocol 
compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol deviations. 
Any electronic queries and items not adequately explained will require additional electronic 
manual queries to be raised to the Investigator by the monitor for clarification/correction. The 
Investigator must ensure that queries are dealt with promptly. All data changes and clarifications 
can be viewed in the audit trail function of the eCRF. 
13.5 
Data Management 
Electronic data capture will be utilised for collecting subject data. Each site is required to have 
a computer and internet connection available for site entry of clinical data. All entries in the 
eCRF will be done under the e-signature of the person performing the action. This e-signature 
consists of an individual and confidential username and password combination. It is declared to be 
the legally binding equivalent of the hand written signature. Only Sponsor authorised users will 
get access to the eCRF as appropriate to their study responsibilities. Site users must have 
successfully undergone software application training prior to entering data into the eCRF. 
Data management will be conducted by a CRO under the responsibility of the Sponsor’s Data 
Management Department. All data management procedures will be completed in accordance with 
the Sponsor’s and the CRO’s Standard Operating Procedures. 
The Sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, and 
suitable queries are raised to resolve any missing or inconsistent data. The Investigator will receive 

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their data, from the clinical study, in an electronic format (PDF files) which will be an exact copy 
of the eCRF, and will include the full audit trail for the study, for archiving purposes and future 
reference. 
Any queries generated during the data management process will be raised within the EDC system. 
It is the monitor’s responsibility to ensure that all queries are resolved by the relevant parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the Sponsor’s Pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be performed by the 
Sponsor’s Data Management Department. Concomitant medications will be coded using the 
World Health Organisation Drug Dictionary and AEs/medical history terms will be coded using 
MedDRA. 
13.6 
Study Management Committees 
13.6.1 
Data and Safety Monitoring Board 
The DSMB will be composed of independent experts including one independent clinician who 
specialises in treating paediatric spasticity, one independent statistician and one independent 
pharmacovigilance expert. Data and Safety Monitoring Board meetings will take place as 
defined in the charter describing the operation of this committee and will depend on recruitment 
rate of the study. The first data review will take place after five subjects have been on treatment 
for at least 6 weeks or 4 months after the first subject has been randomised, whichever occurs 
first. Subsequent meetings will take place at intervals as defined by this committee. 
Safety and efficacy data will be provided to the committee for their review. Possible 
recommendations that the DSMB can make regarding the conduct of the study are described in 
the charter. This includes recommending that the study is stopped for safety reasons. 
The Chair of the DSMB will be responsible for communicating the committee’s 
recommendations to Ipsen.  
The DSMB charter will be available in the Trial Master File. 
13.7 
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the Investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the Sponsor. The Investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed by 
the monitor when closing out the site. The Sponsor will inform the Investigator, in writing, as to 
when these documents no longer need to be retained. 
If the Principal Investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the Sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 
14 
ADMINISTRATION PROCEDURES 
14.1 
Regulatory Approval 
As required by local regulations, the Sponsor’s Regulatory Affairs Group will ensure all legal 
regulatory aspects are covered, and obtain approval of the appropriate regulatory bodies and 
CAs prior to study initiation in regions where an approval is required. 

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14.2 
Publication Policy 
The Sponsor encourages acknowledgement of all individuals/organisations involved in the 
funding or conduct of the study, including medical writers or statisticians subject to the consent 
of each individual and entity concerned, including acknowledgement of the Sponsor. 
The results of this study may be published or communicated to scientific meetings by the 
Investigators involved in the study. For multicentre studies, a plan for scientific publication and 
presentation of the results may be agreed and implemented by the study Investigators or a 
Steering Committee. The Sponsor requires that reasonable opportunity be given to review the 
content and conclusions of any abstract, presentation, or paper before the material is submitted 
for publication or communicated. This condition also applies to any amendments that are 
subsequently requested by referees or journal editors. The Sponsor will undertake to comment 
on the draft documents within the time period agreed in the contractual arrangements, including 
clinical study agreements, governing the relationship between the Sponsor and authors (or the 
author’s institution). Requested amendments will be incorporated by the author, provided they 
do not alter the scientific value of the material. 
If patentability would be adversely affected by publication, this will be delayed until (i) a patent 
application is filed for the content of the publication in accordance with applicable provisions 
of the clinical study agreement concerned, (ii) the Sponsor consents to the publication, or (iii) 
the time period has expired as may be agreed in the contractual arrangements, including clinical 
study agreements, governing the relationship between the Sponsor and authors (or authors’ 
institution) after receipt of the proposed publication by the Sponsor, whichever of (i), (ii) or (iii) 
occurs first. 
The author undertakes to reasonably consider the Sponsor’s request for delay to the proposed 
publication should the Sponsor reasonably deem premature to publish the results obtained at 
the then stage of the study. 
14.3 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. A final CSR will be prepared where any child’s parent(s)/guardian(s) 
have signed an ICF, regardless of whether the study is completed or prematurely terminated. 
Where appropriate, an abbreviated report may be prepared. The CSR will be in compliance with 
any applicable regulatory requirements, national laws in force and will be in English. 
14.4 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study. Financial remuneration will 
cover the cost per included subject, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether costs for pharmacy, laboratory 
and other protocol required services are being paid directly or indirectly. 
Financial Disclosure Statements will be completed, as required. 
14.5 
Insurance, Indemnity and Compensation 
The Sponsor will provide product liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 
15 
PROTOCOL AMENDMENTS 
In the event that an amendment to this protocol is required (see Section 5.1), it will be submitted 
per local regulations. However, for the countries within the European Union (EU), according 

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to the Directive 2001/20/EC, the protocol amendment will be classified into one of the 
following three categories: 
• 
Nonsubstantial Amendments are those that are not considered ‘substantial’ (e.g. 
administrative changes) and as such only need to be notified to the IECs/IRBs or CAs 
for information purposes. 
• 
Substantial Amendments are those considered ‘substantial’ to the conduct of the clinical 
study where they are likely to have a significant impact on: 
• 
the safety or physical or mental integrity of the subjects, 
• 
the scientific value of the study, 
• 
the conduct or management of the study, or 
• 
the quality or safety of the study treatment used in the study. 
In the EU countries, substantial amendments must be notified to the IECs/IRBs and CA. Prior 
to implementation, documented approval must be received from the IECs/IRBs. In the case of 
the CA in the member states, approval or ‘favourable opinion’ can be assumed if the CA has 
raised no grounds for nonacceptance during an allocated time period (to be confirmed with the 
Sponsor’s Regulatory Affairs representative) following acknowledgment of receipt of a valid 
application to make a substantial amendment.  
• 
Urgent Amendments are those that require urgent safety measures to protect the study 
subjects from immediate hazard and as such may be implemented immediately by the 
Sponsor with subsequent IECs/IRBs and CA notification, forthwith. 

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16 
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Carnahan KD, Arner M and Hägglund G. Association between gross motor function 
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Fehlings D, Novak I, Berweck S, et al. Botulinum toxin assessment, intervention and 
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the modified Ashworth scale as clinical tools for assessing poststroke spasticity. Arch 
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37. 
Chin TY and Graham HK. Botulinum toxin A in the management of upper limb spasticity 
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Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. GMFCS  E & R 
Gross Motor Function Classification System Expanded and Revised 2007; Holland 
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Jethwa A, Mink J, Macarthur C, Knights S, Fehlings T, Fehlings D. Development of the 
Hypertonia Assessment Tool (HAT): a discriminative tool for hypertonia in children. 
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Fehlings D, Switzer L, Jethwa A et al. Hypertonia Assessment Tool (HAT) User Manual. 
First Edition: November 2010. Holland Bloorview Kids Rehabilitation Hospital, 
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Krumlinde-Sundholm L, Holmefur M, Kottorp A and Eliasson AC. The Assisting Hand 
Assessment: current evidence of validity, reliability, and responsiveness to change. Dev 
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48. 
Holmefur M, Krumlinde-Sundholm L. Proceedings of the 4th International Cerebral 
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Jackson D, Horn S, Kersten P and Turner-Stokes L. Development of a pictorial scale of 
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50. 
Hicks CL, von Baeyer CL, Spafford P, et al. The Faces Pain Scale  Revised: toward a 
common metric in pediatric pain measurement. Pain 2001;93(2):173-183. 
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Quality of Life Inventory version 4.0 generic core scales in healthy and patient 
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53. 
Varni JW, Burwinkle TM, Berrin SJ et al. The PedsQL in pediatric cerebral palsy: 
reliability, validity, and sensitivity of the Generic Core Scales and Cerebral Palsy 
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54. 
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Child 1969;44(235):291-303. 
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17 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments ................................................................................... 83 
Appendix 2 Study Flow Chart ............................................................................................... 89 
Appendix 3 Modified Ashworth Scale .................................................................................. 93 
Appendix 4 Goal Attainment Scale ....................................................................................... 95 
 
 
Appendix 7 Manual Ability Classification System (MACS) ............................................ 102 
 
Appendix 9 Tanner Grading Scale ..................................................................................... 109 
 
 
 
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Appendix 2 Study Flow Chart 
 
 

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Appendix 3 Modified Ashworth Scale 
 
 
 
 
 
 
 
 
 
 
 

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Modified Ashworth Scale 
Muscle tone will be scored as follows: 
0:  
No increase in muscle tone. 
1: 
Slight increase in muscle tone, manifested by a catch and release or by minimal 
resistance at the end of the range of motion when the affected part is moved in 
flexion or extension. 
1+: Slight increase in muscle tone, manifested by a catch followed by minimal 
resistance throughout the remainder (less than half) of the range of motion. 
2: 
More marked increase in muscle tone through most of the range of motion, but 
affected part(s) easily moved. 
3: 
Considerable increase in muscle tone, passive movement difficult. 
4: 
Affected part(s) rigid in flexion or extension. 
 
 
 

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Appendix 4 Goal Attainment Scale 
 

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Goal Attainment Scale For Measurement of Individual Therapy Goals 
The GAS is a functional scale used to measure progress towards individual therapy goals. 
Individual goals will be defined for each subject by the physician, with the child’s 
parents/guardians, prior to each treatment. Detailed instruction of goal setting and scaling is 
available in the study manual. 
Identification of Goals and Goal Weighting 
Parent(s)/guardian(s) and child, under the supervision of the physician should identify between 
one to three goals and categorise them into the sub-domains as listed in Table 13 for 
achievement. Goals chosen should fulfil the principle of SMART  Specific, Measurable, 
Attainable, Measurable and Timely. These chosen goals will be ranked according to their 
importance to the parent(s)/guardian(s)/child. If choosing more than one goal, one of them has 
to be chosen as very important and rank the other chosen goals accordingly (a little or 
moderately important). If only one goal is chosen, that goal will be rated as very important. 
After goal identification, the physician and/or therapist will rate the level of difficulty of each 
chosen goal.  
 
Table 13 Domains / Subdomains of GAS Goals 
Domain 
Subdomain 
Active Functions 
Reaching 
 
Grasp and release 
 
Use of limb as a ‘helping hand’’/to stabilise 
 
Involving affected arm more in daily activities 
Passive Functions 
Overall ease of care 
 
Hygiene 
 
Dressing 
 
Improve range of movement 
 
Donning/tolerating splints 
Pain 
Pain 
Others 
Other (please specify) 
 
Importance Rating Scale: 
1 = A little (important) 
2 = Moderately (important) 
3 = Very (important) 
Difficulty Rating Scale: 
0 = Not at all 
1 = A little 
2 = Moderately 
3 = Very 

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Goal Attainment Scaling 
Once the goals have been set, the next step is to define ‘expected’ outcome of each goal and 
scale it into the 5-point scale below. The outcome required in order to reach each score of the 
scale has to be determined at baseline (Treatment 1, Day 1) and before any subsequent treatment 
(Day 1 of Treatments 2, 3 and 4). 
+2 = Much more than expected outcome 
+1 = Somewhat more than expected outcome  
0 = Expected outcome  
-1 = Somewhat less than expected outcome  
-2 = Much less than expected outcome  
 
Post-treatment Visits Assessment 
At each post-treatment visit, each chosen goal set for that treatment will be evaluated using the 
following scale: 
+2 = Much more than expected outcome 
+1 = Somewhat more than expected outcome  
0 = Expected outcome  
-1 = Somewhat less than expected outcome  
-2 = Much less than expected outcome  
The score for each goal is based on whether the subject has reached the predetermined level of 
achievement set out at the baseline and subsequent treatment visits. 
 
 

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Appendix 7 Manual Ability Classification System (MACS) 
 
 
 

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Appendix 9 Tanner Grading Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Tanner Grading Scale for Measurement of Breast Development 
Breast development will be assessed using the original version of the Tanner grading scale [54]. 
Pubertal Staging: The Tanner Grading Scale for breast development will be performed for 
female subjects at Day 1 of each treatment, as described in Table 14. 
 
Table 14 Tanner Grading Scale for Breast Development 
Grade 
Description 
Tanner I 
No glandular tissue; areola follows the skin contours of the chest (prepubertal).  
Typically age ≤10 years.  
Tanner II 
Breast bud forms, with small area of surrounding glandular tissue; areola begins to 
widen. Typically age 10 to 11.5 years. 
Tanner III 
Breast begins to become more elevated, and extends beyond the borders of the areola, 
which continues to widen but remains in contour with surrounding breast.  
Typically age 11.5 to 13 years. 
Tanner IV 
Increased breast size and elevation; areola and papilla form a secondary mound 
projecting from the contour of the surrounding breast.  
Typically age 13 to 15 years. 
Tanner V 
Breast reaches final adult size; areola returns to contour of the surrounding breast, with a 
projecting central papilla.  
Typically age ≥15 years.