An International, Multicentre, Prospective, Single-Arm Study to Assess the Effect on Voluntary Movements of AbobotulinumtoxinA 1500 U Administered in Both Upper and Lower Limbs in Conjunction With a Guided Self-Rehabilitation Contract in Adult Subjects With Spastic Hemiparesis
Phase: PHASE4
Conditions: Spastic Hemiparesis
Sponsor: Ipsen

IPSEN GROUP 
F-FR-52120-228 
 
CONFIDENTIAL 
 
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PROTOCOL TITLE: An International, Multicentre, Prospective, Single-Arm Study to Assess 
the Effect on Voluntary Movements of AbobotulinumtoxinA 1500 U Administered in Both 
Upper and Lower Limbs in Conjunction with a Guided Self-Rehabilitation Contract in Adult 
Subjects with Spastic Hemiparesis 
 
STUDY PROTOCOL 
STUDY number: F-FR-52120-228 
Study Short Title: ENGAGE 
Dysport® / 52120 
EudraCT number: 2016-001989-29 
Final Version (including Amendment #1): 02 December 2016 
Final Version (including Amendment #2): 24 January 2018 
 
Sponsor’s Medically Responsible Person: 
Study Sponsor: 
 
Ipsen Pharma SAS 
Ipsen Group 
65 Quai Georges Gorse 
65 Quai Georges Gorse 
92100 Boulogne Billancourt 
92650 Boulogne Billancourt, France 
France 
 
Tel: +33 (0)1 58 33 50 00 
 
Fax: +33 (0)1 58 33 50 01 
 
Monitoring Office: 
Co-ordinating Investigator: 
Premier Research 
Professor JM Gracies, MD, PhD 
29 Rue Taitbout 
Hôpital Henri Mondor-Albert Chenevier 
75009 Paris 
40 Rue de Mesly 
France 
94010 Créteil CEDEX 
 
France 
 
 
 
 
Pharmacovigilance/Emergency Contact: 
  
EU Qualified Person for Pharmacovigilance,  
Ipsen Biopharm Ltd, 
102 Park Drive, Milton Park, Abingdon, Oxon OX14 4RY, England 
Tel: 
 – mobile telephone for emergencies 
 
 (USA only) 
For serious adverse event (SAE) reporting: 
Email: 
 or 
Fax: 
 (USA only) 
 
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
PPD
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PPD
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INVESTIGATOR’S AGREEMENT 
 
Investigator Agreement and Signature: 
I have read and agree to Protocol F-FR-52120-228 entitled “An International, Multicentre, 
Prospective, Single-Arm Study to Assess the Effect on Voluntary Movements of 
AbobotulinumtoxinA 1500 U Administered in Both Upper and Lower Limbs in Conjunction 
with a Guided Self-Rehabilitation Contract in Adult Subjects with Spastic Hemiparesis”. I am 
aware of my responsibilities as an investigator under the guidelines of Good Clinical Practice 
(GCP), local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these guidelines and to appropriately direct and assist the staff under my control, 
who will be involved in the study. 
 
NAME: 
TITLE: 
PRINCIPAL 
 
SIGNATURE: 
 
INVESTIGATOR 
   
   
DATE: 
OFFICE: 
 
 
 
 
 
 
 
 
 
   
Sponsor’s Representative Signature: 
NAME: 
 
TITLE: 
 
SIGNATURE: 
   
   
DATE: 
OFFICE: 
Ipsen Group 
 
65 Quai Georges Gorse 
 
92 650 Boulogne Billancourt 
 
France  
PPD
PPD

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COORDINATING INVESTIGATOR’S AGREEMENT 
 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol F-FR-52120-228 entitled “An International, Multicentre, 
Prospective, Single-Arm Study to Assess the Effect on Voluntary Movements of 
AbobotulinumtoxinA 1500 U Administered in Both Upper and Lower Limbs in Conjunction 
with a Guided Self-Rehabilitation Contract in Adult Subjects with Spastic Hemiparesis”. I am 
aware of my responsibilities as a coordinating investigator under the guidelines of Good 
Clinical Practice (GCP), local regulations (as applicable) and the study protocol. I agree to 
conduct the study according to these guidelines and to appropriately direct and assist the staff 
under my control, who will be involved in the study. 
   
NAME:  
Professor JM Gracies, MD, PhD 
TITLE: 
COORDINATING 
SIGNATURE: 
 
INVESTIGATOR 
   
   
DATE: 
OFFICE: 
Hôpital Henri Mondor – Albert Chenevier 
 
40 Rue de Mesly 
 
94010 Créteil CEDEX 
 
France 
 

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SUMMARY OF CHANGES 
 
The current version of the protocol was released on 02 December 2016 and includes 
Amendment 1. The amendment forms were prepared and are provided in Appendix 1 and 
Appendix 2 (Table 1). 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
02 December 2016 
Appendix 1 
2 
24 January 2018 
Appendix 2 
 

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SYNOPSIS 
Name of sponsor/company: Ipsen Pharma SAS 
Name of finished product: Dysport® 
Name of active ingredient(s): AbobotulinumtoxinA 
Title of study: An International, Multicentre, Prospective, Single-Arm Study to Assess the 
Effect on Voluntary Movements of AbobotulinumtoxinA 1500 U Administered in Both 
Upper and Lower Limbs in Conjunction with a Guided Self-Rehabilitation Contract in 
Adult Subjects with Spastic Hemiparesis 
Study number: F-FR-52120-228 
Number of planned centres: 20 
Planned study period: 
December 2016 to July 2018 
Phase of development: 
Phase IIIb/Phase IV (depending on country) 
Objectives: 
Primary Objective: 
The primary objective is to assess the responder rate as defined by the improvement of 
composite active range of motion (AROM) in the primary targeted limb, either upper limb 
(UL) or lower limb (LL), depending on which one has been selected as a primary treatment 
target (TT), following two consecutive AbobotulinumtoxinA injections combined with a 
Guided Self-rehabilitation Contract (GSC) in subjects with spastic hemiparesis following 
acquired brain injury (ABI). 
 
Secondary Objectives: 
The secondary objectives are as follows: 
• 
to assess the effectiveness of AbobotulinumtoxinA combined with a GSC on: 
- the responder rate as defined by the improvement of composite active range of 
motion (AROM) in the primary targeted limb, either upper limb (UL) or lower 
limb (LL), depending on which one has been selected as a primary treatment target 
(TT), following one AbobotulinumtoxinA injection combined with a Guided 
Self-rehabilitation Contract (GSC). 
- AROM against 10 prespecified muscle groups: 5 in upper and 5 in lower limbs 
- composite AROM against injected muscle groups (any of the 10 prespecified 
muscles) of each limb 
- full composite AROM against five UL muscle groups or full composite AROM 
against five LL muscle groups, regardless of whether the muscle groups were 
injected or not 
- active function in the upper and lower limbs using the Modified Frenchay Scale 
(MFS) and maximal Walking Speed (WS) barefoot, respectively. 
• 
to assess subject satisfaction with regard to the use of a GSC 
• 
to measure the changes in subject and physiotherapist beliefs that a GSC will help to 
improve function 
• 
to assess subject compliance with the GSC 
• 
to assess global benefits by both the investigator and the subject (or caregiver) 

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• 
in subjects not reinjected at Week 12, to assess satisfaction with longer than 12 
weeks interval between 2 injections 
• 
to assess health-related quality of life 
• 
to assess safety parameters. 
 
Exploratory objective: 
The exploratory objective is as follows: 
• 
to assess correlation between full composite AROM and active function (MFS in UL 
and WS in LL). 
Methodology:  
This is a multicentre, prospective, single-arm study to evaluate the efficacy and safety of 
two consecutive injections of AbobotulinumtoxinA administered in both upper and lower 
limbs (total dose of 1500 U per injection) plus daily GSC therapy, in adults with spastic 
hemiparesis due to ABI. The effect of treatment (i.e. AbobotulinumtoxinA+GSC) on 
voluntary movements will be assessed. Each subject will undergo two injection (treatment) 
cycles, receiving AbobotulinumtoxinA 1500 U on Day 1 of each cycle; the two dosing 
occasions will be separated by at least 12 weeks (maximum 20 weeks). 
At the Baseline Visit (Cycle 1), all subjects will undergo screening procedures and baseline 
study assessments after written informed consent has been provided. The primary TT limb 
(UL or LL) will be defined by the investigator, following discussion with the subject. 
AbobotulinumtoxinA (1500 U) will be administered as a split dose, in both the UL and LL; 
the dose given in each limb will be decided by the investigator, based on which was 
considered the primary TT limb at the Baseline Visit and in accordance with the following 
dosing rules: 
• 
electrical stimulation (ES) will be used to target the injection sites; Ultrasound 
guiding could be used in addition to ES in case this technique is used in routine 
clinical practice;  
• 
at least half the total dose (i.e. ≥750 U) must be injected in the primary TT limb 
(the rest of the dose is injected in the secondary TT limb); 
• 
a maximum of 1000 U can be injected in an UL (even if it is the primary TT limb); 
• 
there is no maximum dose that can be injected in a LL, provided that some remainder 
dose (out of the 1500 U total) is used for the UL injections; 
• 
the second AbobotulinumtoxinA injection (Cycle 2) may be given in a different split 
to the first injection (Cycle 1), at the discretion of the investigator. However, the 
same minimal/maximal rules apply, as described above. The primary TT remains the 
same for both AbobotulinumtoxinA injections and the study duration. 
Each subject will also receive a personalised GSC and will be asked to perform daily GSC 
therapy throughout the study. The subject will record in a diary each of the performed 
exercises of the GSC therapy. Telephone calls will be made to the subject every 2 weeks to 
check how the GSC therapy is being performed and that the diary is being filled out every 
day. 
In Cycle 1, postinjection follow-up (FU) visits will be held after the first 
AbobotulinumtoxinA administration, as follows: 
• 
at Week 6; 
• 
at Week 12: the investigator will decide if the subject is still responding to treatment 

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or if a second injection is needed, based on his/her clinical judgement. If a second 
injection is given, this marks the start of Cycle 2 (see below). If a second injection is 
not given, the subject will return at Week 16; 
• 
at Week 16: the investigator will again decide if the subject is still responding to 
treatment or if a second injection is needed, based on his/her clinical judgement. 
If a second injection is given, this marks the start of Cycle 2 (see below). If a second 
injection is not given, the subject will return at Week 20; 
• 
at Week 20: the investigator will again decide if the subject is still responding to 
treatment or if a second injection is needed, based on his/her clinical judgement. 
If a second injection is given, this marks the start of Cycle 2 (see below). If the 
investigator decides that a second injection should not be given, based on his/her 
clinical judgement, the subject will be withdrawn from the study. 
In Cycle 2, postinjection FU visits will be held after the second AbobotulinumtoxinA 
administration, as follows: 
• 
at Week 6; 
• 
at Week 12: the investigator will decide if the subject is still responding to treatment 
or if a further injection is needed, based on his/her clinical judgement. If a further 
injection is needed, the subject completes the study after study assessments have 
been performed (before the injection outside the study is given) (i.e. Final Visit). If a 
further injection is not needed, the subject will return at Week 16; 
• 
at Week 16: the investigator will again decide if the subject is still responding to 
treatment or if a further injection is needed, based on his/her clinical judgement. 
If a further injection is needed, the subject completes the study after study 
assessments have been performed (before the injection outside the study is given) 
(i.e. Final Visit). If a further injection is not needed, the subject will return at 
Week 20; 
• 
at Week 20: the subject completes the study after study assessments have been 
performed, regardless of whether a further injection is needed (i.e. Final Visit). 
The overall duration of the study for each subject will be between 24 and 40 weeks (from 
Baseline Visit to Final Visit). 
Number of subjects planned: 
It is planned to recruit approximately 155 subjects at approximately 20 sites in Europe and 
United States of America (USA), in order to achieve 145 evaluable subjects. Recruitment 
will be stratified by country to ensure that 50% of subjects have the UL as primary TT and 
50% of subjects have the LL as primary TT (with ±10% flexibility). 
Diagnosis and criteria for inclusion: 
Inclusion criteria: 
1) 
Subjects aged at least the national legal adult age. 
2) 
Subjects with hemiparesis due to ABI (i.e. stroke or traumatic brain injury (TBI)) 
presenting with muscle overactivity impeding motor function based on investigator’s 
judgement including, but not limited to, at least one of the following requiring 
botulinum neurotoxin (BoNT) treatment: typical clenched fist; flexed wrist; flexed 
elbow; or plantar flexed foot pattern. 
3) 
At least 12 months since the ABI. 
4) 
Naïve or non-naïve to BoNT treatment; if non-naïve, at least 4 months after the last 

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BoNT injection, of any serotype. 
5) 
Upper limb active function with an overall score between 2 and 7, as assessed by MFS 
locally rated score, if the primary TT limb is the UL. 
6) 
A 10-metre maximal WS barefoot between 0.2 and 1.4 m/s, if the primary TT limb is 
the LL. Maximal WS barefoot will be performed without walking aids. However, a 
cane may be permitted if absolutely necessary (although this may prevent detection of 
treatment-induced improvements). In this case, the same aid will have to be used for all 
WS assessments during the study. 
7) 
Subjects must provide written informed consent to participate in the study prior to any 
study-related procedures. 
8) 
Female subjects of childbearing potential (not surgically sterile or 2 years 
postmenopausal) must use a medically accepted method of contraception and must 
agree to continue use of this method for the duration of the study until the last visit of 
the subjects and for at least 12 weeks post injection. Acceptable methods of 
contraception include total abstinence, male partner has had a vasectomy, double 
barrier method (e.g. male condom plus spermicide, or female diaphragm plus 
spermicide), intrauterine device, or hormonal contraceptive (oral, transdermal, 
implanted and injected).. 
9) 
Subjects must be willing and able to comply with study restrictions and to remain at 
the clinic for the required duration during the study period and willing to return to the 
clinic for the follow-up evaluation as specified in the protocol. 
Exclusion criteria: 
1) Inability to understand protocol procedures and requirements, which, in the opinion of 
the investigator, could negatively impact on protocol compliance, in particularly 
inability to exercise according to the GSC. 
2) 
Previous surgery on the affected muscles and ligaments, tendons, nerve trunks, or 
bones of the treated upper or lower limb. 
3) 
Previous treatment with phenol and/or alcohol in any of the treated limbs any time 
before the study. 
4) 
Any medical condition (including severe dysphagia or breathing difficulties) that may 
increase, in the opinion of the investigator, the likelihood of adverse events (AEs) 
related to BoNT-A treatment. 
5) 
Subjects treated, or likely to be treated, with intrathecal baclofen during the course of 
the study or during the 4 weeks before study entry. 
6) 
Current, planned or received within the last 4 weeks prior to study treatment, treatment 
with any drug that interferes either directly or indirectly with neuromuscular function 
(for example, aminoglycosides). 
7) 
Major neurological impairment other than spastic paresis (including major 
proprioceptive ataxia or apraxia on the paretic side) that could negatively impact on the 
functional performance of the subject. 
8) 
Known disease of the neuromuscular junction (such as Lambert-Eaton myasthenic 
syndrome or myasthenia gravis). 
9) 
Known sensitivity to BoNT-A or any excipient of Dysport. 
10) Infection at the injection site(s). 
11) Current pregnancy or lactation. A pregnancy test will be performed at the start of the 

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study for all female subjects of childbearing potential (i.e. not surgically sterile or 
2 years postmenopausal). 
12) Mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude. 
13) Abnormal baseline findings or any other medical condition(s) that, in the opinion of 
the investigator, might jeopardise the subject’s safety. 
14) Subjects who have participated in any therapeutic clinical study/received any 
investigational agent within 30 days of enrolment. 
Test product, dose, mode of administration: 
AbobotulinumtoxinA (Dysport®) will be supplied as a white lyophilised powder in a vial 
containing 500 U of botulinum toxin type A (BTX-A)-haemagglutinin complex. A total 
dose of 1500 U (split between the UL and LL) will be used in each of two injection 
(treatment) cycles. Each Dysport vial (500 U) will be reconstituted with 2.5 mL sodium 
chloride for intramuscular (i.m.) injection (0.9%). The total volume to be injected on each 
dosing occasion will be 7.5 mL. 
Duration of treatment: 
Each subject will receive two injections of AbobotulinumtoxinA, separated by an interval 
of at least 12 weeks (maximum 20 weeks). Individual subject participation in the study 
(first injection to last FU visit) will be between 24 and 40 weeks. 
Reference therapy, dose and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
A goniometer will be used to measure AROM in the UL and LL at baseline and all 
postinjection FU visits. The MFS will be used to measure active function in the UL and the 
10-metre Walking Speed Test (WST) barefoot at maximal speed will be used to measure 
active function in the LL, at baseline and Week 12, in each injection cycle. Subject 
satisfaction with the GSC will be assessed using a Likert scale at all postinjection FU visits 
but also at baseline for patients who had any GSC done previously. Changes in the subject’s 
and Physiotherapist’s beliefs that the GSC will help to improve functional capacity will be 
assessed using a Likert scale at baseline and all postinjection FU visits. Subjects will record 
in a diary every day the performed exercises of the GSC therapy; the diary will be checked 
at each postinjection FU visit. The diary will be used by the investigator to ensure the 
prescription has been properly followed. The number of days without GSC therapy will be 
derived from the diary data by the investigator and entered into the electronic case report 
form (eCRF): compliance to GSC will be accordingly estimated over the study duration for 
each subject. A global assessment of benefits will be made by both the investigator and 
subject (or caregiver) at the end of both injection cycles using a Likert scale. For the 
subjects who will have an injection planned at either Visit 4 or Visit 5 for the first cycle and 
Visit 8 or Visit 9 for the second cycle (i.e. Week 16 or 20 of each cycle) satisfaction with 
longer treatment interval will be collected at the corresponding reinjection visit or at the last 
cycle visit. Subject quality of life will be assessed by the subject using the European 
Quality of Life 5 Dimensions (EQ-5D 5L) and Short Form 12 (SF-12) scales at baseline 
and the last study visit. 
 

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Safety: 
Safety will be assessed by recording the number, nature and severity of AEs from the time 
that the subject gives informed consent to the end of study or subject withdrawal. Vital 
signs will also be measured at baseline, the second injection and the last study visit. 
Statistical Methods: 
Study Endpoints 
Primary Efficacy Endpoint and Evaluation: 
The primary efficacy endpoint is as follows: 
• 
the percentage of responder subjects at Week 6 after the second injection, according 
to composite AROM in the primary TT limb. 
Composite AROM (XA), regardless of whether the muscle groups were injected or not, as 
measured by goniometer in the primary TT limb (either UL or LL, depending on which one 
has been selected as the primary TT limb), will be calculated as follows: 
- composite XA UL: XA UL = XAEF  + XAWF + XAFF 
- composite XA LL: XA LL = XAsol + XAGN 
 
where for UL: EF=elbow flexors, WF=wrist flexors and FF=extrinsic finger flexors, 
and for LL: Sol=soleus and GN=gastrocnemius muscles. 
Definition of a responder: a subject will be considered a responder if he/she achieves at 
least the predefined improvement threshold - larger or equal to 35° in UL or 5° in LL - in 
the primary TT limb (based on the composite AROM individual change from baseline to 
Week 6 after the second injection). 
Secondary Efficacy Endpoints and Evaluations: 
The secondary efficacy endpoints are as follows: 
• 
the percentage of responder subjects at Week 6 after the first injection, according to 
composite AROM in the primary TT limb 
• 
AROM against 10 prespecified muscle groups, 5 in upper and 5 in lower limbs: mean 
change from baseline at Week 6, Week 12 and re-injection/last cycle visits only 
• 
composite AROM against injected muscle groups (any of the 10 prespecified), in 
upper and lower limbs: mean change from baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
• 
full composite AROM against five UL muscle groups (XA full UL = XASE + XAEF + 
XAWF + XAFF + XAPT) or full composite AROM against five LL muscle groups (XA 
full LL = XAsol + XAGN + XAGM + XAHS + XARF), regardless of whether the muscle 
groups were injected or not: mean change from baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
where for UL: SE=shoulder extensors, EF=elbow flexors, WF=wrist flexors, 
FF=extrinsic finger flexors and PT=pronator teres, 
and for LL: Sol=soleus, GN=gastrocnemius muscles, GM=gluteus maximus, 
HS=hamstrings and RF=rectus femoris 
• 
active UL function measured using MFS: mean change from baseline in MFS overall 
score (i.e. mean score over the 10 tasks assessed locally and centrally by a reviewer 
blinded regarding the date of the video recording/visit number) at Week 12 after each 
injection cycle  
• 
active LL function measured using maximal WS barefoot without walking aids or, if 

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absolutely necessary, with a cane, measured on a 10-metre WST: mean change from 
baseline at Week 12 after each injection cycle. (If a cane is used at the Baseline Visit, 
the same cane is to be used during all WS assessments.) 
• 
subject satisfaction with the GSC: at baseline (only for patients who had GSC 
performed previously), Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in subject’s belief that the GSC will help to improve functional capacity: 
change from baseline to Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in Physiotherapist’s belief that the GSC will help to improve functional 
capacity: change from baseline to Week 6, Week 12 and re-injection/last cycle visits 
only 
• 
subject compliance with the GSC: percentage of days over study period when GSC 
therapy was performed (as determined from the subject diary) 
• 
global assessment of benefits, evaluated by both the investigator and the subject (or 
caregiver): at the end of each cycle  
• 
in subjects with an injection planned at Week 16 or 20 of each cycle: satisfaction 
with longer interval between 2 injections collected at the corresponding reinjection 
visit or the last cycle visit 
• 
quality of life changes, measured on the EQ-5D 5L and SF-12 scales: change from 
baseline to Final Visit. 
Secondary Safety Endpoints and Evaluations: 
• 
Safety will be assessed by recording the number, nature and severity of AEs from the 
time that the subject gives informed consent to the end of study. Other safety data 
will include vital signs. 
Exploratory Endpoint and Evaluation: 
• 
Correlation between full composite AROM and active function (MFS in UL and WS 
in LL) will be explored. 
Statistical analyses 
All statistical analyses will be primarily descriptive and, when p-values are presented, this 
will be for exploratory purposes only. It is planned to perform an interim analysis when all 
subjects are recruited in order to describe baseline data and more specifically injection 
details, for example, dose per limb/injected muscles; this baseline data interim analysis is 
planned after subject enrolment has been completed. 
Sample size calculation 
The sample size was determined based on the primary efficacy endpoint (percentage of 
responder subjects at Week 6 after the second injection according to composite AROM). 
A 60% response rate was assumed based on previous studies (adult UL/LL) with an 
additional benefit of +10% compared with that observed in these studies (approximately 
50% response rate at Week 4 of Cycle 2). The aim of this study will be to estimate this 
proportion with an accuracy of ±8%. Given a two-sided 95% confidence interval, 
145 subjects are required; with an assumed 5% dropout rate, 153 subjects will have to be 
enrolled to achieve a target of 145 evaluable subjects. 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 17 
1 
BACKGROUND INFORMATION ............................................................................ 20 
1.1 
Disease Review .............................................................................................................. 20 
1.2 
Compound Review ........................................................................................................ 20 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 21 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 21 
1.5 
Compliance Statement .................................................................................................. 23 
1.6 
Clinical Trial Rationale ................................................................................................ 24 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 26 
2.1 
Purpose of the Study ..................................................................................................... 26 
2.2 
Study Objectives ........................................................................................................... 26 
3 
STUDY DESIGN ........................................................................................................... 27 
3.1 
General Design and Study Schema ............................................................................. 27 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 30 
3.2.1 
Primary Efficacy Endpoint and Evaluation .............................................. 30 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 30 
3.2.3 
Safety Endpoint and Evaluation................................................................. 31 
3.2.4 
Exploratory Endpoint and Evaluation ....................................................... 31 
3.3 
Randomisation and Blinding ....................................................................................... 31 
3.4 
Study Treatments and Dosage ..................................................................................... 31 
3.5 
Study Duration .............................................................................................................. 32 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 32 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability ......... 33 
3.7.1 
Investigational Medicinal Product Storage and Security .......................... 33 
3.7.2 
Investigational Medicinal Product Preparation ........................................ 33 
3.7.3 
Investigational Medicinal Product Accountability .................................... 33 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 33 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 33 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 35 
4.1 
Inclusion Criteria .......................................................................................................... 35 
4.2 
Exclusion Criteria ......................................................................................................... 35 
4.3 
Subject Withdrawal Criteria and Procedures ........................................................... 36 
5 
STUDY PROCEDURES .............................................................................................. 37 
5.1 
Study Schedule .............................................................................................................. 37 
5.2 
Study Visits .................................................................................................................... 42 
5.2.1 
Injection Cycle 1: Baseline Visit and Postinjection Follow-Up Visits ...... 42 
5.2.1.1 
Baseline Visit ............................................................................................... 42 
5.2.1.2 
Week 6 (± 7 days) ......................................................................................... 43 

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5.2.1.3 
Week 12 (+7 days) ....................................................................................... 43 
5.2.1.4 
Week 16 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at 
Week 12 Postinjection FU Visit After Injection 1) ....................................... 44 
5.2.1.5 
Week 20 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at 
Week 12 or Week 16 Postinjection FU Visit After Injection 1) ................... 45 
5.2.2 
Injection Cycle 2: Postinjection Follow-Up Visits ..................................... 46 
5.2.2.1 
Week 6 (± 7 days) ......................................................................................... 46 
5.2.2.2 
Week 12 (+7 days) ....................................................................................... 46 
5.2.2.3 
Week 16 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at 
Week 12 Postinjection FU Visit After Injection 2) ....................................... 47 
5.2.2.4 
Week 20 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at 
Week 16 Postinjection FU Visit After Injection 2) ....................................... 48 
5.2.3 
Early Withdrawal Visit ................................................................................ 48 
6 
TREATMENT OF SUBJECTS ................................................................................... 49 
6.1 
Study Drugs Administered ........................................................................................... 49 
6.1.1 
AbobotulinumtoxinA (Dysport) .................................................................. 49 
6.1.1.1 
List of muscles recommended to be injected and Dysport Dosing by 
Muscle for Upper Limb Spasticity ............................................................... 50 
6.1.1.2 
List of muscles recommended to be injected and Dysport Dosing by 
Muscle for Lower Limb Spasticity ............................................................... 50 
6.1.2 
Second Study Therapy: GSC ...................................................................... 51 
6.2 
Concomitant Medication/Therapy .............................................................................. 51 
6.3 
Procedures for Monitoring Subject Compliance ....................................................... 52 
7 
ASSESSMENT OF EFFICACY .................................................................................. 53 
7.1 
Primary Efficacy Endpoint and Evaluation ............................................................... 53 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 53 
7.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data .......... 55 
7.3.1 
Active Range of Motion (AROM) ............................................................... 55 
7.3.2 
Modified Frenchay Scale (MFS) ................................................................ 56 
7.3.3 
10-Metre Walking Speed Test (WST) ......................................................... 56 
7.3.4 
Guided Self-Rehabilitation Contract (GSC) .............................................. 56 
7.3.4.1 
Subject Satisfaction ...................................................................................... 56 
7.3.4.2 
Changes in the Subject’s and Physiotherapist’s Beliefs .............................. 57 
7.3.4.3 
Subject Compliance with the GSC ............................................................... 57 
7.3.5 
Subject Satisfaction regarding Longer Injection Intervals (only for 
Subjects with an Injection Planned at Week 16 or 20 of Each Cycle)...... 57 
7.3.6 
Global Assessment of Benefits .................................................................... 58 
7.3.7 
Subject Quality of Life ................................................................................ 58 
7.3.7.1 
European Quality of Life 5 Dimensions (EQ 5D-5L) .................................. 58 
7.3.7.2 
Short-Form 12 (SF-12) ................................................................................ 58 
8 
ASSESSMENT OF SAFETY ....................................................................................... 59 

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8.1 
Adverse Events .............................................................................................................. 59 
8.1.1 
Definition of an Adverse Event .................................................................. 59 
8.1.2 
Categorisation of Adverse Events ............................................................... 59 
8.1.2.1 
Intensity Classification ................................................................................. 59 
8.1.2.2 
Causality Classification ............................................................................... 59 
8.1.2.3 
Assessment of Expectedness ......................................................................... 59 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 59 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 60 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 60 
8.1.3 
Recording and Follow up of Adverse Events ............................................. 60 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 60 
8.1.5 
Pregnancy .................................................................................................... 62 
8.1.6 
Deaths .......................................................................................................... 62 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 62 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 62 
8.2 
Physical Examination ................................................................................................... 62 
8.3 
Vital Signs ...................................................................................................................... 63 
9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS .......... 64 
10 
STATISTICS ................................................................................................................. 65 
10.1 Analyses Populations .................................................................................................... 65 
10.1.1 
Populations Analysed .................................................................................. 65 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ........... 65 
10.2 Sample Size Determination .......................................................................................... 65 
10.3 Significance Testing and Estimations ......................................................................... 65 
10.4 Statistical/Analytical Methods ..................................................................................... 66 
10.4.1 
Demographic and Other Baseline Characteristics .................................... 66 
10.4.2 
Homogeneity of Treatment Groups ............................................................ 66 
10.4.3 
Subject Disposition and Withdrawals ......................................................... 66 
10.4.4 
Pharmacokinetic Data ................................................................................ 66 
10.4.5 
Efficacy Evaluation ..................................................................................... 66 
10.4.5.1 
Primary Efficacy Endpoint .......................................................................... 66 
10.4.5.2 
Secondary Efficacy Endpoints ..................................................................... 67 
10.4.6 
Adjustment for Country/Centre Effect ....................................................... 68 
10.4.7 
Safety Evaluation ........................................................................................ 68 
10.5 Subgroup Analyses ....................................................................................................... 69 
10.6 Interim Analyses ........................................................................................................... 69 
11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 70 
12 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 71 
12.1 Protocol Amendments and Protocol Deviations and Violations ............................... 71 

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12.1.1 
Protocol Amendments ................................................................................. 71 
12.1.2 
Protocol Deviations, Violations and Exceptions ........................................ 71 
12.2 Information to Study Personnel .................................................................................. 71 
12.3 Study Monitoring .......................................................................................................... 71 
12.4 Audit and Inspection .................................................................................................... 72 
12.5 Data Quality Assurance ................................................................................................ 72 
13 
ETHICS ......................................................................................................................... 73 
13.1 Compliance with Good Clinical Practice and Ethical Considerations .................... 73 
13.2 Informed Consent ......................................................................................................... 73 
13.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 74 
13.4 Confidentiality Regarding Study Subjects ................................................................. 74 
14 
DATA HANDLING AND RECORD KEEPING ....................................................... 75 
14.1 Data Recording of Study Data ..................................................................................... 75 
14.2 Data Management ......................................................................................................... 75 
14.3 Record Archiving and Retention ................................................................................. 76 
15 
FINANCING AND INSURANCE ............................................................................... 77 
15.1 Contractual and Financial Details ............................................................................... 77 
15.2 Insurance, Indemnity and Compensation .................................................................. 77 
16 
REPORTING AND PUBLICATIONS OF RESULTS ............................................. 78 
16.1 Publication Policy ......................................................................................................... 78 
16.2 Clinical Study Report ................................................................................................... 78 
17 
REFERENCES .............................................................................................................. 79 
18 
LIST OF APPENDICES .............................................................................................. 81 
 

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LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Procedures and Assessments ................................................................... 38 
Table 3 
Summary of Reinjection Scenarios .................................................................... 41 
Table 4 
Secondary Efficacy Endpoints and Evaluations ............................................... 54 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 29 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition 
ABI 
Acquired brain injury 
AE 
Adverse event 
ALLS 
Adult lower limb spasticity 
ANCOVA 
Analysis of covariance 
AROM 
Active range of motion 
BoNT 
Botulinum neurotoxin 
BoNT-A 
Botulinum neurotoxin type A 
BTX-A 
Botulinum toxin type A 
CA 
Competent authority 
CFR 
Code of Federal Regulations (United States of America) 
CI 
Confidence interval 
CRO 
Contract research organisation 
CSR 
Clinical study report 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EF 
Elbow flexors 
e.g. 
Exempli gratia 
ES 
Electrostimulation 
EQ-5D 5L 
European Quality of Life 5 Dimensions 
FDA 
Food and Drug Administration 
FF 
Extrinsic finger flexors 
FU 
Follow-up 
GCP 
Good Clinical Practice 
GM 
Gluteus maximus 
GN 
Gastrocnemius muscles 
GSC 
Guided Self-rehabilitation Contract 
HS 
Hamstrings 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
i.e. 
Id est 
IEC 
Independent ethics committee 
i.m. 
Intramuscular 

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ABBREVIATION 
Wording Definition 
IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
LL 
Lower limb 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFS 
Modified Frenchay Scale 
mITT 
Modified intent-to-treat 
n, N 
Number 
PI 
Package insert 
PK 
Pharmacokinetic 
PP 
Per protocol 
PT 
Pronator teres 
RF 
Rectus femoris 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System 
SE 
Shoulder extensors 
SF-12 
Short Form 12 
SmPC 
Summary of product characteristics 
Sol 
Soleus 
SOP 
Standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBI 
Traumatic Brain Injury 
TEAE 
Treatment-emergent adverse event 
TT 
Treatment target 
UL 
Upper limb 
US(A) 
United States (of America) 
VAS 
Visual analogue scale 
WF 
Wrist flexors 
WHODRUG 
World Health Organization Drug Dictionary 
WS 
Walking speed 
WST 
Walking speed test 

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ABBREVIATION 
Wording Definition 
XA 
AROM (active range of motion) 

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1 
BACKGROUND INFORMATION 
1.1 
Disease Review 
Spasticity is an increase in velocity-dependent stretch reflexes, with exaggerated tendon jerks, 
resulting from hyperexcitability of the stretch reflex, as one component of the upper motor 
neuron syndrome [1, 2]. Spasticity is associated with various neurological disorders (for 
example, multiple sclerosis, cerebral or spinal cord injuries and cerebrovascular disorders), 
contributing to functional motor disability/impairment, pain and discomfort [3]. For example, 
globally, 15 million people suffer a stroke every year [4] and around half of these may 
eventually develop post-stroke upper-limb (UL) spasticity. As the population ages and 
medicine advances, disability due to post-stroke spasticity will increase and is now emerging 
as a significant global health issue with substantial socioeconomic burdens [5]. Post-stroke 
UL symptoms associated with spasticity include impairment of active and passive functioning 
of the limb (for example, hygiene-related actions, dressing and splint application) and can 
significantly impair both the patient’s and the carer’s quality of life [5]. 
Adult lower limb spasticity (ALLS) is one of the disabling complications of multiple 
neurological disorders such as stroke, multiple sclerosis, spinal cord injury and even some 
central neurodegenerative disorders. People with ALLS can present with a variety of 
abnormal postures. The increased tone due to spasticity can cause significant discomfort and 
patients describe it as, for example, a spasm, cramp or dull pain. If insufficiently managed, 
patients with ALLS are often predisposed to secondary complications of reduced mobility 
such as muscle shortening and joint deformity [6]. These secondary complications can 
themselves cause more systemic complications including deep vein thrombosis and pressure 
ulcers. The integral role of botulinum neurotoxin (BoNT) in the management of focal 
spasticity is recognized by guidelines from around the world [7]. 
1.2 
Compound Review 
Botulinum toxin type A (BTX-A) is a neurotoxin isolated and purified from Clostridium 
botulinum type A bacteria. It acts selectively on peripheral cholinergic nerve endings to 
inhibit acetylcholine release. This produces a weakening of voluntary and involuntary muscle 
contraction, an effect that can be used to therapeutic advantage in the treatment of focal 
dystonias, muscle spasms and muscle spasticity. Dysport® is a BTX-A-haemagglutinin 
complex (United States [US] generic name: AbobotulinumtoxinA), which was first approved 
in the United Kingdom in 1990 and is now licensed in more than 80 countries for various 
indications, including: spastic equinus deformity due to spasticity in adults following a stroke, 
blepharospasm, adult upper and lower limb spasticity, hemifacial spasm, spasmodic torticollis 
(cervical dystonia), paediatric lower limb spasticity and dynamic equinus foot deformity due 
to cerebral palsy, axillary hyperhidrosis and glabellar lines. It is of note that not all indications 
are approved across all regions; for example, Dysport has approval in France for the treatment 
of adult UL and lower limb (LL) spasticity but, in other regions such as the United States of 
America (USA) and Czech Republic, it has approval for adult UL spasticity but not LL 
spasticity (hence, the current study will be a phase IV study in France but a phase IIIb study in 
other countries). 
A more detailed description of the product is given in the investigator’s brochure (IB) [8] and 
Section 3.4, and a detailed description of administration procedures is given in Section 6.1. 

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1.3 
Findings from Nonclinical and Clinical Studies 
Nonclinical pharmacology studies have demonstrated the efficacy of low doses of BTX in 
various cholinergic pathways. Pharmacokinetic (PK) and distribution studies performed with 
BTX-A have demonstrated that the majority of the toxin remains localised at the injection 
site, supporting the local effect of the toxin. The results of single- and repeat-dose toxicity 
studies demonstrated that BTX-A administered in striated muscle possesses no potential for 
producing toxicity unrelated to its pharmacological activity or specific target organ. The 
effects on injected muscles (decrease in muscle and myofibre size) were related to the 
pharmacological activity of BTX-A and were consistent with the results of the 
pharmacodynamic Rat Muscle Force Test. Intramuscular (i.m.) administration of Dysport in 
healthy juvenile rats did not alter male or female rat fertility with toxicological profiles in 
juvenile animals observed to be similar to adults. After local administration, the amount of 
BTX-A in the systemic circulation of animals is below the limit of detection of bioanalytical 
methods validated for use on clinical samples. Therefore, no PK studies have been performed 
in humans. The drug was not teratogenic in rats and rabbits and no effects were observed in 
the pre- and postnatal study on the first (F1 generation) in rats. 
Clinical studies conducted in adult subjects with UL spasticity have shown Dysport 500 U 
and 1000 U to be superior to placebo on muscle tone, spasticity, active range of motion 
(AROM), passive function and clinical benefit after a single treatment cycle. Maintenance of 
this efficacy and progressive improvement of active function could be seen after repeated 
administrations with a trend towards higher efficacy of the 1500 U dose (including 500 U in 
the shoulder) on both passive and active function [9]. Overall, across all studies, Dysport was 
well tolerated in the treatment of subjects with adult UL spasticity. 
Clinical studies conducted in subjects with adult LL spasticity have shown substantial 
evidence of the efficacy of Dysport 1000 U and 1500 U on muscle tone and spasticity 
(statistically significant difference versus placebo with 1500 U), translating into clinical 
benefit. The effect observed after a single treatment cycle was enhanced and accompanied by 
progressive improvements of spasticity, active ankle dorsiflexion and walking speed (WS) 
over repeated cycles. Overall, across all studies, Dysport was well tolerated in the treatment of 
subjects with adult LL spasticity. 
Further details of nonclinical studies, as well as clinical studies in all indications, may be 
found in the IB [8]. 
1.4 
Known and Potential Risks and Benefits to Human Subjects 
In subjects who were treated with Dysport in numerous clinical trials, approximately 25% 
experienced a treatment-emergent adverse event (TEAE). Dysport is generally well tolerated 
although temporary paresis of nontargeted muscle groups can occur. In general, the TEAE 
profile will be dependent on the site of injection. Most TEAEs are of mild or moderate 
severity and of limited duration. Adverse reactions that were seen and are considered 
expected in subjects treated across a variety of indications, including blepharospasm, 
hemifacial spasm, cervical dystonia, spasticity associated with either cerebral palsy or stroke 
and axillary hyperhidrosis, can be found in the Dysport Company Core Safety Information. In 
the following research indications, adverse reactions were reported as follows: 
• 
In paediatric patients treated with Dysport for upper limb spasticity (alone or 
concomitantly with lower limb spasticity) in an observational study 
, 
reported events (of any causality) included injection site reaction, muscle weakness, 
somnolence, constipation, dysphagia, fatigue, flu-like syndrome, ptosis, speech 
disorder, urinary incontinence and ulcerative stomatitis. 
CCI

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• 
In adult patients treated with Dysport for neurogenic detrusor overactivity in an 
interventional 
study 
, 
the 
following 
events 
were 
reported 
as 
treatment-related by the investigator: muscular weakness, asthenia, suprapubic pain, 
pain in extremity and procedural pain. 
• 
The profile of adverse reactions reported during postmarketing use reflects the 
pharmacology of the product and those seen during clinical trials. 
The following information should be taken into consideration when prescribing Dysport: 
• 
Dysport is contraindicated in individuals with known hypersensitivity to any BTX 
preparation or to any of the components in the formulation. 
• 
Adverse effects resulting from distribution of the effects of the toxin to sites remote 
from the site of administration have been reported. Patients treated with therapeutic 
doses may present with excessive muscle weakness. The risk of occurrence of such 
undesirable effects may be reduced by using the lowest effective dose possible and by 
not exceeding the maximum recommended dose. 
• 
Very rare cases of death, occasionally in a context of dysphagia, pneumopathy and/or 
in patients with significant asthenia have been reported after treatment with BTX-A or 
B. Patients with disorders resulting in defective neuromuscular transmission, difficulty 
in swallowing or breathing are more at risk of experiencing these effects. In these 
patients, treatment must be administered under the control of a specialist and only if the 
benefit of treatment outweighs the risk. 
• 
Dysport should be administered with caution to patients with pre-existing swallowing 
or breathing problems including inhalation pneumopathy as these problems can worsen 
following distribution of its effect into the relevant muscles. Aspiration has occurred in 
rare cases and is a risk when treating patients who have a chronic respiratory disorder. 
• 
Dysport should only be used with caution and under close supervision in patients with 
subclinical or clinical evidence of marked defective neuromuscular transmission (for 
example, myasthenia gravis). Such patients may have an increased sensitivity to agents 
such as Dysport, which may result in excessive muscle weakness. 
• 
The recommended posology and frequency of administration for Dysport must not be 
exceeded. 
• 
As with any i.m. injection, Dysport should be used only where strictly necessary in 
patients with prolonged bleeding times, or infection/inflammation at the proposed 
sites(s) of injection. 
• 
Dysport contains a small amount of human albumin. The risk of transmission of viral 
infection cannot be excluded with absolute certainty following the use of human blood 
or blood products. 
• 
Following Dysport treatment, a low number of patients developed neutralising 
antibodies. 
• 
The effects of BTX may be enhanced by drugs interfering directly or indirectly with the 
neuromuscular function (for example, aminoglycosides, curare-like nondepolarising 
blockers) and such drugs should be used with caution in patients treated with BTX. 
• 
The risk of excessive muscle weakness may impair the ability to drive or operate 
machinery. 
• 
Patients and their caregivers must be warned of the necessity to seek immediate 
medical treatment in case of problems with swallowing, speech or respiratory 
problems. 
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• 
There are limited data from the use of Clostridium BTX-A-haemagglutinin complex in 
pregnant women. Animal studies do not indicate any direct or indirect harmful effects 
with respect to pregnancy, embryonal/foetal development, parturition or postnatal 
development other than at high doses causing maternal toxicity. Dysport should be used 
during pregnancy only if the benefit justifies any potential risk to the foetus. Caution 
should be exercised when prescribing to pregnant women. 
• 
It is not known whether Clostridium BTX-A-haemagglutinin complex is excreted in 
human milk. The excretion of Clostridium BTX-A-haemagglutinin complex in milk has 
not been studied in animals. The use of Clostridium BTX-A-haemagglutinin complex 
during lactation cannot be recommended. 
It should also be noted that: 
• 
Dysport units are specific to the preparation and are not interchangeable with other 
preparations of BTX-A. 
• 
Excessive doses may produce distant and profound neuromuscular paralysis. 
• 
Overdose could lead to an increased risk of the neurotoxin entering the bloodstream 
and may cause complications associated with the effects of oral botulinum poisoning 
(for example, dysphagia and dysphonia). Respiratory support may be required where 
excessive doses may cause paralysis of the respiratory muscles. There is no specific 
antidote; antitoxin should not be expected to be beneficial and general supportive care 
is advised. In the event of overdose, the patient should be medically monitored for any 
signs and/or symptoms of excessive muscle weakness or muscle paralysis. 
Symptomatic treatment should be instigated if necessary. 
• 
The safety profile of the indications under study can be in part predicted based on the 
overall experience with Dysport and the safety profile observed in studies performed 
with BTX-A (various brands; including Dysport used independent of Ipsen research) in 
these indications. 
Additional information regarding risks and benefits to human subjects may be found in the 
IB [8]. 
1.5 
Compliance Statement 
The study will 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. 
As this is an electronic data capture (EDC) study, the following regulations must also be 
adhered to: Food and Drug Administration (FDA), 21 Code of Federal Regulations (CFR) 
Part 11, Electronic Records, Electronic Signatures and FDA Guidance for Industry, 
Computerized Systems Used in Clinical Trials. Any episode of noncompliance will be 
documented. 
In addition, the study will adhere to all local regulatory requirements. 
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (for example, 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. 

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1.6 
Clinical Trial Rationale 
In hemiparetic patients, upper and lower limbs can be affected with spastic muscle 
overactivity and often need to be treated at the same time. The goals of management of spastic 
paresis include increasing mobility and range of motion (passive and active), improving 
function (passive and/or active), improving body image, facilitating splint wear and 
decreasing pain. Quite often, those goals can be achieved only when both affected limbs (UL 
and LL) are treated at the same time. However, there are limited published data concerning 
treatment strategies when both limbs require injection. The aim of this study is to provide 
efficacy and safety data on AbobotulinumtoxinA when upper and lower limbs are injected at 
the same time, to improve voluntary movements in subjects with spastic hemiparesis. 
Botulinum neurotoxin type A (BoNT-A) has proven efficacy in treating muscle hypertonia of 
spastic paresis of various aetiologies, as measured by lowering the Modified Ashworth Scale 
score [10, 11]. The recently published results of AbobotulinumtoxinA for the treatment of 
adult UL spasticity (phase III study) demonstrated improvement in AROM and suggested that 
future research into the treatment of spastic paresis with botulinum toxin should use active 
movement and function as primary outcome measures [9]. Therefore, the primary endpoint in 
the current study will be based on AROM. Meaningful functional improvement has not been 
demonstrated consistently across the previous BoNT-A studies to date. The reasons for this 
may be associated with the outcome measures used but also which – if any – rehabilitation 
programs have been used. To date, there is insufficient evidence to support the preferential 
effect of adjunctive therapies following BoNT-A injections. A recent systematic review found 
limited evidence to support or refute the benefit of adjunctive therapies when provided in 
addition to BoNT-A injection for adult focal spastic paresis [7]. However, there is some 
evidence suggesting that a diary-based and antagonist-based rehabilitation system called the 
Guided Self-rehabilitation Contract (GSC) [12] may constitute a useful adjunct to BoNT-A 
injections in order to improve gait. Therefore, in this study, AbobotulinumtoxinA injections 
will be accompanied by GSC therapy for the whole study duration. 
The primary efficacy endpoint will be based on the improvement of composite AROM in the 
primary treatment target (TT) limb (UL or LL). Secondary efficacy endpoints will include: 
other AROM assessments, as well as measures of active function in the UL (Modified 
Frenchay Scale (MFS)) and LL (Walking Speed Test (WST) barefoot at maximal speed); 
evaluations of GSC (subject satisfaction, subject beliefs that the GSC will help to improve 
functional capacity, and subject compliance with the GSC); global assessments of benefits of 
study therapy (by investigator and subject or caregiver); and quality of life assessments by the 
subject (European Quality of Life 5 Dimensions (EQ-5D 5L) and Short Form 12 (SF-12) 
scales). The study will also assess safety through the collection of adverse events (AEs) and 
the assessment of vital signs. 
In clinical practice, Dysport is used at varying concentrations and doses, depending on the 
size, number and location of muscles involved, severity of spasticity, presence of local muscle 
weakness, response to previous treatment and/or AE history with Dysport [13]. In the current 
study, a total dose of 1500 U Dysport will be injected at each cycle, divided between UL and 
LL, with no more than 1000 U being administered into the UL. Although the maximum dose 
of Dysport in most regions is 1000 U, a dose of 1500 U is licensed for local symptomatic 
treatment of spasticity affecting lower limbs in adults in some countries (France, Spain, Italy 
and Brazil). Therefore, this is a tested and approved dose and will be permitted in the current 
study [8]. A maximum of 1000 U will be permitted for injection in the UL in the current 
study, in line with current marketing authorisations. A total of two injections are planned for 
each subject, with each injection separated by at least 12 weeks (maximum 20 weeks). This is 

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in line with clinical studies that have shown improved efficacy after repeated administrations 
(see Section 1.3). 
This will be an open-label study with no placebo control. GSC, which cannot be replaced with 
placebo, is part of the study treatment; therefore, the study was not designed with a placebo 
control for the study treatment. With regard to AbobotulinumtoxinA, there is already 
extensive evidence demonstrating AbobotulinumtoxinA efficacy on spasticity versus placebo 
in upper and lower limbs. Furthermore, it would not be ethical to give subjects with spasticity 
placebo when an effective treatment exists. 
The current study will enrol adult subjects with hemiparesis due to acquired brain injury 
(ABI), presenting with muscle overactivity impeding motor function based on the 
investigator’s judgement, including potentially one of the following requiring BoNT 
treatment: typical clenched fist, flexed wrist, flexed elbow, or plantar flexed foot pattern. All 
subjects must have had the ABI at least 12 months before the study. 

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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The aim of this study is to assess the effect of AbobotulinumtoxinA injected in both the UL 
and LL, given in conjunction with daily GSC therapy, on voluntary movements in subjects 
with hemiparesis due to ABI (see Section 1.6). 
2.2 
Study Objectives 
The primary objective of the study is to assess the responder rate as defined by the 
improvement of composite active range of motion (AROM) in the primary targeted limb, 
either upper limb (UL) or lower limb (LL), depending on which one has been selected as a 
primary treatment target (TT), following two consecutive AbobotulinumtoxinA injections 
combined with a Guided Self-rehabilitation Contract (GSC) in subjects with spastic 
hemiparesis following ABI. 
The secondary objectives of the study are as follows: 
• 
to assess the effectiveness of AbobotulinumtoxinA combined with a GSC on: 
- 
the responder rate as defined by the improvement of composite active range of 
motion (AROM) in the primary targeted limb, either upper limb (UL) or lower 
limb (LL), depending on which one has been selected as a primary treatment 
target (TT), following one AbobotulinumtoxinA injection combined with a 
Guided Self-rehabilitation Contract (GSC) 
- 
AROM against 10 prespecified muscle groups: 5 in upper and 5 in lower limbs 
- 
composite AROM against injected muscle groups (any of the 10 prespecified) of 
each limb 
- 
full composite AROM against five UL muscle groups or full composite AROM 
against five LL muscle groups, regardless of whether the muscle groups were 
injected or not 
- 
active function in the upper and lower limbs using the Modified Frenchay Scale 
(MFS) and maximal Walking Speed (WS) barefoot, respectively. 
• 
to assess subject satisfaction with regard to the use of a GSC 
• 
to measure the changes in subject and physiotherapist beliefs that a GSC will help to 
improve function 
• 
to assess subject compliance with the GSC 
• 
to assess global benefits by both the investigator and the subject (or caregiver) 
• 
in subjects not reinjected at Week 12, to assess satisfaction with longer than 12 weeks 
interval between 2 injections 
• 
to assess health-related quality of life 
• 
to assess safety parameters. 
The exploratory objective is as follows: 
• 
to assess correlation between full composite AROM and active function (MFS in UL 
and WS in LL). 

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3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a multicentre, prospective, single-arm study to evaluate the efficacy and safety of two 
consecutive injections of AbobotulinumtoxinA administered in both upper and lower limbs 
(total dose of 1500 U) in conjunction with daily GSC therapy for at least a six-month 
duration, in adults with spastic hemiparesis due to ABI. The effect of treatment 
(i.e. AbobotulinumtoxinA+GSC) on voluntary movements will be assessed. 
Each subject will undergo two injection (treatment) cycles, receiving AbobotulinumtoxinA 
1500 U on Day 1 of each cycle; the two dosing occasions will be separated by at least 
12 weeks (maximum 20 weeks). The study design is shown in Figure 1. 
It is planned to recruit approximately 155 subjects at approximately 20 sites in Europe and the 
USA, in order to achieve 145 evaluable subjects. Recruitment will be stratified by country to 
ensure that 50% of subjects have the UL as primary TT and 50% of subjects have the LL as 
primary TT (with ±10% flexibility). 
At the Baseline Visit (Cycle 1), all subjects will undergo screening procedures and baseline 
study assessments after written informed consent has been provided. The primary TT limb 
(UL or LL) will be defined by the investigator, following discussion with the subject. If the 
primary TT limb is the upper limb, the secondary TT limb will be the lower limb (and vice 
versa). 
AbobotulinumtoxinA (1500 U) will be administered as a split dose, in both the UL and LL; 
the dose given in each limb will be decided by the investigator, based on which was 
considered the primary TT limb at the Baseline Visit and in accordance with the following 
dosing rules: 
• 
electrical stimulation (ES) will be used to target the injection sites; Ultrasound guiding 
could be used in addition to ES in case this technique is used in routine clinical 
practice; 
• 
at least half the total dose (i.e. ≥750 U) must be injected in the primary TT limb 
(the rest of the dose is injected in the secondary TT limb); 
• 
a maximum of 1000 U can be injected in an UL (even if it is the primary TT limb); 
• 
there is no maximum dose that can be injected in a LL, provided that some remainder 
dose (out of the 1500 U total) is used for the UL injections; 
List of recommended UL and LL muscles and Dysport dose per muscle is provided in 
Sections 6.1.1.1 and 6.1.1.2. 
• 
the second AbobotulinumtoxinA injection (Cycle 2) may be given in a different split to 
the first injection (Cycle 1), at the discretion of the investigator. However, the same 
minimal/maximal rules apply, as described above. The primary TT remains the same 
for both AbobotulinumtoxinA injections and the study duration. 
Each subject will also receive a personalised GSC and will be asked to perform daily GSC 
therapy throughout the study, including the recording in a diary of the performed exercises of 
the prescribed GSC therapy. Telephone calls will be made to the subject every 2 weeks to 
check how the GSC therapy is being performed and that the diary is being filled out every 
day. 
In Cycle 1, postinjection 
follow-up (FU) visits 
will 
be held 
after the first 
AbobotulinumtoxinA administration, as follows: 
• 
at Week 6; 

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• 
at Week 12: the investigator will decide if the subject is still responding to treatment or 
if a second injection is needed, based on his/her clinical judgement. If a second 
injection is given, this marks the start of Cycle 2 (see below). If a second injection is 
not given, the subject will return at Week 16; 
• 
at Week 16: the investigator will again decide if the subject is still responding to 
treatment or if a second injection is needed, based on his/her clinical judgement. 
If a second injection is given, this marks the start of Cycle 2 (see below). If a second 
injection is not given, the subject will return at Week 20; 
• 
at Week 20: the investigator will again decide if the subject is still responding to 
treatment or if a second injection is needed, based on his/her clinical judgement. 
If a second injection is given, this marks the start of Cycle 2 (see below). If the 
investigator decides that a second injection should not be given, based on his/her 
clinical judgement, the subject will be withdrawn from the study. 
In Cycle 2, postinjection FU visits will be held after the second AbobotulinumtoxinA 
administration, as follows: 
• 
at Week 6; 
• 
at Week 12: the investigator will decide if the subject is still responding to treatment or 
if a further injection is needed, based on his/her clinical judgement. If a further 
injection is needed, the subject completes the study after study assessments have been 
performed (before the injection outside the study is given) (i.e. Final Visit). If a further 
injection is not needed, the subject will return at Week 16; 
• 
at Week 16: the investigator will again decide if the subject is still responding to 
treatment or if a further injection is needed, based on his/her clinical judgement. 
If a further injection is needed, the subject completes the study after study assessments 
have been performed (before the injection outside the study is given) (i.e. Final Visit). 
If a further injection is not needed, the subject will return at Week 20; 
• 
at Week 20: the subject completes the study after study assessments have been 
performed, regardless of whether a further injection is needed (i.e. Final Visit). 
 
The overall duration of the study for each subject will be between 24 and 40 weeks (from 
Baseline Visit to Final Visit). 
Subjects who receive two AbobotulinumtoxinA administrations and complete the required 
postinjection FU visits will be considered to have completed the study. 
Subjects who withdraw from the study before completion of scheduled visits will have Early 
Withdrawal Visit assessments performed at their last visit. 

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Figure 1 Study Design 
 
 
 
If no 
If no 
Cycle 1 
Baseline visit 
Injection 1 
Cycle 1 
Week 6 visit 
Cycle 1 
Week 12 visit 
Does subject need another 
AbobotulinumtoxinA injection? 
If yes, give Injection 2 and proceed 
with Cycle 2. 
Cycle 2 
Week 6 visit 
Cycle 2 
Week 12 visit 
Does subject need another 
AbobotulinumtoxinA injection? 
If yes, perform study assessments 
and complete study (Final Visit). 
If no, proceed to Week 16 visit. 
Cycle 1 
Week 16 visit 
Does subject need another 
AbobotulinumtoxinA injection? 
If yes, give Injection 2 and 
proceed with Cycle 2. 
Cycle 1 
Week 20 visit 
Does subject need another 
AbobotulinumtoxinA injection? 
If yes, give Injection 2 and 
proceed with Cycle 2. 
If no, withdraw from study. 
Cycle 2 
Week 16 visit 
Does subject need another 
AbobotulinumtoxinA injection? 
If yes, perform study assessments 
and complete study (Final Visit). 
If no, proceed to Week 20 visit. 
Cycle 2 
Week 20 visit 
Study Complete (Final Visit) 

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3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluation 
The primary efficacy endpoint is as follows: 
• 
the percentage of responder subjects at Week 6 after the second injection, according to 
composite AROM in the primary TT limb. 
Composite AROM (XA), regardless of whether the muscle groups were injected or not, as 
measured by goniometer in the primary TT limb (either UL or LL, depending on which one 
has been selected as the primary TT limb), will be calculated as follows: 
- composite XA UL: XA UL = XAEF  + XAWF + XAFF 
- composite XA LL: XA LL = XAsol + XAGN 
 
where for UL: EF=elbow flexors, WF=wrist flexors and FF=extrinsic finger flexors, 
and for LL: Sol=soleus and GN=gastrocnemius muscles. 
Definition of a responder: a subject will be considered a responder if he/she achieves at least 
the predefined improvement threshold - larger or equal to 35° in UL or 5° in LL - in the 
primary TT limb (based on the composite AROM individual change from baseline to Week 6 
after the second injection). 
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
The secondary efficacy endpoints are as follows: 
• 
the percentage of responder subjects at Week 6 after the first injection, according to 
composite AROM in the primary TT limb 
• 
AROM against 10 prespecified muscle groups, 5 in upper and 5 in lower limbs: mean 
change from baseline at Week 6, Week 12 and re-injection/last cycle visits only 
• 
composite AROM against injected muscle groups (any of the 10 prespecified), in upper 
and lower limbs: mean change from baseline at Week 6, Week 12 and re-injection/last 
cycle visits only 
• 
full composite AROM against five UL muscle groups (XA full UL = XASE + XAEF + 
XAWF + XAFF + XAPT) or full composite AROM against five LL muscle groups (XA full 
LL = XAsol + XAGN + XAGM + XAHS + XARF), regardless of whether the muscle groups 
were injected or not: mean change from baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
where for UL: SE=shoulder extensors, EF=elbow flexors, WF=wrist flexors, 
FF=extrinsic finger flexors and PT=pronator teres, 
and for LL: Sol=soleus, GN=gastrocnemius muscles, GM=gluteus maximus, 
HS=hamstrings and RF=rectus femoris 
• 
active UL function measured using MFS: mean change from baseline in MFS overall 
score (i.e. mean score over the 10 tasks assessed locally and centrally by a reviewer 
blinded regarding the date of the video recording/visit number) at Week 12 after each 
injection cycle 
• 
active LL function measured using maximal WS barefoot without walking aids or, if 
absolutely necessary, with a cane, measured on a 10-metre WST: mean change from 
baseline at Week 12 after each injection cycle. (If a cane is used at the Baseline Visit, 
the same cane is to be used during all WS assessments.) 
• 
subject satisfaction with the GSC: at baseline (only for patients who had GSC 
performed previously), Week 6, Week 12 and re-injection/last cycle visits only 

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• 
changes in subject’s beliefs that the GSC will help to improve functional capacity: 
change from baseline to Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in Physiotherapist’s belief that the GSC will help to improve functional 
capacity: change from baseline to Week 6, Week 12 and re-injection/last cycle visits 
only 
• 
subject compliance with the GSC: percentage of days over study period when GSC 
therapy was performed (as determined from the subject diary) 
• 
global assessment of benefits, evaluated by both the investigator and the subject (or 
caregiver): at the end of each cycle 
• 
in subjects with an injection planned at Week 16 or 20 of each cycle: satisfaction with 
longer interval between 2 injections collected at the corresponding reinjection visit or 
the last cycle visit 
• 
quality of life changes, measured on the EQ-5D 5L and SF-12 scales: change from 
baseline to Final Visit. 
3.2.3 
Safety Endpoint and Evaluation 
Safety will be assessed by recording the number, nature and severity of AEs from the time 
that the subject gives informed consent to the end of study or subject withdrawal. Other safety 
data will include vital signs. 
3.2.4 
Exploratory Endpoint and Evaluation 
The correlation between full composite AROM and active function (MFS in UL and WS in 
LL) will be explored. 
3.3 
Randomisation and Blinding 
This is a nonrandomised, open-label, single-arm study. 
Recruitment will be stratified by country to ensure that 50% of subjects have the UL as 
primary TT and 50% of subjects have the LL as primary TT (with ±10% flexibility). This will 
be controlled at the country level. 
3.4 
Study Treatments and Dosage 
A total dose of AbobotulinumtoxinA 1500 U will be used in each of two injection (treatment) 
cycles. In each subject, the dose of 1500 U will be split between the UL and LL, as 
determined by the investigator, based on which limb was considered the primary TT limb at 
the Baseline Visit and in accordance with prespecified limits. The primary TT will remain the 
same for both AbobotulinumtoxinA injections and the study duration. 
A more detailed description of administration procedures is given in Section 6.1.1. 
All subjects will also perform daily GSC therapy. A detailed description of GSC therapy is 
given in Section 6.1.2. 
The investigational medicinal product (IMP) will be packaged by Dreux, France, and 
delivered to the investigational sites in Europe, or to interim storage in the USA (before 
delivery to study sites in the USA) and in other countries where interim storage will be 
needed. A sufficient quantity of IMP will be supplied as well as an acknowledgement of 
receipt form. 
The sponsor’s representative will receive a Certificate of Analysis for the batch of IMP that 
has been used under their study, Material Data Safety Sheet for the active IMP, and Packaging 
Order which reflects the product release statement.  

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The core label texts for all packaging units 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 IMP labels is displayed below: 
• 
sponsor name 
• 
study number 
• 
pharmaceutical dosage form 
• 
route of administration 
• 
quantity of dose units 
• 
batch number 
• 
specific blank space to enter the subject identification 
• 
“Keep out of reach of children” 
• 
“For clinical study use only” (for nonUS sites) 
• 
“Caution: new drug limited by Federal Law to investigational use” (for US sites) 
• 
name, address and telephone number of the sponsor, contract research organisation 
(CRO) or investigator (the main contact for information on the product, clinical study 
and emergency unblinding) (for sites in the European Union) 
• 
storage conditions 
• 
expiry date. 
The investigator, or designee, will only dispense IMPs to subjects included in this study. Each 
subject will only be given the IMP carrying his/her number. The dispensing for each subject 
will be documented in the electronic case report form (eCRF). 
3.5 
Study Duration 
This study will consist of two open-label injection (treatment) cycles. Each cycle will include 
postinjection FU visits of up to 20 weeks (see Section 3.1). Subjects are expected to 
participate in this study for a minimum of 24 weeks (if they have postinjection FU visits up to 
Week 12 only, following both injections) and a maximum of 40 weeks (if they have 
postinjection FU visits up to Week 20, following both injections). 
The subject’s participation in the study will be considered to have ended at the time of the 
Final Visit. This will be no later than 20 weeks after the second AbobotulinumtoxinA 
injection. 
The overall duration of the study will be between approximately 15 and 18 months. The study 
will be considered to have started when the first subject provides signed informed consent. 
The study will be considered to have ended after the last subject has completed his/her Final 
Visit. 
3.6 
Stopping Rules and Discontinuation Criteria 
In the following circumstances, subjects will be withdrawn from the study early: 
• 
subject consent withdrawal 
• 
subject lost to follow up 
• 
occurrence of an AE that, in the opinion of the investigator, makes the administration 
of the study treatment undesirable 
• 
investigator’s and/or sponsor’s decision to withdraw the subject if it is considered to be 
in the best interest of the subject 
• 
occurrence of a new ABI 

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• 
continuous failure to comply with the provisions of the study protocol, which is likely 
to have an adverse impact on the safety or well-being of the subject, or could jeopardise 
the scientific value of the study 
• 
investigator decides that subject does not need a second AbobotulinumtoxinA 
administration at Week 20 in Cycle 1. 
Subject withdrawal criteria and procedures are described in Section 4.3. 
3.7 
Investigational Medicinal Product Preparation Storage and Accountability 
3.7.1 
Investigational Medicinal Product Storage and Security 
The investigator, or an approved representative (for example, pharmacist), will ensure that all 
IMP and any other study related material is stored in a secured area, under recommended 
temperature (2 to 8°C) monitored storage conditions, in accordance with applicable regulatory 
requirements. 
3.7.2 
Investigational Medicinal Product Preparation 
The investigator, or an approved representative (for example, pharmacist), will ensure that all 
IMP is reconstituted and dispensed by qualified staff members. 
3.7.3 
Investigational Medicinal Product Accountability 
All IMP and any other study related material is to be accounted for on the IMP 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 in the IMP accountability log. 
All used or unused clinical study supplies should be destroyed locally and a certificate of 
destruction should be provided to the sponsor. 
3.8 
Maintenance of Randomisation and Blinding 
Not applicable. 
3.9 
Source Data Recorded on the Case Report Form 
Data will be collected in the eCRF in compliance with FDA 21 CFR Part 11. As required by 
GCP, the sponsor-assigned monitor will verify, by direct reference to the source documents, 
that the data required by the protocol are accurately reported on the eCRF.  
The source documents must, as a minimum, contain 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), IMP 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. 
Definition 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 (for example, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 

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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 
medicotechnical departments involved in the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor’s 
authorised personnel and by local and possibly foreign, competent authorities (CAs). This 
information is included in the informed consent. 

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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfil all of following criteria to be included in the study: 
(1) 
Subjects aged at least the national legal adult age. 
(2) 
Subjects with hemiparesis due to ABI (i.e. stroke or Traumatic Brain Injury (TBI)) 
presenting with muscle overactivity impeding motor function based on investigator’s 
judgement including, but not limited to, at least one of the following requiring BoNT 
treatment: typical clenched fist; flexed wrist; flexed elbow; or plantar flexed foot. 
(3) 
At least 12 months since the ABI. 
(4) 
Naïve or non-naïve to BoNT treatment; if non-naïve, at least 4 months after the last 
BoNT injection, of any serotype. 
(5) 
Upper limb active function with an overall score between 2 and 7, as assessed by MFS 
locally rated score, if the primary TT limb is the UL. 
(6) 
A 10-metre maximal WS barefoot between 0.2 and 1.4 m/s, if the primary TT limb is 
the LL. Maximal WS barefoot will be performed preferably without walking aids. 
However, a cane may be permitted if absolutely necessary (although this may prevent 
detection of treatment-induced improvements). In this case, the same aid will have to 
be used for all WS assessments during the study. 
(7) 
Subjects must provide written informed consent to participate in the study prior to any 
study-related procedures. 
(8) 
Female subjects of childbearing potential (not surgically sterile or 2 years 
postmenopausal) must use a medically accepted method of contraception and must 
agree to continue use of this method for the duration of the study until the last visit of 
the subjects and for at least 12 weeks post injection. Acceptable methods of 
contraception include total abstinence, male partner has had a vasectomy, double 
barrier method (e.g. male condom plus spermicide, or female diaphragm plus 
spermicide), intrauterine device, or hormonal contraceptive (oral, transdermal, 
implanted and injected).. 
(9) 
Subjects must be willing and able to comply with study restrictions and to remain at the 
clinic for the required duration during the study period and willing to return to the 
clinic for the follow-up evaluation as specified in the protocol. 
4.2 
Exclusion Criteria 
Subjects will not be included in the study if any of the following exclusion criteria are met: 
(1) 
Inability to understand protocol procedures and requirements, which, in the opinion of 
the investigator, could negatively impact on protocol compliance, in particularly 
inability to exercise according to the GSC. 
(2) 
Previous surgery on the affected muscles and ligaments, tendons, nerve trunks, or 
bones of the treated upper or lower limb. 
(3) 
Previous treatment with phenol and/or alcohol in any of the treated limbs any time 
before the study. 
(4) 
Any medical condition (including severe dysphagia or breathing difficulties) that may 
increase, in the opinion of the investigator, the likelihood of AEs related to BoNT-A 
treatment. 

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(5) 
Subjects treated, or likely to be treated, with intrathecal baclofen during the course of 
the study or during the 4 weeks before study entry. 
(6) 
Current, planned or received within the last 4 weeks prior to study treatment, treatment 
with any drug that interferes either directly or indirectly with neuromuscular function 
(for example, aminoglycosides). 
(7) 
Major neurological impairment other than spastic paresis (including major 
proprioceptive ataxia or apraxia on the paretic side) that could negatively impact on the 
functional performance of the subject. 
(8) 
Known disease of the neuromuscular junction (such as Lambert-Eaton myasthenic 
syndrome or myasthenia gravis). 
(9) 
Known sensitivity to BoNT-A or any excipient of Dysport. 
(10) Infection at the injection site(s). 
(11) Current pregnancy or lactation. A pregnancy test will be performed at the start of the 
study for all female subjects of childbearing potential (i.e. not surgically sterile or 
2 years postmenopausal). 
(12) Mental condition rendering the subject unable to understand the nature, scope and 
possible consequences of the study and/or evidence of an uncooperative attitude. 
(13) Abnormal baseline findings or any other medical condition(s) that, in the opinion of the 
investigator, might jeopardise the subject’s safety. 
(14) Subjects who have participated in any therapeutic clinical study/received any 
investigational agent within 30 days of enrolment. 
4.3 
Subject Withdrawal Criteria and Procedures 
Subjects are free to withdraw completely from the study at any time upon request and subject 
participation in the study may be stopped at any time at the discretion of the investigator or at 
the request of the sponsor. 
Subjects withdrawn from the study will not be replaced. Under no circumstances will subjects 
be enrolled more than once. 
Whenever possible, if a subject withdraws from the study for whatever reason, they should 
still attend the Early Withdrawal Visit (see Section 5.2.3). If the subject withdraws from the 
study and also withdraws consent for disclosure of future information, no further evaluations 
should be performed and no additional data should be collected. The sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 
Reasons for withdrawal of subjects from the study are given in Section 3.6. 
If the subject is withdrawn 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 eCRF. Withdrawal due to AEs should be distinguished from withdrawal due 
to any other reason. 
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 8.1 in order to assess the safety of the IMP. 

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5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 2. 
A summary of the reinjection scenarios for this study is shown in Table 3. 
 

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Table 2 
Study Procedures and Assessments 
Assessment[a] 
Injection Cycle 1 
Injection Cycle 2 
Early  
 
Baseline/ 
Inj 1 
Postinjection FU visits 
Inj 2[c] 
Postinjection FU visits 
withdrawal 
 
W 6 
(±7 
days) 
W 
12[b] 
(+7 
days) 
W 
16[b] 
(±7 
days) 
W 
20[b] 
(±7 
days) 
W 6 
(±7 
days) 
W 
12[d] 
(+7 
days) 
W 
16[d] 
(±7 
days) 
W 
20[d],[e] 
(±7 days) 
 
Visit 
1 
2 
3 
4 
5 
 
6 
7 
8 
9 
 
Informed consent[f] 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics[g] 
X 
 
 
 
 
 
 
 
 
 
 
Disease history[h] 
X 
 
 
 
 
 
 
 
 
 
 
Previous GSC / physiotherapy[i] 
X 
 
 
 
 
 
 
 
 
 
 
Previous BoNT injection(s)[j] 
X 
 
 
 
 
 
 
 
 
 
 
Significant medical or surgical 
history[k] 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications for UL 
and LL spasticity[l] 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Prior/concomitant medications and 
non-drug therapies[m] 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Concomitant surgical procedures 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Urine pregnancy test[n] 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Vital signs[o] 
X 
 
 
 
 
X 
 
X[p] 
X[p] 
X[p] 
X[p] 
AROM in each muscle group of UL and 
LL[q] 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Selection of primary TT limb 
X 
 
 
 
 
 
 
 
 
 
 
MFS 
X 
 
X 
 
 
 
 
X 
 
 
X 
WST[r] 
X 
 
X 
 
 
 
 
X 
 
 
X 
Number of days without GSC 
therapy[s] 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Subject satisfaction with GSC 
X[v] 
X 
X 
X[t] 
X[t] 
 
X 
X 
X[p] 
X[p] 
X[p] 
Subject satisfaction with longer interval 
between 2 injections  
 
 
 
X[t] 
X[t] 
 
 
 
X[t] 
X[t] 
 

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Assessment[a] 
Injection Cycle 1 
Injection Cycle 2 
Early  
 
Baseline/ 
Postinjection FU visits 
Inj 2[c] 
Postinjection FU visits 
withdrawal 
Subject beliefs that GSC will help to 
improve functional capacity 
X 
X 
X 
X[t] 
X[t] 
 
X 
X 
X[p] 
X[p] 
X[p] 
Physiotherapist beliefs that GSC will 
help to improve functional capacity 
X 
X 
X 
X[t] 
X[t] 
 
X 
X 
X[p] 
X[p] 
X[p] 
Global assessment of benefits by 
investigator 
 
 
X[t] 
X[t] 
X[t] 
 
 
X[p] 
X[p] 
X[p] 
X[p] 
Global assessment of benefits by 
subject (or caregiver) 
 
 
X[t] 
X[t] 
X[t] 
 
 
X[p] 
X[p] 
X[p] 
X[p] 
EQ-5D 5L questionnaire 
X 
 
 
 
 
 
 
X[p] 
X[p] 
X[p] 
X[p] 
SF-12 questionnaire 
X 
 
 
 
 
 
 
X[p] 
X[p] 
X[p] 
X[p] 
AE reporting 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Study drug administration[u] 
X 
 
(X) 
(X) 
(X) 
X 
 
 
 
 
 
Visit status 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
GSC 
GSC therapy will be performed by the subject daily.  
A telephone call will be made from the therapist to the subject every 2 weeks to check the subject is doing the GSC 
therapy daily and recording in the diary. 
 
ABI=Acquired brain injury; AE=Adverse event; AROM=Active range of motion; EQ-5D 5L=European Quality of Life 5 Dimensions; FU=Follow-up; GSC=Guided Self-rehabilitation Contract; 
Inj=AbobotulinumtoxinA injection; LL=Lower limb; MFS=Modified Frenchay Scale; SF-12=Short Form 12; TT=Treatment target; UL=Upper limb; W=Week; WST=Walking 
Speed Test. 
a 
Assessments should be performed before the AbobotulinumtoxinA injection (if scheduled on an injection day). 
b 
Cycle 1: The investigator decides if the subject is still responding to treatment or if a further AbobotulinumtoxinA injection is needed, based on his/her clinical judgement. At 
Week 12, if a second injection is given, this marks the start of Cycle 2; if a second injection is not given, the subject returns at Week 16. At Week 16, if a second injection is given, 
this marks the start of Cycle 2; if a second injection is not given, the subject returns at Week 20. At Week 20, if a second injection is given, this marks the start of Cycle 2; if the 
investigator decides that a second injection should not be given, based on his/her clinical judgement, the subject will be withdrawn from the study. 
c 
Injection 2 will be performed at the Week 12, Week 16 or Week 20 visit after Injection 1, at the discretion of the investigator, based on his/her clinical judgement. 
d 
Cycle 2: The investigator decides if the subject is still responding to treatment or if a further AbobotulinumtoxinA injection is needed, based on his/her clinical judgement. At 
Week 12, if a further injection is needed, the subject completes the study after study assessments have been performed (before the injection is given) (i.e. Final Visit); if a further 
injection is not needed, the subject returns at Week 16. At Week 16, if a further injection is needed, the subject completes the study after study assessments have been performed 
(before the injection is given) (i.e. Final Visit); if a further injection is not needed, the subject returns at Week 20. At Week 20, the subject completes the study after study 
assessments have been performed (regardless of whether a further injection is needed) (i.e. Final Visit). 
e 
For all subjects attending the Week 20 visit (Cycle 2), this will be the Final Visit. 
f 
Informed consent must be obtained before the subject undergoes any study-specific procedures. 
g 
Demographics: sex and date of birth; race and ethnicity will also be collected if permitted according to local regulations. 
h 
Disease history: date and type of ABI, date of spasticity development. 

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i 
Record all details of previous GSC or physiotherapy within 4 months before Baseline.. 
j 
Record if subject is naïve or non-naïve to BoNT treatment; if non-naïve to BoNT treatment, record dates of the first injection and last injection, which limbs were injected, and 
BoNT brand and dose used in the last injection. 
k 
Medical history: any significant past or ongoing medical or surgical conditions (not related to UL or LL spasticity). 
l 
Prior and concomitant medications for UL or LL spasticity: therapies taken from 4 weeks prior to baseline through the study (including the subject’s last study visit). 
m 
Prior and concomitant medications and nondrug therapies: therapies taken from 4 weeks prior to baseline through the study (including the subject’s last study visit). 
n 
Urine pregnancy test: recorded for females of childbearing potential only. 
o 
Measured at Baseline Visit, second injection visit and Final Visit, only (or early withdrawal). Vital signs: diastolic and systolic blood pressure and heart rate measured in the supine 
position after 5 minutes rest. Weight will be measured at baseline, second injection and last visit; height will be measured at baseline only. 
p 
To be performed at the Final Visit (which may be Week 12, Week 16 or Week 20 after Injection 2) or early withdrawal. 
q 
AROM is measured in each muscle group of the UL and LL (irrespective of whether injected or not). 
r 
WST is to be performed in the same condition as at Baseline Visit, for example, if a cane was used at the Baseline Visit, the same cane should be used for this test at other visits. 
s 
The number of days when GSC therapy was not performed since the last visit, as recorded in the subject diary, will be counted and recorded in the eCRF. 
t 
To be performed only at the last postinjection FU visit after Injection 1 (i.e. the visit where second injection is performed, which may be Week 12, Week 16 or Week 20). 
u 
AbobotulinumtoxinA (Dysport) (total dose 1500 U) will be administered by i.m. injection in the subject’s UL and LL, according to the dose split decided by the investigator, 
according to his/her clinical judgement, based on which limb was considered the primary TT limb at the Baseline Visit and prespecified limits. 
v 
Only for subjects who had GSC previously  
 

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Table 3 
Summary of Reinjection Scenarios 
 
Overall week number 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
 
<--------6 weeks----------> 
<--------6 weeks---------> 
<--------6 weeks----------> 
<--------6 weeks----------> 
<-----4 weeks-----> 
<-----4 weeks-----> 
 
 
 
 
 
 
 
 
[a] 
x 
 
 
 
 
 
o 
 
 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[b] 
x 
 
 
 
 
 
o 
 
 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
 
 
 
 
[c] 
x 
 
 
 
 
 
o 
 
 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
 
<--------6 weeks----------> 
<--------6 weeks---------> 
<----4 weeks---> 
<--------6 weeks----------> 
<--------6 weeks----------> 
<-----4 weeks-----> 
<-----4 weeks-----> 
 
 
 
 
[d] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
 
 
 
 
[e] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
[f] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
o 
(FV) 
 
 
 
 
 
<--------6 weeks----------> 
<--------6 weeks---------> 
<----4 weeks---> 
<----4 weeks---> 
<--------6 weeks----------> 
<--------6 weeks----------> 
<-----4 weeks-----> 
<-----4 weeks-----> 
[g] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
(FV) 
 
 
 
 
 
 
 
 
[h] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
(FV) 
 
 
 
 
[i] 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
x 
 
 
 
 
 
o 
 
 
 
 
 
o 
 
 
 
o 
 
 
 
o 
(FV) 
FV=Final Visit; o=Postinjection follow-up visit; x=Injection. 
Note: 
The investigator’s decision whether to give an AbobotulinumtoxinA injection is based on his/her clinical judgement, depending on if the subject is still responding to treatment or if 
a further AbobotulinumtoxinA injection is needed (see Section 3.1). 
a 
Injection 2 given at Week 12 relative to Injection 1, with 2 postinjection FU visits at Weeks 6 and 12 relative to Injection 2. 
b 
Injection 2 given at Week 12 relative to Injection 1, with 3 postinjection FU visits at Weeks 6, 12 and 16 relative to Injection 2. 
c 
Injection 2 given at Week 12 relative to Injection 1, with 4 postinjection FU visits at Weeks 6, 12, 16 and 20 relative to Injection 2. 
d 
Injection 2 given at Week 16 relative to Injection 1, with 2 postinjection FU visits at Weeks 6 and 12 relative to Injection 2. 
e 
Injection 2 given at Week 16 relative to Injection 1, with 3 postinjection FU visits at Weeks 6, 12 and 16 relative to Injection 2. 
f 
Injection 2 given at Week 16 relative to Injection 1, with 4 postinjection FU visits at Weeks 6, 12, 16 and 20 relative to Injection 2. 
g 
Injection 2 given at Week 20 relative to Injection 1, with 2 postinjection FU visits at Weeks 6 and 12 relative to Injection 2. 
h 
Injection 2 given at Week 20 relative to Injection 1, with 3 postinjection FU visits at Weeks 6, 12 and 16 relative to Injection 2. 
i 
Injection 2 given at Week 20 relative to Injection 1, with 4 postinjection FU visits at Weeks 6, 12, 16 and 20 relative to Injection 2. 
 

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5.2 
Study Visits 
5.2.1 
Injection Cycle 1: Baseline Visit and Postinjection Follow-Up Visits 
5.2.1.1 
Baseline Visit 
A signed and dated informed consent form will be obtained before any study-specific 
procedures are performed. 
After written informed consent is obtained, potential subjects will be allocated a subject 
number. Each investigator will maintain a record of all subjects who signed the informed 
consent form. 
The following study assessments will be performed before the AbobotulinumtoxinA injection: 
• 
eligibility check (inclusion/exclusion criteria) 
• 
demographic data (sex and date of birth; race and ethnicity will also be 
collected if permitted according to local regulations) 
• 
disease history: date and type of ABI, date of spasticity development 
• 
previous GSC or physiotherapy history (within 4 months prior to 
baseline) 
• 
subject satisfaction on previous GSC (if applicable) 
• 
if subject is non-naïve to BoNT treatment: dates of the first injection 
and last injection, which limbs were injected, and BoNT brand and 
dose used in the last injection 
• 
medical history, including any significant past or ongoing medical or 
surgical conditions (not related to UL or LL spasticity) 
• 
prior and concomitant medications for UL or LL spasticity (taken from 
4 weeks prior to baseline) 
• 
other prior and concomitant medications and nondrug therapies (taken 
from 4 weeks prior to baseline) 
• 
urine pregnancy test (females of childbearing potential only) 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight, height) 
• 
AEs (collected from after written informed consent and throughout the 
study) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
selection of the primary TT limb (UL or LL) by the investigator, based 
on his/her clinical judgement and in agreement with the subject 
• 
MFS 
• 
WST 
• 
subject and Physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject completion of EQ-5D 5L questionnaire 
• 
subject completion of SF-12 questionnaire 

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• 
preparation 
of 
individual 
subject 
GSC 
by 
the 
investigator/physiotherapist and diary provided to subject (see 
Section 6.1.2). 
After completion of study assessments and confirmation of eligibility, the following will be 
performed: 
• 
selection of dose split in the UL and LL by the investigator, according 
to his/her clinical judgement, based on which limb was considered the 
primary TT limb at the Baseline Visit and prespecified limits (see 
Section 6.1.1) 
• 
AbobotulinumtoxinA 
(Dysport) 
(total 
dose 
1500 U) 
will 
be 
administered by i.m. injection in the subject’s UL and LL, according to 
the agreed dose split. 
Telephone calls will be made to the subject every 2 weeks to check the GSC therapy is being 
performed daily. 
5.2.1.2 
Week 6 (± 7 days) 
The following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist. 
5.2.1.3 
Week 12 (+7 days) 
The following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) (to be measured only 
if second injection is given at this visit) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
MFS 
• 
WST (in the same condition as at Baseline Visit, for example, if a cane 
was used at Baseline Visit, the same cane should be used for this test 
also) 
• 
subject assessment of satisfaction with GSC 

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• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
global assessment of benefits by investigator (only if the second 
injection of AbobotulinumtoxinA is given at this visit) 
• 
global assessment of benefits by subject (or caregiver) (only if the 
second injection of AbobotulinumtoxinA is given at this visit) 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist. 
The investigator will decide if the subject is still responding to treatment or if a second 
AbobotulinumtoxinA injection is needed at this visit, based on his/her clinical judgement. If a 
second injection is not given, the subject will return at Week 16. If a second injection is given, 
this marks the start of Cycle 2 (see Section 5.2.2) and the following procedures will be 
performed: 
• 
selection of dose split in the UL and LL by the investigator, according 
to his/her clinical judgement, based on which limb was considered the 
primary TT limb at the Baseline Visit and prespecified limits (see 
Section 6.1.1) 
• 
AbobotulinumtoxinA 
(Dysport) 
(total 
dose 
1500 U) 
will 
be 
administered by i.m. injection in the subject’s UL and LL, according to 
the agreed dose split. 
5.2.1.4 
Week 16 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at Week 12 
Postinjection FU Visit After Injection 1) 
This visit is performed only if the second injection of AbobotulinumtoxinA was not given at 
the previous visit. 
If this visit is performed, the following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) (to be measured only 
if second injection is given at this visit) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
global assessment of benefits by investigator (only if the second 
injection of AbobotulinumtoxinA is given at this visit) 
• 
global assessment of benefits by subject (or caregiver) (only if the 
second injection of AbobotulinumtoxinA is given at this visit). 

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• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist. 
The investigator will decide if the subject is still responding to treatment or if a second 
AbobotulinumtoxinA injection is needed at this visit, based on his/her clinical judgement. If a 
second injection is not given, the subject will return at Week 20. If a second injection is given, 
this marks the start of Cycle 2 (see Section 5.2.2) and the following procedures will be 
performed: 
• 
in subjects with an injection planned at Week 16 or 20 of each cycle:  
subject satisfaction with longer interval between 2 injections collected 
at the corresponding reinjection visit or the last cycle visit 
• 
selection of dose split in the UL and LL by the investigator, according 
to his/her clinical judgement, based on which limb was considered the 
primary TT limb at the Baseline Visit and prespecified limits (see 
Section 6.1.1) 
• 
AbobotulinumtoxinA 
(Dysport) 
(total 
dose 
1500 U) 
will 
be 
administered by i.m. injection in the subject’s UL and LL, according to 
the agreed dose split. 
5.2.1.5 
Week 20 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at Week 12 or 
Week 16 Postinjection FU Visit After Injection 1) 
This visit is performed only if the second injection of AbobotulinumtoxinA was not given at 
the previous visit. 
If this visit is performed, the following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
global assessment of benefits by investigator 
• 
global assessment of benefits by subject (or caregiver) 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist. 
The investigator will decide if the subject is still responding to treatment or if a second 
AbobotulinumtoxinA injection is needed at this visit, based on his/her clinical judgement. 
If the investigator decides that a second injection should not be given, based on his/her 
clinical judgement, the subject will be withdrawn from the study. If a second injection is 
given, this marks the start of Cycle 2 (see Section 5.2.2) and the following procedures will be 
performed: 

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• 
in subjects with an injection planned at Week 16 or 20 of each cycle: 
subject satisfaction with longer interval between 2 injections collected 
at the corresponding reinjection visit or the last cycle visit 
• 
selection of dose split in the UL and LL by the investigator, according 
to his/her clinical judgement, based on which limb was considered the 
primary TT limb at the Baseline Visit and prespecified limits (see 
Section 6.1.1) 
• 
AbobotulinumtoxinA 
(Dysport) 
(total 
dose 
1500 U) 
will 
be 
administered by i.m. injection in the subject’s UL and LL, according to 
the agreed dose split. 
 
5.2.2 
Injection Cycle 2: Postinjection Follow-Up Visits 
Telephone calls will be made to the subject every 2 weeks to check the GSC therapy is being 
performed daily. 
5.2.2.1 
Week 6 (± 7 days) 
The following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
measurement of AROM in 10 prespecified muscle groups of the UL 
and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist. 
5.2.2.2 
Week 12 (+7 days) 
The following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) (to be measured only 
if this is the Final Visit) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
MFS 
• 
WST (in the same condition as at Baseline Visit, for example, if a cane 
was used at Baseline Visit, the same cane should be used for this test 
also) 
• 
subject assessment of satisfaction with GSC 

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• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist (if this is not the Final Visit). 
The investigator will decide if the subject is still responding to treatment or if a further 
AbobotulinumtoxinA injection is needed at this visit, based on his/her clinical judgement. If a 
further injection is not given, the subject will return at Week 16. If a further injection is 
needed, the subject completes the study after study assessments have been performed (before 
the injection is given) (i.e. this is the Final Visit) and the following procedures will be 
performed: 
• 
global assessment of benefits by investigator 
• 
global assessment of benefits by subject (or caregiver) 
• 
subject completion of EQ-5D 5L questionnaire 
• 
subject completion of SF-12 questionnaire. 
5.2.2.3 
Week 16 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at Week 12 
Postinjection FU Visit After Injection 2) 
If this visit is performed (see Section 5.2.2.2), the following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) (to be measured only 
if this is the Final Visit) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
GSC exercises may be adjusted, based on the clinical judgement of the 
investigator or physiotherapist (if this is not the Final Visit). 
The investigator will decide if the subject is still responding to treatment or if a further 
AbobotulinumtoxinA injection is needed at this visit, based on his/her clinical judgement. If a 
further injection is not given, the subject will return at Week 20. If a further injection is 
needed, the subject completes the study after study assessments have been performed (before 
the injection is given) (i.e. this is the Final Visit) and the following procedures will be 
performed: 
• 
in subjects with an injection planned at Week 16 or 20 of each cycle:  
subject satisfaction with longer interval between 2 injections collected 
at the corresponding reinjection visit or the last cycle visit 
• 
global assessment of benefits by investigator 
• 
global assessment of benefits by subject (or caregiver) 

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• 
subject completion of EQ-5D 5L questionnaire 
• 
subject completion of SF-12 questionnaire. 
5.2.2.4 
Week 20 (± 7 days) (Only if AbobotulinumtoxinA Not Administered at Week 16 
Postinjection FU Visit After Injection 2) 
If this visit is performed (see Section 5.2.2.2), it will be considered the Final Visit and the 
following assessments will be performed: 
• 
AE check 
• 
concomitant medication review 
• 
physical examination 
• 
vital signs (blood pressure and heart rate, weight) 
• 
measurement of AROM against 10 prespecified muscle groups of the 
UL and LL (irrespective of whether injected or not) 
• 
subject assessment of satisfaction with GSC 
• 
subject and physiotherapist completion of Likert scale to assess beliefs 
that GSC will help to improve functional capacity 
• 
subject GSC diary check and record the number of days GSC not 
performed in eCRF 
• 
global assessment of benefits by investigator 
• 
global assessment of benefits by subject (or caregiver) 
• 
in subjects with an injection planned at Week 16 or 20 of each cycle:  
subject satisfaction with longer interval between 2 injections collected 
at the corresponding reinjection visit or the last cycle visit 
• 
subject completion of EQ-5D 5L questionnaire 
• 
subject completion of SF-12 questionnaire. 
5.2.3 
Early Withdrawal Visit 
If the subject withdraws early from the study, the procedures described for Injection Cycle 2, 
Week 12 (see Section 5.2.2.2) should be completed, if possible. 

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6 
TREATMENT OF SUBJECTS 
6.1 
Study Drugs Administered 
This is a single-arm study and all subjects will receive the same study treatment. 
At the Baseline Visit (Cycle 1), all subjects will be allocated a subject number after giving 
written informed consent. Following baseline assessments and confirmation of eligibility for 
the study, AbobotulinumtoxinA (1500 U) will be administered by i.m. injection as a split 
dose, in both the UL and LL (see Section 6.1.1). 
In Cycle 2, all subjects will receive a second administration of AbobotulinumtoxinA (1500 U) 
given as a split dose, in both the UL and LL. The dose split (per limb and per muscle) may be 
different to the dose split given for the first administration of AbobotulinumtoxinA, but it 
must follow the same limits (see Section 6.1.1). 
Each subject will also receive a personalised GSC and will be asked to perform GSC therapy 
daily throughout the study (from Baseline Visit to Final Visit). Details are provided in 
Section 6.1.2. 
Note: For subjects receiving antivitamin K therapy the Investigator will have to ensure that 
the International Normalised Ratio (INR) is below 3.5 within 1 week prior to study treatment 
administration. 
Subjects currently receiving oral anti-spasticity medications (e.g. Baclofen) may be included 
provided the dose will be kept constant during the study.  
 
6.1.1 
AbobotulinumtoxinA (Dysport) 
The IMP, AbobotulinumtoxinA (Dysport®), will be supplied as a white lyophilised powder in 
a vial containing 500 U of BTX-A-haemagglutinin complex. A total dose of 1500 U will be 
used in each of two injection (treatment) cycles. 
Each Dysport vial containing 500 U will be reconstituted with 2.5 mL sodium chloride for 
i.m. injection (0.9%). For the total dose of 1500 U, three vials will be used for each subject on 
each dosing occasion The total volume to be injected on each dosing occasion will be 7.5 mL. 
In each subject, the dose of AbobotulinumtoxinA 1500 U will be split between the UL and 
LL. The dose given in each limb will be decided by the investigator, according to his/her 
clinical judgement, based on which limb was considered the primary TT limb at the Baseline 
Visit and prespecified limits (see dosing rules below). 
The second administration of AbobotulinumtoxinA 1500 U will be given at the Week 12, 
Week 16 or Week 20 visit (after the first AbobotulinumtoxinA injection) (see Section 3.1). 
The primary TT will remain the same for both AbobotulinumtoxinA injections and the study 
duration. 
The following dosing rules will apply: 
• 
electrical stimulation will be used to target the injection sites; 
• 
at least half the total dose (i.e. ≥750 U) must be injected in the primary TT limb. The 
rest of the dose is injected in the secondary TT limb; 
• 
a maximum of 1000 U can be injected in an UL (even if it is the primary TT limb); 
• 
there is no maximum dose that can be injected in a LL, provided that some remainder 
dose (out of the 1500 U total) is used for the UL injections; 

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• 
the second injection (Week 12, 16 or 20) may be given in a different split to the first 
injection, at the discretion of the investigator. However, the same minimal/maximal 
rules apply, as described above. 
Details of study drug packaging and supply are provided in Section 3.4. 
Dose administration details will be recorded in the eCRF, including the doses administered 
and details of the muscle groups that were injected. List of recommended muscles to be 
injected based on subject needs is presented in Section 6.1.1.1 for upper limb and Section 
6.1.1.2 for lower limbs. Any muscle injected will be recorded in the eCRF. 
6.1.1.1 
List of muscles recommended to be injected and Dysport Dosing by Muscle for 
Upper Limb Spasticity  
 
MUSCLES 
DOSES 
Flexor carpi radialis (FCR)  
100 – 200 U 
Flexor carpi ulnaris (FCU)  
100 – 200 U 
Flexor digitorum profundus (FDP)  
100 – 200 U 
Flexor digitorum superficialis (FDS)  
100 – 200 U 
Flexor Pollicis Longus  
100 – 200 U 
Adductor Pollicis  
25 – 50 U 
Brachialis  
200 – 400 U 
Brachioradialis  
100 – 200 U 
Biceps Brachii (BB)  
200 – 400 U 
Pronator Teres  
100 – 200 U 
Triceps Brachii (long head)  
150 – 300 U 
Pectoralis Major  
150 – 300 U 
Subscapularis  
150 – 300 U 
Latissimus Dorsi  
150 – 300 U 
 
6.1.1.2 
List of muscles recommended to be injected and Dysport Dosing by Muscle for 
Lower Limb Spasticity  
 
MUSCLES 
DOSES 
Soleus muscle  
300 – 550 U 
Gastrocnemius Medial Head  
100 – 450 U 
Gastrocnemius Lateral Head  
100 – 450 U 
Tibialis posterior  
100 – 250 U 
Flexor digitorum longus  
50 – 200 U 
Flexor digitorum brevis  
50 – 200 U 
Flexor hallucis longus  
50 – 200 U 
Flexor hallucis brevis  
50 – 100 U 
Rectus femoris  
100 – 400 U 
Hamstrings  
100 – 400 U 
Adductor magnus  
100 – 300 U 
Adductor Longus  
50 – 150 U 
Adductor Brevis  
50 – 150 U 
Gracilis  
100 – 200 U 
Gluteus maximus  
100 – 400 U 
 
 

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6.1.2 
Second Study Therapy: GSC 
At the first visit, the investigator will prescribe the rehabilitation programme for the GSC 
[12]. The GSC is a motivational tool, which will be described in detail in the Study 
Operational Manual. The physiotherapist will teach each subject the stretching postures and 
exercises to perform on a daily basis throughout the study. These will be tailored to the 
individual subject’s needs and will form the GSC therapy. The main focus will be on the 
primary TT limb (as determined at the Baseline Visit) and then the other limb. All muscle 
groups requiring active training and/or stretching should be trained. 
The subjects will be given a diary at the Baseline Visit. As part of the GSC, they will be asked 
to record in this diary each day whether they have performed the GSC therapy. A copy of the 
diary and details regarding diary completion will be provided in the Study Operational 
Manual. 
Telephone calls will be made to the subjects every 2 weeks to encourage them, check the GSC 
therapy is being performed daily and that they are completing the diary. The exercises may be 
adjusted at study visits, based on the clinical judgement of the investigator or physiotherapist. 
At each postbaseline FU visit, the subjects will return the diary. The investigator will count 
the number of days when GSC therapy was not performed and will record this in the eCRF. 
6.2 
Concomitant Medication/Therapy 
All previous GSC or physiotherapy will be recorded in the eCRF. 
It will be recorded if subject is naïve or non-naïve to BoNT treatment. If non-naïve to BoNT 
treatment, the dates of the first injection and last injection, details of which limbs were 
injected, and the BoNT brand and dose used in the last injection will be recorded in the eCRF. 
Prior and concomitant medications for UL or LL spasticity, taken from 4 weeks prior to 
baseline through the study (including the subject’s last study visit) will be recorded in the 
eCRF. Other prior and concomitant medications and nondrug therapies taken from 4 weeks 
prior to baseline through the study (including the subject’s last study visit) will also be 
recorded in the eCRF.  
For each therapy, the generic name or trade name, dosage, route, start and end dates and 
indication will be recorded in the eCRF. 
The following concomitant medications are not permitted during this study (see also 
Section 4.2): 
• 
any other form of BoNT is not allowed; 
• 
drugs which affect neuromuscular transmission, such as aminoglycoside antibiotics, 
should be used with caution; 
• 
any anti-spasticity medication (such as Baclofen, tizanidine, eperisone or 
benzodiazepines), which is expected to change in dosage during the study is not 
allowed (anti-spasticity medications on a stable dose are permitted). 
The following concomitant medications are permitted during this study but they must be 
monitored closely and every effort should be made to keep their dose and dose regimen 
constant throughout the course of the study: 
• 
changes in pain medication are acceptable if absolutely necessary and according to 
clinical judgment and will be recorded in the eCRF; 
• 
concomitant use of anticholinergic drugs (which may potentiate systemic 
anticholinergic effects) is permitted if the dosage has been stable for 6 weeks prior to 
study treatment and is expected to remain at this stable dose throughout the study; 

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• 
anticoagulant treatment if INR > 3.5 during the study. 
6.3 
Procedures for Monitoring Subject Compliance 
Administrations of AbobotulinumtoxinA will be administered at the clinic by the investigator. 
Telephone calls will be made every 2 weeks to the subject to remind him/her to perform the 
GSC therapy every day and fill out the diary. At each postbaseline FU visit, subjects will 
return their diary. The diary will be checked and the number of days when GSC therapy was 
not performed since the last visit will be recorded in the eCRF. 
The investigator will be responsible for monitoring subject compliance. Subjects can be 
withdrawn from the study at any time if the investigator or the sponsor determines that the 
subject is not in compliance with the study protocol (see Section 3.6). 

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7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedule in Table 2. 
7.1 
Primary Efficacy Endpoint and Evaluation 
The primary efficacy endpoint is as follows: 
• 
the percentage of responder subjects at Week 6 after the second injection, according to 
composite AROM in the primary TT limb. 
Composite AROM (XA), regardless of whether the muscle groups were injected or not, as 
measured by goniometer in the primary TT limb (either UL or LL, depending on which one 
has been selected as the primary TT limb), will be calculated as follows: 
- 
composite XA UL: XA UL = XAEF  + XAWF + XAFF 
- 
composite XA LL: XA LL = XAsol + XAGN 
where for UL: EF=elbow flexors, WF=wrist flexors and FF=extrinsic finger flexors, 
and for LL: Sol=soleus and GN=gastrocnemius muscles. 
Definition of a responder: a subject will be considered a responder if he/she achieves at least 
the predefined improvement threshold - larger or equal to 35° in UL or 5° in LL - in the 
primary TT limb (based on the composite AROM individual change from baseline to Week 6 
after the second injection). 
7.2 
Secondary Efficacy Endpoints and Evaluations 
The secondary efficacy endpoints are as follows: 
• 
the percentage of responder subjects at Week 6 after the first injection, according to 
composite AROM in the primary TT limb 
• 
AROM against 10 prespecified muscle groups, 5 in upper and 5 in lower limbs: mean 
change from baseline at Week 6, Week 12 and re-injection/last cycle visits only 
• 
composite AROM against injected muscle groups (any of the 10 prespecified), in upper 
and lower limbs: mean change from baseline at Week 6, Week 12 and re-injection/last 
cycle visits only 
• 
full composite AROM against five UL muscle groups (XA full UL = XASE + XAEF + 
XAWF + XAFF + XAPT) or full composite AROM against five LL muscle groups (XA full 
LL = XAsol + XAGN + XAGM + XAHS + XARF), regardless of whether the muscle groups 
were injected or not: mean change from baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
where for UL: SE=shoulder extensors, EF=elbow flexors, WF=wrist flexors, 
FF=extrinsic finger flexors and PT=pronator teres,  
and for LL: Sol=soleus, GN=gastrocnemius muscles, GM=gluteus maximus, 
HS=hamstrings and RF=rectus femoris 
• 
active UL function measured using MFS: mean change from baseline in MFS overall 
score (i.e. mean score over the 10 tasks assessed locally and centrally by a reviewer 
blinded regarding the date of video recording/visit number) at Week 12 after each 
injection cycle 
• 
active LL function measured using maximal WS barefoot without walking aids or, if 
absolutely necessary, with a cane, measured on a 10-metre WST: mean change from 
baseline at Week 12 after each injection cycle. (If a cane is used at the Baseline Visit, 
the same cane is to be used during all WS assessments.) 

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• 
subject satisfaction with the GSC: at baseline (only for subject who had GSC 
performed previously), Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in subject’s beliefs that the GSC will help to improve functional capacity: 
change from baseline to Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in Physiotherapist’s belief that the GSC will help to improve functional 
capacity: change from baseline to Week 6, Week 12 and re-injection/last cycle visits 
only 
• 
subject compliance with the GSC: percentage of days over study period when GSC 
therapy was performed (as determined from the subject diary) 
• 
global assessment of benefits, evaluated by both the investigator and the subject (or 
caregiver): at the end of each cycle 
• 
in subjects with an injection planned at Week 16 or 20 of each cycle: satisfaction with 
longer interval between 2 injections collected at the corresponding reinjection visit or 
the last cycle visit 
• 
quality of life changes, measured on the EQ-5D 5L and SF-12 scales: change from 
baseline to Final Visit. 
Secondary efficacy endpoints and evaluations are summarised in Table 4. 
 
Table 4 
Secondary Efficacy Endpoints and Evaluations 
Measure 
Timepoint 
Variable 
Endpoint 
Voluntary movements 
measured using 
goniometer to 
determine AROM 
Baseline, Week 6, 
Week 12 and 
re-injection/last cycle 
visits 
AROM (XA) 
• 
Percentage of responder subjects at 
Week 6 after the first injection, 
according to composite AROM in the 
primary TT limb 
• 
Mean change from baseline to each 
postbaseline timepoint in AROM 
against 10 prespecified muscle groups 
• 
Mean change from baseline to each 
postbaseline timepoint in composite 
AROM against injected muscle 
groups (any of the 10 prespecified) 
• 
Mean change from baseline to each 
postbaseline timepoint in full 
composite AROM against five UL 
muscle groups or five LL muscle 
groups, regardless of whether the 
muscle groups were injected or not 
Active function in the 
UL measured using 
MFS 
Baseline, Week 12 
(postinjections 1 
and 2) 
MFS overall 
score 
• 
Mean change from baseline to 
Week 12 in MFS overall score 
assessed locally and centrally by a 
reviewer blinded regarding the date of 
video recording/visit number 
Active function in the 
LL measured using 
10-metre WST[a] 
Baseline, Week 12 
(postinjections 1 
and 2) 
Maximal WS 
(m/s) 
• 
Mean change from baseline to 
Week 12 in maximal WS 
Subject satisfaction 
with the GSC measured 
on a Likert scale 
Baseline[b], Week 6, 
Week 12 and 
re-injection/last cycle 
visits 
Likert scale 
scores 
• 
Scores at each timepoint 

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Measure 
Timepoint 
Variable 
Endpoint 
Subject’s beliefs that 
GSC will help to 
improve functional 
capacity 
Baseline, Week 6, 
Week 12 and 
re-injection/last cycle 
visits 
Likert scale 
scores 
• 
Change from baseline to each 
postbaseline timepoint in scores 
Physiotherapist’s 
beliefs that GSC will 
help to improve 
functional capacity 
Baseline, Week 6, 
Week 12 and 
re-injection/last cycle 
visits 
Likert scale 
scores 
• 
Change from baseline to each post 
baseline timepoint in scores 
Subject compliance 
with the GSC 
Baseline to Final 
Visit 
Days when 
GSC therapy 
was 
documented 
• 
Percentage of days over study period 
when GSC therapy was performed (as 
determined from the subject diary) 
Subject satisfaction 
with longer interval 
between 2 injections 
Week 16 or 
Week 20, depending 
on which is last visit 
cycle 1 and cycle 2 
Likert scale 
scores 
• 
Scores at each timepoint 
Benefits of treatment 
assessed by 
investigator and subject 
(or caregiver) 
Last visit of each 
injection cycle 
(i.e. Week 12 or 
Week 16 or 
Week 20, depending 
on which is last visit 
postinjection) 
Global 
assessment 
• 
Scores at each timepoint 
Quality of life 
measured using the 
EQ-5D 5L and SF-12 
scales 
Baseline, Final Visit 
(postinjection 2) 
EQ-5D 5L 
descriptive 
data and VAS, 
SF-12 scores 
• 
Change from baseline in scores 
AROM=Active range of motion; EQ-5D 5L= European Quality of Life 5 Dimensions; GSC=Guided Self-rehabilitation 
Contract; LL=Lower limb; MFS=Modified Frenchay Scale; SF-12=Short Form 12; UL=Upper limb; VAS=Visual analogue 
scale; WS=Walking Speed. 
a 
The WST is to be performed barefoot without walking aids or, if absolutely necessary, with a cane. If a cane is 
used at the Baseline Visit, the same cane is to be used during all WS assessments. 
b 
for previously GSC treated subjects 
 
7.3 
Methods and Timing of Assessing, Recording and Analysing Efficacy Data 
All scales and methods of measurement will be described in detail in the Study Operational 
Manual. Methods for assessing efficacy data are summarised below. The timing of 
assessments is discussed in Section 5. Procedures for recording efficacy data are discussed in 
Section 14.1 and methods of analyses are discussed in Section 10.4.5. 
7.3.1 
Active Range of Motion (AROM) 
The AROM will be measured in the UL and LL using a goniometer, using zero as the 
theoretical position of minimal stretch for the muscle assessed. The subject will be asked to 
perform the active movement as far as possible against that muscle and the angle will be 
measured. 
The investigator will use the goniometer to measure the angle of joint movement with respect 
to the following 10 prespecified muscle groups (injected or noninjected) in the UL and LL: 
• 
UL: 
shoulder extensors, elbow flexors*, wrist flexors*, extrinsic finger flexors* and 
pronator teres 
• 
LL: 
soleus*, gastrocnemius muscles*, gluteus maximus, hamstrings and rectus 
femoris. 

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* These measurements will be used for determination of the composite AROM against the 
injected muscle groups of the primary TT limb, for the primary efficacy endpoint (depending 
on whether the primary TT limb is the UL or LL). 
Details will be provided in the Study Operational Manual. The definition of responders and 
details of calculations using the AROM measurements are provided in Section 10.4.5. 
7.3.2 
Modified Frenchay Scale (MFS) 
The MFS will be used to measure active function in the UL [14]. The MFS consists of 
10 tasks (for example, opening and closing a jam jar), each of which is assessed on a visual 
analogue scale (VAS) from “No movement” to “Normal”. 
While performing the tasks, each subject will be videotaped. The investigator will record the 
MFS scores in the eCRF. The baseline mean MFS score assessed by each local investigator 
will be used for the purpose of the eligibility check. When evaluating active function at 
postbaseline FU visits, the investigator will review the baseline video for comparison 
purposes. Details will be provided in the Study Operational Manual. 
 
At each visit and for each rating, the MFS overall scores will be obtained by averaging all 
individual task scores, provided that at least 8 out of the 10 are not missing. If 3 or more 
individual task scores are missing, the overall score will be left missing. 
On top of the local MFS scores assessed by the investigators, a central review will be 
conducted at the Coordinating investigator’s site of Prof Gracies: if possible, videos will be 
scored by only one reviewer. Videos will be provided for a given subject in a blinded manner 
for the visit order. All videos should be assessed only when the subject has completed the 
study.  
The efficacy endpoint analysis will be performed both on the locally rated MFS mean score 
and on the centrally rated MFS mean score. if available  
7.3.3 
10-Metre Walking Speed Test (WST) 
The 10-metre WST will be used to measure active function in the LL [15]. The subject will 
perform the WST barefoot without a walking aid. If it is absolutely necessary that the subject 
uses a cane, this may be permitted provided that the same cane is used at the Baseline Visit 
and all other WS assessments for that subject. The subject will be given instructions to walk at 
his/her maximum speed. Details will be provided in the Study Operational Manual. 
The time taken (in seconds) for the subject to walk from the start to the end of the 10 metres 
will be recorded in the eCRF. Walking speed (m/s) over the 10-metre distance will used in the 
efficacy endpoint analysis.  
7.3.4 
Guided Self-Rehabilitation Contract (GSC) 
Information regarding the GSC is provided in Section 6.1.2. Details will be provided in the 
Study Operational Manual. 
Efficacy measures associated with the GSC are described below. 
7.3.4.1 
Subject Satisfaction 
Subjects will record their satisfaction with the GSC. To assess this, subjects will be asked the 
following question: 
“How satisfied are you TODAY regarding the GSC?” 
Responses will be recorded using a 5-level Likert scale, as follows: 
• 
completely satisfied (+2) 

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• 
rather satisfied (+1) 
• 
neither satisfied nor dissatisfied (0) 
• 
rather dissatisfied (-1) 
• 
completely dissatisfied (-2). 
7.3.4.2 
Changes in the Subject’s and Physiotherapist’s Beliefs 
Subjects and physiotherapists will record whether they believe the GSC will help to improve 
their functional capacity. To assess this, subjects and physiotherapists will be asked the 
following question: 
 for subjects: “Do you believe that GSC will help to improve your arm and leg 
function?”  
 for physiotherapists:  “Do you believe that GSC will help to improve your patient’s 
arm and leg function?”  
Responses will be recorded using a 5-level Likert scale, as follows: 
• 
very true of what I believe (+2) 
• 
somewhat true of what I believe (+1) 
• 
no opinion / don’t know (0) 
• 
somewhat untrue of what I believe (-1) 
• 
very untrue of what I believe (-2). 
Changes in subject and physiotherapist beliefs from baseline to postinjection timepoints will 
be assessed. 
7.3.4.3 
Subject Compliance with the GSC 
As part of the GSC, she subjects will be given a diary at the Baseline Visit. They will be 
asked to record in this diary each day whether they have performed the GSC therapy. At each 
postbaseline FU visit, subjects will bring the GSC diary. The investigator will count the 
number of days when GSC therapy was not performed since the last visit and will record this 
in the eCRF. 
Using the total number of study days and the total number of days when GSC therapy was not 
performed, the number of days when GSC was performed will be calculated. This will be 
used to determine the percentage subject compliance with GSC therapy. 
7.3.5 
Subject Satisfaction regarding Longer Injection Intervals (only for Subjects with 
an Injection Planned at Week 16 or 20 of Each Cycle)  
For subjects who will not be reinjected at Week 12 of a given cycle, subjects will record their 
satisfaction with longer interval between 2 injections collected at the corresponding 
reinjection visit or the last cycle visit (week 16 or week 20 for each cycle). To assess this, 
subjects will be asked the following question: 
“Are you satisfied with a longer interval between 2 injections?” 
• 
Yes  
• 
No  
• 
No opinion 
 

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7.3.6 
Global Assessment of Benefits 
A global assessment of the benefits of the study therapy (i.e. AbobotulinumtoxinA+GSC) will 
be made by the investigator and the subject (or the caregiver). The subject’s caregiver will 
perform the global assessment only in those cases when the subject is not capable to do this. 
To assess the global assessment of benefits, the following question will be asked: 
“How would you rate the overall response to study therapy (AbobotulinumtoxinA plus GSC) 
since baseline?” 
Responses on the global assessment will be recorded using a 5-level Likert scale, as follows: 
• 
much better (+2) 
• 
a bit better (+1) 
• 
the same (0) 
• 
a bit worse (-1) 
• 
much worse (-2). 
7.3.7 
Subject Quality of Life 
7.3.7.1 
European Quality of Life 5 Dimensions (EQ 5D-5L) 
Subjects will be asked to complete the EQ 5D-5L instrument to assess their current health 
status [16, 17]. The EQ 5D-5L is a generic, preference-based measure of health-related 
quality of life. The questions are answered based on how the subject is feeling “today”. 
The EQ 5D-5L instrument consists of two parts: the EQ 5D descriptive system and the EQ 
VAS. The EQ 5D descriptive system includes questions for each of the following five 
dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension has five levels: no problems, slight problems, moderate problems, severe problems 
and extreme problems. The VAS records the subject’s self-rated health on a vertical 20-cm 
VAS where the endpoints are labelled “The best health you can imagine” and “The worst 
health you can imagine”. This measure can be used as a quantitative measure of health, as 
judged by the individual subjects. 
7.3.7.2 
Short-Form 12 (SF-12) 
Subjects will be asked to complete the SF-12 health survey to assess their general health and 
wellbeing [18]. The SF-12 is a short form survey consisting of 12 questions, which are a 
subset of the SF-36 health survey [19, 20]. Most of the questions are answered based on how 
the subject has been feeling over the previous 4 weeks. The SF-12 was updated with 
improvements (Version 2) and this version will be used in this current study [21]. 
The SF-12 covers eight domains, including physical functioning, role-physical, body pain, 
general health, vitality, social functioning, role-emotional and mental health. 

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8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
Adverse events will be monitored from the time that the subject gives informed consent and 
throughout the study (see Section 3.5 for a definition of the study duration) and will be 
elicited by direct, nonleading questioning or by spontaneous reports. Further details for AE 
reporting can be found in Section 8.1.2. 
8.1.1 
Definition of an Adverse Event 
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 be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, electrocardiogram). In clinical 
studies an AE can include an undesirable medical condition occurring at any time, including 
run in or washout periods, even if no IMP has been administered.  
This definition includes events occurring from the time of the subject giving informed consent 
until the end of the study (as defined in Section 3.5). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity 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 well being, significant impairment of 
function or incapacitation. 
8.1.2.2 
Causality Classification 
The relationship of an AE to IMP administration will be classified according to the following: 
• 
Related: reports including good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive dechallenge and/or 
rechallenge) to assume a causal relationship with IMP administration in the sense that it 
is plausible, conceivable or likely. 
• 
Not 
related: 
reports 
including 
good 
reasons 
and 
sufficient 
information 
(e.g. implausible time sequence and/or attributable to concurrent disease or other drugs) 
to rule out a causal relationship with IMP administration. 
8.1.2.3 
Assessment of Expectedness 
The reference document for assessing expectedness of AEs/events in this study will be the IB. 
8.1.2.4 
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 IMP schedule of administration (change in dosage, delay in 
administration, IMP discontinuation); 
• 
they require intervention or a diagnosis evaluation to assess the risk to the subject; 

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• 
they are considered as clinically significant by the investigator. 
8.1.2.5 
Abnormal Physical Examination Findings  
Clinically significant changes, in the judgement of the investigator, in physical examination 
findings (abnormalities) will be recorded as AEs. 
8.1.2.6 
Other Investigation Abnormal Findings 
Abnormal test findings as judged by the investigator as clinically significant (for example, 
vital signs changes) that result in a change in IMP dosage or administration schedule, or in 
discontinuation of the IMP, or require intervention or diagnostic evaluation to assess the risk 
to the subject, should be recorded as AEs.  
8.1.3 
Recording and Follow up of Adverse Events 
At each visit and each phone call, the subject should be asked a non leading question such as: 
“How have you felt since starting the new treatment/the last assessment?” 
All observed or volunteered AEs, regardless of treatment group or suspected causal 
relationship to IMP, will be recorded on the AE page(s) of the eCRF. Events involving drug 
reactions, accidents, illnesses with onset during the treatment phase of the study, or 
exacerbation’s of pre-existing illnesses should be recorded. 
Any AEs already recorded and designated as “continuing” should be reviewed at each 
subsequent assessment. 
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 a serious 
adverse event (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. IMP or other illness). The investigator is required to 
assess causality and record that assessment on the eCRF. Follow up of the AE, after the date 
of IMP discontinuation, is required if the AE or its sequelae persist. Follow up is required 
until the event or its sequelae resolve or stabilise at a level acceptable to the investigator and 
the sponsor’s clinical monitor or his/her designated representative. 
8.1.4 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of treatment group or suspected relationship to IMP 
must be reported immediately (within 24 hours of the investigator’s knowledge of the event) 
to the pharmacovigilance contact specified at the beginning of this protocol. If the immediate 
report is submitted by telephone, this must be followed by detailed written reports using the 
SAE report form. 
A SAE is any AE that: 
(1) 
results in death 
(2) 
is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a 
more severe form, might have caused death 
(3) 
results in in-patient hospitalisation or prolongation of 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 life functions 
(5) 
results in congenital anomaly/birth defect in the offspring of a subject who received the 
IMP 

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(6) 
is an important medical event that may not result in death, be life threatening, or require 
hospitalisation when, based upon appropriate medical judgement, may jeopardise the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 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 in-patient hospitalisation, or the 
development of drug dependency or drug abuse. 
In addition to the above criteria, any additional AE that the sponsor or an investigator 
considers serious should be immediately reported to the sponsor and included in the corporate 
SAEs database system. 
• 
Hospitalisation is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit. 
• 
Prolongation of hospitalisation is defined as any extension of an in-patient 
hospitalisation beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the investigator or treating physician. For 
protocol-specified hospitalisation in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. 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 adverse experience and thus is not subject to immediate 
reporting to the sponsor.  
• 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
screening 
documentation. 
Hospitalisation 
for 
a 
preplanned 
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. 
Any SAE must be reported immediately (within 24 hours), independent of the circumstances 
or suspected cause, if it occurs or comes to the attention of the investigator at any time during 
the study period. 
Any AE/SAE with a suspected causal relationship to IMP administration occurring at any 
other time after completion of the study must be promptly reported. 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
study number 
• 
centre number 
• 
subject number 
• 
AE (including investigator assessment of causality) 
• 
investigator’s name and contact details. 
The additional information included in the SAE form must be provided to the sponsor or 
representative as soon as it is available. The investigator should always provide an assessment 
of causality for each event reported to the sponsor. 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. 

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8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP has 
interfered with a contraceptive method. If pregnancy occurs during the study, the outcome of 
the pregnancy will then need to be collected poststudy and it may be necessary to discontinue 
administration of the IMP.  
Information regarding pregnancies must be collected on the AE page of the eCRF and 
reported to the sponsor within 24 hours. The sponsor will request further information from the 
investigator as to the course and outcome of the pregnancy using the Standard Pregnancy 
Outcome Report Form.  
The investigator must instruct all female subjects to inform them immediately should they 
become pregnant during the 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 conclusion of the pregnancy, which may involve follow up 
after the subject’s involvement in the study has ended. 
Pregnancies with a conception date within 180 days after subject’s last dose of IMP must be 
reported to the investigator for onward reporting to the sponsor. 
 
8.1.6 
Deaths 
All AEs resulting in death during the study period 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:  
• 
AE term: lead cause of death (e.g. multiple organ failure, pneumonia, myocardial 
infarction) 
• 
outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be “death” or “sudden death”. 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal 
due 
to 
AEs 
should 
be 
distinguished 
from 
discontinuation/withdrawal due to other reasons (see Section 4.3). 
If the IMP is discontinued due to a SAE, it must be reported immediately to the sponsor’s 
designated representative (see Section 8.1.4). 
In all cases, the investigator must ensure the subject receives appropriate medical follow up 
(see Section 8.1.3). 
8.1.8 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The sponsor will ensure that processes are in place for submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the CAs, 
IECs and other investigators concerned by the IMP. Reporting will be done in accordance 
with the applicable regulatory requirements. 
For study centres in the USA, Investigational New Drug application Safety Reports will be 
submitted directly to the investigators. It is the investigators’ responsibility to notify their IRB 
in a timely manner. 
8.2 
Physical Examination 
Physical examinations will be performed by a physician at the visits indicated in Table 2.  

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Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. 
A urine pregnancy test will be performed at the Baseline Visit for all female subjects of 
childbearing potential. 
8.3 
Vital Signs 
Blood pressure and heart rate will be recorded after 5 minutes of rest in a supine position at 
the visits indicated in Table 2.  
Body weight will be measured at the visits indicated in Table 2. Height will be measured at 
the Baseline Visit only. 
See Section 8.1.2.6 for abnormal vital signs results that should be recorded as AEs in the 
eCRF. 

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9 
ASSESSMENTS OF PHARMACOKINETICS/PHARMACODYNAMICS 
Pharmacokinetics and pharmacodynamics are not assessed in this study. 

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10 
STATISTICS 
10.1 
Analyses Populations 
The following populations will be used during the statistical analyses: 
• 
Screened population: all subjects screened (i.e. who signed the informed consent). 
• 
Safety population: all subjects who received at least one dose of study medication. 
• 
Intent-to-treat (ITT) population: all subjects who received at least one dose of study 
medication. The ITT population will be identical to the safety population and will be 
denoted throughout as safety/ITT population. 
• 
Modified intent-to-treat (mITT) population: all treated subjects having the primary 
efficacy outcome assessed at Week 6 after the second injection. 
• 
Per protocol (PP) population: all subjects in the mITT population for whom no major 
protocol violations/deviations occurred. 
10.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint will be performed on the mITT 
population. In addition, safety/ITT and PP analyses will be performed as secondary analyses. 
10.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation will be described in the Protocol Deviation Document and its 
impact on inclusion in each analysis population (mITT, safety/ITT and PP populations) for 
any subject will be specified. The final list of protocol deviations impacting all populations 
will be reviewed during the final data review meeting held prior to database lock. 
10.2 
Sample Size Determination 
The sample size was determined based on the primary efficacy endpoint (percentage of 
responder subjects at Week 6 after the second injection according to composite AROM). 
A 60% response rate was assumed based on previous studies (adult UL/LL) with an additional 
benefit of +10% compared with that observed in these studies (approximately 50% response 
rate at Week 4 of Cycle 2). The aim of this study will be to estimate this proportion with an 
accuracy of ±8%. Given a two-sided 95% confidence interval (CI), 145 subjects are required; 
with an assumed 5% dropout rate, 153 subjects will have to be enrolled to achieve a target of 
145 evaluable subjects (i.e. subjects included in the mITT population). These calculations 
have been performed with nQuery using CI for proportions and assuming normal 
approximation. 
10.3 
Significance Testing and Estimations 
As this is a descriptive efficacy study, no formal statistical testing will be performed and all 
the analyses will be primarily descriptive in nature. When appropriate and unless otherwise 
specified, two-sided 95% CIs will be displayed and if p-values are presented, they will be for 
exploratory purposes only. 
Descriptive statistics will include number of measures (n), n missing and the following: 
• 
mean, standard deviation, minimum, median, maximum and 95% CIs for means for 
interval-type variables 
• 
counts and percentages of each category for categorical nominal variables 
• 
both the above for categorical ordinal variables. 

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10.4 
Statistical/Analytical Methods 
The statistical analyses will be performed by an external CRO, managed by the sponsor’s 
Biometry Department. 
A statistical analysis plan (SAP) describing the planned statistical analysis in detail with 
tables, figures and listings templates will be developed as a separate document. 
Statistical evaluation will be performed using Statistical Analysis System (SAS)® (Version 9 
or higher). 
10.4.1 
Demographic and Other Baseline Characteristics 
All demographic and baseline characteristics will be listed for the safety/ITT population. 
Descriptive summary statistics for demographic and baseline characteristics will be presented 
for the mITT population. If the safety/ITT population differs from the mITT population by 
more than 10%, summary statistics for demographic and baseline characteristics will also be 
presented for the safety/ITT population. 
10.4.2 
Homogeneity of Treatment Groups 
Not applicable as this is a single treatment arm study. 
10.4.3 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in each of the mITT, 
safety/ITT and PP populations will be tabulated by country and centre. The reasons for 
subject exclusions from each of the populations will also be tabulated. In addition, the 
numbers of subjects who were treated, discontinued and completed the study treatment will be 
tabulated for each population. Primary reasons for discontinuation of study treatment will be 
tabulated. 
10.4.4 
Pharmacokinetic Data 
There are no PK analyses planned for this study. 
10.4.5 
Efficacy Evaluation 
10.4.5.1 Primary Efficacy Endpoint 
As indicated in Section 7.1, the primary efficacy endpoint is as follows: 
• 
the percentage of responder subjects at Week 6 after the second injection, according to 
composite AROM in the primary TT limb. 
Composite AROM (XA), regardless of whether the muscle groups were injected or not, as 
measured by goniometer in the primary TT limb (either UL or LL, depending on which one 
has been selected as the primary TT limb), will be calculated as follows: 
- 
composite XA UL: XA UL = XAEF  + XAWF + XAFF 
- 
composite XA LL: XA LL = XAsol + XAGN 
where for UL: EF=elbow flexors, WF=wrist flexors and FF=extrinsic finger flexors,  
and for LL: Sol=soleus and GN=gastrocnemius muscles. 
Definition of a responder: a subject will be considered a responder if he/she achieves at least 
the predefined improvement threshold - larger or equal to 35° in UL or 5° in LL - in the 
primary TT limb (based on the composite AROM individual change from baseline to Week 6 
after the second injection). 

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Primary Efficacy Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint will be summarized descriptively as a binary variable using the 
mITT population. 
Secondary Efficacy Analysis of the Primary Efficacy Endpoint 
The following analyses will be conducted in support of the primary efficacy analysis. 
The primary efficacy analysis will be repeated using the safety/ITT population where subjects 
with missing responder status at Week 6 after the second injection will have their last 
postbaseline responder status used instead. Subjects with no postbaseline responder status are 
considered nonresponders. 
Additionally, the primary efficacy analysis will be repeated based on the PP population. 
Exploratory Analysis of the Primary Efficacy Endpoint 
The odds ratio for the primary efficacy endpoint and its associated two-sided 95% CI will be 
estimated from a logistic regression model with primary TT and country as fixed factors and 
composite AROM value at baseline as covariate. Further details will be provided in the SAP. 
10.4.5.2 Secondary Efficacy Endpoints 
As discussed in Section 7.2, the secondary efficacy variables are as follows: 
• 
the percentage of responder subjects at Week 6 after the first injection, according to 
composite AROM in the primary TT limb 
• 
AROM against 10 prespecified muscle groups, 5 in upper and 5 in lower limbs: mean 
change from baseline at Week 6, Week 12 and re-injection/last cycle visits only 
• 
composite AROM against injected muscle groups (any of the 10 prespecified), in upper 
and lower limbs: mean change from baseline at Week 6, Week 12 and re-injection/last 
cycle visits only 
• 
full composite AROM against five UL muscle groups (XA full UL = XASE + XAEF + 
XAWF + XAFF + XAPT) or full composite AROM against five LL muscle groups (XA full 
LL = XAsol + XAGN + XAGM + XAHS + XARF), regardless of whether the muscle groups 
were injected or not: mean change from baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
where for UL: SE=shoulder extensors, EF=elbow flexors, WF=wrist flexors, 
FF=extrinsic finger flexors and PT=pronator teres,  
and for LL: Sol=soleus, GN=gastrocnemius muscles, GM=gluteus maximus, 
HS=hamstrings and RF=rectus femoris 
• 
active UL function measured using MFS: mean change from baseline in MFS overall 
score (i.e. mean score over the 10 tasks assessed locally and centrally by a reviewer 
blinded regarding the date of video recording/visit number) at Week 12 after each 
injection cycle 
• 
active LL function measured using maximal WS barefoot without walking aids or, if 
absolutely necessary with a cane, measured on a 10-metre WST: mean change from 
baseline at Week 12 after each injection cycle. (If a cane is used at the Baseline Visit, 
the same cane is to be used during all WS assessments.) 
• 
subject satisfaction with the GSC: at baseline (only for patients who had GSC 
performed previously), Week 6, Week 12 and re-injection/last cycle visits only 
• 
changes in subject’s beliefs that the GSC will help to improve functional capacity: 
change from baseline to Week 6, Week 12 and re-injection/last cycle visits only 

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• 
changes in Physiotherapist’s belief that the GSC will help to improve functional 
capacity: change from baseline to Week 6, Week 12 and re-injection/last cycle visits 
only 
• 
subject compliance with the GSC: percentage of days over study period when GSC 
therapy was performed (as determined from the subject diary) 
• 
global assessment of benefits, evaluated by both the investigator and the subject (or 
caregiver): at the end of each cycle  
• 
in subjects with an injection planned at Week 16 or 20 of each cycle satisfaction with 
longer interval collected at the corresponding reinjection visit or the last cycle visit.  
• 
quality of life changes, measured on the EQ-5D 5L and SF-12 scales: change from 
baseline to Final Visit. 
Analysis of the Secondary Efficacy Endpoints 
The secondary efficacy endpoints will be summarised descriptively at each relevant visit 
using the safety/ITT population. Unless otherwise specified, missing values will not be 
imputed. 
Additionally, adjusted mean change from baseline in AROM variables at each relevant 
postbaseline timepoint and associated two-sided 95% CIs will be estimated from an analysis 
of covariance (ANCOVA) model with primary TT and country as fixed effects and the 
appropriate baseline AROM value as covariate. Active UL and LL functions and quality of 
life questionnaires will be summarised in a similar way as AROM variables. 
Percentage of responder subjects at Week 6 after the first injection, according to composite 
AROM in the primary TT limb, will be analysed in a similar way as for the primary efficacy 
endpoint. 
Using the total number of study days and the total number of days when GSC therapy was not 
performed (as recorded in the eCRF from the subject diary), the number of days when GSC 
was performed will be calculated. This percentage of days over the study period when GSC 
therapy was performed will be calculated by subject and summarized descriptively as a 
categorical ordinal variable. 
10.4.6 
Adjustment for Country/Centre Effect 
Descriptive analysis of the primary efficacy endpoint will be performed by country. 
10.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings using the safety population. 
Analyses and summary tables will be based on the safety population. 
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be classified by MedDRA preferred term and system organ class. 
Adverse event listings will be presented by subject, system organ class and preferred term. 
The incidence of all reported AEs, TEAEs and SAEs will be tabulated separately. In addition, 
summary tables for TEAEs will be presented by maximum intensity, drug relationship and 
TEAEs associated with premature withdrawal of study medication. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the first dose of IMP, or  
• 
it was present prior to receiving the first dose of IMP but the intensity increased during 
the active phase of the study. 
All TEAEs will be flagged in the AE listings. 

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Concomitant medication will be coded using the World Health Organization Drug Dictionary 
(WHODRUG) and will be summarised with the number and percentage of subjects receiving 
concomitant medication by drug class and preferred drug name. 
Summary statistics (mean, median, standard deviation, and range, as appropriate) will be 
presented for vital signs (blood pressure and heart rate, weight) at each assessment with 
change from baseline. 
10.5 
Subgroup Analyses 
Descriptive statistics for the primary efficacy endpoint will be provided within each category 
of the following variables: race, ethnicity, sex, age (<65 years, ≥65 years), primary TT (UL, 
LL), naïve or non-naïve to BoNT treatment, and naïve or non-naïve to GSC. Additional 
subgroup analyses may be planned in the SAP according to clinical interest. 
10.6 
Interim Analyses 
It is planned to perform an interim analysis in order to describe baseline data and more 
specifically injection details, for example, dose per limb/injected muscles; this baseline data 
interim analysis is planned after subject enrolment has been completed. 

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11 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
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 12.4 and to any other locations used for the purpose of the study in 
question (for example, laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 

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12 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Protocol Amendments and Protocol Deviations and Violations 
12.1.1 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior 
written approval or favourable opinion of a written amendment by the IEC/IRB, except when 
necessary to eliminate immediate safety concerns to the subjects or when the change involves 
only logistics or administration. The principal investigator and the sponsor will sign the 
protocol amendment. 
12.1.2 
Protocol Deviations, Violations and Exceptions 
A protocol deviation is nonadherence to protocol specific study procedures or schedules that 
does not involve inclusion/exclusion criteria, primary objective evaluation criteria and/or GCP 
guidelines. Deviations are considered minor and do not impact the study. 
A protocol violation is any significant divergence from the protocol, i.e. nonadherence on the 
part of the subject, the investigator, or the sponsor to protocol specific inclusion/exclusion 
criteria, primary objective evaluation criteria and/or GCP guidelines. Protocol violations will 
be identified and recorded, by study centre personnel, on the eCRF. 
As a matter of policy, the sponsor will not grant exceptions to protocol specific entry criteria 
to allow subjects to enter a study. If under extraordinary circumstances such action is 
considered ethically, medically and scientifically justified for a particular subject, prior 
approval from the sponsor and the responsible IRB/IEC, in accordance with the standard 
operating procedure (SOP), is required before the subject will be allowed to enter the study. If 
investigative centre personnel learn that a subject who did not meet protocol eligibility criteria 
was entered in a study (a protocol violation), they must immediately inform the sponsor. Such 
subjects will be discontinued from the study, except in an exceptional instance following 
review and written approval by the sponsor and the responsible IRB/IEC, according to the 
applicable SOP. 
12.2 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of subject management, both before starting any study 
procedures and during the course of the study (for example, when new staff become 
involved). The investigator must assure that all study staff members are qualified by 
education, experience and training to perform their specific responsibilities. These study staff 
members must be listed on the study centre authorisation form, which includes a clear 
description of each staff member’s responsibilities. This list must be updated throughout the 
study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
12.3 
Study Monitoring 
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. 

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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 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the eCRFs according to the sponsor monitoring manual, of the 
subject’s visit and on an ongoing basis to allow regular review by the study monitor, both 
remotely by the internet and during site visits. The central study monitor at the sponsor 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 (for example, 
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 identification. 
12.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 11). 
12.5 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility 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. 

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13 
ETHICS 
13.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, 
the Declaration of Helsinki and ICH GCP Guidelines, FDA, 21 CFR Part 11, Electronic 
Records, Electronic Signatures and FDA Guidance, Industry Computerized Systems Used in 
Clinical Trials (Section 1.5). 
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the investigator/institution should have written and dated 
approval/favourable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent form, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (for example, 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. 
13.2 
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, subject’s 
legally acceptable representative or impartial witness. Written informed consent must be 
obtained prior to the subject entering the study (before initiation of any study-related 
procedure and administration of the IMP). Sufficient time will be allowed to discuss any 
questions raised by the subject. 
The sponsor will provide a sample informed consent form. 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 language readily understood by the subject. Each subject’s original 
consent form, personally signed and dated by the subject or by the subject’s legally acceptable 
representative and by the person who conducted the informed consent discussion, will be 
retained by the investigator. The investigator will supply subjects with a copy of their signed 
informed consent. 
The consent form may need to be revised during the study should important new information 
become available that may be relevant to the safety of the subject 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 subjects subsequently entered into the study and 
those currently in the study sign the amended form. This is documented in the same way as 
previously described. Subjects who have completed the study should be informed of any new 
information that may impact on their welfare/wellbeing. 
The investigator should, with the consent of the subject, inform the subject’s primary 
physician about their participation in the clinical study. 

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13.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
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, prior 
to study initiation in regions where an approval is required. 
13.4 
Confidentiality Regarding Study Subjects 
The investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, subjects will be identified not by their 
names, but by an identification code (for example, initials and identification number). 
Personal medical information may be reviewed for the purpose of verifying data recorded on 
the eCRF. This review may be conducted by the study monitor, properly authorised persons 
on behalf of the sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 

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14 
DATA HANDLING AND RECORD KEEPING 
14.1 
Data Recording of Study Data 
In compliance with GCP, the medical records/medical notes, etc., should be clearly marked 
and permit easy identification of a subject’s participation in the specified clinical study. 
The investigator must record all data relating to protocol procedures, IMP administration, 
laboratory data, safety data and efficacy ratings on the eCRFs provided for the study. The 
investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff having certified user access to the eCRF. Subject 
completed diaries and questionnaires will be printed or electronic. 
The investigator must, as a minimum, provide an electronic signature (e-signature) to each 
case report book to attest to the accuracy and completeness of all the data. If any changes are 
made to the eCRF, after a form has been locked and electronically signed, the investigator 
will be required to perform an additional e-signature authorising agreement with any new 
information or changes to the eCRF. 
All corrections on the eCRF will be automatically tracked and a reason for change is always 
required. In the eCRF, the audit trail function will allow the changes made to be viewed on 
each item entered. 
14.2 
Data Management 
Electronic data capture (EDC) 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 electronic signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of the handwritten signature. 
Only sponsor authorised users will have access to the eCRF as appropriate to their study 
responsibilities. Users must have successfully undergone software application training prior to 
entering data into the eCRF. 
Data management will be conducted by a CRO, directed by the sponsor’s data management 
department. All data management procedures will be completed in accordance with the sponsor 
and the contracted CRO SOPs. Prior to data being received in-house at the assigned CRO, it will 
be monitored at the investigator site, (for further details please see Section 12.3 Monitoring 
Procedures). The eCRF and other data documentation removed from the investigator site(s) will 
be tracked by the CRO and the monitor. 
The sponsor will ensure that an appropriate eCRF is developed to capture the data accurately 
and suitable queries are raised to resolve any missing or inconsistent data. The investigator 
will receive their data, from the clinical study, in an electronic format (PDF files) which will 
be an exact copy of the eCRF and will include the full audit trail, for archiving purposes and 
future reference. 
Any queries generated during the data management process will also be tracked by the 
contracted data management CRO/will be raised within the EDC system. It is the central 
study 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 
a CRO, directed by the sponsor’s Biometry Group and reviewed and approved by the sponsor. 

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Concomitant medications will be coded using the WHODRUG and AEs/medical history 
terms will be coded using the MedDRA. 
14.3 
Record Archiving and Retention 
During the prestudy and initiation visits, the monitor must ensure the archiving facilities are 
adequate and archiving/retention responsibilities of the investigator have been discussed.  
Study documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or planned marketing applications 
in an ICH region (that is at least 15 years) or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the product. However, these documents should be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. The investigator should take measures to prevent accidental or 
premature destruction of these documents. The final archiving arrangements will be confirmed 
by the monitor when closing out the site. The sponsor will inform the investigator, in writing, 
as to when these documents no longer need to be retained. 
If the principal investigator relocates or retires, or otherwise withdraws his/her responsibility 
for maintenance and retention of study documents, the sponsor must be notified (preferably in 
writing) so that adequate provision can be made for their future maintenance and retention. 

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15 
FINANCING AND INSURANCE 
15.1 
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 need to be completed, as requested by FDA 21 CFR 
Part 54. 
15.2 
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. 

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16 
REPORTING AND PUBLICATIONS OF RESULTS 
16.1 
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 trial 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 trial agreement concerned, (ii) the sponsor consents to the 
publication, or (iii) the time period as may be agreed in the contractual arrangements, 
including clinical trial 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. 
16.2 
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 subject has signed 
informed consent, 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. 

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17 
REFERENCES 
1. 
Bakheit AMO. Botulinum toxin treatment of muscle spasticity. Milton Keynes, UK: 
AuthorHouse™ UK Ltd.; 2007. 
2. 
Gracies JM. Pathophysiology of spastic paresis. II. Emergence of muscle overactivity. 
Muscle Nerve 2005;31(5):552-71. 
3. 
Simpson DM. Treatment of spasticity with botulinum toxin. Muscle Nerve 
2000;23:447-9. 
4. 
Mackay JMG. The Atlas of Heart Disease and Stroke. Geneva, Switzerland: World 
Health Organization; 2004. 
5. 
Zorowitz RD, Gillard PJ, Brainin M. Poststroke spasticity: sequelae and burden on 
stroke survivors and caregivers. Neurology 2013;80(3 Suppl 2):S45-52. 
6. 
Gracies JM. Pathophysiology of spastic paresis. I. Paresis and soft tissue changes. 
Muscle Nerve 2005;31(5):535-51. 
7. 
Dashtipour K, Chen JJ, Walker HW, Lee MY. Systematic literature review of 
abobotulinumtoxinA in clinical trials for adult upper limb spasticity. Am J Phys Med 
Rehabil 2015;94(3):229-38. 
8. 
Ipsen. Investigator’s Brochure: Dysport therapeutic indications. Version 13.0 
(including Addendum 1). 02 February 2016. 
9. 
Gracies JM, Brashear A, Jech R, et al. Safety and efficacy of abobotulinumtoxinA for 
hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a 
double-blind randomised controlled trial. Lancet Neurol 2015;14(10):992-1001. 
10. 
Hesse S, Mach H, Fröhlich S, et al. An early botulinum toxin A treatment in subacute 
stroke patients may prevent a disabling finger flexor stiffness six months later: a 
randomized controlled trial. Clin Rehabil 2012; 26(3):237-45. 
11. 
Rosales RL, Kong KH, Goh KJ, et al. Botulinum toxin injection for hypertonicity of 
the upper extremity within 12 weeks after stroke: a randomized controlled trial. 
Neurorehabil Neural Repair 2012;26(7):812-21. 
12. 
Gracies JM. Guided self-rehabilitation contract in spastic paresis. Switzerland: Springer 
International Publishing, 2016:118p. (eBook) 
13. 
Ipsen. Dysport 300 units, Dysport 500 units. Summary of product characteristics. 
31 January 2016. 
14. 
Gracies JM, Hefter H, Simpson D, et al. Botulinum toxin in spasticity. In: Moore P, 
Naumann M, editors. Handbook of botulinum toxin. Oxford, UK: Blackwell Science; 
2002:221–74. 
15. 
Salbach NM, Mayo NE, Higgins J, et al. Responsiveness and predictability of gait 
speed and other disability measures in acute stroke. Arch Phys Med Rehabil 
2001;82;1204-12. 
16. 
EuroQol Group. EuroQol – a new facility for the measurement of health-related quality 
of life. Health Policy 1990;16(3):199-208. 
17. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-36. 
18. 
Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction 
of scales and preliminary tests of reliability and validity. Med Care 1996;34(3):220-33. 

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19. 
Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care 1992;30(6):473-83. 
20. 
Ware JE, Snow KK, Kosinski M, et al. SF-36® Health Survey Manual and 
Interpretation Guide. Boston, USA: The Health Institute; 1993. 
21. 
Ware JE Jr, Kosinski M, Turner-Bowker DM, et al. How to score Version 2 of the 
SF-12® health survey (with a supplement documenting version 1). Lincoln, USA: 
QualityMetric Incorporated; 2002. 

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18 
LIST OF APPENDICES 
 
Appendix 1 Amendment Form #1 ............................................................................ 82 
Appendix 2 Amendment Form #2 .......................................................................... 101 
 

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Appendix 1 Amendment Form #1 
 

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STUDY NUMBER: 
F-FR-52120-228 
PROTOCOL TITLE: 
An International, Multicentre, Prospective, 
Single-Arm Study to Assess the Effect on 
Voluntary Movements of AbobotulinumtoxinA 
1500 U Administered in Both Upper and Lower 
Limbs in Conjunction with a Guided 
Self-Rehabilitation Contract in Adult Subjects 
with Spastic Hemiparesis 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Final Version (including Amendment #1): 
02 December 2016 
 
 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
30 JUNE 2016 
02 DECEMBER 2016 
Page  
Section 
WAS 
IS 
1 
Cover page 
 
 
, 
QPPV, 
Global 
Patient 
Safety, 
Ipsen 
Group, 
190 Bath Road, Slough, Berkshire 
SL1 3XE, England 
 
 
 
 
 QPPV, Global Patient Safety, 
Ipsen Group, 
102 
Park 
Drive, 
Milton 
Park, 
Abingdon, Oxfordshire OX14 4RY, 
England 
 
5 
 
Synopsis: 
Secondary 
Objective 
 
AROM against each injected 
muscle group of each limb  
 
composite AROM against 
injected muscle groups of 
each limb 
 
AROM against 10 prespecified  
muscle groups: 5 in upper and 5 in 
lower limbs 
 
composite AROM against injected 
muscle groups (any of the 10 
prespecified) of each limb  
5 
 
Synopsis: 
Secondary 
Objective 
 
to measure the changes in 
subject beliefs that a GSC 
will help to improve function 
 
to measure the changes in subject 
and physiotherapist beliefs that a 
GSC will help to improve function 
6 
 
Synopsis: 
Secondary 
Objective 
 
 
in subjects not reinjected at Week 
12, to assess satisfaction with 
longer than 12 weeks interval 
between 2 injections 
6 
 
Synopsis: 
Methodology 
 
electrical stimulation will be 
used to target the injection 
sites; 
 
 
electrical stimulation (ES) will be 
used to target the injection sites; 
Ultrasound guiding could be used 
in addition to ES in case this 
technique is used in routine 
clinical practice; 
PPD
PPD

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7 
Synopsis: 
Diagnosis 
and 
criteria 
for inclusion  
Inclusion criteria: 
 
2) Subjects with hemiparesis due 
to ABI (…) 
Inclusion criteria: 
 
2) Subjects with hemiparesis due to ABI 
(i.e. stroke or traumatic brain injury 
(TBI)) (…) 
8 
Synopsis: 
Diagnosis 
and criteria 
for inclusion  
Exclusion criteria: 
 
 
 
 
 
13) Anticoagulant treatment with 
international normalised ratio 
(INR) >3.5 within a week prior to 
injection. 
 
Exclusion criteria: 
5) Subjects treated, or likely to be 
treated, with intrathecal baclofen 
during the course of the study or 
during the 4 weeks before study entry. 
(…) 
 
Deleted 
 
 
 
 
9 
Synopsis: 
Criteria for 
evaluation 
efficacy 
Subject satisfaction with the GSC 
will be assessed using a likert 
scale at all postinjection FU visits. 
Changes in the subject’s beliefs 
that the GSC will help (…). A 
global assessment of benefits will 
be made by both the investigator 
and subject (or caregiver) at the 
end of both injection cycles using 
a Likert scale.  
 
 
Subject satisfaction with the GSC will 
be assessed using a likert scale at all 
postinjection FU visits but also at 
baseline for patients who had any 
GSC done previously. Changes in the 
subject’s and physiotherapist’s beliefs 
that the GSC will help (…). A global 
assessment of benefits will be made by 
both the investigator and subject (or 
caregiver) at the end of both injection 
cycles using a Likert scale. For the 
subjects who will have an injection 
planned at either Visit 4 or Visit 5 for 
the first cycle and Visit 8 or Visit 9 for 
the second cycle (i.e. Week 16 or 20 of 
each cycle) satisfaction with longer 
treatment interval will be collected at 
the corresponding reinjection visit or 
at the last cycle visit. 
10 
Synopsis: 
Criteria for 
evaluation 
Safety 
Safety will be assessed by 
recording the number, nature and 
severity of AEs from the time that 
the subject gives informed 
consent to the end of study. 
Safety will be assessed by recording the 
number, nature and severity of AEs from 
the time that the subject gives informed 
consent to the end of study or subject 
withdrawal. 

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10 
 
Synopsis: 
Statistical 
method 
Secondary 
Endpoints 
and 
Evaluations 
 
AROM against each injected 
muscle group, in upper of 
lower limbs ; mean change 
from baseline at Week 6, 
Week 12 and re-injection/last 
cycle visits only 
 
composite 
AROM 
against 
injected muscle groups in 
upper and lower limbs; mean 
change 
from 
baseline 
at 
Week 6, 
Week 12 
and 
re-injection/last cycle visits 
only 
 AROM against 10 prespecified  
muscle groups, 5 in upper and 5 in 
lower limbs: mean change from 
baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 composite AROM against injected 
muscle groups (any of the 10 
prespecified) in upper and lower 
limbs: mean change from baseline at 
Week 6, Week 12 and 
re-injection/last cycle visits only 

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11 
Synopsis: 
Statistical 
Method 
 
subject satisfaction with the 
GSC: Week 6, Week 12 and 
re-injection/last cycle visits 
only 
 
 
changes in subject’s belief 
that the GSC will help to 
improve functional capacity: 
change 
from 
baseline 
to 
Week 6, Week 12 and re 
injection/last cycle visits only 
 
 
 
 
 
 
 
 
 
 
subject compliance with the 
GSC: percentage of days over 
study 
period 
when 
GSC 
therapy was performed (as 
determined from the subject 
diary) 
 
global assessment of benefits, 
evaluated 
by 
both 
the 
investigator and the subject 
(or caregiver): at the end of 
each cycle  
 
subject satisfaction with the GSC: at 
baseline (only for patients who 
had GSC performed previously), 
Week 6, 
Week 12 
and 
re-injection/last cycle visits only 
 
changes in subject’s belief that the 
GSC will help to improve functional 
capacity: change from baseline to 
Week 
6, 
Week 
12 
and 
re 
injection/last cycle visits only 
 
changes in Physiotherapist’s belief 
that the GSC will help to improve 
functional capacity: change from 
baseline to Week 6, Week 12 and 
re-injection/last cycle visits only 
 
in subjects with an injection 
planned at Week 16 or 20 of each 
cycle: satisfaction with longer 
interval 
between 
2 
injections 
collected at the corresponding 
reinjection visit or the last cycle 
visit 
 
subject compliance with the GSC: 
percentage of days over study 
period when GSC therapy was 
performed (as determined from the 
subject diary)  
 
 
global 
assessment 
of 
benefits, 
evaluated by both the investigator 
and the subject (or caregiver): at the 
end of each cycle  
 
in subjects with an injection 
planned at Week 16 or 20 of each 
cycle: satisfaction with longer 
interval 
between 
2 
injections 
collected at the corresponding 
reinjection visit or the last cycle 
visit 
18 
Abbreviation 
 
ES  
Electrostimulation 
TBI  
Traumatic Brain Injury 
25 
Section 2.2 
 
AROM against each injected 
muscle group of each limb  
 
composite AROM against 
injected muscle groups of each 
limb 
 
AROM against 10 prespecified  
muscle groups: 5 in upper and 5 
in lower limbs 
 
composite AROM against injected 
muscle groups (any of the 10 
prespecified) of each limb  

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25 
 
Section 2.2 
 
to measure the changes in 
subject beliefs that a GSC 
will help to improve function 
 
to measure the changes in subject 
and physiotherapist beliefs that a 
GSC will help to improve function 
25 
 
Section 2.2 
 
 
in subjects not reinjected at Week 
12, to assess satisfaction with 
longer than 12 weeks interval 
between 2 injections 
26 
Section 3.1 
 
electrical stimulation will be 
used to target the injection 
sites; 
 
electrical stimulation (ES) will be 
used to target the injection sites; 
Ultrasound guiding could be used 
in addition to ES in case this 
technique is used in routine 
clinical practice; 
 
(…) 
 
List of recommended UL and LL 
muscles and Dysport dose per 
muscle is provided in Sections 
6.1.1.1 and 6.1.1.2. 
29 
Section 3.2.2 
 
AROM against each injected 
muscle group of each limb ; 
mean change from baseline at 
Week 6, Week 12 and 
re-injection/last cycle visits 
only 
 
composite AROM against 
injected muscle groups of 
each limb ; mean change from 
baseline at Week 6, Week 12 
and re-injection/last cycle 
visits only 
 
AROM against 10 prespecified  
muscle groups, 5 in upper and 5 
in lower limbs: mean change from 
baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
composite AROM against injected 
muscle groups (any of the 10 
prespecified) in upper and lower 
limbs: mean change from baseline 
at Week 6, Week 12 and 
re-injection/last cycle visits only 

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29-30 
Section 3.2.2 
 
subject satisfaction with the 
GSC: Week 6, Week 12 and 
re-injection/last cycle visits 
only 
 
changes in subject’s belief 
that the GSC will help to 
improve functional capacity: 
change from baseline to 
Week 6, Week 12 and re 
injection/last cycle visits only 
 
 
 
 
 
subject compliance with the 
GSC: percentage of days over 
study period when GSC 
therapy was performed (as 
determined from the subject 
diary) 
 
global assessment of benefits, 
evaluated by both the 
investigator and the subject 
(or caregiver): at the end of 
each cycle 
 
subject satisfaction with the GCS: at 
baseline (only for patients who 
had GSC performed previously), 
Week 6, Week 12 and 
re-injection/last cycle visits only 
 
changes in subject’s belief that the 
GSC will help to improve functional 
capacity: change from baseline to 
Week 6, Week 12 and re 
injection/last cycle visits only 
 
changes in Physiotherapist’s belief 
that the GSC will help to improve 
functional capacity: change from 
baseline to Week 6, Week 12 and 
re-injection/last cycle visits only 
 
subject compliance with the GSC: 
percentage of days over study 
period when GSC therapy was 
performed (as determined from the 
subject diary) 
 
 
global assessment of benefits, 
evaluated by both the investigator 
and the subject (or caregiver): at the 
end of each cycle 
 
in subjects with an injection 
planned at Week 16 or 20 of each 
cycle: satisfaction with longer 
interval between 2 injections 
collected at the corresponding 
reinjection visit or the last cycle 
visit 
30 
Section 3.2.3 
Safety will be assessed by 
recording the number, nature and 
severity of AEs from the time that 
the subject gives informed 
consent to the end of study. 
Safety will be assessed by recording the 
number, nature and severity of AEs from 
the time that the subject gives informed 
consent to the end of study or subject 
withdrawal. 
34 
Section 4.1 
(2) Subjects with hemiparesis due 
to ABI 
(2) Subjects with hemiparesis due to 
ABI (i.e. stroke or Traumatic Brain 
Injury (TBI))  

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35 
Section 4.2 
Exclusion criteria: 
 
 
 
 
 
13) Anticoagulant treatment with 
international normalised ratio 
(INR) >3.5 within a week prior to 
injection. 
Exclusion criteria: 
5) Subjects treated, or likely to be 
treated, with intrathecal baclofen 
during the course of the study or 
during the 4 weeks before study entry. 
(…) 
 
Deleted 
 
 
 
37-39 
Section 5.1 
 
Table 1 
W x 
 
Previous BoNT-A injection(s)[j] 
 
Subject satisfaction with GSC 
measured at W6, W12, w16 and 
W20 for Cycle 1 
 
 
 
 
 
 
 
 
Table Footnotes: 
i Record all details of previous 
GSC or physiotherapy 
j Record if subject is naïve or non 
naïve to BoNT-A treatment; if 
non naïve to BoNT-A treatment, 
record dates of the first injection 
and last injection, which limbs 
were injected, and BoNT-A brand 
and dose used in the last injection. 
(…) 
t To be performed only at the last 
postinjection FU visit after 
Injection 1 (which may be 
Week 12, Week 16 or Week 20). 
(…) 
 
 
Table 1 
W x ± 7 days for all visits, except W12 
+ 7 days 
Previous BoNT injection(s)[j] 
 
Subject satisfaction with GSC measured 
at Baseline, W6, W12, w16 and W20 
for Cycle 1 
 
Subject satisfaction with longer 
interval between 2 injections measured 
at W16 and W20 for both cycles 
 
Physiotherapist beliefs that GSC will 
help to improve functional capacity 
measured at all visits 
 
Table Footnotes: 
i Record all details of previous GSC or 
physiotherapy within 4 months before 
Baseline 
j Record if subject is naïve or non naïve 
to BoNT treatment; if non naïve to 
BoNT treatment, record dates of the first 
injection and last injection, which limbs 
were injected, and BoNT brand and dose 
used in the last injection. 
(…) 
t To be performed only at the last 
postinjection FU visit after Injection 1 
(i.e. the visit where second injection is 
performed, which may be Week 12, 
Week 16 or Week 20). 
(…) 
v Only for subjects who had GSC 
previously. 

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41 
Section 
5.2.1.1 
• previous GSC or physiotherapy 
history  
 
 
• if subject is non-naïve to BoNT-
A treatment: dates of the first 
injection and last injection, 
which limbs were injected, and 
BoNT-A brand and dose used in 
the last injection 
• (…) 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• Subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
• previous 
GSC 
or 
physiotherapy 
history (within 4 months prior to 
baseline) 
• subject satisfaction on previous 
GSC (if applicable) 
• if subject is non-naïve to BoNT 
treatment: dates of the first injection 
and last injection, which limbs were 
injected, and BoNT brand and dose 
used in the last injection 
 
• (…) 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• Subject and Physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
42 
Section 
5.2.1.2 
5.2.1.2 Week 6  
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.1.2 Week 6 (±7 days) 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
42 
Section 
5.2.1.3 
5.2.1.3 Week 12  
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.1.3 Week 12 (+7 days) 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 

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43 
Section 
5.2.1.4 
5.2.1.4 Week 16 (…) 
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.1.4 Week 16 (±7 days) (…) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
(…) 
• in subjects with an injection 
planned at Week 16 or 20 of each 
cycle:  subject satisfaction with 
longer interval between 2 injections 
collected at the corresponding 
reinjection visit or the last cycle visit 
44 
Section 
5.2.1.5 
5.2.1.5 Week 20 (…) 
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.1.5 Week 20 (±7 days) (…) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
(…) 
• in subjects with an injection 
planned at Week 16 or 20 of each 
cycle:  subject satisfaction with 
longer interval between 2 injections 
collected at the corresponding 
reinjection visit or the last cycle visit 

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45 
Section 
5.2.2.1 
5.2.2.1 Week 6  
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• Subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.2.1 Week 6 (±7 days) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
45 
Section 
5.2.2.2 
5.2.2.2 Week 12  
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.2.2 Week 12 (+7 days) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• (…) 
• subject and physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
46 
Section 
5.2.2.3 
5.2.2.3 Week 16 (…) 
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• Subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.2.3 Week 16 (±7 days) (…) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
(…) 
• in subjects with an injection 
planned at Week 16 or 20 of each 
cycle:  subject satisfaction with 
longer interval between 2 injections 
collected at the corresponding 
reinjection visit or the last cycle visit 

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47 
Section 
5.2.2.4 
5.2.2.4 Week 20 (…) 
 
• measurement of AROM against 
each muscle group of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of 
satisfaction with GSC 
• subject completion of Likert 
scale to assess beliefs that GSC 
will help to improve functional 
capacity 
5.2.2.4 Week 20 (±7 days) (…) 
 
• measurement of AROM against 10 
prespecified muscle groups of the UL 
and LL (irrespective of whether 
injected or not) 
• subject assessment of satisfaction 
with GSC 
• subject 
and 
physiotherapist 
completion of Likert scale to assess 
beliefs that GSC will help to improve 
functional capacity 
(…) 
• in subjects with an injection 
planned at Week 16 or 20 of each 
cycle:  subject satisfaction with 
longer interval between 2 injections 
collected at the corresponding 
reinjection visit or the last cycle visit 
48 
Section 6.1 
 
Note: 
For 
subjects 
receiving 
antivitamin 
K 
therapy 
the 
Investigator will have to ensure that 
the International Normalised Ratio 
(INR) is below 3.5 within 1 week prior 
to study treatment administration. 
Subjects currently receiving oral anti-
spasticity medications (e.g. Baclofen) 
may be included provided the dose 
will be kept constant during the study. 
49 
Section 6.1.1 
 
List of recommended muscles to be 
injected based on subject needs is 
presented in Section 6.1.1.1 for upper 
limb and Section 6.1.1.2 for lower 
limbs. Any muscle injected will be 
recorded in the eCRF. 

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49 
Section 6.1.1 
 
6.1.1.1 List of muscles recommended 
to be injected and Dysport Dosing by 
Muscle for Upper Limb Spasticity  
MUSCLES 
DOSES 
Flexor carpi radialis 
(FCR)  
100 – 200 U 
Flexor carpi ulnaris 
(FCU)  
100 – 200 U 
Flexor digitorum 
profundus (FDP)  
100 – 200 U 
Flexor digitorum 
superficialis (FDS)  
100 – 200 U 
Flexor Pollicis Longus  100 – 200 U 
Adductor Pollicis  
25 – 50 U 
Brachialis  
200 – 400 U 
Brachioradialis  
100 – 200 U 
Biceps Brachii (BB)  
200 – 400 U 
Pronator Teres  
100 – 200 U 
Triceps Brachii (long 
head)  
150 – 300 U 
Pectoralis Major  
150 – 300 U 
Subscapularis  
150 – 300 U 
Latissimus Dorsi  
150 – 300 U 
 
6.1.1.2 List of muscles recommended 
to be injected and Dysport Dosing by 
Muscle for Lower Limb Spasticity  
MUSCLES 
DOSES 
Soleus muscle  
300 – 550 U 
Gastrocnemius Medial 
Head  
100 – 450 U 
Gastrocnemius Lateral 
Head  
100 – 450 U 
Tibialis posterior  
100 – 250 U 
Flexor digitorum 
longus  
50 – 200 U 
Flexor digitorum 
brevis  
50 – 200 U 
Flexor hallucis longus  50 – 200 U 
Flexor hallucis brevis  50 – 100 U 
Rectus femoris  
100 – 400 U 
Hamstrings  
100 – 400 U 
Adductor magnus  
100 – 300 U 
Adductor Longus  
50 – 150 U 
Adductor Brevis  
50 – 150 U 
Gracilis  
100 – 200 U 
Gluteus maximus  
100 – 400 U 

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50 
Section 6.2 
It will be recorded if subject is 
naïve or non-naïve to BoNT-A 
treatment. If non-naïve to BoNT-
A treatment, the dates of the first 
injection and last injection, details 
of which limbs were injected, and 
the BoNT-A brand and dose used 
in the last injection will be 
recorded in the eCRF. 
 
It will be recorded if subject is naïve or 
non-naïve 
to 
BoNT 
treatment. 
If 
non-naïve to BoNT treatment, the dates 
of the first injection and last injection, 
details of which limbs were injected, and 
the BoNT brand and dose used in the 
last injection will be recorded in the 
eCRF. 
52 
Section 7.2 
• AROM against each injected 
muscle group, in upper and 
lower limbs: mean change from 
baseline at Week 6, Week 12 
and re-injection/last cycle visits 
only 
• composite 
AROM 
against 
injected muscle groups, in 
upper and lower limbs: mean 
change 
from 
baseline 
at 
Week 6, 
Week 12 
and 
re-injection/last 
cycle 
visits 
only 
• (…) 
• subject satisfaction with the 
GSC: at Week 6, Week 12 and 
re-injection/last 
cycle 
visits 
only 
• AROM 
against 
10 
prespecified 
muscle groups, 5 in upper and 5 in 
lower limbs: mean change from 
baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
 
• composite AROM against injected 
muscle groups (any of the 10 
prespecified), in upper and lower 
limbs: mean change from baseline at 
Week 6, Week 12 and re-injection/last 
cycle visits only 
 
• (…) 
• subject satisfaction with the GSC: at 
baseline (only for patients who had 
GSC 
performed 
previously), 
Week 6, 
Week 12 
and 
re-injection/last cycle visits only 
 

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53 
Section 7.2 
 
changes in subject’s belief 
that the GSC will help to 
improve functional capacity: 
change from baseline to 
Week 6, Week 12 and re 
injection/last cycle visits only 
 
 
 
 
subject compliance with the 
GSC: percentage of days over 
study period when GSC 
therapy was performed (as 
determined from the subject 
diary) 
 
global assessment of benefits, 
evaluated by both the 
investigator and the subject 
(or caregiver): at the end of 
each cycle 
 
 
changes in subject’s belief that the 
GSC will help to improve functional 
capacity: change from baseline to 
Week 6, Week 12 and re 
injection/last cycle visits only 
 
changes in Physiotherapist’s belief 
that the GSC will help to improve 
functional capacity: change from 
baseline to Week 6, Week 12 and 
re injection/last cycle visits only 
 
subject compliance with the GSC: 
percentage of days over study 
period when GSC therapy was 
performed (as determined from the 
subject diary) 
 
global assessment of benefits, 
evaluated by both the investigator 
and the subject (or caregiver): at the 
end of each cycle 
 
in subjects with an injection 
planned at Week 16 or 20 of each 
cycle:  subject satisfaction with 
longer interval between 2 
injections collected at the 
corresponding reinjection visit or 
the last cycle visit 
53-54 
Section 7.2 
 
Table 3 
Measure: Voluntary movements 
measured using goniometer to 
determine AROM 
• Endpoint: Mean change from 
baseline to each postbaseline 
timepoint in AROM against 
each injected muscle group 
• Mean change from baseline to 
each postbaseline timepoint in 
composite AROM against 
injected muscle groups 
 
Measure: Subject satisfaction with 
the GSC measured on a Likert 
scale 
Timelines: Week 6, Week 12 and 
re-injection/last cycle visits  
 
Table 4 
Measure: 
Voluntary 
movements 
measured using goniometer to determine 
AROM 
• Endpoint: Mean change from baseline 
to each postbaseline timepoint in 
AROM against 10 prespecified 
muscle groups 
• Mean change from baseline to each 
postbaseline timepoint in composite 
AROM against injected muscle 
groups (any of 10 prespecified)  
 
Measure : Subject satisfaction with the 
GSC measured on a Likert scale 
Timelines: Baseline, Week 6, Week 12 
and re-injection/last cycle visits  
 
New raw added 
Measure : Physiotherapist’s beliefs 
that GSC will help to improve 
functional capacity 
Timelines: Baseline, Week 6, Week 12 

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and re-injection/last cycle visits 
Variable: Likert scale scores 
Endpoint: Change from baseline to 
each post baseline timepoint in scores 
(…)New raw added 
Measure : Subject satisfaction with 
longer interval between 2 injections 
Timelines: 
Week 16 
or 
Week 20, 
depending on which is last visit cycle 1 
and cycle 2 
Variable: Likert scale scores 
Endpoint: Scores at each timepoint 
 
Footnote added 
AROM=Active 
range 
of 
motion; 
EQ-5D 5L= European Quality of Life 
5 Dimensions; 
GSC=Guided 
Self-rehabilitation 
Contract; 
LL=Lower 
limb; 
MFS=Modified 
Frenchay 
Scale; 
SF-12=Short 
Form 12; 
UL=Upper 
limb; 
VAS=Visual 
analogue 
scale; 
WS=Walking Speed. 
a The WST is to be performed 
barefoot without walking aids or, if 
absolutely necessary, with a cane. If a 
cane is used at the Baseline Visit, the 
same cane is to be used during all WS 
assessments. 
b for previously GSC treated subjects 
54 
Section 7.3.1 
The investigator will use the 
goniometer to measure the angle 
of joint movement with respect to 
all the following muscle groups 
(injected or noninjected) in the 
UL and LL: 
The investigator will use the goniometer 
to measure the angle of joint movement 
with respect to the following 10 
prespecified muscle groups (injected or 
noninjected) in the UL and LL: 
55 
Section 7.3.2 
The MFS overall score (i.e. mean 
score over the 10 tasks) will be 
used in the efficacy endpoint 
analysis. At each visit and for 
each rating, the MFS overall score 
will be obtained by averaging all 
individual task scores, provided 
that at least 7 out of the 10 are not 
missing. If 4 or more individual 
task scores are missing, the 
overall score will be left missing. 
The MFS overall score (i.e. mean score 
over the 10 tasks) will be used in the 
efficacy endpoint analysis. At each visit 
and for each rating, the MFS overall 
score will be obtained by averaging all 
individual task scores, provided that at 
least 8 out of the 10 are not missing. 
If 3 or more individual task scores are 
missing, the overall score will be left 
missing. 

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55-56 
Section 
7.3.4.2 
 
7.3.4.2 Changes in the Subject’s 
Beliefs 
 
Subjects will record whether they 
believe the GSC will help to 
improve their functional capacity. 
To assess this, subjects will be 
asked the following question: 
 
 
“Do you believe that GSC 
will help to improve your 
arm and leg function?”  
 
 
 
(…) 
Changes in subject beliefs from 
baseline to postinjection 
timepoints will be assessed. 
 
7.3.4.2 Changes in the Subject’s and 
Physiotherapist’s Beliefs 
 
Subjects and physiotherapists will 
record whether they believe the GSC 
will help to improve their functional 
capacity. To assess this, subjects and 
physiotherapists will be asked the 
following question: 
 
for subjects: “Do you believe that 
GSC will help to improve your 
arm and leg function?”  
 
for physiotherapists: “Do you 
believe that GSC will help to 
improve your patient’s arm and 
leg function?”  
(…) 
Changes in subject and physiotherapist 
beliefs from baseline to postinjection 
timepoints will be assessed. 
56 
Section 7.3.5 
 
 
7.3.5 Subject satisfaction regarding 
longer injection intervals (only for 
subjects with an injection planned at 
Week 16 or 20 of each cycle)  
 
For 
subjects 
who 
will 
not 
be 
reinjected at Week 12 of a given cycle, 
subjects will record their satisfaction 
with 
longer 
interval 
between 
2 
injections 
collected 
at 
the 
corresponding reinjection visit or the 
last cycle visit (week 16 or week 20 for 
each cycle). To assess this, subjects 
will be asked the following question: 
“Are you satisfied with a longer 
interval between 2 injections?” 
• 
Yes 
• 
No  
• 
No opinion 
59 
Section 8.1.3 
At each visit, the subject should 
be asked a non leading question 
such as: “How have you felt since 
starting the new treatment/the last 
assessment?” 
At each visit and each phone call, the 
subject should be asked a non leading 
question such as: “How have you felt 
since starting the new treatment/the last 
assessment?” 

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62 
Section 8.3 
Blood pressure and heart rate will 
be recorded after 5 minutes of rest 
in a supine position at the visits 
indicated in Table 2. Diastolic and 
systolic blood pressure and heart 
rate will be assessed with an 
automated 
device 
so 
that 
measurements are independent of 
the observer.  
Blood pressure and heart rate will be 
recorded after 5 minutes of rest in a 
supine position at the visits indicated in 
Table 2.  
66-67 
Section 
10.4.5.2 
• AROM against each injected 
muscle group, in upper and 
lower limbs: mean change from 
baseline at Week 6, Week 12 
and re-injection/last cycle visits 
only 
• composite 
AROM 
against 
injected muscle groups, in 
upper and lower limbs: mean 
change 
from 
baseline 
at 
Week 6, 
Week 12 
and 
re-injection/last 
cycle 
visits 
only 
• (…) 
• subject satisfaction with the 
GSC:  at Week 6, Week 12 and 
re-injection/last cycle visits only 
• changes in subject’s beliefs that 
the GSC will help to improve 
functional capacity: change 
from baseline to Week 6, 
Week 12 and re-injection/last 
cycle visits only 
• AROM 
against 
10 
prespecified 
muscle groups, 5 in upper and 5 in 
lower limbs: mean change from 
baseline at Week 6, Week 12 and 
re-injection/last cycle visits only 
• composite AROM against injected 
muscle groups (any of the 10 
prespecified), in upper and lower 
limbs: mean change from baseline at 
Week 6, 
Week 12 
and 
re-injection/last cycle visits only 
 
• (…) 
• subject satisfaction with the GSC:  at 
baseline (only for patients who had 
GSC performed previously), 
Week 6, Week 12 and 
re-injection/last cycle visits only 
• changes in subject’s beliefs that the 
GSC will help to improve functional 
capacity: change from baseline to 
Week 6, Week 12 and re-injection/last 
cycle visits only 
• changes in Physiotherapist’s belief 
that the GSC will help to improve 
functional capacity: change from 
baseline to Week 6, Week 12 and 
re-injection/last cycle visits only 
• (…) 
• in subjects with an injection 
planned at Week 16 or 20 of each 
cycle satisfaction with longer 
interval collected at the 
corresponding reinjection visit or 
the last cycle visit. 
68 
10.5 
BoNT-A 
BoNT 

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SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-52120-228 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version (including Amendment #1): 02 December 2016 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
- 
To clarify the ABI diseases authorised  
- 
To exclude subjects who have received (within 4 weeks 
before study entry) or might receive intrathecal baclofen 
- 
To remove the INR>3,5 in exclusion criteria as this is not an 
exclusion but a recommendation for dosing and clarify this is 
only for antivitamin K and no new oral anticoagulant in 
Section 6.1 
- 
To clarify the recommended dose and muscles to be injected 
according to Study Drug labelling 
- 
To add the subject satisfaction with GSC at baseline in case 
he/she had GSC previously 
- 
To add new assessment such as the Physiotherapist belief in 
the GSC therapy at study start and during the study. 
- 
To add the subject satisfaction in case of longer interval of 
injection 
- 
To authorise the use of Ultrasound guiding in addition to ES 
in case this technique is used in routine clinical practice 
- 
To add a visit windows of ± 7 days for all visits and +7 days 
only for W12 visit 
- 
To add the record of any AE during the routine phone call 
done by the physiotherapist 
- 
To remove the automated device for taking blood pressure. 
- 
To clarify that previous BoNT treatment will be collected for 
all previous BoNT 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one) 
 
 

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Appendix 2 Amendment Form #2 
 
 

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PAGE 102/105 
 
 
 
STUDY NUMBER: 
F-FR-52120-228 
PROTOCOL TITLE: 
An International, Multicentre, Prospective, 
Single-Arm Study to Assess the Effect on 
Voluntary Movements of AbobotulinumtoxinA 
1500 U Administered in Both Upper and Lower 
Limbs in Conjunction with a Guided 
Self-Rehabilitation Contract in Adult Subjects 
with Spastic Hemiparesis 
AMENDED PROTOCOL VERSION 
NUMBER & DATE 
Final Version (including Amendment #2): 24 
January 2018 
THE FOLLOWING AMENDMENT(S) IS/ARE PROPOSED: 
Version Date 
02 DECEMBER 2016 
24 JANUARY 2018 
Page  
Section 
WAS 
IS 
1 
Cover 
 
 
 
 
 
 
 QPPV, Global 
Patient Safety, Ipsen Group, 
  
EU 
Qualified 
Person 
for 
Pharmacovigilance,  
Ipsen Biopharm Ltd 
8 
Synopsis 
Diagnosis 
and criteria 
for inclusion 
 
5) 
Upper 
limb 
active 
function with an overall score 
between 2 and 7, as assessed by 
MFS, if the primary TT limb is 
the UL. 
5) 
Upper limb active function with 
an overall score between 2 and 7, as 
assessed by MFS the locally rated 
score, if the primary TT limb is the UL. 
10 
Synopsis 
Statistical 
Methods  
• 
active 
UL 
function 
measured 
using 
MFS: 
mean change from baseline 
in MFS overall score (i.e. 
mean 
score 
over 
the 
10 tasks score) at Week 12 
after each injection cycle  
 
• 
active UL function measured 
using MFS: mean change from 
baseline in MFS overall score 
(i.e. mean score over the 10 tasks 
assessed locally and centrally 
by 
a 
reviewer 
blinded 
regarding the dates of video 
recording/visit 
number) 
at 
Week 12 after each injection 
cycle  
30 
Section 3.2.2 
 
• 
active 
UL 
function 
measured 
using 
MFS: 
mean change from baseline 
in MFS overall score (i.e. 
mean 
score 
over 
the 
10 tasks score) at Week 12 
after each injection cycle  
 
• 
active UL function measured 
using MFS: mean change from 
baseline in MFS overall score 
(i.e. mean score over the 10 tasks 
assessed locally and centrally 
by 
a 
reviewer 
blinded 
regarding the date of video 
recording/visit 
number) 
at 
Week 12 after each injection 
cycle  
 
PPD
PPD

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35 
Section 4.1 
 
5) 
Upper 
limb 
active 
function with an overall score 
between 2 and 7, as assessed by 
MFS, if the primary TT limb is 
the UL. 
 
5) 
Upper limb active function with 
an overall score between 2 and 7, as 
assessed by MFS locally rated score, if 
the primary TT limb is the UL. 
 
54 
Section 7.2 
 
• 
active 
UL 
function 
measured 
using 
MFS: 
mean change from baseline 
in MFS overall score (i.e. 
mean 
score 
over 
the 
10 tasks score) at Week 12 
after each injection cycle  
 
• 
active UL function measured 
using MFS: mean change from 
baseline in MFS overall score 
(i.e. mean score over the 10 tasks 
assessed locally and centrally 
by 
a 
reviewer 
blinded 
regarding the date of video 
recording/visit 
name) 
at 
Week 12 after each injection 
cycle  
 
55 
Table 4 
Column End 
point 
 
Mean change from baseline to 
Week 12 in MFS overall score  
Mean change from baseline to Week 12 
in MFS overall score assessed locally 
and centrally by a reviewer blinded 
regarding the date of video 
recording/visit number) 
57 
Section 7.3.2 
 
When evaluating active function 
at postbaseline FU visits, the 
investigator 
will 
review 
the 
baseline video for comparison 
purposes. Details will be provided 
in the Study Operational Manual. 
The central MFS overall score 
(i.e. mean score over the 10 tasks) 
will be used in the efficacy 
endpoint analysis.  
 
At each visit and for each rating, the 
MFS overall scores will be obtained 
by averaging all individual task 
scores, provided that at least 8 out of 
the 10 are not missing. If 3 or more 
individual task scores are missing, the 
overall score will be left missing. 
On top of the local MFS scores 
assessed by the investigators, a central 
review will be conducted at the 
Coordinating investigator’s site of 
Prof Gracies: if possible, videos will 
be scored by only one reviewer. 
Videos will be provided for a given 
subject in a blinded manner for 
the visit order. All videos should be 
assessed only when the subject has 
completed the study.  
The efficacy endpoint analysis will be 
performed both on the locally rated 
MFS mean score and on the centrally 
rated MFS mean score, if available 
 

IPSEN GROUP 
F-FR-52120-228 
 
CONFIDENTIAL 
 
PROTOCOL FINAL (INCLUDING AMENDMENT #2): 24 JANUARY 2018 
PAGE 104/105 
 
 
68 
Section 
10.4.5.2 
 
• 
active 
UL 
function 
measured using MFS: 
mean 
change 
from 
baseline in MFS overall 
score (i.e. mean score 
over the 10 tasks) at 
Week 12 
after 
each 
injection cycle 
 
• 
active UL function measured 
using MFS: mean change from 
baseline in MFS overall score 
(i.e. mean score over the 
10 tasks assessed locally and 
centrally by a reviewer blinded 
regarding the date of video 
recording/visit 
number) 
at 
Week 12 after each injection 
cycle 
 

IPSEN GROUP 
F-FR-52120-228 
 
CONFIDENTIAL 
 
PROTOCOL FINAL (INCLUDING AMENDMENT #2): 24 JANUARY 2018 
PAGE 105/105 
 
 
SUMMARY & OUTCOME OF CHANGES: 
STUDY NUMBER 
F-FR-52120-228 
AMENDED PROTOCOL 
VERSION NUMBER & 
DATE 
Final Version (including Amendment #2): 24 January 2018 
 
SUBSTANTIAL  
 
NON-SUBSTANTIAL  
 
 
REASON(S) FOR CHANGES 
 
- 
To add the central scoring of MFS 
OTHER ACTION REQUIRED? 
CRF UPDATE  
 
Yes 
 
  
No 
 
 
 
(tick one) 
 
LOCAL CONSENT FORM UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
DATABASE UPDATE  
Yes 
 
  
No 
 
 
 
(tick one) 
 
REPORTING & ANALYSIS PLAN 
(RAP) UPDATE 
Yes 
 
  
No 
 
 
 
(tick one)