Conditions: Urinary Incontinence Overactive Bladder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 258
Healthy volunteers: no

Brief summary:
The purpose of this study is to provide confirmatory evidence of the safety and efficacy of two Dysport® doses (600 units \[U\] and 800 U), compared to placebo in reducing urinary incontinence (UI) in adult subjects treated for neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) or multiple sclerosis (MS).

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: Botulinum toxin type A intervention 2: Botulinum toxin type A intervention 3: Placebo intervention 4: Placebo
Intervention descriptions: intervention 1: 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points. intervention 2: 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points intervention 3: AbobotulinumtoxinA Placebo 600 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points intervention 4: AbobotulinumtoxinA Placebo 800 U intra detrusor injection in two treatment periods (Initial and Retreatment phase) delivered at 30 injection points

Protocol document:
Prot_000.pdf: 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 2/139 
 
 
INVESTIGATOR’S AGREEMENT 
  
  
Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-52120-223 entitled “A phase III, multicentre, 
randomised, double blind, parallel group, placebo controlled study to assess the efficacy and 
safety of one or more intradetrusor treatments of 600 or 800 units of Dysport® for the treatment 
of urinary incontinence in subjects with neurogenic detrusor overactivity due to spinal cord 
injury or multiple sclerosis”. 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 Innovation 
 
5 Avenue du Canada 
 
91940 Les Ulis Cedex 
 
France 
 
Tel: +33 (0)1 60 92 20 00 
 
 
 
PPD
PPD
PPD


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 3/139 
 
 
COORDINATING INVESTIGATOR’S AGREEMENT 
Coordinating Investigator Agreement and Signature: 
I have read and agree to Protocol D-FR-52120-223 entitled “A phase III, multicentre, 
randomised, double blind, parallel group, placebo controlled study to assess the efficacy and 
safety of one or more intradetrusor treatments of 600 or 800 units of Dysport® for the treatment 
of urinary incontinence in subjects with neurogenic detrusor overactivity due to spinal cord 
injury or multiple sclerosis”. 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: 
 
TITLE: 
COORDINATING 
 
SIGNATURE: 
 
INVESTIGATOR 
 
DATE: 
OFFICE: 
 
 
 
PPD


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 4/139 
 
 
Summary of Changes 
The current version of the protocol was released on 16 April 2018 and includes 
Amendment 2. For all protocol amendments, amendment forms were prepared and are 
provided in Appendix 2.0. 
Table 1 
List of Protocol Amendments 
Amendment 
Release date 
Amendment form 
1 
17 March 2016 
Appendix 2 
2 
16 April 2018 
Appendix 2 
 
 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 5/139 
 
 
SYNOPSIS 
Name of sponsor/company: Ipsen Innovation 
Name of finished product: Dysport® for Injection  
Name of active ingredient: AbobotulinumtoxinA (Clostridium BTX-A-haemagglutinin 
complex) 
Title of study: A phase III, multicentre, randomised, double blind, parallel group, placebo 
controlled study to assess the efficacy and safety of one or more intradetrusor treatments 
of 600 or 800 units of Dysport® for the treatment of urinary incontinence in subjects with 
neurogenic detrusor overactivity due to spinal cord injury or multiple sclerosis. 
Study number: D-FR-52120-223 
Number of planned sites: Approximately 90 study sites 
Planned study period: 
First quarter 2016 (estimated first subject randomised) until  
last quarter 2020 (estimated last subject last visit) 
Phase of development: 
Phase III  
Objectives: 
Target Population: 
Subjects with urinary incontinence (UI) caused by neurogenic detrusor overactivity (NDO) 
due to either spinal cord injury (SCI) or multiple sclerosis (MS), who have not been 
adequately managed with oral medication and who routinely require clean intermittent 
catheterisation (CIC) to manage their bladder function. 
Primary Study Objective:  
• 
To assess the efficacy of two Dysport® doses (600 units (U) and 800 U), compared 
to placebo in reducing UI from Baseline to Week 6 following the first investigational 
medicinal product (IMP) administration. 
Secondary Study Objectives: 
• 
To assess the efficacy of two Dysport® doses (600 U and 800 U), compared to 
placebo in improving bladder diary measures, urodynamic and patient-reported 
efficacy endpoints following the first IMP administration, including assessing 
duration of effect. 
• 
To assess the efficacy of two Dysport® doses (600 U and 800 U) in improving 
bladder diary measures, urodynamic and patient-reported efficacy endpoints 
following retreatment IMP administrations, including assessing duration of effect. 
• 
To assess the safety of two Dysport® doses (600 U and 800 U) for the treatment of 
UI due to NDO.  
Methodology:  
Study design 
This is a phase III, multicentre, randomised, double blind, parallel group, placebo 
controlled study to assess the efficacy and safety of two Dysport® doses (600 U and 800 U) 
administered to the bladder of adult subjects with SCI or MS, and UI due to NDO.  


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 6/139 
 
 
 
This study has two treatment periods: 
• 
A double blind placebo controlled period, during which subjects receive a single 
IMP treatment administration of either 600 U or 800 U Dysport® or placebo. 
• 
A subsequent double blind active treatment period, during which subjects can 
receive multiple active IMP retreatment administrations of either 600 U or 800 U 
Dysport®. 
 
The study contains two subsets: 
• 
Urodynamic subset (planned ≥200 subjects) 
o All subjects in this subset must have standardised urodynamics (as 
described in the Study Specific Urodynamic Manual) during Screening 
and at Week 6 following each study treatment 
o Screening standardised urodynamics must confirm the presence of NDO 
• 
Non-Urodynamic subset  
o All subjects in this subset must have documented urodynamic proven 
NDO in the 12 months prior to Screening. If not, then urodynamics must 
be performed per local practice during Screening to confirm the diagnosis 
of NDO 
o Urodynamics will not be performed in the post-screening period in this 
subset 
 
Duration of subject participation 
104 weeks (24 months) to 116 weeks depending on the timing of final IMP administration.  
Screening  
Screening period will last for up to 30 days (but can be extended in certain circumstances, 
see Section 5.2.1), during which time informed consent will be obtained and eligibility for 
study participation will be assessed. Subjects will complete a 7-day bladder diary, 
urodynamic assessment (as applicable), patient-reported outcome questionnaires and have 
blood and urine samples taken.  
Randomisation/treatment 
The Treatment Visit should occur up to 14 days after screening period (but can be extended 
where a UTI has occurred, see Section 5.2.3). At the Treatment Visit (Day 1), subjects who 
meet all the eligibility criteria will be randomised (in a 2:2:1:1 ratio) to one of four 
treatment sequences: 
Sequence 
Subjects 
Treatment 1 
Subsequent retreatment(s) 
1 
110 subjects 
600 U Dysport® 
600 U Dysport® 
2 
110 subjects 
800 U Dysport® 
800 U Dysport® 
3 
55 subjects 
Placebo 
600 U Dysport® 
4 
55 subjects 
Placebo 
800 U Dysport® 
During analysis of study Treatment 1, the two placebo containing sequences will be pooled 
into a single arm. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 7/139 
 
 
Randomisation will be stratified by aetiology of NDO (SCI or MS) and also by previous 
intradetrusor botulinum toxin type A (BTX-A) usage (BTX-A naive vs. BTX-A non-naive 
in the bladder). 
IMP administration may be performed using local anaesthesia (if required) or a short-
duration general anaesthesia (if required), and will consist of 30 cystoscopically placed 
injections (0.5 mL per injection point) of the IMP evenly distributed throughout the bladder 
(avoiding the trigone). 
 
 
 
Follow-up (after the first IMP administration): 
• 
Week 1 (Day 8) (telephone) 
• 
Week 2 (Day 15) (clinic visit) 
• 
Week 4 (Day 29) (telephone) 
• 
Week 6 (Day 43) (clinic visit; primary timepoint) 
• 
Week 12 (Day 85) (clinic visit) 
• 
Every 12 weeks (telephone visits; until retreatment received or end of study (EOS) 
at Week 104 116). 
Details of the procedures performed at each visit following the first treatment are shown in 
Table 2.  
Retreatment assessment 
A subject may request retreatment at any time ≥12 weeks after their most recent study 
treatment. 
If the request occurs between scheduled visits or at a scheduled telephone visit then the 
subject will require a Retreatment Assessment Visit prior to receiving study retreatment 
(some retreatment criteria can be assessed prior to the Retreatment Assessment Visit).  
If the request occurs at a scheduled visit then the Retreatment Assessment Visit procedures 
should be performed at the same visit.  
Retreatment criteria 
The retreatment criteria are as follows: 
1) 
Retreatment requested by subject; 
2) 
More than 12 weeks (84 days) since the previous IMP administration; 
3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
5) 
In the investigator’s opinion it is safe and appropriate to provide a retreatment. 
Retreatment should ideally occur within 14 days of confirmation of eligibility for 
retreatment and can occur up to and including Week 104 following the first IMP 
administration.  
Retreatment follow-up 
Follow-up after each retreatment follows the same schedule as the first IMP administration: 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 8/139 
 
 
• 
Week 1 (Day 8) (telephone) 
• 
Week 2 (Day 15) (clinic visit) 
• 
Week 4 (Day 29) (telephone) 
• 
Week 6 (Day 43) (clinic visit) 
• 
Week 12 (Day 85) (clinic visit) 
• 
Every 12 weeks (telephone visits; until retreatment received or EOS at Week 104
116). 
Details of the procedures performed at each Retreatment Follow-up Visit are contained in 
Table 3. 
End of Study Visit 
The EOS Visit will take place between 104 and 116 weeks after the first 
IMP administration (Day 1). Subjects may receive study retreatment up to and including 
Week 104 and a minimum of 12 weeks of follow-up is required after each 
IMP administration. For those subjects completing the study, the EOS Visit will occur: 
• 
104 weeks after the first IMP administration; if it has been more than 12 weeks since 
the previous IMP administration 
• 
At the Week 12 Retreatment Follow-up Visit, if the subject received their most 
recent IMP administration between Week 92 and Week 104 following their first 
IMP administration. 
Early discontinuation  
A subject who discontinues early should, if at all possible, be followed-up for at least 
12 weeks following their most recent IMP administration and should attend the EOS Visit. 
Number of subjects planned: 330 randomised subjects. 
Diagnosis and criteria for inclusion: 
Inclusion criteria 
The following inclusion criteria will be assessed at the beginning of the Screening process: 
1) 
Written informed consent prior to any study-related procedure. 
2) 
Male or female, aged 18 to 80 years inclusive. 
3) 
UI for at least 3 months prior to Screening as a result of NDO due to SCI or MS. 
4) 
Subjects with SCI must have a stable neurological injury at T1 level or below which 
occurred at least 6 months prior to Screening. 
OR 
Subjects with MS must be clinically stable in the investigator’s opinion, with no 
exacerbation (relapse) of MS for at least 3 months prior to Screening. 
5) 
Subjects in the non-urodynamic subset only, must have NDO (defined as the 
presence of involuntary detrusor contractions during the storage phase of 
urodynamic filling cystometry) on a historic urodynamic assessment performed in 
the 12 months prior to Screening  
• 
If urodynamics are not performed in the 12 months prior to Screening or if 
results are not available, then a urodynamic filling cystometry assessment 
must be performed during Screening, per local practice (see inclusion 
criterion # 16). 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 9/139 
 
 
6) 
Subjects must have had an inadequate response 
 
oral medications used in the treatment of NDO (e.g. anticholinergics, beta-3 
agonists) and/or have intolerable side-effects. 
7) 
 
  
 
 
 
. 
9) 
Routinely performing CIC to ensure adequate bladder emptying
 
 
 
 
 
 
 
 
11) 
Female subjects of childbearing potential must have a negative pregnancy test result 
and be willing to use reliable contraceptive measures throughout study participation. 
Reliable forms of contraception are: 
• 
hormonal contraceptives (e.g. oral, patch, injection) 
• 
double barrier (e.g. male condom plus spermicide, or female diaphragm plus 
spermicide) 
• 
intrauterine device 
• 
male partner has had a vasectomy 
• 
total abstinence from intercourse with male partners (periodic abstinence is 
not acceptable). 
Female subjects meeting any of the following criteria are not considered to be of 
childbearing potential: 
• 
postmenopausal (≥47 years of age and amenorrhoeic for at least 
12 consecutive months) 
• 
have been sterilised surgically (e.g. bilateral tubal ligation) 
• 
have had a hysterectomy 
• 
have had a bilateral oophorectomy. 
12) 
Documented urinary tract ultrasound is available in the 6 months prior to Screening, 
confirming that no medical issues exist that would preclude entry to the study (e.g. 
bladder stones or unexplained renal mass).  
• 
If not performed in the 6 months prior to Screening or results are not available, 
then a urinary tract ultrasound must be conducted during Screening. 
13) 
Ability to complete all study requirements in the opinion of the investigator, 
including regularly completing the 7-day bladder diary and attending all scheduled 
study visits. The caregiver may assist with the completion of study documentation 
and procedures (including the bladder diary and questionnaires), if required.  
 
: 
CCI
CCI
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 10/139 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Exclusion criteria 
The following exclusion criteria will be assessed throughout the Screening process: 
1) 
Any current condition (other than NDO) that may impact on bladder function, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2) 
Previous or current, tumour or malignancy affecting the spinal column or spinal 
cord, or any other nonstable cause of SCI. 
3) 
Surgery less than 6 months prior to Screening for bladder stones. 
4) 
Surgery less than 6 months prior to Screening for uterine prolapse, cystocele or 
rectocele. 
5) 
Previous open surgery for NDO, e.g. augmentation cystoplasty. 
6) 
Previous urethral stent placement or sphincterotomy. 
7) 
Previous or current diagnosis of, or symptoms/signs/investigations suggestive of, 
significant urological or pelvic disease, 
 
 
 
 
 
 
 
 
 
 
 
 
 
CC
I
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 11/139 
 
 
8) 
Previous or current uninvestigated haematuria. 
 
 
 
 
 
9) 
Any condition that will prevent cystoscopic treatment administration or CIC usage, 
e.g. urethral strictures. 
10) 
Current indwelling bladder catheter, or removal of indwelling bladder catheter less 
than 4 weeks prior to Screening. 
11) 
BTX-A treatment within 9 months prior to Screening for any urological condition 
(e.g. detrusor or urethral sphincter treatments). 
12) 
BTX-A treatment within 3 months prior to Screening for any non-urological 
condition. 
13) 
Bladder instillation with any pharmacologic agent less than 3 months prior to 
Screening. 
14) 
Use of capsaicin or resiniferatoxin less than 6 months prior to Screening.  
15) 
Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence 
within 4 weeks prior to Screening. Any implanted neuromodulation device must be 
switched off at least 4 weeks prior to Screening and must remain off throughout 
study participation. 
16) 
Any concomitant therapy usage that, in the investigator’s opinion, would interfere 
with the evaluation of safety or efficacy of the IMP, and/or confound the study 
results. 
17) 
History of chronic drug or alcohol abuse. 
18) 
Female subject who is pregnant or planning to become pregnant during the study, or 
is currently lactating (breastfeeding). 
19) 
Any medical condition or disease that might interfere with neuromuscular function, 
 
 
20) 
Use of medications that affect neuromuscular transmission, 
 
 
 
 
 
 
 
  
21) 
 
. 
22) 
Known hypersensitivity to BTX-A or to any components in the IMP formulation 
(including cow’s milk protein). 
23) 
History of allergy to, or intolerance to, the anaesthetic or antibiotic agents that the 
investigator intends to use during the study.  
24) 
Unable to stop medications with anticoagulant/antiplatelet effects for at least 3 days 
prior to each IMP administration and to recommence the day following each IMP 
administration (low molecular weight heparins may be used within 3 days of IMP 
administration). 
25) 
Any condition that may cause excessive bleeding (e.g. haemophilia or clotting factor 
deficiencies). 
CCI
CCI
CCI
CCI




IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 13/139 
 
 
 
Criteria for evaluation: 
Efficacy:  
Primary efficacy endpoint: 
• 
Mean change from study Baseline (assessed at Screening) to Week 6 after the first 
IMP administration in the weekly number of UI episodes:  
• 
measured on a 7-day bladder diary. 
Secondary efficacy endpoints 
Timepoints following the first and subsequent treatments for efficacy endpoint assessments 
are listed in Table 2 and Table 3: 
• 
Bladder diary measures: 
• 
weekly number of UI episodes  
• 
daily urinary frequency (total, spontaneous void only, CIC only) 
• 
24-hour voided volume (total, spontaneous void only, CIC only) 
• 
volume per void (total, spontaneous void only, CIC only). 
• 
Urodynamic measures (urodynamic subset only): 
• 
maximum cystometric capacity (MCC) 
• 
maximum detrusor pressure (MDP) during storage 
• 
volume at first involuntary detrusor contraction (Vol@1stIDC) 
• 
maximum detrusor pressure at first involuntary detrusor contraction 
(PdetMax@1stIDC) 
• 
end fill pressure (EFP) 
• 
detrusor compliance (DC). 
• 
Patient-reported outcome questionnaires: 
• 
incontinence quality of life (I-QoL) total summary score 
• 
EuroQol 5-dimension 5-level (EQ-5D-5L) 
• 
modified patient global impression - improvement (mPGI-I) score. 
• 
Proportion of subjects at post-treatment timepoints following the first and 
subsequent treatments with: 
• 
no episodes of UI (i.e. continence is achieved) 
• 
UI response at several levels (i.e. ≥30% improvement, ≥50% improvement, 
≥75% improvement, etc.) 
• 
no IDCs on urodynamic assessment (i.e. urodynamic cure is achieved) 
(urodynamic subset only). 
• 
Duration of effect following the first and subsequent treatments.  
A hierarchical analysis will be performed in the order listed for the following secondary 
efficacy measures at Week 6 after the first IMP administration: 
• 
proportion of subjects with no episodes of UI (i.e. continence is achieved) 
• 
mean change from study Baseline in the I-QoL total summary score. 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 14/139 
 
 
Safety: 
• 
adverse events (AEs) 
• 
vital signs 
• 
laboratory blood parameters (haematology and serum chemistry) 
• 
laboratory urine parameters (laboratory urinalysis/microscopy, culture and 
sensitivity) 
• 
development of BTX-A antibodies  
• 
usage of concomitant medications and therapies. 
Statistical methods: 
Primary efficacy endpoint 
The primary efficacy endpoint will be analysed using a mixed model. This model will 
include treatment group, and stratification variables and baseline value as fixed covariates.  
Secondary efficacy endpoints 
Secondary efficacy endpoints will be assessed according to their scale (categorical or 
continuous), using a logistic regression model, mixed model, or survival analysis-type 
methods (e.g. Kaplan-Meier plots, log-rank statistics).  
Safety endpoints 
The safety analysis will be descriptive in nature; inferential assessment of treatment group 
differences for safety outcomes is not planned. Subject incidence of each system organ 
class and preferred term will be tabulated. 
Antibody testing 
The number and percentage of subjects with the presence of neutralising BTX-A antibodies 
at Screening will be summarised. The number of seroconverters (subjects having a negative 
result at Screening and at least one positive result at any post-treatment timepoint) for 
neutralising antibodies will be reported for each treatment group.  
Sample size considerations 
The sample size is based on the desire to detect a statistically significant treatment 
difference in the weekly number of UI episodes at Week 6 following the first treatment in 
the two Dysport® arms compared to the placebo arm. Assuming a weekly decrease of 21 UI 
episodes in each Dysport® arm and a weekly decrease of 12 UI episodes in the placebo 
arm, with a common standard deviation of 20 UI episodes, 80% power, and an alpha of 
0.025 (as testing of both the 600 U and 800 U doses vs. the placebo dose will be performed 
simultaneously), a sample size of N=96 subjects per group (a total of 288 subjects) is 
needed. Dropout between randomisation and Week 6 (primary efficacy timepoint) is 
expected to be 10%, and thus a total of 318 subjects would be needed to be enrolled. 
However, in order to ensure that the development program will deliver adequate Dysport 
exposure data to meet ICH E1 guideline recommendations, a total of 330 subjects are 
planned to be randomised. 
Control of type one error 
Experiment wise control of type one error for the primary endpoint will be performed using 
a conservative approach. The primary efficacy hypotheses are as follows: 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 15/139 
 
 
• 
Ho: There is no difference between treatment with 600 U or 800 U Dysport® and 
treatment with placebo with respect to the change from pretreatment to Week 6 after 
the first study treatment in the number of UI episodes per week. 
• 
Ha: There is a difference between treatment with 600 U or 800 U Dysport® and 
treatment with placebo with respect to the change from pretreatment to Week 6 after 
the first study treatment in the number of UI episodes per week. 
As there are multiple primary tests being performed simultaneously (two primary tests), a 
Hochberg correction will be applied. If both p-values for the two primary tests (the test of 
800 U vs. placebo and the test of 600 U vs. placebo) are lower than 0.05, both will be 
declared statistically significant. If one of the primary tests has a p-value greater than or 
equal to 0.05, then the other test will be declared statistically significant if its p-value is 
lower than 0.025.  
The two ordered secondary endpoints will be tested for both doses at the 0.05 level (using 
a hierarchical methodology) if, for both doses, the two primary tests achieve a p-value 
lower than 0.05. If one of the primary tests has a p-value greater than or equal to 0.05, and 
the other has a p-value lower than 0.025, secondary endpoints will be assessed (using 
hierarchical methodology) for the dose group with p-value lower than 0.025 at the 0.025 
significance level. All other secondary endpoints will be tested at a significance level of 
0.05. 
  
 
 
 
 
 
   
 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 16/139 
 
 
Table 2 
Study Procedures and Assessments for First Treatment and Follow-Up Until Retreatment or End of Study 
 
Screening 
Treatment 
Post-Treatment 1 Follow-up 
End of Study/ 
Withdrawal  
Screening 
Visit 1 
Screening 
Visit 2 
[i] [r] 
Treatment Visit  
(Day 1)  
[i] 
Week 1 
Visit  
(Day 8) 
Week 2  
Visit 
(Day 15) 
Week 4  
Visit 
(Day 29) 
Week 6  
Visit 
(Day 43) 
Week 12 
Visit 
(Day 85) 
Routine Visit 
every 12 weeks (84 
days) until 
retreatment occurs 
End of Study 
Visit 
(Week 104 to 
Week 116) [q] 
Clinic 
Clinic 
Clinic 
Telepho
ne [n] 
Clinic 
Telepho
ne [n] 
Clinic 
Clinic 
Telephone [n] 
Clinic 
Visit window (days) 
-30 to -1 [r] 
Within 14 days of 
Screening Visit 2 [i] ±3 days 
±3 days 
±3 days 
±3 days 
±7 days  
±14 days 
±14 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/NDO history  
X 
 
 
 
 
 
 
 
 
 
Prior medications and therapies 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Concomitant medications and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant treatments for NDO [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (symptom-based) 
X 
 
 
 
 
 
X 
 
 
X 
Vital signs 
X [f] 
 
X [m] 
 
X 
 
X 
X 
 
X 
Urinary tract ultrasound  
X [g] 
 
 
 
 
 
 
 
 
 
Urine pregnancy test [b] 
X 
 
X 
 
 
 
 
 
 
 
Laboratory urinalysis/microscopy [c] 
X 
 
 
 
 
 
X 
X 
 
X 
Urine culture [c]  
X 
 
 
 
 
 
X [o] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology and serum chemistry 
X 
 
 
 
 
 
X 
 
 
X 
Anti BTX-A antibodies 
X 
 
 
 
 
 
X 
 
 
X 
Dispense bladder diary & training [d] 
X 
 
 
 
 
 
 
 
 
 
Bladder diary review  
 
X [k] 
 
 
X[k] 
 
X[k] 
X [k] 
X [k] 
X [k] 
I-QoL and EQ-5D-5L 
 
 
X 
 
 
 
X 
X 
 
X 
mPGI-I [e] 
 
 
 
 
X 
 
X 
X 
X 
X 
Urodynamics (filling cystometry)  
 
X [l] 
 
 
 
 
X [o] 
 
 
 
Randomisation  
 
 
X 
 
 
 
 
 
 
 
IMP administration  
 
 
X 
 
 
 
 
 
 
 
BTX-A=botulinum toxin type A; EOS=End of Study; EQ-5D-5L=EuroQol 5-dimension 5-level; IMP=investigational medicinal product; I-QoL=incontinence quality of life;  
mPGI-I=modified patient global impression - improvement; NDO=neurogenic detrusor overactivity. 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 17/139 
 
 
a 
Concomitant treatments for NDO (e.g. anticholinergics, beta-3 agonists, clean intermittent catheterisation rate) should remain stable during the first 12 weeks after Treatment 1 
(preferably for the entire duration of the study). 
b  
Pregnancy test to be performed only in females of childbearing potential. Must be performed prior to randomisation on the day of treatment. 
c 
Laboratory urinalysis/microscopy and urine culture to be performed at any follow-up visit if there is a suspicion of urinary tract infection based on subject symptoms.  
d 
Bladder diary device to be returned when subject completes study (e.g. in the event of screen failure, EOS Visit, Early Withdrawal Visit, etc.) 
e  
mPGI-I will be completed on the electronic bladder diary device and should be completed at home prior to the visit. 
f  
Body weight and height will be measured at Screening Visit 1 only. 
g  
Urinary tract ultrasound is only required if no adequate documented urinary tract ultrasound is available in the 6 months prior to Screening (see inclusion criterion # 12). 
h 
 
 
. 
i 
Treatment Visit should occur within 14 days of Screening Visit 2 (where a UTI occurs and impacts the ability to perform IMP administration the time to the Treatment Visit can be 
extended until the UTI is resolved). Both visits may be performed on the same day, as long as all Screening Visit 2 procedures are performed prior to the Treatment Visit procedures 
and antibiotics were commenced 3 or more days prior to treatment. 
j 
 
. 
 
n.  
k 
Site should check if bladder diary has been commenced at least 8 days prior to visit. If not commenced then site should contact subject to remind subject (and/or caregiver) to commence 
collecting bladder diary data. Electronic bladder diary data may be reviewed by the site prior to the visit (recommended, to check if bladder diary is fully completed). 
l 
Screening urodynamics should only be performed in subjects in the urodynamic subset (perform standardised urodynamics) or in subjects in the non-urodynamic subset who do not 
have a documented urodynamic assessment from the 12 months prior to Screening (perform urodynamics per local practice). In addition, urodynamics should only be performed if 
the subject is eligible based on a valid Screening 7-day bladder diary. 
m 
At the Treatment Visit, vital signs will be recorded before and at least 30 minutes after treatment administration. In addition blood pressure and heart rate will be monitored during the 
entire treatment procedure in subjects with spinal cord injury with vertebral lesions above the T6 level. 
n 
Telephone Visits may be conducted as clinic visits, if required in the investigator’s opinion. 
o 
Subjects in urodynamic subset only. 
p 
 
 
  
q 
The EOS Visit should be scheduled for Week 104 for subjects who had their most recent IMP administration at Week 92 or earlier; and at the same time as the Week 12 postretreatment 
Visit for subjects who had their most recent study retreatment after Week 92.  
r 
The time to Screening Visit 2 can be extended to obtain an appropriately and fully completed bladder diary or to obtain a valid bladder diary. In addition, where a UTI occurs after 
completion of the bladder diary and impacts the ability to perform urodynamics the time to Screening Visit 2 can be extended until the UTI is resolved. 
CCI
CCI
CCI
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 18/139 
 
 
Table 3 
Study Procedures and Assessments for Retreatment and Follow-Up Until Subsequent Retreatment or End Of Study 
 
Retreatment 
Postretreatment Follow-up 
End of Study/ 
Withdrawal  
Retreatment 
Assessment 
Visit  
[d] 
Retreatment 
Visit  
(Day 1 of 
treatment cycle)  
Week 1  
Visit [i] 
(Day 8) 
Week 2  
Visit [i] 
(Day 15) 
Week 4 
Visit [i] 
(Day 29) 
Week 6  
Visit [i] 
(Day 43) 
Week 12  
Visit [i] 
(Day 85) 
Routine Visit 
every 12 weeks 
(84 days) 
(until retreatment 
occurs) [i] 
End of Study Visit 
(Week 104 to Week 
116 relative to date 
of first treatment) 
[m] 
Clinic 
Clinic 
Telephone 
[j] 
Clinic 
Telephone 
[j] 
Clinic 
Clinic 
Telephone [j] 
Clinic 
Visit window (days) 
Within 14 
days of 
request 
Within 14 days 
of confirmed 
eligibility 
±3 days [i] ±3 days [i] ±3 days [i] ±3 days [i] ±7 days [i] 
±14 days [i] 
±14 days 
Concomitant medications and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments for NDO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retreatment criteria  
X [e] 
X [e] 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (symptom based) 
X 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X [h] 
 
X 
 
X 
X 
 
X 
Urine pregnancy test [a] 
 
X 
 
 
 
 
 
 
 
Laboratory urinalysis/microscopy [b] 
X 
 
 
 
 
X 
X 
 
X 
Urine culture [b]  
X 
 
 
 
 
X [k] 
 
 
 
Dispense antibiotics 
X [f] 
 
 
 
 
X[l] 
 
 
 
Haematology and serum chemistry 
X 
 
 
 
 
X 
 
 
X 
Anti BTX-A antibodies 
X 
 
 
 
 
 
 
 
X 
Bladder diary review 
X [g] 
 
 
X [g] 
 
X [g] 
X [g] 
X [g] 
X [g] 
I-QoL and EQ-5D-5L 
X 
 
 
 
 
X 
X 
 
X 
mPGI-I [c] 
X 
 
 
X 
 
X 
X 
X 
X 
IMP administration 
 
X 
 
 
 
 
 
 
 
Urodynamics (filling cystometry) 
 
 
 
 
 
X[k] 
 
 
 
BTX-A=botulinum toxin type A; EOS=End of Study; EQ-5D-5L=EuroQol 5-dimension 5-level; IMP=investigational medicinal product; I-QoL=incontinence quality of life; mPGI-I=modified 
patient global impression - improvement; NDO=neurogenic detrusor overactivity. 
a 
Pregnancy test to be performed only in females of childbearing potential. Must be performed prior to retreatment administration on the day of retreatment. 
b 
Laboratory urinalysis/microscopy and urine culture to be performed at any follow-up visit if there is a suspicion of urinary tract infection based on subject symptoms.  
c 
mPGI-I will be completed on the electronic bladder diary device and should be completed at home prior to the visit. 


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 19/139 
 
 
d 
The retreatment assessment can be performed at the same time as a scheduled visit (if a subject requests retreatment at the scheduled visit) or it can be performed as an unscheduled 
visit if the subject requests treatment between scheduled visits (subject should be requested to complete the 7-day bladder diary prior to attending for the unscheduled retreatment 
assessment visit). The Retreatment Assessment Visit may be repeated, for example, if a subject initially fails the retreatment criteria and makes a request for retreatment at a later time. 
e 
If the retreatment criteria are not met then the subject should continue on the follow-up schedule of the most recent treatment until the subject requests retreatment again.  
f 
Empiric antibiotics should be provided to cover the retreatment procedure 
). However, if there are any concerns 
regarding risk of infection, then adapted antibiotics should be used. This will require waiting for the urine culture results to be available from the Retreatment Assessment Visit before 
dispensing adapted antibiotics. 
 
.  
g 
Bladder diary device to be returned when subject completes study (e.g. in the event of screen failure, EOS Visit, Early Withdrawal Visit, etc.). Site should check if bladder diary has 
been commenced at least 8 days prior to visit. If not commenced then the site should contact the subject to remind the subject (and/or caregiver) to commence with collecting bladder 
diary data. Electronic bladder diary data may be reviewed by the site prior to the visit (recommended to check if bladder diary is fully completed). 
h 
At the Retreatment Visit, vital signs will be recorded before and at least 30 minutes after treatment administration. In addition blood pressure and heart rate will be monitored during 
the entire treatment procedure in subjects with spinal cord injury with lesions above the T6 level.  
i 
Visit window and timing relative to most recent Retreatment Visit 
j 
Telephone Visits may be conducted as clinic visits, if required in the investigator’s opinion. 
k 
Subjects in urodynamic subset only 
l 
Subjects in urodynamic subset only. Empiric antibiotics should be provided to cover the Week 6 urodynamic procedure (
 
). If there are any concerns regarding risk of infection, additional urine for culture and sensitivity should be sent to the central laboratory 1 to 2 weeks prior to the Week 6 
urodynamic assessment and adapted antibiotics based on the urine culture sensitivities should be used instead of empiric antibiotics. 
m 
The EOS Visit will occur at Week 104 for subjects who had their most recent IMP administration at Week 92 or earlier. The EOS Visit will occur at the same time as the Week 12 
postretreatment Visit for subjects who had their most recent study retreatment after Week 92.  
CCI
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 20/139 
 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................ 26 
1 
BACKGROUND INFORMATION ............................................................................ 28 
1.1 
Introduction ................................................................................................................... 28 
1.1.1 
Disease Review ............................................................................................ 28 
1.1.2 
Medical Management and Unmet Need ..................................................... 29 
1.2 
Name and Description of Investigational Medicinal Product ................................... 29 
1.3 
Findings from Nonclinical and Clinical Studies ......................................................... 29 
1.3.1 
Summary of Nonclinical Studies ................................................................ 29 
1.3.2 
Summary of Clinical Studies ...................................................................... 30 
1.4 
Known and Potential Risks and Benefits to Human Subjects .................................. 30 
1.5 
Selection of Investigational Medicinal Products and Dosages .................................. 31 
1.6 
Population to be Studied .............................................................................................. 31 
1.7 
Placebo Usage During Treatment 1............................................................................. 32 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 33 
2.1 
Purpose of the Study ..................................................................................................... 33 
2.2 
Study Objectives ........................................................................................................... 33 
3 
STUDY DESIGN ........................................................................................................... 34 
3.1 
General Design and Study Schema ............................................................................. 34 
3.2 
Primary and Secondary Endpoints and Evaluations ................................................ 38 
3.2.1 
Primary Efficacy Endpoint and Evaluations ............................................. 38 
3.2.2 
Secondary Efficacy Endpoints and Evaluations ........................................ 38 
3.2.2.1 
Overview of Secondary Measures ................................................................ 38 
3.2.2.2 
Hierarchical Analysis of Secondary Endpoints ........................................... 39 
3.2.3 
Safety Endpoints and Evaluations ............................................................. 39 
3.3 
Randomisation and Blinding ....................................................................................... 39 
3.3.1 
Randomisation ............................................................................................ 39 
3.3.2 
Blinding of Investigational Medicinal Product ......................................... 41 
3.3.3 
Maintenance of Randomisation and Blinding ........................................... 41 
3.4 
Study Duration .............................................................................................................. 42 
3.5 
Stopping Rules and Discontinuation Criteria ............................................................ 42 
3.6 
Source Data Recorded on the Case Report Form ...................................................... 42 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 44 
4.1 
Inclusion Criteria .......................................................................................................... 44 
4.2 
Exclusion Criteria ......................................................................................................... 45 
4.3 
Retreatment Criteria .................................................................................................... 47 
4.4 
Subject Withdrawal Criteria and Procedures ........................................................... 47 
5 
STUDY PROCEDURES .............................................................................................. 49 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 21/139 
 
 
5.1 
Study Schedule .............................................................................................................. 49 
5.2 
Study Visits .................................................................................................................... 54 
5.2.1 
Screening Period ......................................................................................... 54 
5.2.1.1 
Screening Visit 1 .......................................................................................... 54 
5.2.1.2 
Screening Visit 2 .......................................................................................... 55 
5.2.2 
Procedures for Screening and Enrolment ................................................. 56 
5.2.2.1 
Informed Consent ......................................................................................... 56 
5.2.2.2 
Other Data to be Collected at Screening ..................................................... 56 
5.2.2.3 
Urinary Tract Ultrasound at Screening ....................................................... 57 
5.2.3 
Treatment Visit (Day 1) ............................................................................... 57 
5.2.4 
Follow-up Period (after First Treatment and Retreatments) .................... 58 
5.2.4.1 
Week 1 and Week 4 Telephone Visits ........................................................... 58 
5.2.4.2 
Week 2 Clinic Visit ....................................................................................... 58 
5.2.4.3 
Week 6 Clinic Visit after First Treatment .................................................... 60 
5.2.4.4 
Week 6 Clinic Visit after Retreatments ........................................................ 61 
5.2.4.5 
Week 12 Clinic Visit ..................................................................................... 62 
5.2.4.6 
Routine Telephone Visits Every 12 weeks .................................................... 62 
5.2.5 
Retreatment Period ..................................................................................... 63 
5.2.5.1 
Retreatment Request at a Scheduled Telephone Follow-up Visit ................ 63 
5.2.5.2 
Retreatment Request during an unscheduled contact .................................. 64 
5.2.5.3 
Retreatment Request at a scheduled Clinic Follow-up Visit ....................... 64 
5.2.5.4 
Retreatment Assessment Visit ...................................................................... 64 
5.2.6 
Retreatment Visit ......................................................................................... 65 
5.2.7 
End of Study Visit or Early Withdrawal Visit ............................................ 66 
6 
TREATMENT OF SUBJECTS ................................................................................... 68 
6.1 
Investigational Medicinal Product Administered ...................................................... 68 
6.1.1 
Dysport® ....................................................................................................... 68 
6.1.2 
Placebo ........................................................................................................ 68 
6.1.3 
Investigational 
Medicinal 
Product 
Storage, 
Preparation 
and 
Accountability .............................................................................................. 68 
6.1.3.1 
Investigational Medicinal Product Storage and Security ............................ 68 
6.1.3.2 
Investigational Medicinal Product Preparation .......................................... 69 
6.1.3.3 
Investigational Medicinal Product Accountability ...................................... 69 
6.1.4 
Investigational Medicinal Product Packaging, Release, and Labelling ... 69 
6.1.5 
Compliance .................................................................................................. 70 
6.2 
Procedures Associated with Investigational Medicinal Product Administration ... 70 
6.2.1 
Antibiotic Prophylaxis ................................................................................. 70 
6.2.2 
Anticoagulant/Antiplatelet Usage............................................................... 70 
6.2.3 
Anaesthesia .................................................................................................. 70 
6.2.4 
Safety Monitoring During Treatment Administration .............................. 71 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 22/139 
 
 
6.3 
Intradetrusor Treatment Paradigm ............................................................................ 72 
6.3.1 
Pretreatment Activities ................................................................................ 72 
6.3.2 
Detailed Administration Guidance ............................................................. 72 
6.3.3 
Post-treatment Observation ........................................................................ 74 
6.4 
Concomitant Medications and Therapies ................................................................... 75 
6.4.1 
Permissible Medications and Therapies ..................................................... 75 
6.4.1.1 
Clean Intermittent Catheterisation .............................................................. 75 
6.4.1.2 
Antibiotic Prophylaxis ................................................................................. 76 
6.4.1.3 
Antibiotics for Symptomatic UTI ................................................................. 83 
6.4.1.4 
Definition of Urinary Tract Infection .......................................................... 83 
6.4.2 
Prohibited Medications/Therapies ............................................................. 83 
6.4.2.1 
Concomitant treatment for Neurogenic Detrusor Overactivity ................... 84 
7 
ASSESSMENT OF EFFICACY .................................................................................. 85 
7.1 
Primary Efficacy Endpoint and Evaluations ............................................................. 85 
7.2 
Secondary Efficacy Endpoints and Evaluations ........................................................ 85 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data ......... 90 
7.3.1 
Bladder Diary .............................................................................................. 90 
7.3.2 
Urodynamic Examination........................................................................... 90 
7.3.2.1 
Subjects in the Urodynamic Subset .............................................................. 90 
7.3.2.2 
Subjects not in the Urodynamic Subset ........................................................ 91 
7.3.3 
Patient Reported Questionnaires ................................................................ 91 
7.3.3.1 
Incontinence Quality of Life ......................................................................... 92 
7.3.3.2 
EuroQol 5-dimension 5-level ....................................................................... 92 
7.3.3.3 
Modified Patient Global Impression of Improvement ................................. 92 
8 
ASSESSMENT OF SAFETY ....................................................................................... 93 
8.1 
Adverse Events .............................................................................................................. 93 
8.1.1 
Definition of an Adverse Event .................................................................. 93 
8.1.2 
Categorisation of Adverse Events ............................................................... 93 
8.1.2.1 
Intensity Classification ................................................................................. 93 
8.1.2.2 
Causality Classification ............................................................................... 93 
8.1.2.3 
Assessment of Expectedness ......................................................................... 93 
8.1.2.4 
Laboratory Test Abnormalities .................................................................... 93 
8.1.2.5 
Abnormal Physical Examination Findings .................................................. 94 
8.1.2.6 
Other Investigation Abnormal Findings ...................................................... 94 
8.1.2.7 
Definition of Urinary Tract Infection Adverse Events ................................. 94 
8.1.2.8 
Adverse Events related to Progression of Neurogenic Detrusor 
Overactivity .................................................................................................. 94 
8.1.2.9 
Neurological Adverse Events in Subjects with Multiple Sclerosis ............... 94 
8.1.2.10 
Suspicion of Exacerbation (Relapse) of Multiple Sclerosis ......................... 94 
8.1.2.11 
Adverse Events of Special Interest ............................................................... 95 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 23/139 
 
 
8.1.3 
Recording and Follow-up of Adverse Events ............................................. 95 
8.1.4 
Reporting of Serious Adverse Events ......................................................... 95 
8.1.5 
Pregnancy .................................................................................................... 97 
8.1.6 
Deaths .......................................................................................................... 97 
8.1.7 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events .......................................................................................................... 98 
8.1.8 
Reporting to Competent Authorities/ Independent Ethics Committees/ 
Institutional Review Boards/ Other Investigators ...................................... 98 
8.2 
Clinical Laboratory Tests ............................................................................................ 98 
8.2.1 
Haematology ................................................................................................ 98 
8.2.2 
Serum Chemistry ......................................................................................... 99 
8.2.3 
Laboratory urinalysis/microscopy .............................................................. 99 
8.2.4 
Urine Culture and Sensitivity ................................................................... 100 
8.2.5 
Pregnancy Test .......................................................................................... 100 
8.2.6 
Antibody Testing ....................................................................................... 100 
8.2.7 
Other Laboratory Safety Tests .................................................................. 100 
8.2.8 
Blood Volume to be Collected During the Study ..................................... 101 
8.3 
Physical Examination ................................................................................................. 101 
8.4 
Vital Signs .................................................................................................................... 101 
9 
STATISTICS ............................................................................................................... 102 
9.1 
Analysis Populations ................................................................................................... 102 
9.1.1 
Populations Analysed ................................................................................ 102 
9.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses ......... 102 
9.2 
Sample Size Determination ........................................................................................ 102 
9.3 
Significance Testing and Estimations ....................................................................... 103 
9.4 
Statistical/Analytical Methods ................................................................................... 104 
9.4.1 
Demographic and Other Baseline Characteristics .................................. 104 
9.4.2 
Homogeneity of Treatment Groups .......................................................... 104 
9.4.3 
Data Imputation ........................................................................................ 104 
9.4.4 
Subject Disposition and Withdrawals ....................................................... 104 
9.4.5 
Efficacy Evaluation ................................................................................... 105 
9.4.6 
Adjustment for Country/Site Effect .......................................................... 106 
9.4.7 
Safety Evaluation ...................................................................................... 106 
9.4.8 
Antibody Testing ....................................................................................... 106 
9.5 
Subgroup Analyses ..................................................................................................... 106 
9.6 
Urodynamics Subset ................................................................................................... 107 
9.7 
Primary Analyses ........................................................................................................ 107 
10 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................. 108 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 109 
11.1 Protocol Amendments and Protocol Deviations ...................................................... 109 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 24/139 
 
 
11.1.1 
Protocol Amendments ............................................................................... 109 
11.1.2 
Protocol Deviations and Exceptions......................................................... 109 
11.2 Information to Study Personnel ................................................................................ 109 
11.3 Study Monitoring ........................................................................................................ 110 
11.4 Audit and Inspection .................................................................................................. 110 
11.5 Data Quality Assurance .............................................................................................. 110 
12 
ETHICS ....................................................................................................................... 111 
12.1 Compliance with Good Clinical Practice and Ethical Considerations .................. 111 
12.2 Informed Consent ....................................................................................................... 111 
12.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................... 112 
12.4 Confidentiality Regarding Study Subjects ............................................................... 112 
13 
DATA HANDLING AND RECORD KEEPING ..................................................... 113 
13.1 Data Recording of Study Data ................................................................................... 113 
13.2 Data Management ....................................................................................................... 113 
13.3 Record Archiving and Retention ............................................................................... 114 
14 
FINANCING AND INSURANCE ............................................................................. 115 
14.1 Contractual and Financial Details ............................................................................. 115 
14.2 Insurance, Indemnity and Compensation ................................................................ 115 
15 
REPORTING AND PUBLICATIONS OF RESULTS ........................................... 116 
15.1 Publication Policy ....................................................................................................... 116 
15.2 Clinical Study Report ................................................................................................. 116 
16 
REFERENCES ............................................................................................................ 117 
17 
LIST OF APPENDICES ............................................................................................ 119 
17.1 Electronic Bladder Diary ........................................................................................... 120 
17.2 Subject and Caregiver Training ................................................................................ 120 
17.3 Screening Bladder Diary Review ............................................................................... 121 
17.3.1 
Assessment of 24 Hour Voided Volume at Screening ............................. 121 
17.4 Request for Retreatment ............................................................................................ 121 
17.5 Alerts and Telephone Reminders .............................................................................. 122 
17.6 Bladder Diary Review and Validity .......................................................................... 122 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 25/139 
 
 
LIST OF TABLES 
Table 1 
List of Protocol Amendments ............................................................................... 4 
Table 2 
Study Procedures and Assessments for First Treatment and Follow-Up 
Until Retreatment or End of Study .................................................................... 16 
Table 3 
Study Procedures and Assessments for Retreatment and Follow-Up Until 
Subsequent Retreatment or End Of Study ....................................................... 18 
Table 4 
Study Procedures and Assessments for First Treatment and Follow-Up 
Until Retreatment or End of Study .................................................................... 50 
Table 5 
Study Procedures and Assessments for Retreatment and Follow-Up Until 
Subsequent Retreatment or End Of Study ....................................................... 52 
Table 6 
Order of Procedures for Screening Visit 1 ........................................................ 54 
Table 7 
Order of Procedures for Screening Visit 2 ........................................................ 55 
Table 8 
Order of Procedures for Treatment Visit (Day 1) ............................................ 57 
Table 9 
Order of Procedures for Week 1 and Week 4 Telephone Visits ..................... 58 
Table 10 
Order of procedures for Week 2 Clinic Visit .................................................... 59 
Table 11 
Order of Procedures for Week 6 Clinic Visit After First Treatment ............. 60 
Table 12 
Order of Procedures for Week 6 Clinic Visit After Retreatments ................. 61 
Table 13 
Order of Procedures for Week 12 Clinic Visit .................................................. 62 
Table 14 
Order of Procedures for Routine 12-Weekly Telephone Visits ...................... 63 
Table 15 
Order of Procedures for Retreatment Assessment Visit.................................. 65 
Table 16 
Order of Procedures for Retreatment Visit ...................................................... 66 
Table 17 
Order of Procedures for End of Study Visit or Early Withdrawal Visit ....... 67 
Table 18 
Procedures for Antibiotic Prophylaxis and Combining Visits ........................ 79 
Table 19 
Efficacy Endpoints During Initial Treatment and Retreatment ..................... 85 
Table 20 
Urodynamic Parameters ..................................................................................... 91 
Table 21 Estimate of minimum delta required for MCC (example urodynamic 
parameter) .......................................................................................................... 107 
Table 22 
List of Protocol Amendments ........................................................................... 125 
 
LIST OF FIGURES 
Figure 1 
Study Design ........................................................................................................ 36 
Figure 2 
Visit Flow Chart .................................................................................................. 37 
Figure 3 
Schematic of Intradetrusor Injection Locations in the Bladder ..................... 74 
Figure 4 
Antibiotic Prophylaxis Options at Screening for Screening Urodynamics 
and Treatment 1 .................................................................................................. 78 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 26/139 
 
 
LIST OF ABBREVIATIONS 
ABBREVIATION 
Wording Definition  
AE 
Adverse event 
AESI 
Adverse event of special interest 
ASIA 
American Spinal Injury Association 
BP 
Blood pressure 
BTX 
Botulinum toxin 
BTX-A 
Botulinum toxin type A 
BTX-A-HAC 
Clostridium BTX-A-haemagglutinin complex 
CA 
Competent Authority 
CFR 
Code of Federal Regulations (of the United States of 
America) 
CIC 
Clean intermittent catheterisation 
CMC SC 
Chemistry Manufacturing and Control Supply Chain 
(relates to sponsor) 
CRO 
Contract Research Organisation 
CSR 
Clinical study report 
Da 
Dalton 
DC 
Detrusor compliance 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EFP 
End fill pressure 
EOS 
End of Study 
EQ-5D-5L 
EuroQol 5-dimension 5-level 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Heart rate 
IB 
Investigator’s brochure 
ICH 
International Conference on Harmonisation 
IDC 
Involuntary detrusor contraction 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
I-QoL 
Incontinence quality of life 
IRB 
Institutional Review Board 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 27/139 
 
 
ABBREVIATION 
Wording Definition  
IRT 
Interactive response technology 
MCC 
Maximum cystometric capacity 
MDP 
Maximum detrusor pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intention to treat  
mPGI-I 
Modified patient global impression - improvement  
MS 
Multiple sclerosis 
NDO 
Neurogenic detrusor overactivity 
PdetMax@1stIDC 
Maximum detrusor pressure at first involuntary detrusor 
contraction 
PP 
Per protocol 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCI 
Spinal cord injury 
SOP 
Standard operating procedure 
U 
Unit 
UI 
Urinary incontinence 
USA 
United States of America 
UTI 
Urinary tract infection 
Vol@1stIDC 
Volume at first involuntary detrusor contraction 
WHODRUG 
World Health Organisation Drug Dictionary 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 28/139 
 
 
1 
BACKGROUND INFORMATION 
1.1 
Introduction 
Dysport® contains botulinum toxin type A (BTX-A) neurotoxin complex derived from the 
bacterium Clostridium botulinum. It prevents acetylcholine release at neuromuscular junctions, 
blocking neuronal transmission which in turn results in weakness or paresis of the injected 
muscle. Over a period of months, nerve function returns, thus treatment may need to be repeated 
periodically as required. Dysport® has been found to be of significant value in the treatment of 
a variety of ophthalmological and neurological disorders including blepharospasm, hemifacial 
spasm, spasticity and cervical dystonia. Further details can be found in the investigator’s 
brochure (IB). 
1.1.1 
Disease Review 
The central and peripheral nervous systems control storage of urine in the bladder and also 
control voiding to eliminate the urine. During the bladder cycle storage phase in healthy adults, 
inhibitory neuronal signals prevent detrusor muscle contraction, while excitatory inputs keep 
the urethral sphincters closed; so that urine in the bladder is stored until voluntary voiding is 
initiated. At the time of voluntary voiding there is a reverse of this process with a coordinated 
contraction of the detrusor muscle and relaxation of the urethral sphincters to enable controlled 
voluntary voiding. Thus, in the normal situation the detrusor muscle only contracts during the 
bladder cycle voiding phase and remains relaxed during the storage phase.  
However, neurological disruption of the lower urinary tract may lead to disinhibition of the 
detrusor muscle and the occurrence of involuntary detrusor contractions (IDCs) during the 
storage phase, also known as detrusor overactivity. Urodynamic testing is required to identify 
IDCs during the bladder cycle storage phase, which typically appear as phasic rises in bladder 
pressure during filling cystometry [1].  
Many diseases and events affecting the nervous system controlling the lower urinary tract can 
result in neurogenic detrusor overactivity (NDO); including multiple sclerosis (MS), spinal cord 
injury (SCI), Parkinson’s disease, stroke and brain tumours. Unlike supraspinal lesions, MS and 
SCI both affect the spinal cord and share common characteristics. Since they are also relatively 
prevalent and often result in NDO, they have been frequently assessed together in clinical 
studies evaluating treatments for NDO. Neurogenic bladder dysfunction affects up to 80% of 
individuals with MS and SCI, with the majority of these individuals having NDO and urinary 
incontinence (UI) [2]. 
The principal NDO-related symptom is UI, which is an involuntary loss of urine due to IDCs 
during the bladder storage phase. Since patients with NDO can experience frequent UI episodes, 
along with other symptoms, such as increased urinary frequency, their quality of life (QoL) may 
be significantly impaired [2].  
Patients with NDO, particularly those with suprasacral lesions, may also have voiding 
dysfunction due to the disruption of the innervation of the urethral sphincter mechanism. Such 
patients require regular clean intermittent catheterisation (CIC) to effectively empty the bladder. 
In addition, the regular emptying of the bladder using CIC may also help reduce UI frequency, 
however UI still often occurs between CIC usages. If there is a loss of coordinated detrusor and 
urethral sphincter activity then the patient may develop detrusor sphincter dyssynergia. This 
can result in markedly elevated bladder pressures due to detrusor contractions occurring against 
a closed bladder outlet. The raised bladder pressure due to NDO and detrusor sphincter 
dyssynergia may contribute to upper urinary tract damage and renal impairment [2]. The regular 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 29/139 
 
 
use of CIC in these patients is key, not only for assisting with voiding and reducing UI, but also 
for managing the raised bladder pressure.  
1.1.2 
Medical Management and Unmet Need 
The goals of treatment of NDO are: 
• 
Treating UI and thus improving QoL 
• 
Reducing bladder pressure to prevent upper urinary tract damage. 
The current first line pharmacologic treatment for NDO consists of oral medications such as 
anticholinergics, which are often used in conjunction with CIC. However, long term treatment 
may be suboptimal, with patients stopping medication due to lack of efficacy and/or bothersome 
side-effects, particularly at the high doses required to control NDO symptoms [2].  
For a long time, surgical bladder augmentation represented the only therapeutic option for 
patients who failed to respond to oral medications. However, this is major reconstructive 
surgery, which carries with it the associated risks of significant invasive open surgery and 
requires a long hospital stay. It is also frequently associated with serious postoperative 
complications such as metabolic disturbance and renal function deterioration [3].  
Intradetrusor injection of BTX-A as a treatment for NDO was first reported in 1991 [4]. 
Subsequently there have been many publications of studies in this indication, using different 
BTX-A compounds [5, 6, 7]. This growing evidence supporting the efficacy and safety of BTX-
A led to international recommendations supporting its use as a second-line therapy. Recently, 
two positive pivotal phase III studies led to the approval of onabotulinumtoxinA in NDO to 
treat UI in many countries including the United States of America (USA) and a number of 
European countries [8, 9]. 
1.2 
Name and Description of Investigational Medicinal Product 
BTX-A is a potent neurotoxin isolated from the bacterium Clostridium botulinum, a gram-
positive, spore-forming anaerobe. BTX-A, a single chain protein with a molecular weight of 
approximately 150000 Daltons (Da), is one of seven different serotypes (classed A through G) 
of botulinum toxin (BTX) produced by this organism. Proteins endogenous to the bacterium 
cleave the single chain protein, resulting in a di-chain neurotoxin containing a light chain 
(molecular weight of approximately 50000 Da) and a heavy chain (molecular weight ca. 
100000 Da) that remain linked by inter-chain disulfide and noncovalent bonds. 
Dysport® is a freeze dried preparation of Clostridium BTX-A-haemagglutinin complex (BTX-
A-HAC) formulated with lactose (bulking agent) and human serum albumin. A more detailed 
description of the product is provided in Section 6.1.1 and Section 6.1.2. 
Further details can also be found in the Dysport® IB. 
1.3 
Findings from Nonclinical and Clinical Studies 
1.3.1 
Summary of Nonclinical Studies 
An extensive nonclinical development program for Dysport® exists, including pharmacology, 
distribution, and toxicology studies (including repeat use). In this program, animals were treated 
by intramuscular administration of Dysport® in striated muscles (gluteus and gastrocnemius 
muscles). To support the NDO indication, the sponsor has added specific in vivo studies 
including pharmacology and toxicology studies in rats and monkeys. In these NDO bridging 
studies, animals were treated by administration of Dysport® into the detrusor muscle. 
A chronic rat model of SCI (considered as a relevant experimental model mimicking the voiding 
pattern of patients with NDO) was used to test the efficacy of intradetrusor injections of 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 30/139 
 
 
Dysport®. When considering the clinically relevant voiding contraction parameters, 22.5 units 
(U) of Dysport®/rat (67.5 U/kg), administered at either four or eight injection points, 
significantly decreased maximal pressure when compared with placebo, without affecting the 
voiding efficiency. In the toxicity studies, the no observed adverse effect level was assessed 
after single administration of Dysport® to be 67 U/kg in rats, and 40 U/kg in monkeys. At doses 
above the no observed adverse effect level, body weight loss, decreased activity, and signs of 
irregular breathing were reported in both species. Doses of 150 U/kg in rat and 80 U/kg in 
monkey were considered to be above the maximal tolerated dose as they were associated with 
mortality. No histopathological modification of the bladder or adjacent reproductive organs was 
detected. 
The program conducted by intradetrusor administration of Dysport® complements the extensive 
program conducted in striated muscles and provides a robust safety and efficacy data set 
enabling proper evaluation adequate to support the use of Dysport® as a treatment in patients 
with NDO. 
Further details may be found in the current Dysport® IB. 
1.3.2 
Summary of Clinical Studies 
The efficacy of Dysport® as a treatment of UI related to NDO has been reported in several 
published studies [10, 11, 12, 13, 14, 15, 16]. Administered doses were 500 U, 750 U, or 1000 U 
in the detrusor muscle. Positive efficacy data were reported with all the doses for UI, 
urodynamic parameters, patient satisfaction and patient QoL. A possible dose effect was 
suggested in some studies, in particular, lower efficacy was observed with Dysport® 500 U 
compared with 750 U for clinical and urodynamic data in a randomised trial of 77 patients with 
NDO [15]. All doses were well tolerated with the only adverse event (AE) of note being 
transient muscular weakness occurring in 14 out of 427 patients (3.3%) after treatment with 
1000 U (10 patients) and 750 U (4 patients) of Dysport®. All of these events resolved 
spontaneously within 4 to 8 weeks [12, 13, 14, 15]. 
An exploratory phase IIa placebo controlled study in 47 adult patients with NDO secondary to 
SCI or MS has been conducted (Ipsen Study Y-52-52120-155) [17]. The study compared a total 
dose of 750 U of Dysport® with placebo, divided as either 15 or 30 intradetrusor injection points 
(all at a volume of 0.5 mL per injection point). A dose of 750 U Dysport® showed a decrease 
in daily incontinence frequency by 76% (15 injection points) and 88% (30 injection points) at 
the 12-week timepoint. Improvements were observed in clinical and urodynamic variables, and 
patient QoL. No unexpected safety events occurred, although three muscular weakness episodes 
were reported as serious adverse events (SAEs) in 3 subjects with SCI treated at the higher 
concentration (750 U divided in 15 injection points), all of whom came from a single research 
site. The findings may therefore be attributed to either a site effect or a drug-concentration effect 
(double the drug concentration per injection site compared to the 30 injection points group). 
The study was not designed for a formal comparison between these two administration modes, 
but the benefit/risk profile appeared to be more favourable at the dose of 750 U in 30 injection 
points compared to 750 U in 15 injection points. The administration at 30 injection points 
remains the current gold standard for injecting BTX-A in the detrusor in NDO patients, and 
will be utilised in this phase III study. 
1.4 
Known and Potential Risks and Benefits to Human Subjects 
Dysport® was first approved for the treatment of blepharospasm and hemifacial spasm in the 
United Kingdom in 1990. Since then Dysport® has been approved in over 80 countries for a 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 31/139 
 
 
range of indications. The posology and safety of Dysport® has been established in numerous 
clinical studies and there is over 20 years of postmarketing experience. 
Dysport® is generally well-tolerated, although temporary paralysis of nontargeted muscle 
groups may occur. AEs resulting from a possible remote spread of the toxin from its site of 
injection have been very rarely reported (including excessive muscle weakness, dysphagia, and 
aspiration pneumonia). Local spread of the toxin from the injection site has also been reported 
and therefore the safety profile is dependent on the site of injection. Most AEs are of mild or 
moderate severity and of limited duration. The profile of adverse reactions reported during 
postmarketing use reflects the pharmacology of the product and AEs seen during clinical 
studies. There have been occasional reports of hypersensitivity. Adverse reactions that are 
considered expected in patients treated across a variety of indications can be found in the current 
Dysport® IB and in the Dysport® Company Core Safety Information. 
In adult patients treated with Dysport® for NDO in the Ipsen phase IIa study [17], the reported 
treatment-related AEs included muscular weakness, asthenia, suprapubic pain, pain in 
extremity, and procedural pain. The benefits included decreased UI with a maximal effect 
observed as early as Week 6. These findings were consistent with improvements reported with 
other BTX-A formulations in phase III placebo controlled studies [8, 9]. Importantly, the 
decrease in UI was consistent with improvements in objective urodynamic parameters and also 
translated into improvements in QoL. 
Based on the available clinical data, the benefit/risk balance of doses of 600 U and 800 U of 
Dysport®, is considered to be favourable for further evaluation in this patient population (see 
Section 1.5). Additional information regarding potential risks and benefits may be found in the 
current Dysport® IB. 
1.5 
Selection of Investigational Medicinal Products and Dosages 
Published data provide information from over 400 patients with NDO treated with doses 
ranging from 500 to 1000 U Dysport®. Across a number of clinical studies, all doses were 
reported as efficacious. However, the 500 U dose has been reported to be less effective 
compared to higher doses [15, 11], while the 1000 U dose was associated with a higher 
incidence of treatment-related AEs [10, 11, 13].  
Results from the Ipsen placebo controlled phase IIa study, which used the exploratory dose of 
750 U, demonstrated a favourable benefit/risk balance [17] (Section 1.3.2). It is expected that a 
difference of 200 U will allow dose discrimination based on the balance between efficacy and 
safety; therefore for phase III, doses of 600 U and 800 U have been selected for further 
evaluation. The dose of 600 U is anticipated to have greater efficacy than that reported with 500 
U; while the 800 U dose is expected to demonstrate a higher degree of efficacy, without 
jeopardizing the safety profile and thus providing a second clinically relevant dose. Thus, it is 
anticipated that with a 200 U difference, the two doses are sufficiently differentiated to enable 
an evaluation of the benefit/risk of both doses without significantly increasing the safety risk.  
1.6 
Population to be Studied 
This study will recruit adult subjects with UI caused by NDO due to either SCI or MS, who 
have not been adequately managed with oral medication.  
In order to ensure a homogenous population of subjects with SCI and MS for efficacy and safety 
assessments, all subjects will be required to be routinely performing CIC to manage bladder 
function, prior to study entry. This is also expected to reduce the risk of urinary tract infection 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 32/139 
 
 
(UTI) due to impaired voiding following BTX-A treatment, which is observed in subjects not 
performing CIC. 
In addition to BTX-A bladder-naive subjects who have never previously received intradetrusor 
BTX-A for UI, the study will also enrol BTX-A bladder-non-naive subjects, who have 
previously received intradetrusor BTX-A for NDO. This will reflect real world usage and it has 
been demonstrated previously that treatment response does not vary significantly following 
retreatment in subjects treated with intradetrusor BTX-A for UI due to NDO [18]. In order to 
be eligible for entry into the study, more than 9 months must have elapsed since any previous 
intradetrusor BTX-A treatment administration.  
1.7 
Placebo Usage During Treatment 1 
The use of placebo during the first IMP treatment administration ensures a rigorous, 
scientifically appropriate study design to assess the efficacy and safety of Dysport® in the 
treatment of UI due to NDO. The use of placebo is justified because: 
• 
Although UI due to NDO is a symptomatic condition, which can lead to significantly 
impaired quality of life, it is not life-threatening. Therefore, a single administration of 
placebo with the opportunity to receive active IMP treatment from as early as 12 weeks 
later ensures that all subjects have the opportunity to receive the active IMP without 
prolonged delay. All further study treatment administrations will be active IMP, for up 
to 2 years post randomisation, ensuring all subjects also have the opportunity to be 
treated with active IMP multiple times during the study, if required. 
• 
Treatment with BTX-A may be associated with an increased risk of UTIs in an NDO 
population that is already susceptible to UTIs. In order to accurately estimate the true 
incidence of UTIs associated with the active IMP, compared to the background incidence 
and the incidence due to the treatment administration procedure, a placebo group 
comparison is required. 
• 
OnabotulinumtoxinA, is not authorised or marketed for the treatment of UI due to NDO 
in all the planned countries where this Dysport® phase 3 program is to be conducted; 
therefore, its use as an active comparator in these countries would not be appropriate. An 
objective of this program is to confirm the efficacy of Dysport® in this indication 
 
 
 
 
The study has been designed to ensure that subjects who receive placebo during the first study 
IMP administration are not exposed to the risks of being untreated for their condition. 
• 
Subjects who require oral medication (such as anticholinergics) to reduce their UI and 
bladder pressure can continue these during the study. This ensures that subjects remain 
managed on their established medications without any withholding of usual oral 
treatment. Thus, there is no risk of being temporarily exposed to “no treatment” if they 
initially receive placebo. 
• 
All subjects in the study will be required to continue to perform CIC to manage their 
bladder function, this ensures that the bladder is regularly and adequately emptied thus 
reducing the risks of upper urinary tract damage and UTIs. Thus any safety risk of 
temporarily receiving inactive IMP are minimised due to the requirement for all subjects 
to use CIC in the study. 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 33/139 
 
 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
Dysport® is currently not registered in the indication of NDO. Following the positive outcome 
of the phase IIa proof-of-concept Study (Y-52-52120-155) [17], this phase III study is intended 
to provide confirmatory evidence of the safety and efficacy of Dysport® for the treatment of 
NDO 
 
2.2 
Study Objectives 
Target Population: 
Subjects with UI caused by NDO due to either SCI or MS, who have not been adequately 
managed with oral medication and who routinely require CIC to manage their bladder function. 
Primary Study Objective:  
• 
To assess the efficacy of two Dysport® doses (600 U and 800 U), compared to placebo 
in reducing UI from Baseline to Week 6 following the first IMP administration. 
Secondary Study Objectives: 
• 
To assess the efficacy of two Dysport® doses (600 U and 800 U), compared to placebo 
in improving bladder diary measures, urodynamic and patient-reported efficacy 
endpoints following the first IMP administration, including assessing duration of effect 
• 
To assess the efficacy of two Dysport® doses (600 U and 800 U) in improving bladder 
diary measures, urodynamic and patient-reported efficacy endpoints following 
retreatment IMP administrations, including assessing duration of effect 
• 
To assess the safety of two Dysport® doses (600 U and 800 U) for the treatment of UI 
due to NDO. 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 34/139 
 
 
3 
STUDY DESIGN 
3.1 
General Design and Study Schema 
This is a phase III, multicentre, randomised, double blind, parallel group, placebo controlled 
study to assess the efficacy and safety of two doses of Dysport® (600 U and 800 U) in adult 
subjects with SCI or MS with UI due to NDO, who have not been adequately managed with 
oral medication and who routinely require CIC to manage their bladder function. The study will 
be conducted at approximately 90 study sites and 330 subjects are planned. 
This study has two treatment periods: 
• 
A double blind placebo controlled period, where subjects receive a single IMP treatment 
administration of either 600 U or 800 U Dysport® or placebo 
• 
A subsequent double blind active treatment period, where subjects can receive multiple 
active IMP retreatment administrations of either 600 U or 800 U Dysport®. This second 
period commences when subjects receive their first study retreatment. 
 
There is significant variability of local clinical practice in conducting urodynamic (filling 
cystometry) assessments. Due to the difficulties in standardising and performing study specific 
urodynamics in a global program, this study will include sites that are unable to alter their local 
site practice sufficiently to perform standardised urodynamics. The study therefore has two 
subsets:  
• 
Urodynamic subset (planned ≥200 subjects) 
o All subjects in this subset must have standardised urodynamics (as described in 
the Study Specific Urodynamic Manual) during Screening and at Week 6 
following each study treatment 
o Screening standardised urodynamics must confirm the presence of NDO 
• 
Non-Urodynamic subset  
o All subjects in this subset must have documented urodynamic proven NDO in 
the 12 months prior to Screening. If not, then urodynamics must be performed 
per local practice during Screening to confirm the diagnosis of NDO 
o Urodynamics will not be performed in the post-screening period in this subset 
 
Eligibility will be assessed during Screening (up to 30 days per subject although can be 
extended in certain circumstances  see Section 5.2.1) although can be extended in certain 
circumstances  see Section 5.2.1). All subjects will complete study Baseline safety and 
efficacy evaluations (including bladder diary, urodynamics (if required) and patient-reported 
outcomes) during this period. Eligible subjects will be randomised to receive either 600 U 
Dysport®, 800 U Dysport®, or placebo during the initial IMP administration which will occur 
up to 14 days after screening period (can be extended where UTI prevents administration of 
IMP  see Section 5.2.3). The IMP will be administered into the detrusor via cystoscopy divided 
into 30 injection points of 0.5 mL each, which will be evenly distributed throughout the detrusor 
(avoiding the trigone). See Section 6 for full details of the treatment procedure. The Screening 
period is composed of two visits (Screening Visit 1 and Screening Visit 2). However, 
particularly for subjects not undergoing urodynamics at Screening, the investigator may choose 
to skip Screening Visit 2 and proceed directly to the treatment visit (combining Screening Visit 
2 with treatment visit procedures and assessments). See Section 5.2.3 for further details. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 35/139 
 
 
 
Subjects will be followed-up by telephone at Week 1 and Week 4; and will attend clinic visits 
at Week 2, Week 6 (primary study timepoint), and Week 12. Thereafter telephone visits will be 
scheduled every 12 weeks until end of study (EOS), or until retreatment is required. Details of 
the procedures performed at each study visit are described in Section 5. 
The study design allows for subjects to request retreatment if clinically required after a 
minimum of 12 weeks following the previous IMP administration (see Section 5.2.5.3). The 
retreatment request may come at a scheduled visit or between visits. Subjects who request 
retreatment will be assessed and if they satisfy the retreatment criteria (Section 4.3) a 
Retreatment Visit will be scheduled for administration of the retreatment. All retreatments 
within the study are double blind treatments of either 600 U or 800 U of Dysport®. Follow-up 
after each retreatment will be per the same schedule as the first treatment (although antibody 
testing at Week 6 is performed only after the first IMP administration).  
Subjects should exit the study 104 weeks (2 years) after the first IMP administration. However, 
all subjects will be followed-up for at least 12 weeks after each retreatment; therefore, a subject 
who receives a study retreatment between Week 92 and Week 104 will have their study exit 
delayed until the Follow-up Visit scheduled for 12 weeks after their most recent retreatment. 
An overview of the study design is presented in Figure 1 and a visit flow chart is presented in 
Figure 2.  


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 36/139 
 
 
Figure 1 Study Design 
 
U=unit; EOS=End of Study. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 37/139 
 
 
Figure 2 Visit Flow Chart 
 
EOS=End of Study 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 38/139 
 
 
3.2 
Primary and Secondary Endpoints and Evaluations 
3.2.1 
Primary Efficacy Endpoint and Evaluations 
Mean change from study Baseline (assessed at Screening) to Week 6 after the first IMP 
administration in the weekly number of UI episodes: 
• 
measured on a 7-day bladder diary. 
Seven-day bladder diaries that contain data recorded on at least 5 days will be included in the 
analysis. Where there are 1 or 2 days with no data, the arithmetic means will be used from the 
bladder diary parameters recorded on the 5 or 6 days that do have events recorded; for the days 
with no recorded bladder diary data. 
3.2.2 
Secondary Efficacy Endpoints and Evaluations 
3.2.2.1 
Overview of Secondary Measures 
Mean change from study Baseline (assessed at Screening) or from treatment cycle baseline 
(assessed at Retreatment Assessment Visit) to post-treatment timepoints (timepoints listed in 
Table 4 and Table 5): 
• 
Bladder diary measures: 
• 
weekly number of UI episodes  
• 
daily urinary frequency (total, spontaneous void only, CIC only) 
• 
24-hour voided volume (total, spontaneous void only, CIC only) 
• 
volume per void (total, spontaneous void only, CIC only). 
• 
Urodynamic filling cystometry measures (urodynamic subset only): 
• 
maximum cystometric capacity (MCC) 
• 
maximum detrusor pressure (MDP) during storage 
• 
volume at first involuntary detrusor contraction (Vol@1stIDC) (subjects without a 
post-treatment IDC will have their Vol@1stIDC imputed from their MCC) 
• 
maximum detrusor pressure at first involuntary detrusor contraction 
(PdetMax@1stIDC) 
• 
end fill pressure (EFP) 
• 
detrusor compliance (DC). 
• 
Patient-reported outcome questionnaires: 
• 
incontinence quality of life (I-QoL) total summary score 
• 
EuroQol 5-dimension 5-level (EQ-5D-5L) 
• 
modified patient global impression - improvement (mPGI-I) score (to be assessed 
at each timepoint without comparison to baseline). 
Proportion of subjects at post-treatment timepoints following the first and subsequent 
treatments with: 
• 
no episodes of UI (i.e. continence is achieved) 
• 
UI response at several levels (i.e. ≥30% improvement, ≥50% improvement, ≥75% 
improvement etc.) 
• 
no IDCs on urodynamic assessment (i.e. urodynamic cure is achieved) (urodynamic 
subset only). 
Duration of effect following the first and subsequent treatments measured by: 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 39/139 
 
 
• 
time to request retreatment 
• 
time to eligibility for retreatment 
• 
time between treatments. 
3.2.2.2 
Hierarchical Analysis of Secondary Endpoints 
A hierarchical analysis will be performed in the order listed for the following secondary efficacy 
endpoints at Week 6 after the first IMP administration: 
(1) 
Proportion of subjects with no episodes of UI (i.e. continence is achieved): 
 
measured by 7-day bladder diary. 
(2) 
Mean change from study Baseline (assessed at Screening) in the I-QoL total summary 
score: 
 
measured by patient-reported questionnaire. 
See Section 9.3 for further details regarding control of type one error for these secondary 
efficacy endpoints. See Table 19 in Section 7.2 for the full list of secondary efficacy endpoints 
for both the initial treatment and for retreatments. 
3.2.3 
Safety Endpoints and Evaluations 
Safety will be assessed throughout the study by evaluating: 
• 
AEs 
• 
vital signs 
• 
laboratory blood parameters (haematology and serum chemistry) 
• 
laboratory urine parameters (laboratory urinalysis/microscopy, culture and sensitivity) 
• 
development of BTX-A antibodies 
• 
usage of concomitant medications and therapies. 
Timepoints for safety evaluations are detailed in Table 4 and Table 5. 
3.3 
Randomisation and Blinding 
3.3.1 
Randomisation 
The randomisation will be done in a 2:2:1:1 ratio to one of four treatment sequences: 
Sequence 
Subjects 
Treatment 1 
Subsequent retreatment(s) 
1 
110 subjects 
600 U Dysport® 
600 U Dysport® 
2 
110 subjects 
800 U Dysport® 
800 U Dysport® 
3 
55 subjects 
Placebo 
600 U Dysport® 
4 
55 subjects 
Placebo 
800 U Dysport® 
During analysis of study Treatment 1, the two placebo containing sequences will be pooled into 
a single arm. 
Randomisation will be stratified by: 
1) 
Aetiology of NDO (SCI or MS) 
2) 
Previous intradetrusor BTX-A usage for UI (BTX-A naive vs. BTX-A non-naive in the 
bladder). 
The sponsor’s randomisation manager who is a statistician independent from the study, will 
prepare three lists which will be performed in blocks and will be based on computer-generated 
randomisation lists: 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 40/139 
 
 
• 
List A: a list of randomisation numbers, which will be produced in an unbalanced ratio 
2:2:1:1 for the four treatment sequences and which will be stratified by aetiology and 
prior intradetrusor BTX-A usage for UI 
• 
List B: a list of double blind treatment numbers, which will be specified on the treatment 
packs to be dispatched to the sites in order to dispense the drug in Treatment 1 and 
possibly for subsequent retreatments. It will be produced in a balanced ratio 1:1:1 for 
600 U Dysport®, 800 U Dysport® and placebo 
• 
List C: a list of double blind treatment numbers, which will be specified on the treatment 
packs to be dispatched to the sites in order to dispense the drug for retreatments (but not 
in Treatment 1). It will be produced in a balanced ratio 1:1 for 600 U Dysport® and 800 U 
Dysport®. 
 
In order to maintain a balanced treatment sequence ratio of 2:2:1:1 in both the urodynamic and 
non-urodynamic subsets, the randomisation number(s) may be skipped in accordance with the 
procedure below. The purpose of skipping randomisation number(s) will be to ensure that the 
number of subjects in each treatment sequence will remain within five subjects of the required 
number to maintain a treatment sequence ratio of 2:2:1:1 within the subset. Any skipped 
randomisation number(s) will then be used in priority at subsequent randomisations. This 
process will be programmed into the interactive response technology (IRT) and will occur 
automatically (with no human intervention).  
 
Using the following values for the concerned subset: 
a = number of subjects in sequence 1 
b = number of subjects in sequence 2 
c = number of subjects in sequence 3 
d = number of subjects in sequence 4  
 
The IRT will skip randomisation number(s) to maintain the following conditions: 
• 
RANGE(a/2,b/2,c,d)<5 
• 
RANGE(a,b)<5 
• 
RANGE(c,d)<5 
• 
RANGE(a,c+d)<5 
• 
RANGE(b,c+d)<5 
• 
RANGE(a+c,b+d)<5  
 
The assignment of randomisation and treatment numbers at drug dispensing (at Treatment 1 
and subsequent retreatments) will be managed by IRT. 
After eligibility is confirmed at the Treatment Visit (Day 1), subjects will be assigned by IRT 
to a randomisation number and to the associated treatment sequence, in a sequential order 
within each site (and within each level of strata). A treatment number will also be allocated by 
the IRT each time the drug is dispensed, according to the allocated treatment sequence. The 
IRT will also manage all the logistical aspects of treatments and associated incidents (e.g. drug 
supplies, replacement of lost, damaged, quarantined, expiring and expired kits). 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 41/139 
 
 
This service provides investigators, site co-ordinators and project team members with a 24 hour 
per day, 7 day per week service (additional details may be found in the IRT reference manual 
provided to each site). In case of medical or technical randomisation or dispensation queries, a 
24-hour helpline is available  see supporting information in the investigator site file. 
Randomised subjects who terminate their study participation for any reason before 
administration of the first dose of randomised IMP will retain their randomisation and treatment 
numbers (i.e. these numbers will not be reused). The next subject will be given another 
randomisation number and another treatment number, even if he/she should receive the same 
treatment.  
Subjects who leave the study early will not be replaced. 
The sponsor’s randomisation manager will keep the master lists. A copy of the list of treatment 
numbers (Lists B and C) will be confidentially supplied to the Chemistry Manufacturing and 
 
 
 to the Contract Research Organisation (CRO) in charge of IRT. Similarly, a 
copy of the list of randomisation numbers (List A) will also be confidentially supplied to the 
CRO in charge of IRT will be kept confidential in a secure location. Access to the randomisation 
lists must be restricted until authorisation is given to release them for final analysis. 
3.3.2 
Blinding of Investigational Medicinal Product 
All IMP administrations, including retreatments, will be double blind, although only the first 
treatment is placebo controlled. Subjects, investigators and all study staff will remain blinded 
to treatment assignment throughout the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
  
  
 
 
 
 
  
3.3.3 
Maintenance of Randomisation and Blinding 
The dose(s) administered as allocated by the randomisation sequence should remain blinded 
throughout the study. However, in the event of an SAE or unexpected AE, which requires the 
identification of the study treatment group, the investigator should first contact the 
pharmacovigilance representative as outlined in the protocol. The investigator should then 
review the case status and all pertinent information with the representative from Global Patient 
Safety who will consult with the therapeutic area drug safety physician prior to any code break.  
In case of a medical emergency requiring an urgent unblinding, the investigator and/or 
Global Patient Safety may break the blind by asking the IRT to obtain the subject’s treatment 
identification. In addition, hard copy sealed code-break envelopes will be prepared by the 
sponsor’s randomisation manager, and held by Global Patient Safety at Ipsen in case of IRT 
CCI
PPD


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 42/139 
 
 
failure. The final decision to unblind rests with the investigators as they are ultimately 
responsible for subject safety. 
If a code break is performed using the IRT, the investigator must store the email notification 
revealing unblinded treatment in a sealed envelope. The investigator will then sign, date, and 
provide reason for the code break on the Emergency Code break form, and on the sealed 
envelope. The date and reason for identifying the treatment group will be recorded in the 
electronic case report form (eCRF). 
3.4 
Study Duration 
For subjects, the study will consist of a Screening period of up to 30 days (can be extended in 
certain circumstances  see Section 5.2.1), with randomisation at the Treatment Visit (Day 1) 
up to 14 days later (can be extended if UTI prevents IMP administration - see Section 5.2.3). 
Follow-up for each subject is planned to be 24 months (104 weeks) after the first IMP 
administration. However, as retreatments can occur up to Week 104, and 12 weeks of follow-
up will occur following each study retreatment, the maximum planned subject participation 
following randomisation is 116 weeks. Each subject’s participation in the study will be 
considered to have ended at the time of their last study visit, including follow-up for AEs after 
the last IMP administration:  
• 
 
 
 
 
 
 The study 
will be considered to have started when the first subject has provided signed informed consent 
and to have ended after the last subject has completed their last study visit.  
3.5 
Stopping Rules and Discontinuation Criteria 
During the conduct of the study, SAEs will be reviewed (see Section 8.1.4) as they are reported 
from the study sites to identify safety concerns.  
The sponsor may terminate this study at any time. Reasons for termination include but are not 
limited to: 
• 
The incidence or severity of AEs in this or other studies point to a potential health hazard 
for study subjects 
• 
Insufficient subject enrolment 
• 
Any information becoming available that substantially changes the expected benefit/risk 
profile of the study treatments. 
A subject may discontinue participation in the study at any time for any reason (e.g. lack of 
efficacy, withdrawal of consent, AE) (see Section 4.4).  
The investigator and/or sponsor can withdraw a subject from the study at any time for any 
reason (e.g. protocol deviation as defined in Section 11.1.2, noncompliance with the protocol 
conditions or AE). 
3.6 
Source Data Recorded on the Case Report Form 
Data will be collected by using an eCRF in compliance with Food and Drug Administration 
(FDA) 21 Code of Federal Regulations (CFR) Part 11. As required by Good Clinical Practice 
(GCP), the sponsor-assigned or sponsor designee-assigned monitor will verify, by direct 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 43/139 
 
 
reference to the source documents, that the data required by the protocol are accurately reported 
on the eCRF.  
The source documents must, at 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 International Conference on Harmonisation (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 (e.g. hospital records, clinical 
and office charts, laboratory notes, memoranda, subject diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medicotechnical departments involved 
in the clinical study). 
The subject must have consented to their medical records being viewed by the sponsor or 
sponsor’s representative’s authorised personnel, and by local, and possibly foreign, Competent 
Authorities (CAs). This information is included in the informed consent. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 44/139 
 
 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
The following inclusion criteria will be assessed at the beginning of the Screening process: 
1) 
Written informed consent prior to any study related procedure. 
2) 
Male or female, aged 18 to 80 years inclusive. 
3) 
UI for at least 3 months prior to Screening as a result of NDO due to SCI or MS. 
4) 
Subjects with SCI must have a stable neurological injury at T1 level or below which 
occurred at least 6 months prior to Screening. 
OR 
Subjects with MS must be clinically stable in the investigator’s opinion, with no 
exacerbation (relapse) of MS for at least 3 months prior to Screening. 
5) 
Subjects in the non-urodynamic subset only, must have NDO (defined as the presence of 
involuntary detrusor contractions during the storage phase of urodynamic filling 
cystometry) on a historic urodynamic assessment performed in the 12 months prior to 
Screening  
 If urodynamics are not performed in the 12 months prior to Screening or if 
results are not available, then a urodynamic filling cystometry assessment must 
be performed during Screening, per local practice (see inclusion criterion # 16). 
6) 
Subjects must have an inadequate response 
 of oral medications used 
in the treatment of NDO (e.g. anticholinergics, beta-3 agonists) and/or have intolerable 
side-effects. 
7) 
 
  
8) 
 
 
 
9) 
Routinely performing CIC to ensure adequate bladder emptying 
 
 
 
 
 
 
 
 
11) 
Female subjects of childbearing potential must have a negative pregnancy test result and 
be willing to use reliable contraceptive measures throughout study participation. 
Reliable forms of contraception are: 
• 
hormonal contraceptives (e.g. oral, patch, injection) 
• 
double barrier (e.g. male condom plus spermicide, or female diaphragm plus 
spermicide) 
• 
intrauterine device 
• 
male partner has had a vasectomy 
• 
total abstinence from intercourse with male partners (periodic abstinence is not 
acceptable). 
CCI
CCI
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 45/139 
 
 
Female subjects meeting any of the following criteria are not considered to be of 
childbearing potential: 
• 
postmenopausal (≥47 years of age and amenorrhoeic for at least 12 consecutive 
months) 
• 
have been sterilised surgically (e.g. bilateral tubal ligation) 
• 
have had a hysterectomy 
• 
have had a bilateral oophorectomy. 
12) 
Documented urinary tract ultrasound is available in the 6 months prior to Screening, 
confirming that no medical issues exist that would preclude entry to the study (e.g. 
bladder stones or unexplained renal mass).  
• 
If not performed in the 6 months prior to Screening or results are not available, 
then a urinary tract ultrasound must be conducted during Screening. 
13) 
Ability to complete all study requirements in the opinion of the investigator, including 
regularly completing the 7-day bladder diary and attending all scheduled study visits. 
The caregiver may assist with the completion of study documentation and procedures 
(including the bladder diary and questionnaires), if required.  
The following inclusion criteria will be assessed following completion of screening bladder 
diary: 
14) 
An average of at least two episodes per day of UI recorded on the screening bladder 
diary. 
 
 
 
 
 
 
 
 
  
 
 
 
4.2 
Exclusion Criteria 
The following exclusion criteria will be assessed throughout the Screening process: 
1) 
Any current condition (other than NDO) that may impact on bladder function, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CC
I
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 46/139 
 
 
2) 
Previous or current, tumour or malignancy affecting the spinal column or spinal cord, or 
any other nonstable cause of SCI. 
3) 
Surgery less than 6 months prior to Screening for bladder stones. 
4) 
Surgery less than 6 months prior to Screening for uterine prolapse, cystocele or rectocele. 
5) 
Previous open surgery for NDO, e.g. augmentation cystoplasty. 
6) 
Previous urethral stent placement or sphincterotomy. 
7) 
Previous or current diagnosis of, or symptoms/signs/investigations suggestive of, 
significant urological or pelvic disease, 
 
 
 
 
 
 
 
 
 
 
 
 
 
8) 
Previous or current uninvestigated haematuria. 
 
 
. 
9) 
Any condition that will prevent cystoscopic treatment administration or CIC usage, e.g. 
urethral strictures. 
10) 
Current indwelling bladder catheter, or removal of indwelling bladder catheter less than 
4 weeks prior to Screening. 
11) 
BTX-A treatment within 9 months prior to Screening for any urological condition (e.g. 
detrusor or urethral sphincter treatments). 
12) 
BTX-A treatment within 3 months prior to Screening for any non-urological condition. 
13) 
Bladder instillation with any pharmacologic agent less than 3 months prior to Screening. 
14) 
Use of capsaicin or resiniferatoxin less than 6 months prior to Screening.  
15) 
Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence 
within 4 weeks prior to Screening. Any implanted neuromodulation device must be 
switched off at least 4 weeks prior to Screening and must remain off throughout study 
participation. 
16) 
Any concomitant therapy usage that, in the investigator’s opinion, would interfere with 
the evaluation of safety or efficacy of the IMP, and/or confound the study results. 
17) 
History of chronic drug or alcohol abuse. 
18) 
Female subject who is pregnant or planning to become pregnant during the study, or is 
currently lactating (breastfeeding). 
19) 
Any medical condition or disease that might interfere with neuromuscular function, 
 
. 
20) 
Use of medications that affect neuromuscular transmission, 
 
 
  
 
 
 
CCI
CCI
C
C
I
C
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 47/139 
 
 
22) 
Known hypersensitivity to BTX-A or to any components in the IMP formulation 
(including cow’s milk protein). 
23) 
History of allergy to, or intolerance to, the anaesthetic or antibiotic agents that the 
investigator intends to use during the study.  
24) 
Unable to stop medications with anticoagulant/antiplatelet effects for at least 3 days prior 
to each IMP administration and to recommence the day following each IMP 
administration (low molecular weight heparins may be used within 3 days of IMP 
administration). 
25) 
Any condition that may cause excessive bleeding (e.g. haemophilia or clotting factor 
deficiencies). 
26) 
Any condition or situation which, in the investigator’s opinion, puts the subject at 
significant risk, may confound the study results, or may interfere with the subject’s 
participation in the study. 
27) 
Treatment with any new investigational drug or device in the 4 weeks prior to Screening 
or scheduled to be used during the study period. 
 
 
 
 
 
 
  
 
 
 
 
4.3 
Retreatment Criteria 
For a study retreatment to occur all of the below retreatment criteria must be met. 
Assessed prior to or during the Retreatment Assessment Visit: 
1) 
Retreatment requested by subject; 
2) 
More than 12 weeks (84 days) since the previous IMP administration; 
3) 
 
 
 
 
 
5) 
In the investigator’s opinion it is safe and appropriate to provide a retreatment. 
 
 
 
4.4 
Subject Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each subject is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy (see Section 8.1.5), or other reasons concerning the health or wellbeing of the 
subject, or in the case of lack of cooperation. In addition, a subject may be withdrawn from the 
study as described in Section 3.5 (stopping rules and discontinuation criteria), Section 6.4.2 
(concomitant medications not permitted) and Section 8.1.7 (discontinuation due to AEs).  
CCI
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 48/139 
 
 
Should a subject decide to withdraw from the study after administration of IMP, or should the 
investigator decide to withdraw the subject, all efforts will be made to complete and report the 
observations up to the time of withdrawal as thoroughly as possible. A complete final evaluation 
at the time of the subject’s withdrawal should be made (see Section 5.2.7) and an explanation 
given of why the subject is withdrawing or being withdrawn from the study.  
As far as possible, all efforts should be made to ensure the subject attends the Withdrawal (EOS) 
Visit, with at least 12 weeks follow-up after their most recent IMP administration.  
The reason for and date of withdrawal from the study must be recorded on the eCRF. If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an AE, or clinically significant laboratory test abnormality, monitoring will 
continue until the event has resolved or stabilised, until the subject is referred to the care of a 
local health care professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made. The specific AE must be recorded on the eCRF.  


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 49/139 
 
 
5 
STUDY PROCEDURES 
5.1 
Study Schedule 
The schedule of procedures and assessments during the study is summarised in Table 4 for 
Screening and Treatment 1 follow-up and in Table 5 for retreatment assessment and follow-up. 


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 50/139 
 
 
Table 4 
Study Procedures and Assessments for First Treatment and Follow-Up Until Retreatment or End of Study 
 
Screening 
Treatment 
Post-Treatment 1 Follow-up 
End of Study/ 
Withdrawal  
Screening 
Visit 1 
Screening 
Visit 2 
[i] [r] 
Treatment Visit  
(Day 1)  
[i] 
Week 1 
Visit  
(Day 8) 
Week 2  
Visit 
(Day 15) 
Week 4  
Visit 
(Day 29) 
Week 6  
Visit 
(Day 43) 
Week 12 
Visit 
(Day 85) 
Routine Visit 
every 12 weeks (84 
days) until 
retreatment occurs 
End of Study 
Visit 
(Week 104 to 
Week 116) [q] 
Clinic 
Clinic 
Clinic 
Telepho
ne [n] 
Clinic 
Telepho
ne [n] 
Clinic 
Clinic 
Telephone [n] 
Clinic 
Visit window (days) 
-30 to -1 [r] 
Within 14 days of 
Screening Visit 2 [i] ±3 days 
±3 days 
±3 days 
±3 days 
±7 days  
±14 days 
±14 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
 
 
 
 
Medical/surgical/NDO history  
X 
 
 
 
 
 
 
 
 
 
Prior medications and therapies 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Concomitant medications and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant treatments for NDO [a] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (symptom-based) 
X 
 
 
 
 
 
X 
 
 
X 
Vital signs 
X [f] 
 
X [m] 
 
X 
 
X 
X 
 
X 
Urinary tract ultrasound  
X [g] 
 
 
 
 
 
 
 
 
 
Urine pregnancy test [b] 
X 
 
X 
 
 
 
 
 
 
 
Laboratory urinalysis/microscopy [c] 
X 
 
 
 
 
 
X 
X 
 
X 
Urine culture [c]  
X 
 
 
 
 
 
X [o] 
 
 
 
 
 
 
 
 
 
 
] 
 
 
 
Haematology and serum chemistry 
X 
 
 
 
 
 
X 
 
 
X 
Anti BTX-A antibodies 
X 
 
 
 
 
 
X 
 
 
X 
Dispense bladder diary & training [d] 
X 
 
 
 
 
 
 
 
 
 
Bladder diary review  
 
X [k] 
 
 
X[k] 
 
X[k] 
X [k] 
X [k] 
X [k] 
I-QoL and EQ-5D-5L 
 
 
X 
 
 
 
X 
X 
 
X 
mPGI-I [e] 
 
 
 
 
X 
 
X 
X 
X 
X 
Urodynamics (filling cystometry)  
 
X [l] 
 
 
 
 
X [o] 
 
 
 
Randomisation  
 
 
X 
 
 
 
 
 
 
 
IMP administration  
 
 
X 
 
 
 
 
 
 
 
BTX-A=botulinum toxin type A; EOS=End of Study; EQ-5D-5L=EuroQol 5-dimension 5-level; IMP=investigational medicinal product; I-QoL=incontinence quality of life;  
mPGI-I=modified patient global impression - improvement; NDO=neurogenic detrusor overactivity. 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 51/139 
 
 
a 
Concomitant treatments for NDO (e.g. anticholinergics, beta-3 agonists, clean intermittent catheterisation rate) should remain stable during the first 12 weeks after Treatment 1 
(preferably for the entire duration of the study). 
b  
Pregnancy test to be performed only in females of childbearing potential. Must be performed prior to randomisation on the day of treatment. 
c 
Laboratory urinalysis/microscopy and urine culture to be performed at any follow-up visit if there is a suspicion of urinary tract infection based on subject symptoms.  
d 
Bladder diary device to be returned when subject completes study (e.g. in the event of screen failure, EOS Visit, Early Withdrawal Visit, etc.) 
e  
mPGI-I will be completed on the electronic bladder diary device and should be completed at home prior to the visit. 
f  
Body weight and height will be measured at Screening Visit 1 only. 
g  
Urinary tract ultrasound is only required if no adequate documented urinary tract ultrasound is available in the 6 months prior to Screening (see inclusion criterion #12). 
h 
 
 
 
i 
Treatment Visit should occur within 14 days of Screening Visit 2 (where a UTI occurs and impacts the ability to perform IMP administration the time to the Treatment Visit can be 
extended until the UTI is resolved). Both visits may be performed on the same day, as long as all Screening Visit 2 procedures are performed prior to the Treatment Visit procedures 
and antibiotics were commenced 3 or more days prior to treatment. 
j 
 
 
  
k 
Site should check if bladder diary has been commenced at least 8 days prior to visit. If not commenced then site should contact subject to remind subject (and/or caregiver) to commence 
collecting bladder diary data. Electronic bladder diary data may be reviewed by the site prior to the visit (recommended, to check if bladder diary is fully completed). 
l 
 
 
 
m 
At the Treatment Visit, vital signs will be recorded before and at least 30 minutes after treatment administration. In addition blood pressure and heart rate will be monitored during the 
entire treatment procedure in subjects with spinal cord injury with vertebral lesions above the T6 level. 
n 
Telephone Visits may be conducted as clinic visits, if required in the investigator’s opinion. 
o 
Subjects in urodynamic subset only. 
p 
 
 
  
q 
The EOS Visit should be scheduled for Week 104 for subjects who had their most recent IMP administration at Week 92 or earlier; and at the same time as the Week 12 postretreatment 
Visit for subjects who had their most recent study retreatment after Week 92. 
r 
The time to Screening Visit 2 can be extended to obtain an appropriately and fully completed bladder diary or to obtain a valid bladder diary. In addition, where a UTI occurs after 
completion of the bladder diary and impacts the ability to perform urodynamics the time to Screening Visit 2 can be extended until the UTI is resolved. 
 
CCI
CCI
CCI
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 52/139 
 
 
Table 5 
Study Procedures and Assessments for Retreatment and Follow-Up Until Subsequent Retreatment or End Of Study 
 
Retreatment 
Postretreatment Follow-up 
End of Study/ 
Withdrawal  
Retreatment 
Assessment 
Visit  
[d] 
Retreatment 
Visit  
(Day 1 of 
treatment cycle)  
Week 1  
Visit [i] 
(Day 8) 
Week 2  
Visit [i] 
(Day 15) 
Week 4 
Visit [i] 
(Day 29) 
Week 6  
Visit [i] 
(Day 43) 
Week 12  
Visit [i] 
(Day 85) 
Routine Visit 
every 12 weeks 
(84 days) 
(until retreatment 
occurs) [i] 
End of Study Visit 
(Week 104 to Week 
116 relative to date 
of first treatment) 
[m] 
Clinic 
Clinic 
Telephone 
[j] 
Clinic 
Telephone 
[j] 
Clinic 
Clinic 
Telephone [j] 
Clinic 
Visit window (days) 
Within 14 
days of 
request 
Within 14 days 
of confirmed 
eligibility 
±3 days [i] ±3 days [i] ±3 days [i] ±3 days [i] ±7 days [i] 
±14 days [i] 
±14 days 
Concomitant medications and therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant treatments for NDO 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retreatment criteria  
X [e] 
X [e] 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination (symptom based) 
X 
 
 
 
 
X 
 
 
X 
Vital signs 
X 
X [h] 
 
X 
 
X 
X 
 
X 
Urine pregnancy test [a] 
 
X 
 
 
 
 
 
 
 
Laboratory urinalysis/microscopy [b] 
X 
 
 
 
 
X 
X 
 
X 
Urine culture [b]  
X 
 
 
 
 
X [k] 
 
 
 
 
 
 
 
 
 
 
 
 
 
Haematology and serum chemistry 
X 
 
 
 
 
X 
 
 
X 
Anti BTX-A antibodies 
X 
 
 
 
 
 
 
 
X 
Bladder diary review 
X [g] 
 
 
X [g] 
 
X [g] 
X [g] 
X [g] 
X [g] 
I-QoL and EQ-5D-5L 
X 
 
 
 
 
X 
X 
 
X 
mPGI-I [c] 
X 
 
 
X 
 
X 
X 
X 
X 
IMP administration 
 
X 
 
 
 
 
 
 
 
Urodynamics (filling cystometry) 
 
 
 
 
 
X[k] 
 
 
 
BTX-A=botulinum toxin type A; EOS=End of Study; EQ-5D-5L=EuroQol 5-dimension 5-level; IMP=investigational medicinal product; I-QoL=incontinence quality of life; mPGI-I=modified 
patient global impression - improvement; NDO=neurogenic detrusor overactivity. 
a 
Pregnancy test to be performed only in females of childbearing potential. Must be performed prior to retreatment administration on the day of retreatment. 
b 
Laboratory urinalysis/microscopy and urine culture to be performed at any follow-up visit if there is a suspicion of urinary tract infection based on subject symptoms.  
c 
mPGI-I will be completed on the electronic bladder diary device and should be completed at home prior to the visit. 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 53/139 
 
 
d 
The retreatment assessment can be performed at the same time as a scheduled visit (if a subject requests retreatment at the scheduled visit) or it can be performed as an unscheduled 
visit if the subject requests treatment between scheduled visits (subject should be requested to complete the 7-day bladder diary prior to attending for the unscheduled retreatment 
assessment visit). The Retreatment Assessment Visit may be repeated, for example, if a subject initially fails the retreatment criteria and makes a request for retreatment at a later time. 
e 
If the retreatment criteria are not met then the subject should continue on the follow-up schedule of the most recent treatment until the subject requests retreatment again.  
f 
 
 
 
  
g 
Bladder diary device to be returned when subject completes study (e.g. in the event of screen failure, EOS Visit, Early Withdrawal Visit, etc.). Site should check if bladder diary has 
been commenced at least 8 days prior to visit. If not commenced then the site should contact the subject to remind the subject (and/or caregiver) to commence with collecting bladder 
diary data. Electronic bladder diary data may be reviewed by the site prior to the visit (recommended to check if bladder diary is fully completed). 
h 
At the Retreatment Visit, vital signs will be recorded before and at least 30 minutes after treatment administration. In addition blood pressure and heart rate will be monitored during 
the entire treatment procedure in subjects with spinal cord injury with lesions above the T6 level.  
i 
Visit window and timing relative to most recent Retreatment Visit 
j 
Telephone Visits may be conducted as clinic visits, if required in the investigator’s opinion. 
k 
Subjects in urodynamic subset only 
l 
 
 
 
m 
The EOS Visit will occur at Week 104 for subjects who had their most recent IMP administration at Week 92 or earlier. The EOS Visit will occur at the same time as the Week 12 
postretreatment Visit for subjects who had their most recent study retreatment after Week 92.  
 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 54/139 
 
 
5.2 
Study Visits 
5.2.1 
Screening Period 
The Screening period (Days -30 to -1) consists of two study visits: 
• 
Screening Visit 1 
• 
Screening Visit 2 
The time to Screening Visit 2 can be extended to more than 30 days to obtain an appropriately 
and fully completed bladder diary or to obtain a valid bladder diary (see Section 17.6). In 
addition, where a UTI occurs after completion of the bladder diary and impacts the ability to 
perform urodynamics the time to Screening Visit 2 can be extended until the UTI is resolved. 
5.2.1.1 
Screening Visit 1 
The suggested order of procedures for Screening Visit 1 is shown in Table 6. 
Table 6 
Order of Procedures for Screening Visit 1 
Suggested order of 
procedures 
Comment 
Details of 
procedure 
1. Informed consent 
 
Must be performed before all other study procedures 
Section 5.2.2.1 
2. Demographic data 
 
Section 5.2.2.2 
3. Medical/surgical/NDO 
history 
 
Section 5.2.2.2 
4. Prior medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant medications 
and therapies 
 
Section 5.2.2.2 
Section 6.4 
6. Prior and concomitant 
treatments for NDO 
 
Section 5.2.2.2 
7. Inclusion/exclusion criteria 
 
Section 4.1 
Section 4.2 
8. Adverse events 
To be monitored and collected from the time the subject 
signs the informed consent form 
Section 8.1 
9. Vital signs 
Must be performed prior to any invasive procedure at 
the visit. Body weight and height to be measured as part 
of vital signs at Screening Visit 1. 
Section 8.4 
10. Physical examination 
(symptom based) 
Clinically significant abnormalities should be reported 
as medical history. 
Section 8.3 
11. Urine pregnancy test 
To assess inclusion criterion # 11 and exclusion 
criterion # 18 
Section 8.2.5 
12. Laboratory 
urinalysis/microscopy 
 
Section 8.2.3 
13. Urine culture 
To select adapted antibiotics for screening urodynamics 
and Treatment 1 (if empiric antibiotics are instead 
dispensed at Screening then this urine culture will still 
need to collected) 
Section 8.2.4 
Section 6.4.1.3 
14. Haematology and serum 
chemistry 
To assess exclusion criterion #29 when results are 
available 
Section 8.2.1 
Section 8.2.2 
15. Anti BTX-A antibodies 
Results will not be available until after study completion 
Section 8.2.6 
16. Urinary tract ultrasound 
Only if necessary per inclusion criterion #12 
Section 5.2.2.3 
17. Dispense bladder diary 
Including training subject (and caregiver) on proper 
usage of bladder diary 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 55/139 
 
 
 
18. Dispense antibiotics 
(empiric) 
 
Empiric antibiotics (at least a 7-day course starting 
3 days prior to treatment visit) may be dispensed if all 
the conditions described in Section 6.4.1.2 are met. 
Otherwise adapted antibiotics should be dispensed later 
in screening when urine culture results are available.  
Section 6.4.1.2 
 
BTX-A=botulinum toxin type A; NDO=neurogenic detrusor overactivity. 
5.2.1.2 
Screening Visit 2 
Electronic bladder diary data may be reviewed by the site prior to Screening Visit 2. If there 
has been no issue with bladder diary completion (see Section 17.6) and the subject is ineligible 
(inclusion criterion #14, inclusion criterion #15, and exclusion criterion #28) then the subject 
may be considered as a “screen failure” at that point, and does not need to attend Screening 
Visit 2 (arrangements should be made to return the bladder diary device to the site). See 
Appendix 1 for details. 
The suggested order of procedures for Screening Visit 2 is shown in Table 7. 
Table 7 
Order of Procedures for Screening Visit 2 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. Bladder diary review 
Must confirm bladder diary eligibility 
(inclusion criterion #14, inclusion criterion #15, 
and exclusion criterion #28) prior to 
commencing urodynamic (filling cystometry) 
procedure. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
2. Concomitant medications and 
therapies 
In particular, antibiotic prophylaxis for the 
urodynamic procedure should be recorded. 
Section 5.2.2.2 
Section 6.4 
3. Concomitant treatments for NDO 
 
Section 5.2.2.2 
4. Inclusion/exclusion criteria 
Including check of laboratory results to verify 
exclusion criterion #29. 
Section 4.1 
Section 4.2 
5. Adverse events 
 
Section 8.1 
6. Dispense antibiotics (adapted) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Section 6.4.1.2 
7. Urodynamics (filling cystometry)  

  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Section 7.3.2 and 
Study Specific 
Urodynamic 
Manual 
Section 5.2.3 
Section 6.4.1.2 
Table 18 
CCI
C
CI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 56/139 
 
 
 
 
 
 
). 
IDC=involuntary detrusor contraction; IMP=investigational medicinal product; NDO=neurogenic detrusor 
overactivity. 
5.2.2 
Procedures for Screening and Enrolment  
5.2.2.1 
Informed Consent 
Signed and dated informed consent must be obtained prior to performing any Screening 
procedures.  
After informed consent is obtained, subjects will be allocated a subject number. All screened 
subjects must be identifiable throughout the study. The investigator will maintain a list of 
subject numbers and names to enable records to be found at a later date if required. 
Patients who fail Screening cannot be re-screened for entry into this trial. 
5.2.2.2 
Other Data to be Collected at Screening 
For full details of data collection refer to the eCRF completion guide. Data will be collected for 
the following variables: 
• 
Demographic data 
• 
Date or year of birth, sex, race, and ethnicity according to local regulations 
• 
Medical/surgical/NDO history 
In particular relevant underlying neurological condition details including: 
• 
all subjects: 
• 
date of development of NDO symptoms. 
• 
subjects with SCI: 
• 
neurological level of stable SCI injury 
• 
date of stable SCI injury 
• 
cause of stable SCI (e.g. traumatic, vascular/infarction, focal mechanical 
compression)  
• 
American Spinal Injury Association (ASIA) Grade (A, B, C, D, E) 
• 
neurological syndrome (e.g. complete SCI, incomplete SCI, anterior cord, 
central cord, Brown-Sequard etc.). 
• 
subjects with MS: 
• 
date of onset of MS (initial diagnosis) 
• 
level of mobility (requirement for wheelchair)  
• 
classification (relapsing remitting, secondary progressive, primary 
progressive, relapsing progressive). 
• 
Prior medications and therapies: 
• 
all non-NDO medications within the last 30 days 
• 
all previous medications taken for NDO (regardless of time period) in particular: 
• 
any previous BTX-A usage (including brand/trade name, dose, indication 
and location of injections) 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 57/139 
 
 
• 
previous usage of anticholinergic, beta-3 agonist, or any other medication 
for bladder/lower urinary tract symptoms 
• 
previous neuromodulation or electrostimulation usage (including date of 
insertion for implanted devices and date of switching device off) 
• 
previous catheterisation usage (including use of indwelling catheter and 
CIC). 
• 
Concomitant medications and therapies (see Section 6.4) 
• 
Concomitant treatments for NDO (see Section 6.4.2.1). 
5.2.2.3 
Urinary Tract Ultrasound at Screening 
This is only required if the subject does not have an adequate documented urinary tract 
ultrasound available from within 6 months prior to Screening which confirms that no medical 
issues exist that would preclude entry into the study (e.g. bladder stones or unexplained renal 
mass). 
If required the ultrasound may be performed at any time during the Screening period. 
The results must be reviewed by the investigator prior to randomisation. 
5.2.3 
Treatment Visit (Day 1) 
The Treatment Visit should be performed within 14 days of Screening Visit 2. However, where 
a UTI occurs and impacts the ability to perform IMP administration the time to the Treatment 
Visit can be extended until the UTI is resolved. 
The suggested order of procedures for the Treatment Visit is shown in Table 8. 
Table 8 
Order of Procedures for Treatment Visit (Day 1) 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be the first procedure performed at 
this visit.  
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. Concomitant medications and 
therapies 
In particular, antibiotic prophylaxis for the 
treatment administration should be recorded. 
Section 5.2.2.2 
Section 6.4 
3. Concomitant treatments for NDO 
 
Section 6.4.2.1 
4. Inclusion/exclusion criteria 
 
Section 4.1 
Section 4.2 
5. Adverse events 
Timing of adverse event (pre- or post-
treatment) must be recorded. 
Section 8.1 
6. Vital signs 
Must be performed prior to and approximately 
30 minutes after treatment administration. 
Section 8.4 
7. Urine pregnancy test 
Must be performed prior to randomisation (even 
if negative at Screening) in females of 
childbearing potential. If positive then subject 
must be considered a screen failure (inclusion 
criterion #11 and exclusion criterion #18). 
Section 8.2.5 
8. Randomisation 
Must be performed only: 
 when all inclusion and exclusion criteria are 
confirmed (final eligibility); 
 if prophylactic antibiotics were commenced 
3 or more days prior; 
 if the subject does not have any symptoms 
suggestive of a UTI; 
 if medications with anticoagulant effects 
were stopped at least 3 days earlier. 
Section 3.3.1 
Section 6.3.1 
Section 6.2.1 
Section 6.2.2 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 58/139 
 
 
Under no circumstances will subjects be 
randomised more than once in the study. 
9. IMP administration  
Subjects to be observed for at least 30 minutes 
following administration.  
Section 6 
EQ-5D-5L=EuroQol 5-dimension 5-level; IMP=investigational medicinal product; I-QoL=incontinence quality of 
life; NDO=neurogenic detrusor overactivity; UTI=urinary tract infection. 
It is permissible to perform the Treatment Visit on the same day as Screening Visit 2: 
• 
If prophylactic antibiotics were started 3 days prior to the combined Screening Visit 
2/Treatment Visit. See Section 6.4.1.2 Table 18 and Figure 3. 
• 
If all Screening Visit 2 procedures are performed first and the subject is assessed as being 
eligible for treatment. 
If Screening Visit 2 and the Treatment Visit are performed on the same day then procedures 
that are common to both visits do not need to be performed twice. The option to perform a 
combined Screening Visit 2/Treatment Visit may be particularly relevant for subjects who do 
not require a urodynamic assessment during Screening. 
 
5.2.4 
Follow-up Period (after First Treatment and Retreatments) 
Routine Follow-up Visits after the first treatment and after retreatments are almost identical, 
therefore visit details in this section refers to follow-up for both the first treatment and 
retreatments (any differences in follow-up will be highlighted).  
5.2.4.1 
Week 1 and Week 4 Telephone Visits 
The subject should be contacted by telephone and the following should be discussed. Telephone 
Visits may be conducted as clinic visits if required, in the investigator’s opinion. 
The suggested order of procedures for Week 1 and Week 4 Telephone Visits is shown in 
Table 9. 
Table 9 
Order of Procedures for Week 1 and Week 4 Telephone Visits 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
2. Concomitant treatments for NDO 
 
Section 6.4.2.1 
3. Adverse Events 
 
Section 8.1 
4. Reminder to commence 7-day 
bladder diary  
Should ideally be completed in the 7 days 
immediately prior to the next visit. Should not 
be commenced: 
 Any earlier than 10 days prior to the Week 2 
Visit 
 Any earlier than 14 days prior to the Week 6 
Visit. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
NDO=neurogenic detrusor overactivity. 
5.2.4.2 
Week 2 Clinic Visit 
The suggested order of procedures for Week 2 Clinic Visit is shown in Table 10. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 59/139 
 
 
Table 10 Order of procedures for Week 2 Clinic Visit 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
2. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
3. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
4. Concomitant treatments for NDO 
 
Section 6.4.2.1 
5. Adverse events 
 
Section 8.1 
6. Vital signs 
 
Section 8.4 
mPGI-I=modified patient global impression – improvement; NDO=neurogenic detrusor overactivity. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 60/139 
 
 
5.2.4.3 
Week 6 Clinic Visit after First Treatment 
The Week 6 Visit following the first study treatment is the primary study timepoint.  
The suggested order of procedures shown in Table 11 is to be performed at the Week 6 Visit 
following the first study treatment. For activities required at the Week 6 Visit after retreatments, 
refer to Section 5.2.4.4. 
Table 11 Order of Procedures for Week 6 Clinic Visit After First Treatment 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be performed prior to any other 
procedures at this visit.  
 
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
3. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
4. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant treatments for NDO 
 
Section 6.4.2.1 
6. Adverse events 
 
Section 8.1 
7. Vital signs 
Must be performed prior to any physical 
procedure at the visit. 
Section 8.4 
8. Physical examination (symptom 
based) 
New clinically significant abnormalities should 
be reported as AEs. 
Section 8.3 
9. Laboratory urinalysis/ microscopy 
 
Section 8.2.3 
10. Urine culture 
Subjects in the urodynamic subset only. 
Must be taken before commencing prophylactic 
empiric antibiotics for the urodynamics (can 
also be used for optional adapted prophylactic 
antibiotic selection).  
Section 6.4.1.2 
Section 8.2.4 
Table 18 
11. Haematology and serum chemistry 
 
Section 8.2.1 
Section 8.2.2 
12. Anti BTX-A antibodies 
To be sampled from subject at the same time as 
the haematology and serum chemistry samples. 
Section 8.2.6 
13. Dispense antibiotics 
Subjects in the urodynamic subset only. 
Empiric (or optional adapted) prophylactic 
antibiotics prior to the urodynamic procedure. 
Section 6.4.1.2 
14. Urodynamics (filling cystometry) 
Subjects in the urodynamic subset only. 
Section 7.3.2 and 
Study Specific 
Urodynamic 
Manual 
15. Remind subject to complete the 
bladder diary 
Should ideally be completed in the 7 days 
immediately prior to the next visit. Should not 
be commenced any earlier than 14 days prior to 
the Week 12 Visit 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 61/139 
 
 
AE=adverse 
event; 
BTX-A=botulinum 
toxin 
type A; 
EQ-5D-5L=EuroQol 
5-dimension 
5-level; 
I-
QoL=incontinence quality of life; mPGI-I=modified patient global impression – improvement; NDO=neurogenic 
detrusor overactivity. 
5.2.4.4 
Week 6 Clinic Visit after Retreatments 
The suggested order of procedures in Table 12 is to be performed at the Week 6 Visit following 
any retreatment. For activities required at the Week 6 Visit after the first treatment, refer to 
Section 5.2.4.3. 
Table 12 Order of Procedures for Week 6 Clinic Visit After Retreatments 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be performed prior to any other 
procedures at this visit.  
 
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
3. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
4. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant treatments for NDO 
 
Section 6.4.2.1 
6. Adverse events 
 
Section 8.1 
7. Vital signs 
Must be performed prior to any physical 
procedure at the visit. 
Section 8.4 
8. Physical examination (symptom 
based) 
New clinically significant abnormalities should 
be reported as AEs. 
Section 8.3 
9. Laboratory urinalysis/ microscopy 
 
Section 8.2.3 
10. Urine Culture 
Subjects in the urodynamic subset only. 
Must be taken before commencing prophylactic 
empiric antibiotics for the urodynamics (can 
also be used for optional adapted prophylactic 
antibiotics) 
Section 6.4.1.2, 
Urine Culture and 
Sensitivity 8.2.4 
and Table 18 
11. Haematology and serum chemistry 
 
Section 8.2.1 
Section 8.2.2 
12. Dispense antibiotics 
Subjects in the urodynamic subset only. 
Empiric (or optional adapted) prophylactic 
antibiotics prior to the urodynamic procedure. 
Section 6.4.1.2 
13. Urodynamics (filling cystometry) 
Subjects in the urodynamic subset only.  
Section 7.3.2 and 
Study Specific 
Urodynamic 
Manual  
14. Remind subject to complete the 
bladder diary 
Should ideally be completed in the 7 days 
immediately prior to the next visit. Should not 
be commenced any earlier than 14 days prior to 
the Week 12 Visit 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
AE=adverse event; EQ-5D-5L=EuroQol 5-dimension 5-level; I-QoL=incontinence quality of life;  
mPGI-I=modified patient global impression – improvement; NDO=neurogenic detrusor overactivity. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 62/139 
 
 
5.2.4.5 
Week 12 Clinic Visit 
The suggested order of procedures for Week 12 Clinic Visit is shown in Table 13. 
Table 13 Order of Procedures for Week 12 Clinic Visit 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be performed prior to any other 
procedures at this visit.  
 
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
3. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
4. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant treatments for NDO 
 
Section 6.4.2.1 
6. Adverse events 
 
Section 8.1 
7. Vital signs 
Must be performed prior to any physical 
procedure at the visit. 
Section 8.4 
8. Laboratory urinalysis/microscopy 
 
Section 8.2.3 
9. Remind subject to complete the 
bladder diary 
Should ideally be completed in the 7 days 
immediately prior to the next scheduled visit. 
Should not be commenced any earlier than 14 
days prior to the next scheduled visit (unless 
retreatment request occurs prior to the next 
scheduled visit) 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
EQ-5D-5L=EuroQol 5-dimension 5-level; I-QoL=incontinence quality of life; mPGI-I=modified patient global 
impression – improvement; NDO=neurogenic detrusor overactivity. 
5.2.4.6 
Routine Telephone Visits Every 12 weeks  
The subject should be contacted by telephone and the following should be discussed. Telephone 
Visits may be conducted as clinic visits if required, in the investigator’s opinion. 
The suggested order of procedures for Routine Telephone Visits every 12 weeks is shown in 
Table 14. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 63/139 
 
 
Table 14 Order of Procedures for Routine 12-Weekly Telephone Visits 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. mPGI-I 
This should be performed electronically by the 
subject prior to attending the telephone or clinic 
visit, otherwise subject should complete during 
the visit prior to undergoing any other 
procedures. 
Section 7.3.3.3 
2. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
3. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
4. Concomitant treatments for NDO 
 
Section 6.4.2.1 
5. Adverse events 
 
Section 8.1 
6. Remind subject to complete the 
bladder diary 
Should ideally be completed in the 7 days 
immediately prior to the next scheduled visit. 
Should not be commenced any earlier than 14 
days prior to the next scheduled visit (unless 
retreatment request occurs prior to the next 
scheduled visit) 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
mPGI-I=modified patient global impression – improvement; NDO=neurogenic detrusor overactivity. 
5.2.5 
Retreatment Period 
Subjects may request retreatment after a minimum of 12 weeks following the previous 
treatment. Retreatment request may occur at: 
• 
A scheduled Telephone Follow-up Visit: 
• 
eligibility for retreatment to be assessed as far as possible 
• 
Retreatment Assessment Visit to be scheduled if the subject is potentially eligible. 
• 
During an unscheduled contact, between visits: 
• 
subject to be instructed to commence 7-day bladder diary to assess eligibility 
• 
eligibility for retreatment to be assessed as far as possible 
• 
Retreatment Assessment Visit to be scheduled if the subject is potentially eligible. 
• 
A scheduled Clinic Follow-up Visit: 
• 
Retreatment Assessment Visit procedures to be performed at this visit if bladder 
diary indicates potential eligibility for retreatment. 
5.2.5.1 
Retreatment Request at a Scheduled Telephone Follow-up Visit 
If the subject requests retreatment at a scheduled Telephone Visit, a preliminary assessment of 
eligibility should be performed to the extent possible by telephone, based on current 
(commenced within 14 days prior to the scheduled Telephone Visit) electronic 7-day bladder 
diary data and discussion with the subject. If the subject is clearly not eligible for retreatment 
(see Section 4.3 for retreatment criteria) then the Retreatment Assessment Visit should not be 
scheduled. The retreatment request and reason(s) for ineligibility should be documented. 
If the subject is potentially eligible for retreatment, then the Retreatment Assessment Visit 
should be scheduled. Ideally this visit should occur within 14 days of retreatment request. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 64/139 
 
 
Alternatively, a combined Retreatment Assessment Visit/Treatment Visit may be scheduled, if 
urine sample and dispensing of antibiotics can be performed in accordance with Section 6.4.1.2. 
5.2.5.2 
Retreatment Request during an unscheduled contact 
If it has been more than 12 weeks since the last IMP administration, and the subject requests 
retreatment between scheduled visits then the subject should be asked to commence the 7-day 
bladder diary collection. As soon as possible after completing the diary, the bladder diary data 
should be reviewed by the site. 
If the subject is clearly not eligible for retreatment (e.g. safety issues, or on the basis of current 
UI frequency) then the Retreatment Assessment Visit should not be scheduled. The retreatment 
request and reason(s) for ineligibility should be documented. 
If the subject is potentially eligible for retreatment, then the Retreatment Assessment Visit 
should be scheduled. Ideally this visit should occur within 14 days of retreatment request. 
Alternatively, a combined Retreatment Assessment Visit/Treatment Visit may be scheduled, if 
urine sample and dispensing of antibiotics can be performed in accordance with Section 6.4.1.2. 
5.2.5.3 
Retreatment Request at a scheduled Clinic Follow-up Visit 
If the subject requests retreatment at a scheduled visit, a preliminary assessment of eligibility 
should be performed as far as possible based on current (commenced within 14 days prior to 
the scheduled clinic visit) electronic 7-day bladder diary data and discussion with the subject. 
If the subject is clearly not eligible for retreatment (see Section 4.3 for retreatment criteria) then 
the Retreatment Assessment Visit procedures should not be performed. The retreatment request 
and reason(s) for ineligibility should be documented. 
If the subject is potentially eligible for retreatment, then the Retreatment Assessment Visit 
procedures should be performed at the clinic visit in accordance with Section 5.2.5.4. 
5.2.5.4 
Retreatment Assessment Visit 
The suggested order of procedures for Retreatment Assessment Visit is shown in Table 15. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 65/139 
 
 
Table 15 Order of Procedures for Retreatment Assessment Visit 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be performed prior to any other 
procedures at this visit.  
 
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
3. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
4. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant treatments for NDO 
 
Section 6.4.2.1 
6. Adverse events 
 
Section 8.1 
7. Retreatment criteria  
Assess all retreatment criteria. If subject does 
not meet retreatment criteria then the following 
procedures do not need to be performed and 
subject should continue follow-up per current 
schedule. 
Section 4.3 
8. Vital signs 
Must be performed prior to any physical 
procedure at the visit. 
Section 8.4 
9. Physical examination (symptom 
based) 
New clinically significant abnormalities should 
be reported as AEs. 
Section 8.3 
10. Laboratory urinalysis/microscopy 
 
Section 8.2.3 
11. Urine culture 
Must be taken before commencing prophylactic 
empiric antibiotics for the treatment procedure 
(can also be used for optional adapted 
prophylactic antibiotic selection). 
Section 6.4.1.3 
12. Haematology and serum chemistry 
 
Section 8.2.1 
Section 8.2.2 
13. Anti BTX-A antibodies 
To be sampled from subject at the same time as 
the haematology and serum chemistry samples. 
Section 8.2.6 
14. 
 
 
 
 
Section 6.4.1.2 
AE=adverse event; BTX-A=botulinum toxin type A; EQ-5D-5L=EuroQol 5-dimension 5-level; I-
QoL=incontinence quality of life; mPGI-I=modified patient global impression – improvement; NDO=neurogenic 
detrusor overactivity. 
The Retreatment Assessment Visit may be repeated, for example, if a subject initially fails the 
retreatment criteria and makes a request for retreatment at a later time. 
5.2.6 
Retreatment Visit 
The Retreatment Visit should ideally be performed within 14 days of confirmed eligibility for 
retreatment.  
It may be performed on the same day as the Retreatment Assessment Visit only if urine culture 
was taken and prophylactic antibiotics (empiric or adapted) were commenced at least 3 days 
prior to the combined visit. 
The suggested order of procedures for Retreatment Visit is shown in Table 16. 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 66/139 
 
 
Table 16 Order of Procedures for Retreatment Visit 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
2. Concomitant treatments for 
NDO 
 
Section 6.4.2.1 
3. Retreatment criteria 
Confirm subject still meets all retreatment criteria. 
Section 4.3 
4. Adverse events 
Timing of adverse event (pre- or postretreatment) 
must be recorded. 
Section 8.1 
5. Vital signs 
Must be performed prior to and approximately 30 
minutes after treatment administration. 
Section 8.4 
6. Urine pregnancy test 
Must be performed prior to commencing IMP 
reconstitution in females of childbearing potential. If 
positive then subject must not receive retreatment. 
Section 8.2.5 
7. IMP administration 
Must be performed only: 
 If all retreatment criteria are met 
 If prophylactic antibiotics were commenced 3 or 
more days prior 
 If the subject does not have any symptoms 
suggestive of a UTI 
 If medications with anticoagulant effects were 
stopped at least 3 days earlier. 
Subjects to be observed for at least 30 minutes 
following administration. 
Section 6 
Section 6.2.1 
Section 6.2.2 
Section 6.3 
Section 6.3.1 
 
IMP=investigational medicinal product; NDO=neurogenic detrusor overactivity; UTI=urinary tract infection. 
5.2.7 
End of Study Visit or Early Withdrawal Visit 
The procedures at an EOS Visit and an Early Withdrawal Visit are identical. 
For those subjects completing the study, the EOS Visit will occur: 
• 
104 weeks after the first IMP administration; if it has been more than 12 weeks since the 
previous IMP administration 
• 
At the Week 12 Retreatment Follow-up Visit, if the subject received their most recent 
IMP administration between Week 92 and Week 104 following their first IMP 
administration. 
For those subjects who withdraw prematurely from the study (see Section 4.4), final evaluations 
will be performed at an Early Withdrawal Visit.  
The suggested order of procedures for EOS Visit or Early Withdrawal Visit is shown in 
Table 17. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 67/139 
 
 
Table 17 Order of Procedures for End of Study Visit or Early Withdrawal Visit 
Suggested order of procedures 
Comment 
Details of 
procedure 
1. I-QoL and EQ-5D-5L 
This must be performed prior to any other 
procedures at this visit.  
 
Section 7.3.3 
Section 7.3.3.1 
Section 7.3.3.2 
2. mPGI-I 
This should be performed electronically by the 
subject prior to attending the visit, otherwise 
subject should complete during the visit prior to 
undergoing any other procedures. 
Section 7.3.3.3 
3. Bladder diary review 
May be reviewed prior to the visit. Review 
should occur during the visit if it has not been 
done beforehand. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
4. Concomitant medications and 
therapies 
 
Section 5.2.2.2 
Section 6.4 
5. Concomitant treatments for NDO 
 
Section 6.4.2.1 
6. Adverse events 
 
Section 8.1 
7. Vital signs 
Must be performed prior to any physical 
procedure at the visit. 
Section 8.4 
8. Physical examination (symptom 
based) 
New clinically significant abnormalities should 
be reported as AEs. 
Section 8.3 
9. Laboratory urinalysis/ microscopy 
 
Section 8.2.3 
10. Haematology and serum chemistry 
 
Section 8.2.1 
Section 8.2.2 
11. Anti BTX-A antibodies 
To be sampled from subject at the same time as 
the haematology and serum chemistry samples. 
Section 8.2.6 
12. Collect bladder diary 
The bladder diary device should be collected 
from the subject. 
Section 7.3.1 and  
Bladder Diary 
Usage 
 Bladder Diary 
Usage 
 
AE=adverse event; BTX-A=botulinum toxin type A; EQ-5D-5L=EuroQol 5-dimension 5-level; I-
QoL=incontinence quality of life; mPGI-I=modified patient global impression – improvement; NDO=neurogenic 
detrusor overactivity. 
Subjects who participate in the study in compliance with the protocol and attend the EOS Visit 
will be considered to have completed the study. 
Subjects with ongoing AEs or clinically significant laboratory test abnormalities (as determined 
by the investigator) will be monitored as described in Section 8.1.3 and Section 8.1.2.4, 
respectively. 




IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 69/139 
 
 
6.1.3.2 
Investigational Medicinal Product Preparation 
The IMP 
 will be reconstituted at 
the investigational site with sterile, preservative-free, sodium chloride for injection (0.9%); to 
a total volume of 15 mL. The method of reconstitution and preparation is identical regardless 
of the treatment assignment (800 U Dysport®, 600 U Dysport®, or placebo). 
Following reconstitution, the IMP may be stored for up to 4 hours at +2°C to +8°C in the vials 
in controlled and aseptic conditions. The product does not contain any antimicrobial agent; it is 
therefore recommended that the product be used immediately after reconstitution. The IMP 
should not be frozen and should be protected from light. 
Detailed instructions for storage, reconstitution, and preparation before treatment 
administration will be provided in the IMP instruction leaflet and IMP manual.  
The investigator, or an approved representative (e.g. pharmacist), will ensure that all IMP is 
reconstituted and dispensed/administered by qualified staff members according to the 
procedures detailed in the IMP instruction leaflet, IMP manual and this protocol. 
6.1.3.3 
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.  
Any reconstituted unused IMP has to be inactivated using bleach and used/partly used vials 
should be destroyed after use at the site for safety reason. In addition, all disposable ancillary 
materials (e.g. needles and syringes) must be discarded in suitable containers intended for 
incineration after use at the site. 
However, labels and empty boxes as well as unused supplies must be retained for verification 
and accountability (by the sponsor or sponsor’s representative) prior to destruction. They will 
be destroyed preferably at the site; if not, at the interim storage facility or returned to CMC SC 
for destruction (Beaufour Ipsen Industrie, 20 Rue d’Ethe Virton, 28100 Dreux, France). 
The investigator should ensure adequate records are maintained in the IMP accountability log. 
6.1.4 
Investigational Medicinal Product Packaging, Release, and Labelling 
The IMP will be packaged and released by Beaufour Ipsen Industrie (CMC SC) and delivered 
to the investigational sites or interim storage facilities. 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 IMP batches of the 
study, and the certificate of compliance which reflects the product release statement, and will 
provide them to sites according to local requirements. 
The core label texts for all packaging units will be translated and/or adjusted, to be in 
compliance with applicable regulatory requirements (e.g. Good Manufacturing Practice 
guidelines (Volume 4 Annex 13)), 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 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 70/139 
 
 
• 
investigator’s name (to be completed by the site) 
• 
treatment number 
• 
“For clinical study use only” (outside of the USA) 
• 
“Caution: new drug limited by Federal Law to Investigational use” (within the USA) 
• 
storage conditions 
• 
expiry date. 
The investigator, or designee, will only administer the IMP to subjects included in this study. 
Each subject will only be administered the IMP carrying his/her number. The dispensing for 
each subject will be documented in the eCRF. 
6.1.5 
Compliance 
The IMP will be administered periodically in the study by the investigator, thus, monitoring of 
subject compliance with IMP administration is not applicable.  
Drug accountability records, documenting that the subject received allocated IMP 
administration, will be maintained by the investigator. 
6.2 
Procedures Associated with Investigational Medicinal Product Administration 
6.2.1 
Antibiotic Prophylaxis 
All subjects must receive appropriate prophylactic antibiotics 
 
 
 
• 
Treatment 1: 
• 
antibiotics must be adapted based on screening culture and sensitivity (empiric may be 
used only if the conditions listed in Section ‘Antibiotic Prophylaxis During Screening’ 
are all met). 
• 
Retreatments: 
• 
antibiotics may be empiric or adapted. 
See Section 6.4.1.2 for full details on antibiotic prophylaxis within the study. 
The choice of antibiotic, dose, and start and stop dates must be recorded in the eCRF. 
6.2.2 
Anticoagulant/Antiplatelet Usage  
Medications with anticoagulant effects must be stopped at least 3 days prior to IMP 
administration and only restarted on the day following IMP administration. They may be 
stopped for a longer period if deemed necessary in the opinion of the investigator. These 
medications include but are not limited to: 
• 
Warfarin and other coumadin derivatives 
• 
Acetylsalicylic acid (including low-dose aspirin) 
• 
Clopidogrel/ticlopidine. 
If medically indicated, low molecular weight heparins are permitted with the last dose of 
administration 24 hours prior to IMP administration and may be restarted on the day following 
IMP administration. 
6.2.3 
Anaesthesia 
Local or general anaesthesia may be used if required. The choice of anaesthesia for the 
treatment procedure should be determined by the investigator and/or anaesthetist 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 71/139 
 
 
(anaesthesiologist) to ensure appropriate safety and comfort for the subject (taking into account 
factors such as risk of autonomic dysreflexia, spasticity and tolerance to cystoscopic 
procedures). It is acceptable to perform the procedure with no anaesthesia if medically 
appropriate. 
The following anaesthetic options (either alone or in combination) are permitted: 
(a) 
Local anaesthesia to the urethra: 
• 
e.g. intra-urethral lidocaine gel (or similar local anaesthetic gel), to facilitate 
comfortable cystoscope insertion. 
(b) 
Local anaesthesia to the bladder wall via instillation: 
• 
e.g. 1 2% lidocaine solution (or similar local anaesthetic solution), to reduce 
sensation of the intradetrusor injections 
• 
instilled immediately prior to the procedure and must remain in the bladder for 
approximately 30 minutes to ensure sufficient anaesthesia 
• 
prior to commencing the intradetrusor injections the local anaesthetic solution 
must be drained, then the bladder must be instilled (rinsed) with saline and drained 
again. 
(c) 
Sedation: 
• 
oral, inhalational, or intravenous sedative(s) 
• 
used per local site practice and if medically required. 
(d) 
General anaesthesia: 
• 
light and short duration general anaesthesia 
• 
used per local site practice and if medically required 
• 
must be administered by an appropriately qualified anaesthetist (anaesthesiologist) 
• 
neuromuscular blocking agents are however prohibited. 
Details of anaesthetic(s) used must be recorded in the eCRF. 
6.2.4 
Safety Monitoring During Treatment Administration 
Appropriate resuscitation equipment and trained personnel must be available at the site to treat 
any life-threatening emergencies (e.g. anaphylaxis, autonomic dysreflexia or cardiorespiratory 
arrest) during the IMP administration and during the immediate post-treatment observation 
period.  
All subjects must be monitored throughout the procedure if sedatives or general anaesthesia are 
being used, per local site practice. 
In addition, subjects with SCI with a vertebral lesion above T6 are at a greater risk of developing 
autonomic dysreflexia during invasive procedures [19]. Therefore these subjects must: 
• 
Have their blood pressure (BP) and heart rate (HR) continually monitored throughout the 
treatment administration procedure. There is no need to record BP or HR monitoring 
data, other than abnormalities that are clinically significant in the investigator’s opinion; 
which should be reported as AEs. 
If there are any symptoms or signs of autonomic dysreflexia developing, then: 
• 
Immediate treatment for the autonomic dysreflexia should be instituted per local site 
practice and appropriate guidelines 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 72/139 
 
 
• 
The treatment procedure should be immediately stopped until the autonomic dysreflexia 
has resolved. The treatment procedure should only be recommenced if deemed clinically 
safe 
• 
An occurrence of autonomic dysreflexia during treatment administration must be 
reported as an AE. 
6.3 
Intradetrusor Treatment Paradigm 
IMP administration must only be performed by the investigator(s) who is/are authorised to 
provide IMP administration in this study. The procedure should be performed with an 
appropriate assistant (e.g. subinvestigator, study co-ordinator or nurse). The entire procedure 
must be performed in an aseptic manner. 
The treatment will be administered as 30 evenly distributed intradetrusor injections sparing the 
trigone. Each injection point will deliver a volume of 0.5 mL. The injections may be 
administered by either a flexible or rigid cystoscope and each injection should be to a depth of 
approximately 2 mm. Commercially available cystoscopic bladder injection needles should be 
used.  
6.3.1 
Pretreatment Activities 
Prior to commencing the procedure the investigator must confirm: 
• 
All pretreatment study visit procedures have been conducted 
• 
There are no symptoms suggestive of an active UTI on the day of treatment 
• 
The urine pregnancy test is negative (childbearing females only) 
• 
Appropriate prophylactic antibiotics were commenced at least 3 days earlier (see Section 
6.2.1) 
• 
Medications with anticoagulant effects were stopped at least 3 days earlier 
(see Section 6.2.2) 
• 
Eligibility for treatment has been fully achieved (inclusion/exclusion criteria for 
Treatment 1; retreatment criteria for subsequent treatments) 
• 
All required equipment is available (e.g. cystoscope and injection needle) and has been 
appropriately cleaned/sterilised as per local practice 
• 
Appropriate safety monitoring (see Section 6.2.4) has been instituted 
• 
The syringes containing reconstituted IMP and saline flush are available. 
6.3.2 
Detailed Administration Guidance 
(1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 73/139 
 
 
(6) 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 74/139 
 
6.3.3 
Post-treatment Observation 
Vital signs should be recorded approximately 30 minutes following the procedure. 
If sedation or general anaesthesia was used then post-treatment observation must also be 
performed according to local site practice (e.g. monitoring of BP and HR until recovered). 
For any AEs that occur on the day of treatment/retreatment it should be clearly documented if 
the AE occurred before or after the treatment procedure. 
All subjects must be observed for a minimum of 30 minutes following the IMP administration. 
Subjects should only leave the clinic when it is safe and appropriate, according to the 
investigator’s judgement and local site practice. 
Subjects should be instructed to contact the site if there are any AEs post-treatment. 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 75/139 
 
 
6.4 
Concomitant Medications and Therapies 
The following should be recorded in the eCRF: 
• 
Any prior or concomitant NDO therapy or medication given to a subject before Screening 
or during the study 
• 
Any prior or concomitant non-NDO therapy or medication given to a subject in the 
30 days before Screening or during the study. 
6.4.1 
Permissible Medications and Therapies 
The following concomitant medications are permitted but they must be monitored closely and 
the dose and dose regimen should preferable remain constant throughout the study: 
• 
Oral medication for NDO (e.g. anticholinergics and beta-3 agonists): 
• 
must be stable for 4 weeks prior to Screening (inclusion criterion #7) 
• 
must remain stable for at least 12 weeks following the first IMP administration 
(inclusion criterion #8) 
• 
preferably should remain stable throughout the study 
• 
subjects should be counselled to only change these medications following 
discussion with the investigator. Change in usage will not be considered as a 
protocol deviation if it occurs after 12 weeks following the first IMP 
administration. 
• 
Medications/therapies required for other conditions (including for SCI and MS), as long 
as the treatment has no known interaction with the IMP is not listed in the prohibited 
medications (Section 6.4.2), or is not expected to have any significant lower urinary tract 
effects according to clinical judgement of the investigator, that may confound the study 
results. 
6.4.1.1 
Clean Intermittent Catheterisation 
All subjects in this study have significant bladder dysfunction and voiding difficulty, requiring 
routine CIC usage to adequately and regularly drain urine from the bladder.  
At Screening, subjects must be routinely performing CIC to manage their bladder function, and 
ensure regular and adequate bladder emptying. 
 
 
 
 
 
 
 
 
 
 
 
The CIC regimen should be maintained throughout the study; 
 
 
 
 
 
 
 
 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 76/139 
 
 
6.4.1.2 
Antibiotic Prophylaxis 
Antibiotic prophylaxis is required in the study to cover: 
(a) 
All urodynamic procedures: 
• 
 
. 
(b) 
All IMP cystoscopic treatment administration procedures: 
• 
 
 
The minimum duration of the antibiotics can be lengthened per clinical judgment of the 
investigator. 
Antibiotics may be: 
• 
Adapted: 
• 
based on a recent urine culture and sensitivity test from the subject to determine 
the most appropriate antibiotic. 
• 
Empiric: 
• 
based on the best judgement of the investigator, using knowledge of the likely 
bacteria, the individual subject and local antibiotic resistance and sensitivity 
patterns.  
• 
the investigator should ensure that there is no potential risk of colonisation with 
resistant bacteria to the chosen antibiotic (e.g. multiple recent courses of the same 
class of antibiotic). 
Permitted Antibiotics 
All oral antibiotics (except aminoglycoside antibiotics) available locally for the treatment of 
UTIs may be used at the discretion of the investigator.  
The investigator must ensure that the subject has no known history of contraindications 
(e.g. allergy) to any antibiotics that are dispensed during the study. 
Appropriate Usage of Prophylactic Antibiotics 
 
 
 
  
 
 
 
 
 
 
  
 
 
Antibiotic Prophylaxis During Screening 
 
 
CCI
CCI
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 77/139 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Antibiotic Prophylaxis During Follow-up  
 
 
 
  
 
 
  
 
 
C
C
I
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 78/139 
 
 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 79/139 
 
 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 80/139 
 
 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 81/139 
 
 
CCI


IPSEN GROUP 
 
 
 
 
 
D-FR-52120-223  
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
 
 
 
 
 
PAGE 82/139 
 
 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 83/139 
 
 
6.4.1.3 
Antibiotics for Symptomatic UTI 
Subjects with NDO may demonstrate atypical symptoms for UTI. If there is any suspicion of a 
UTI then the subject should be immediately commenced on appropriate antibiotics: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
6.4.1.4 
Definition of Urinary Tract Infection 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
6.4.2 
Prohibited Medications/Therapies 
Prohibited throughout the study: 
• 
Treatment at any anatomical location with any BTX (with the exception of IMP 
treatments and retreatments as part of this study) 
• 
Medications that affect neuromuscular transmission, such as curare-like depolarising 
agents, lincosamides, polymyxins, anticholinesterases and aminoglycoside antibiotics 
(exclusion criterion #20). 
Prohibited in the 9 months prior to Screening: 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 84/139 
 
 
• 
BTX for any urological condition, e.g. detrusor or urethral sphincter treatments 
(exclusion criterion #11).  
Prohibited in the 6 months prior to Screening and throughout the study: 
• 
Capsaicin or resiniferatoxin (exclusion criterion #14). 
Prohibited in the 3 months prior to Screening and throughout the study: 
• 
BTX for any non-urological condition (exclusion criterion #12) 
• 
Bladder installation with any pharmacologic agent (exclusion criterion #13). 
Prohibited in the 4 weeks prior to Screening and throughout the study: 
• 
Indwelling bladder catheter (exclusion criterion #10) 
• 
Any neuromodulation/electrostimulation usage for urinary symptoms/incontinence 
(exclusion criterion #15) 
• 
 
 
 
• 
Any new investigational drug or device (exclusion criterion #27). 
6.4.2.1 
Concomitant treatment for Neurogenic Detrusor Overactivity 
These data are to be collected at Screening and at other timepoints. In particular, the following 
should be collected:  
• 
Daily CIC frequency (at Screening, and if there is a clinically significant change in 
frequency postbaseline) 
• 
Current anticholinergic or beta-3 agonist usage (at Screening, and if there is a change in 
medication/frequency/dosage postbaseline). 
CCI
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 85/139 
 
 
7 
ASSESSMENT OF EFFICACY 
For the timing of assessments in this study, refer to the schedules in Table 4, Table 5, and 
Table 19. 
7.1 
Primary Efficacy Endpoint and Evaluations 
See Section 3.2.1. 
7.2 
Secondary Efficacy Endpoints and Evaluations 
See Section 3.2.2 and Table 19. 
Table 19 Efficacy Endpoints During Initial Treatment and Retreatment 
Measure 
Planned timepoints 
(dependent on 
timing of 
retreatments) 
Variable  
Endpoint 
Weekly number of 
urinary incontinence 
episodes on 7-day 
bladder diary 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Weekly number of 
urinary incontinence 
episodes 
 Mean change from study 
baseline to each subsequent 
timepoint within the treatment 
cycle in weekly number of 
urinary incontinence episodes 
 Proportion of subjects with no 
episodes of urinary 
incontinence (i.e. continence 
is achieved) at each timepoint 
 Proportion of subjects with a 
urinary incontinence response 
at several levels (i.e. ≥30% 
improvement, ≥50% 
improvement, ≥75% 
improvement etc.) at each 
timepoint 
Total daily urinary 
frequency (CIC and 
spontaneous voiding) 
on 7-day bladder diary 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit 
Total daily urinary 
frequency 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in total 
daily urinary frequency 
 
Daily spontaneous 
voiding frequency on 
7-day bladder diary 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Daily spontaneous 
voiding frequency 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 
daily spontaneous voiding 
frequency  


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 86/139 
 
 
Measure 
Planned timepoints 
(dependent on 
timing of 
retreatments) 
Variable  
Endpoint 
Daily CIC frequency on 
7-day bladder diary 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Daily CIC frequency 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 
daily CIC frequency  
Total 24-hour voided 
volume on 1 day of 
7-day bladder diary 
(CIC and spontaneous 
voiding) 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Total 24-hour voided 
volume 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in total 
24-hour voided volume 
24-hour voided volume 
on 1 day of 7-day 
bladder diary 
(spontaneous voiding 
only) 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
24-hour voided 
volume (spontaneous 
voiding only) 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 24-
hour voided volume (spontaneous 
voiding only) 
 
24-hour voided volume 
on 1 day of 7-day 
bladder diary (CIC 
only) 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
 
24-hour voided 
volume (CIC only) 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 24-
hour voided volume (CIC only) 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 87/139 
 
 
Measure 
Planned timepoints 
(dependent on 
timing of 
retreatments) 
Variable  
Endpoint 
Total volume per void 
(spontaneous and CIC) 
on 1 day of 7-day 
bladder diary 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Total volume per void 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in total 
volume per void  
Volume per void 
(spontaneous voiding 
only) on 1 day of 7-day 
bladder diary 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Volume per void 
(spontaneous voiding 
only) 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 
volume per void (spontaneous 
voiding only) 
 
Volume per void (CIC 
only) on 1 day of 7-day 
bladder diary 
 
Study Baseline 
(Screening) or 
treatment cycle 
baseline 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
Volume per void 
(CIC only) 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in 
volume per void (CIC only) 
 
MCC measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
MCC 
 
Mean change from study Baseline 
to Week 6 after each treatment in 
MCC 
 
MDP during storage 
measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
MDP 
 
Mean change from study Baseline 
to Week 6 after each treatment in 
MDP 
 
Vol@1stIDC measured 
by urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
Vol@1stIDC  
Mean change from study Baseline 
to Week 6 after each treatment in 
Vol@1stIDC 
 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 88/139 
 
 
Measure 
Planned timepoints 
(dependent on 
timing of 
retreatments) 
Variable  
Endpoint 
PdetMax@1stIDC 
measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
PdetMax@1stIDC 
 
Mean change from study 
Baseline to Week 6 after each 
treatment in PdetMax@1stIDC 
 
Presence of IDCs 
measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
Presence of IDCs 
Proportion of subjects with no 
IDCs on urodynamic assessment 
(i.e. urodynamic cure is achieved) 
after each treatment   
 
EFP measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
EFP 
 
Mean change from study 
Baseline to Week 6 after each 
treatment in EFP  
DC measured by 
urodynamic filling 
cystometry 
Urodynamic subset 
only 
Study Baseline 
(Screening), Week 6 
DC 
 
Mean change from study 
Baseline to Week 6 after each 
treatment in DC 
Treatment response 
according to I-QoL 
total and domain 
summary score 
Study Baseline 
(Treatment Visit) or 
treatment cycle 
baseline 
Week 6  
Week 12 
EOS Visit. 
I-QoL total summary 
and domain score 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in I-
QoL total summary and domain 
score 
Treatment response 
according to EQ-5D-
5L 
Study Baseline 
(Treatment Visit) or 
treatment cycle 
baseline 
Week 6  
Week 12 
EOS Visit. 
EQ-5D-5L score 
Mean change from study baseline 
to each subsequent timepoint 
within the treatment cycle in EQ-
5D-5L score 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 89/139 
 
 
Measure 
Planned timepoints 
(dependent on 
timing of 
retreatments) 
Variable  
Endpoint 
Treatment response 
according to mPGI-I 
score 
Week 2 
Week 6  
Week 12 
Every 12 weeks 
thereafter until 
retreatment 
EOS Visit. 
mPGI-I score 
Mean mPGI-I score at each 
timepoint following each IMP 
administration 
Duration of effect 
measured by time from 
previous treatment 
until next treatment 
requested 
 
(if subsequently found 
to be eligible for 
retreatment) 
 
 Treatment Visit 
(Day 1) until date of 
request of first 
retreatment (for first 
treatment cycle) 
 Retreatment Visit 
until date of request 
of next retreatment 
(for second and 
subsequent 
treatment cycles) 
Time to request 
retreatment 
 Mean number of days before 
retreatment is requested 
 Median number of days before 
retreatment is requested 
Duration of effect 
measured by time from 
previous treatment 
until subject is 
confirmed eligible for 
next treatment  
 
 
 Treatment Visit 
(Day 1) until date 
subject is confirmed 
as eligible for 
retreatment (for first 
treatment cycle) 
 Retreatment Visit 
until date subject is 
confirmed as eligible 
for next retreatment 
(for second and 
subsequent 
treatment cycles) 
 
 
Time to eligibility for 
retreatment 
 Mean number of days before 
eligible for retreatment  
 Median number of days before 
eligible for retreatment 
Duration of effect 
measured by time 
between two treatment 
administrations 
 Treatment Visit 
(Day 1) until first 
Retreatment Visit 
(for first treatment 
cycle) 
 Retreatment Visit 
until next 
retreatment visit (for 
second and above 
treatment cycles) 
Time between 
treatments 
 Mean number of days between 
two treatment administrations 
 Median number of days 
between two treatment 
administrations  
CIC=clean intermittent catheterisation; DC=detrusor compliance; EFP=end fill pressure; EOS=end of study; 
EQ-5D-5L=EuroQol 5-dimension 5-level; IDC=involuntary detrusor contraction; IMP=investigational medicinal 
product; I-QoL=incontinence quality of life; MCC=maximum cystometric capacity; MDP=maximum detrusor 
pressure; mPGI-I=modified patient global impression – improvement; PdetMax@1stIDC=maximum detrusor 
pressure at first involuntary detrusor contraction; Vol@1stIDC=volume at first involuntary detrusor contraction. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 90/139 
 
 
7.3 
Methods and Timing of Assessing, Recording, and Analysing Efficacy Data 
Methods for assessing efficacy data are described below. Timing of efficacy assessments are 
discussed in Section 5. Procedures for recording efficacy data are discussed in Section 13.1, 
and methods of analysis are discussed in Section 9.4.5. 
7.3.1 
Bladder Diary 
A 7-day bladder diary will be completed by subjects (with the caregiver’s assistance if 
necessary) at Screening and regularly throughout the study to record the following parameters: 
• 
Weekly number of UI episodes 
• 
Daily urinary frequency (total, spontaneous void only, CIC only) 
• 
24-hour voided volume (total, spontaneous void only, CIC only) 
• 
Volume per void (total, spontaneous void only, CIC only). 
Refer to  
Bladder Diary Usage 
 Bladder Diary Usage 
 for full details regarding bladder diary usage. 
7.3.2 
Urodynamic Examination 
7.3.2.1 
Subjects in the Urodynamic Subset 
Subjects in the urodynamic subset will undergo a standardised urodynamic (filling cystometry) 
assessment at Screening and again at Week 6 following each IMP administration. 
Urodynamics 
will be conducted according to 
International 
Continence Society 
recommendations [20]. Full details of the urodynamic procedures including standardisation, 
training, equipment setup, subject preparation, trace annotations, calculations and central 
review process are contained in a separate Study Specific Urodynamic Manual.  
All urodynamic procedures will be covered with a minimum of 2 days of appropriate 
prophylactic antibiotics. See Section 6.4.1.2 for further details on antibiotic prophylaxis in the 
study.  
All urodynamic data will be reviewed by independent central reviewers to determine the final 
values for the urodynamic parameters. The central reader’s determination will be used for 
analysis purposes. 
During Screening the site will determine if the subject has NDO via the presence of IDCs 
(inclusion criterion #16); without confirmation from the central reader. 
The following urodynamic parameters will be obtained (Table 20): 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 91/139 
 
 
Table 20 Urodynamic Parameters 
Parameter 
Unit 
Calculation 
MCC 
mL 
Total instilled volume or instilled volume just prior to the terminal IDC 
minus  
incontinent volume  
MDP 
cm H2O 
Peak detrusor pressure during storage (filling) phase 
minus 
trace baseline pressure 
Presence of IDC(s) 
N/A 
N/A 
Vol@1stIDC 
mL 
Instilled volume when first IDC commences 
PdetMax@1stIDC 
cm H2O 
Peak detrusor pressure during first IDC 
minus 
trace baseline pressure 
EFP  
 
cm H2O 
Detrusor pressure at end of filling or just prior to the terminal IDC 
minus 
trace baseline pressure  
DC 
 
mL/cm H2O 
Change in bladder volume 
divided by 
change in detrusor pressure 
(usually measured as MCC divided by EFP) 
DC=detrusor compliance; EFP=end fill pressure; IDC=involuntary detrusor contraction; MCC=maximum 
cystometric capacity; MDP=maximum detrusor pressure; PdetMax@1stIDC=maximum detrusor pressure at first 
involuntary detrusor contraction; Vol@1stIDC=volume at first involuntary detrusor contraction. 
7.3.2.2 
Subjects not in the Urodynamic Subset 
Subjects not in the urodynamic subset must have a documented urodynamic assessment 
confirming NDO in the 12 months prior to Screening (inclusion criterion #5). 
If not performed in the 12 months prior to Screening or if documentary evidence (e.g. 
urodynamic trace confirming NDO) is not available then a urodynamic (filling cystometry) 
assessment must be performed during Screening at Screening Visit 2. This should be performed 
per local practice and will be used only to confirm the diagnosis of NDO.  
The subject must receive adapted antibiotic prophylaxis as described in Section 6.4.1.2.  
During Screening the site will determine if the historic (inclusion criterion #5) or Screening 
(inclusion criterion #16) urodynamic trace for subjects in the non-urodynamic subset 
demonstrate the presence of NDO, without confirmation from the central reader. Following 
Screening, the urodynamic traces will be submitted to the central reader to retrospectively 
confirm the presence of NDO only. It will not be possible to analyse the data as the procedures 
will not have been performed in a standardised study specific manner.  
7.3.3 
Patient Reported Questionnaires 
In order to ensure accurate and unbiased subject questionnaire completion the following 
guidelines should be adhered to: 
• 
The mPGI-I should be completed by the subject (with the caregiver’s assistance, if 
necessary) prior to the visit (expected to be performed at the beginning of the bladder 
diary collection period). If it has not been completed prior to the visit it should be 
completed as the first activity at the visit 
• 
The I-QoL and EQ-5D-5L should be completed by the subject (with the caregiver’s 
assistance, if necessary), at the beginning of the site visit 
• 
Questionnaires should be checked for completeness, in the subject’s presence (every 
question should be answered) 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 92/139 
 
 
• 
Study site personnel should not change responses on the questionnaires. 
7.3.3.1 
Incontinence Quality of Life 
The I-QoL is a highly used, widely recommended, validated, disease-specific questionnaire 
designed to measure the effect of UI on subjects’ QoL [21, 22, 23, 24]. It contains 22 items 
covering three domains of QoL: 
• 
Avoidance and limiting behaviour 
• 
Psychosocial impact 
• 
Social embarrassment.  
Subjects use a 5-point response scale with values ranging from 1 (extremely) to 5 (not at all). 
Each domain can be scored separately, and a total score can be calculated. Higher scores 
represent a better QoL.  
7.3.3.2 
EuroQol 5-dimension 5-level 
The EQ-5D-5L is a widely used non-disease-specific, validated instrument developed by the 
EuroQol Group (Rotterdam, The Netherlands, www.euroqol.org) to assess health status. It 
consists of five dimensions covering: 
• 
Mobility 
• 
Self-care 
• 
Usual activities 
• 
Pain/discomfort 
• 
Anxiety/depression. 
Each dimension has five responses and therefore records five levels of severity.  
The EQ-5D-5L also contains a visual analogue scale to record the subject’s self-rated health. 
7.3.3.3 
Modified Patient Global Impression of Improvement 
The subject’s global impression of treatment response will be assessed using the mPGI-I scale. 
The mPGI-I will be completed on the electronic device used for the bladder diary. It should be 
completed before the visit, but may be completed at the beginning of the visit if not completed 
beforehand.  
Subjects will assess any change in their UI compared to the situation immediately prior to their 
most recent treatment using a 7-point rating scale (“Very much better”, “Much better”, “A little 
better”, “No change”, “A little worse”, “Much worse”, “Very much worse”). 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 93/139 
 
 
8 
ASSESSMENT OF SAFETY 
8.1 
Adverse Events 
AEs will be monitored from the time that the subject gives informed consent and throughout 
the study (see Section 3.4 for a definition of the study duration) and will be elicited by direct, 
nonleading questioning, or as volunteered by a subject. 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 3.4). 
8.1.2 
Categorisation of Adverse Events 
8.1.2.1 
Intensity Classification 
AEs will be classified as mild, moderate or severe according to the following criteria: 
• 
Mild: symptoms do not alter the subject’s normal functioning 
• 
Moderate: symptoms produce some degree of impairment to function, but are not 
hazardous, uncomfortable or embarrassing to the subject 
• 
Severe: symptoms definitely hazardous to wellbeing, significant impairment of function 
or incapacitation. 
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 
current Dysport® 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 dose, delay in 
administration, IMP discontinuation) 
• 
They require intervention or a diagnostic evaluation to assess the risk to the subject 




IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 95/139 
 
 
(2) 
 
 
 
 
8.1.2.11 Adverse Events of Special Interest 
The effects of Dysport® and all BTX products may spread from the area of injection to produce 
symptoms consistent with BTX effects. These symptoms have been reported hours to weeks 
after injection. Remote spread of toxin that affects swallowing and breathing can be life 
threatening, and there have been reports of death. The risk of symptoms is increased in subjects 
who have underlying conditions (e.g. disorders of the neuromuscular junction) that would 
predispose them to these symptoms.  
Dysport® is contraindicated in individuals with known hypersensitivity to any BTX preparation 
or to any of the components in the formulation. 
Adverse events of special interest (AESIs) for Dysport® are AEs that suggest a possible remote 
spread of effect of the toxin or hypersensitivity. A list of preferred terms of AESIs is provided 
in the Statistical Analysis Plan (SAP). 
All AEs will be monitored by the sponsor to determine if they meet the criteria of AESIs. These 
AESIs will be further analysed to determine if there is a plausible possibility that they represent 
distant spread of toxin or hypersensitivity. In order to perform the analysis, variables including 
alternate aetiology (medical history, concomitant medication, or diagnosis which could account 
for the symptoms), location of Dysport® administration, and temporal relationship to Dysport® 
administration will be considered by the sponsor.  
8.1.3 
Recording and Follow-up of Adverse Events 
At each visit, the subject should be asked a nonleading 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 of pre-
existing illnesses should be recorded (see also Section 8.1.2.7 and Section 8.1.2.10). 
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 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 
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 96/139 
 
 
report is submitted by telephone, this must be followed by detailed written reports using the 
SAE report form. 
An 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 
(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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 97/139 
 
 
The following information is the minimum that must be provided to the sponsor 
pharmacovigilance contact within 24 hours for each SAE: 
• 
Study number 
• 
Site number 
• 
Subject number 
• 
AE 
• 
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. 
8.1.5 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IMP may have 
interfered with the effectiveness of a contraceptive method. The outcome of any pregnancy will 
then need to be collected even if this occurs after the end of the study.  
Information regarding pregnancies must be collected on the AE page of the eCRF and on the 
Standard Pregnancy Report Form, including pregnancies with normal progress and outcome. A 
Standard Pregnancy Report Form must be completed by the Investigator and provided to the 
Sponsor’s Pharmacovigilance department within 24 hours of the knowledge of the pregnancy 
in any study subject. 
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 the outcome of the pregnancy becomes known, which may involve 
follow-up after the subject’s involvement in the study has ended. 
Pregnancies with a conception date during study participation (or within 12 weeks of the subject 
being dosed with IMP, if early discontinuation) must also be reported to the investigator for 
onward reporting to the sponsor.  
8.1.6 
Deaths 
All AEs resulting in death either during the study period or within 12 weeks (84 days) after the 
last dose of IMP, 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”. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 98/139 
 
 
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 insufficient response to the IMP (see Section 4.4). Every 
effort should be made to try to attribute withdrawal to a single episode of a particular AE and 
not AEs in general. 
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/ Independent Ethics Committees/ Institutional 
Review Boards/ Other Investigators 
The sponsor or sponsor’s representative will ensure that processes are in place for submission 
of reports of Suspected Unexpected Serious Adverse Reactions occurring during the study to 
the CAs, Independent Ethics Committees (IECs) and other investigators concerned by the IMP. 
Reporting will be done in accordance with the applicable regulatory requirements. 
For study sites in the USA, Investigational New Drug application Safety Reports will be 
submitted directly to the investigators. It is the investigators’ responsibility to notify their 
Institutional Review Board (IRB) in a timely manner. 
8.2 
Clinical Laboratory Tests 
Blood and urine samples will be collected as indicated in the schedule of assessments in Table 4 
and 
Table 5, 
for 
the 
evaluation 
of 
haematology, 
serum 
chemistry, 
laboratory 
urinalysis/microscopy, urine culture and sensitivity, and anti BTX-A antibodies. Analysis will 
be performed by central laboratories. Full details regarding clinical laboratory tests are 
contained in the study central laboratory manual and trial master file. 
The investigator will review the laboratory urinalysis/microscopy, urine culture and sensitivity, 
haematology, and serum chemistry laboratory results; document the review, and record any 
clinically relevant changes occurring or observed during the study in the AE section of the 
eCRF (see Section 8.1.2.4 for abnormal laboratory tests that should be recorded as AEs, and 
Section 8.2.3 regarding specific information related to laboratory urinalysis/microscopy). 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to Baseline or to a level deemed acceptable by the 
investigator and the sponsor’s clinical monitor (or his/her designated representative) or until the 
abnormality is explained by an appropriate diagnosis (see Section 8.2.3 for specific details 
regarding laboratory urinalysis/microscopy abnormalities).  
8.2.1 
Haematology 
Blood 
samples 
(approximately 
3.0 mL) 
will 
be 
collected 
in 
a 
potassium 
ethylenediaminetetraacetic acid tube to assess the following parameters: 
• 
Red blood cell count 
• 
Haemoglobin 
• 
Haematocrit 
• 
Mean corpuscular volume 
• 
Mean corpuscular haemoglobin 
• 
Mean corpuscular haemoglobin concentration 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 99/139 
 
 
• 
White blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and others) 
• 
Platelet count. 
At Screening, the investigator should only randomise the subject if in the investigator’s opinion 
there are no clinically significant abnormalities that require further investigation or 
management.  
For handling of abnormalities identified after Screening, refer to Section 8.1.2.4. 
8.2.2 
Serum Chemistry 
Blood samples (approximately 4.0 mL) will be collected in an activator gel tube to assess the 
following parameters: 
• 
Urea, creatinine, total bilirubin, conjugated bilirubin 
• 
Chloride, bicarbonate, sodium, potassium, calcium, inorganic phosphate 
• 
Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
• 
Albumin, total protein, total cholesterol, triglycerides, fasting glucose. 
At Screening: 
• 
The investigator should review the serum creatinine to determine eligibility (exclusion 
criterion #29) 
• 
In addition, the investigator should only randomise the subject if in the investigator’s 
opinion there are no clinically significant abnormalities that require further investigation 
or management.  
For handling of abnormalities identified after Screening, refer to Section 8.1.2.4. 
8.2.3 
Laboratory urinalysis/microscopy 
Fresh urine samples (at least 10 mL) will be collected to assess the following parameters: pH, 
protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and specific 
gravity. Microscopy will be performed, if indicated, but results will not be collected in the 
eCRF.  
Due to the frequent urethral instrumentation (e.g. CIC) and the voiding dysfunction in this 
population, it is anticipated that there will be frequent abnormalities on laboratory 
urinalysis/microscopy testing (e.g. microscopic haematuria).  
Screening 
The investigator should determine the clinical significance of any abnormalities for the 
individual subject and should only continue with Screening and randomisation/treatment if in 
the investigator’s opinion it is safe and appropriate. If there are any unexpected clinically 
significant findings then the subject should be considered as a screen failure and appropriately 
investigated/managed.  
During follow-up 
If in the opinion of the investigator there are any clinically significant abnormalities (or 
changes) specific for the individual subject in urinalyses/microscopy, then the subject should 
be appropriately investigated and managed and this should be recorded as an AE in the eCRF 
(see Section 6.4.1.3 for further details regarding UTIs). 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 100/139 
 
 
If there is any suspicion of a symptomatic UTI, laboratory urinalysis/microscopy and urine 
culture and sensitivity should be sent to the central laboratory (prior to commencing antibiotics, 
if possible). See Section 6.4.1.3 for further details. 
Discretionary dipstick urinalysis 
Urine dipstick may also be used at the discretion of the investigator when required for a rapid 
assessment (e.g. if there is a suspicion of a UTI), although laboratory urinalysis/microscopy, 
and urine culture and sensitivity samples should be sent to the central laboratory for formal 
confirmation of findings. See Section 6.4.1.3 for managing a symptomatic UTI and Section 
6.4.1.4 for the definition of a UTI.  
8.2.4 
Urine Culture and Sensitivity 
Fresh urine samples (at least 10 mL) for culture and sensitivity will be collected prior to 
invasive study procedures to: 
• 
Assist in adapted antibiotic prophylaxis selection (see Section 6.4.1.2) for the procedure; 
or  
• 
If empiric antibiotics are used to cover the procedure, to ensure that a baseline urine 
culture (prior to the procedure) is available to allow for rapid switching of antibiotics to 
an appropriate (adapted) antibiotic if the subject develops a symptomatic UTI following 
the procedure (see Section 6.4.1.3). 
During follow-up, if there is any suspicion of a symptomatic UTI, laboratory 
urinalysis/microscopy and urine culture and sensitivity should be sent to the central laboratory 
(prior to commencing antibiotics, if possible). See Section 6.4.1.3 for further details. 
8.2.5 
Pregnancy Test 
A urine sample will be collected for a human chorionic gonadotropin pregnancy test as per the 
schedule in Table 4 and Table 5, for all female subjects of childbearing potential. If this is found 
to be positive, it will be followed-up with a serum pregnancy test (β-human chorionic 
gonadotropin). 
Any subject becoming pregnant during the study will be withdrawn. All pregnancies that occur 
during the study are to be reported as described in Section 8.1.5. 
8.2.6 
Antibody Testing 
Blood samples (2 × 6 mL samples) will be collected and serum samples will be sent to the 
central laboratory for subsequent antibody testing per the schedule in Table 4 and Table 5 for 
the assay of putative antitoxin-A antibodies. 
Batch shipping to specific laboratories in charge of the analyses will be arranged by the central 
laboratory at appropriate intervals. All samples will be tested for the presence of binding 
antibodies with a validated assay. Samples found positive for the presence of binding antibodies 
will be analysed for the presence of neutralizing antibodies using another validated assay. Full 
details regarding the processing, labelling and shipment processes for these samples are 
provided in the study manual. 
These data will only be provided to the site after the end of the study (database lock). 
8.2.7 
Other Laboratory Safety Tests 
Other laboratory safety tests may be performed at the discretion of the investigator to ensure 
the safety of the subjects. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 101/139 
 
 
8.2.8 
Blood Volume to be Collected During the Study 
The blood volume collected during the 24-month course of the study depends on the number of 
treatment cycles received. Assuming 3 mL of blood sampled for each haematology test, 4 mL 
of blood sampled for each biochemistry test (for serum chemistry), and 12 mL of blood sampled 
for each antibody test: 
• 
A subject who receives a single study treatment will provide 57 mL of blood 
• 
For each additional treatment cycle, the subject will provide a further 26 mL of blood. 
A subject who receives 3 study treatments will therefore provide 109 mL of blood during their 
study participation. 
The maximum amount of blood collected at a single visit is 19 mL (for visits at which samples 
are collected for all blood tests). 
8.3 
Physical Examination 
Symptom-driven physical examinations will be conducted per the schedule in Table 4 and 
Table 5, and may also be performed at any other time during the study if clinically indicated. 
The first physical examination is conducted at Screening Visit 1. Accordingly, any physical 
examination abnormalities observed at this visit are to be recorded as medical history, and not 
as AEs. Any new clinically significant physical examination findings (abnormalities) observed 
during the study will be reported as AEs. Please see Section 8.1.2.9 and Section 8.1.2.10 
regarding neurological AEs, or findings that may represent an MS exacerbation.  
Any physical examination findings (abnormalities) persisting at the end of the study will be 
followed by the investigator until resolution or until reaching a clinically stable endpoint. 
8.4 
Vital Signs 
Vital signs consist of HR, respiratory rate, BP and body temperature: 
• 
HR, respiratory rate and BP should be measured in the sitting or supine position, but must 
be performed consistently throughout the study 
• 
Body temperature should be measured using a consistent method throughout the study 
(oral or tympanic is preferred). 
Screening Visit 1 
Body weight and height will also be measured as part of the vital sign assessment at Screening 
Visit 1 only. 
Treatment and Retreatment Visits 
During the Treatment and Retreatment Visits vital signs must be measured: 
• 
Prior to treatment administration; 
and  
• 
Approximately 30 minutes after completion of treatment administration. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 102/139 
 
 
9 
STATISTICS 
9.1 
Analysis Populations 
The following populations will be used during statistical analyses: 
• 
Screened population: All subjects screened (i.e. who signed the informed consent) 
• 
Safety population: All subjects who received at least one IMP administration (including 
only partial administration) of the IMP. Subjects will be analysed as treated (actual 
treatment) 
• 
Modified intention to treat (mITT) population: All randomised subjects who received 
at least one IMP administration. Subjects will be analysed as randomised (planned 
treatment) 
• 
Per protocol (PP) population: All subjects in the mITT population who have no 
impacting major protocol deviations (i.e. that could potentially affect the primary 
efficacy endpoint outcome for the subject) as described in the protocol deviations 
document. Subjects will be analysed as randomised. 
• 
Urodynamic population: All subjects in the mITT population included in the 
urodynamic subset at randomisation. 
 
The following protocol deviations will impact the PP population (for further details of protocol 
deviations see Sections 9.1.2 and 11.1.2): 
1) 
Subject does not receive the full first administration of the IMP 
2) 
Subject does not have a valid (nonmissing) UI data point at the Week 6 Visit following 
the first administration of the IMP. 
9.1.1 
Populations Analysed 
The primary analysis based on the primary efficacy endpoint will be performed on the mITT 
population. In addition, a supportive analysis will be conducted on the PP population. 
The analyses of safety data will be performed based on the safety population. 
The analyses of urodynamic parameters will be performed on the urodynamic population. 
 
9.1.2 
Subject Allocation and Reasons for Exclusion from the Analyses 
Any major protocol deviation (see Section 11.1.2 for definition) will be described in the 
Protocol Deviation Document and its impact on inclusion in each analysis population (mITT, 
PP and safety populations) for any subject will be specified. The final list of protocol deviations 
impacting the safety, mITT and PP populations will be reviewed prior to database lock, before 
any unblinding of treatment groups. The list may be updated up to the database lock to include 
any additional major protocol deviations impacting inclusion in the PP population. 
9.2 
Sample Size Determination 
The sample size is based on the ability to detect a statistically significant treatment difference 
in the weekly number of UI episodes at Week 6 following treatment in the two Dysport® arms 
compared to the placebo arm. 
Assuming a decrease of 21 UI episodes per week in each Dysport® arm and a decrease of 12 UI 
episodes per week in the placebo arm, with a common standard deviation of 20 UI episodes, 
80% power, and an alpha of 0.025 (as testing of both the 600 U and 800 U doses vs. the placebo 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 103/139 
 
 
dose will be performed simultaneously), a sample size of N=96 subjects per dose group for the 
primary analysis (a total of 288 subjects) is needed. 
Assuming a treatment group random allocation ratio 1:1:1, a sample size of 106 subjects in each 
treatment group will have 80% power to detect a difference in UI of 9 episodes (the difference 
between UI in Dysport® 600 U and Dysport® 800 U groups and in placebo group assuming a 
common standard deviation equal to 20 episodes and a dropout rate equal to 10% with a 0.025 
two-sided type one error rate. A total of 318 subjects would therefore need to be enrolled. 
However, in order to ensure that the development program will deliver adequate Dysport 
exposure data to meet ICH E1 guideline recommendations, a total of 330 subjects are planned 
to be randomised. 
9.3 
Significance Testing and Estimations 
All statistical tests will be performed two-sided with a type one error rate set at 5%. 
Experiment-wise control of type one error for the primary endpoint will be performed using a 
conservative approach. The primary efficacy hypotheses are as follows: 
(1) Ho: There is no difference between treatment with 600 U or 800 U Dysport® and 
treatment with placebo with respect to the change from pretreatment to Week 6 after the 
first study treatment in the number of UI episodes per week.  
(2) Ha: There is a difference between treatment with 600 U or 800 U Dysport® and 
treatment with placebo with respect to the change from pretreatment to Week 6 after the 
first study treatment in the number of UI episodes per week. 
For the primary endpoint, due to multiple comparisons of more than two treatments, a Hochberg 
correction will be applied to control the global type one error at 5% significance level. If both 
p-values for the two primary tests (the test of 800 U vs. placebo and the test of 600 U vs. 
placebo) are lower than 0.05, both will be declared statistically significant. If one of the primary 
tests has a p-value greater or equal to 0.05, then the other test will be declared statistically 
significant if its p-value is lower than 0.025 (and thus half of the overall experiment wise alpha 
of 0.05).  
The two ordered secondary endpoints will be tested for both doses at the 0.05 level (using a 
hierarchical methodology) if, for both doses, the two primary tests achieve a p-value lower than 
0.05. If one of the primary tests has a p-value greater or equal to 0.05, and the other has a p-
value lower than 0.025, secondary endpoints will be assessed (using hierarchical methodology) 
for the dose group with p-value lower than 0.025, at the 0.025 significance level.  
In order to control the family-wise type one error, the following hierarchical testing procedure 
will be applied for the testing of the superiority of both Dysport® doses to placebo for the 
primary and selected secondary endpoints (ordered as described in Section 3.2.2.2): 
• 
Step 1: The 800 U Dysport® and 600 U Dysport® doses will be compared to placebo on 
the primary endpoint. If the p-values associated with both doses are <0.05 then both doses 
will be declared statistically significant and the testing will proceed at the 0.05 level from 
step 2 onwards. If one dose has p≥0.05 but the other has p<0.025 (significant dose) then 
testing will proceed at the 0.025 level from step 2 onwards on the significant dose only. 
If both dose groups have p≥0.05 or one dose group has p≥0.05 and the other dose group 
has p≥0.025, the testing procedure will be stopped 
• 
Step 2: The 800 U Dysport® and 600 U Dysport® doses will be compared to placebo for 
the first secondary endpoint. Testing will be at the significance level defined in step 1 
(0.05 or 0.025). If the p-value associated with this test is lower than the significance level 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 104/139 
 
 
defined in step 1 then it will be considered significant and testing will proceed to step 3. 
Otherwise the testing procedure will be stopped 
• 
Step 3: The 800 U Dysport® and 600 U Dysport® doses will be compared to placebo 
for the second secondary endpoint. Testing will be at the significance level defined in 
step 2 (0.05 or 0.025). If the p-value associated with this test is lower than the 
significance level defined in step 2 then it will be considered significant. 
The above testing rules ensure that the hierarchical procedure controls the experiment-wise type 
one error (i.e. over the three tests) at the 0.05 level for relevant secondary endpoints.  
In the event the hierarchical testing procedure is stopped at the end of any particular step, the 
testing of the following steps will be considered descriptive only and no formal statistical 
conclusion will be drawn. 
Each other secondary endpoint not included within the hierarchical testing procedure will be 
analysed for exploratory purposes only to compare each Dysport® dose to placebo at a 0.05 
type one error rate.  
9.4 
Statistical/Analytical Methods 
Statistical analyses will be performed by an external CRO, managed by the sponsor’s Biometry 
Department. 
A SAP describing the planned statistical analysis in detail will be developed as a separate 
document. 
Statistical evaluation will be performed using Statistical Analysis System® (version 9.1 or 
higher). 
9.4.1 
Demographic and Other Baseline Characteristics 
In order to ensure balance of treatment groups, descriptive summary statistics (number of 
patients, mean, standard deviation, standard error mean, 95% confidence interval, median, 
minimum, maximum) or frequency counts of demographic and baseline data (medical history, 
pre-existing conditions and ongoing medical history, prior medications/therapies etc.) will be 
presented by treatment group and overall for the mITT and urodynamic populations.  
Unless prohibited by local regulation, race and ethnicity are collected to ensure data robustness 
for safety and efficacy evaluation, and to prevent adverse reactions or improve benefits in the 
target population.  
9.4.2 
Homogeneity of Treatment Groups 
In order to assess the homogeneity of treatment groups at Baseline, 95% confidence intervals 
will be provided to detect any clinical nonhomogeneity.  
9.4.3 
Data Imputation 
No imputation is planned for the primary analysis of the primary endpoint. For sensitivity 
analyses, imputation will be performed using a multiple imputation approach for handling 
missing data on the mITT population . 
9.4.4 
Subject Disposition and Withdrawals 
The numbers and percentages of subjects enrolled and included in the analysis populations 
mentioned in Section 9.1.1 will be tabulated by country and site. The reasons for subject 
exclusions from each of the populations will also be tabulated. In addition, the numbers of 
subjects who were randomised, treated, prematurely discontinued and completed at each of the 
study periods (e.g. double blind treatment period, active follow-up period) will be tabulated by 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 105/139 
 
 
treatment group (600 U, 800 U, placebo for Treatment 1; 600 U, 800 U for subsequent 
treatments). Primary reasons for discontinuation of study treatment will be tabulated. 
9.4.5 
Efficacy Evaluation 
As indicated in Section 7.1, the primary efficacy variable is the change in the weekly number 
of UI episodes from Baseline (Day 1) to Week 6 after the first treatment.  
Secondary efficacy variables are: 
• 
weekly number of UI episodes 
• 
proportion of subjects with no episodes of UI 
• 
I-QoL total summary score (as well as individual domain scores i.e. avoidance and 
limiting behaviour, psychosocial impact, and social embarrassment) 
• 
urinary frequency (total, spontaneous only, CIC only)  
• 
24-hour voided volume (total, spontaneous only, CIC only) 
• 
volume per void (total, spontaneous only, CIC only) 
• 
EQ-5D-5L score 
• 
mPGI-I score 
• 
proportion of subjects with UI response at several levels (i.e. ≥30% improvement, ≥50% 
improvement, ≥75% improvement, etc.) 
• 
time to retreatment request 
• 
time to eligibility for retreatment 
• 
time between treatments. 
Efficacy assessments performed only in the urodynamic population are described in 
Section 9.6. 
Full details of these assessments and timings are given in Section 7.2. 
The study Baseline value will be defined as the last value available prior to the first study IMP 
treatment administration.  
The aetiology of NDO (SCI or MS) and prior intradetrusor BTX-A usage for UI (BTX-naive 
and BTX-non-naive) will be used as covariates in the primary model. The results of the 
treatment effect will be presented for each subgroup formed by the covariates (see Section 9.5 
for further details). In order to assess the impact of missing data on the conclusion of the primary 
analysis, a sensitivity analysis of the primary efficacy endpoint will be performed using a 
multiple imputation approach. 
If the parametric assumptions of the analysis are not satisfied, then a suitable transformation or 
a nonparametric procedure will be sought. 
Secondary efficacy endpoints will be assessed according to their scale (categorical or 
continuous), using a logistic regression model, mixed model, or survival analysis-type methods 
(e.g. Kaplan-Meier plots, log-rank statistics). 
Time to event data will be analysed by using survival methods. The results will be presented 
both in summary tables and graphically in Kaplan-Meier plots. 
Responders defined as subjects having an improvement in UI will be presented at several levels 
(i.e. ≥30% of improvement, ≥50% of improvement, ≥75% of improvement, etc.) for exploratory 
purposes. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 106/139 
 
 
9.4.6 
Adjustment for Country/Site Effect 
No stratification for country/site is to be performed, and no adjustment for country or site effect 
is planned. 
9.4.7 
Safety Evaluation 
All safety data will be included in the subject data listings. Analyses and summary tables will 
be based upon the safety population. 
All AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) (current version at the time of database lock), and will be classified by MedDRA 
preferred term and system organ class. AE listings will be presented by subject, system organ 
class and preferred term. 
Incidence of all reported AEs/treatment emergent AEs, AESIs, and SAEs will be tabulated by 
treatment group (600 U, 800 U, placebo for Treatment 1 and 600 U, 800 U for subsequent 
treatment(s)) and overall. In addition, summary tables will be presented by maximum intensity, 
drug relationship and AEs associated with premature withdrawal of IMP. 
A treatment emergent AE 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 at any 
point in the study following the first dose of IMP.  
Concomitant medication will be coded by using World Health Organisation Drug Dictionary 
(WHODRUG; current version at the time of database lock) and will be summarised by 
treatment group (600 U, 800 U, placebo for Treatment 1 and 600 U, 800 U for subsequent 
treatment(s)) and overall, with the number and percentage of subjects receiving concomitant 
medication by drug class and preferred drug name. 
Summary statistics (mean, median, standard deviation, standard error mean, and range as 
appropriate) by treatment group and overall will be presented for vital signs, laboratory safety 
tests, laboratory urinalysis/microscopy etc. at each assessment with change from Baseline. For 
laboratory safety data, abnormal values will be flagged in the data listings and a list of clinically 
significant abnormal values will be presented. Shift tables from Baseline of the number and 
percentage of subjects with low, normal or high values and normal or abnormal examinations 
will be presented by treatment group (600 U, 800 U, placebo for Treatment 1 and 600 U, 800 U 
for subsequent treatment(s)).  
9.4.8 
Antibody Testing 
The number and percentage of subjects with the presence of neutralising BTX-A antibodies  at 
Baseline will be described. The number of seroconverters (subjects having a negative result at 
Baseline and at least one positive result at one post-treatment timepoint) for neutralising 
antibodies will be reported for each treatment group. 
9.5 
Subgroup Analyses 
Descriptive statistics for the primary and selected secondary endpoints (to be defined in the 
SAP) will be provided for the mITT population within each category of the randomisation 
stratification variables: aetiology of NDO (SCI or MS) and also BTX-A bladder naive and 
BTX-A bladder non-naive). Additional subgroup analyses will be planned according to clinical 
interest and detailed in the SAP. 
Subjects will also be categorised as follows: 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 107/139 
 
 
(1) 
No previous BTX-A treatment at any anatomical location 
(2) 
No previous intradetrusor BTX-A usage for UI but with previous BTX-A treatment at 
any other anatomical location 
(3) 
Previous intradetrusor BTX-A usage for UI, with or without previous BTX-A treatment 
of any other anatomical location (stratified according to this category). 
9.6 
Urodynamics Subset 
At least 200 subjects will be included in the urodynamics subset. The analysis of MCC 
(representative urodynamic parameter) will reach a power of 90% with an alpha of 0.05, if the 
treatment groups are well-balanced, using the assumptions described in Table 21. 
Table 21 Estimate of minimum delta required for MCC (example urodynamic parameter) 
 
Change from Baseline 
to Week 6 following 
first treatment in 
placebo group 
[= a] 
Change from Baseline 
to Week 6 following 
first treatment in 
Dysport group 
[= b] 
Common 
standard 
deviation 
Minimum delta to 
reach 200 subjects with 
90% power and an 
alpha 0.05 
[= b-a] 
MCC 
(mL) 
15.5 
120 
212.9 
104.5 
MCC=maximum cystometric capacity. 
Urodynamic secondary endpoints will be evaluated using a hierarchical analysis for the 
following ordered parameters:  
• 
MCC 
• 
MDP during storage  
• 
Vol@1stIDC  
• 
Proportion of subjects with no IDCs on urodynamic assessment  
The full hierarchical methodology will be detailed in the statistical analysis plan.  
All other secondary endpoints related to urodynamics will be presented for exploratory 
purposes. 
9.7 
Primary Analyses 
 
 
 
 
 
  
CCI


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 108/139 
 
 
10 
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 11.4, and to any other locations used for the purpose of the study in question 
(e.g. laboratories). 
In the event of the site being notified directly of a regulatory inspection, the investigator must 
notify the sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 109/139 
 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Protocol Amendments and Protocol Deviations  
11.1.1 
Protocol Amendments 
In the event that an amendment to this protocol is required (see Section 12.1), it will be 
classified into one of the following three categories: 
• 
Nonsubstantial Amendments are those that are not considered ‘substantial’ (e.g. 
administrative changes) and as such only need to be notified to the IECs/IRBs or 
regulatory authorities for information purposes. 
• 
Substantial Amendments are those considered ‘substantial’ to the conduct of the clinical 
trial where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects; 
- 
the scientific value of the trial; 
- 
the conduct or management of the trial; or 
- 
the quality or safety of the study drug used in the trial. 
Substantial amendments must be submitted to and approved by the IECs/IRBs 
and relevant regulatory authorities, according to local regulations. 
• 
Urgent Amendments are those that require urgent safety measures to protect the trial 
subjects from immediate hazard and as such may be implemented immediately by the 
sponsor with subsequent IECs/IRBs and regulatory authority notification, forthwith.  
The coordinating investigator as well as the principal investigator and the sponsor will sign the 
protocol amendment. 
11.1.2 
Protocol Deviations and Exceptions 
All protocol deviations will be identified and recorded by the sponsor or sponsor’s 
representative (see Sections 11.3, 11.4, and 11.5). 
A major protocol deviation 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.  
Generally, a protocol deviation qualifies as major if: 
1) 
The deviation has harmed or posed a significant or substantive risk of harm to the 
research subject 
2) 
The deviation compromises the scientific integrity of the data collected for the study 
3) 
The deviation is a wilful or knowing breach of human subject protection regulations, 
policies, or procedures on the part of the investigator(s) 
4) 
The deviation involves a serious or continuing noncompliance with any applicable 
human subject protection regulations, policies, or procedures 
5) 
The deviation is inconsistent with Ipsen’s research, medical, and ethical principles. 
See also Section 9.1.2 for details on the impact of major protocol deviations on the inclusion of 
subjects in each analysis population. 
A minor protocol deviation is any significant divergence from the protocol that does not impact 
the study results.  
11.2 
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 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 110/139 
 
 
procedures and during the course of the study (e.g. when new staff become involved). The 
investigator must assure that all study staff members are qualified by education, experience, 
and training to perform their specific responsibilities. These study staff members must be listed 
on the study site 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. 
11.3 
Study Monitoring 
The investigator is responsible for the validity of all data collected at the site. 
The sponsor or sponsor’s representative is responsible for monitoring these 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. 
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 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 study monitor will use functions of the electronic data capture (EDC) 
system to address any queries raised while reviewing the data entered by the study site personnel 
in a timely manner. 
Whenever a subject name is revealed on a document required by the sponsor (e.g. laboratory print 
outs) the name must be blacked out permanently by the site personnel, leaving the initials visible, 
and annotated with the subject number as identification. 
Enrolment will be monitored across study sites to attempt to balance the study population 
between subjects with MS and subjects with SCI, if possible. 
11.4 
Audit and Inspection 
Authorised personnel from external CAs and the sponsor’s authorised Quality Assurance 
personnel may carry out inspections and audits (see Section 10). 
11.5 
Data Quality Assurance 
Monitored eCRFs transferred electronically from the investigational site to the assigned Data 
Management group at the CRO will be reviewed (secondary monitoring) for completeness, 
accuracy, consistency, and protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol deviations. 
Any electronic queries and items not adequately explained will require additional electronic 
manual queries to be raised to the investigator by the monitor for clarification/correction. The 
investigator must ensure that queries are dealt with promptly. All data changes and clarifications 
can be viewed in the audit trail function of the eCRF. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 111/139 
 
 
12 
ETHICS 
12.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IECs/IRBs, informed consent regulations, all 
applicable local regulations, the Declaration of Helsinki and ICH GCP Guidelines (Section 1 or 
1.6). 
In addition, this study will adhere to FDA, 21 CFR Part 11, Electronic Records, Electronic 
Signatures, and FDA, Guidance for Industry: Computerized Systems Used in Clinical Trials, and 
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 (e.g. advertisements, if any), 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. 
12.2 
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 or subject’s 
legally acceptable representative. 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 or sponsor’s representative will provide a sample informed consent form. The final 
version controlled form must be agreed to by the sponsor or sponsor’s representative 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 impartial witness, if 
applicable, 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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 112/139 
 
 
12.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the sponsor’s or sponsor’s representative’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. 
12.4 
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 by a unique 
subject identification code. 
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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 113/139 
 
 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
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. In the event of premature 
termination, all records up to the time of premature termination should be completed. If the subject 
did not receive IMP the primary reason for not administering IMP should be recorded. 
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. 
13.2 
Data Management 
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 CRO standard 
operating procedures (SOPs) or with sponsor SOPs if CRO SOPs do not exist. The data will be 
monitored at the investigator site (for further details please see Section 11.3 Study Monitoring). 
Any 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.  
Any queries generated during the data management process 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 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. 
The sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be performed by the 
sponsor’s Central Coding Group, and reviewed and approved by the sponsor. Concomitant 
medications will be coded using WHODRUG (current version at the time of database lock), 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 114/139 
 
 
and AEs/medical history terms will be coded using MedDRA (current version at the time of 
database lock). 
13.3 
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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 115/139 
 
 
14 
FINANCING AND INSURANCE 
14.1 
Contractual and Financial Details 
The investigator (and/or, as appropriate, the hospital administrative representative) and the 
sponsor’s representative 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. 
14.2 
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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 116/139 
 
 
15 
REPORTING AND PUBLICATIONS OF RESULTS 
15.1 
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. 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. 
15.2 
Clinical Study Report 
In order to support regulatory submission an ICH E3-compliant clinical study report (CSR) may 
be prepared prior to completion of the study. See Section 9.7 for details regarding this interim 
analysis. 
A final 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. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 117/139 
 
 
16 
REFERENCES 
 
1. 
Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary 
tract function: report from the standardisation sub-committee of the International 
Continence Society. Urology 2003;61(1):37-49. 
2. 
Haab F. Chapter 1: The conditions of neurogenic detrusor overactivity and overactive 
bladder. Neurourol Urodyn 2014;33:S2-5. 
3. 
Biers SM, Venn SN, Greenwell TJ. The past, present, and future of augmentation 
cystoplasty. BJU Int 2012;109:1280 93. 
4. 
Jankovic J, Brin MF. Therapeutic uses of botulinum toxin. N Engl J Med 
1991;324(17):1186-94. 
5. 
Patel AK, Patterson JM, Chapple CR. Botulinum toxin injections for neurogenic and 
idiopathic detrusor overactivity: a critical analysis of results. Eur Urol 2006;50:684-709. 
6. 
Mangera A, Andersson, K-E, Apostolidis A, et al. Contemporary management of lower 
urinary tract disease with botulinum toxin A: a systematic review of botox 
(OnabotulinumtoxinA) and Dysport® (AbobotulinumtoxinA). Eur Urol 2011;60:784 95. 
7. 
Mangera A, Apostolidis A, Andersson K-E, et al. An updated systemic review and 
statistical comparison of standardised mean outcomes for the use of botulinum toxin in 
the management of lower urinary tract disorders. Eur Urol 2014;65:981 90. 
8. 
Cruz F, Herschorn S, Aliotta P, et al. Efficacy and safety of onabotulinumtoxinA in 
patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, 
double-blind, placebo-controlled trial. Eur Urol 2011;60:742-50. 
9. 
Ginsberg D, Gousse A, Keppenne V, et al. Phase 3 efficacy and tolerability study of 
onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity. 
J Urol 2012;187:2131-9. 
10. 
Del Popolo G, Filocamo MT, Li Marzi V, et al. Neurogenic detrusor overactivity treated 
with English botulinum toxin a: 8-year experience of one single centre. Eur Urol 
2008;53(5):1013-19. 
11. 
Ruffion A, Capelle O, Paparel P, et al. What is the optimum dose of type A botulinum 
toxin for treating neurogenic bladder overactivity? BJU Int 2006;97(5):1030-4. 
12. 
Ehren I, Volz D, Farrelly E, et al. Efficacy and impact of botulinum toxin A on quality 
of life in patients with neurogenic detrusor overactivity: a randomised, placebo 
controlled, double-blind study. Scand J Urol Nephrol 2007;41(4):335-40. 
13. 
Grosse J, Kramer G, Stöhrer M. Success of repeat detrusor injections of botulinum a 
toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol 
2005;47(5):653-9. 
14. 
Grosse J, Kramer G, Jakse G. Comparing two types of botulinum-A toxin detrusor 
injections in patients with severe neurogenic detrusor overactivity: a case-control study. 
BJU Int 2009;104(5):651-6. 
15. 
Grise P, Ruffion A, Denys P, et al. Efficacy and tolerability of botulinum toxin type a in 
patients with neurogenic detrusor overactivity and without concomitant anticholinergic 
therapy: comparison of two doses. Eur Urol 2010;58:759-66. 


IPSEN GROUP 
D-FR-52120-223  
 
CONFIDENTIAL 
 
PROTOCOL: FINAL VERSION 3.0: 16 APRIL 2018 
PAGE 118/139 
 
 
16. 
Patki PS, Hamid R, Arumugam K, et al. Botulinum toxin-type A in the treatment of drug-
resistant neurogenic detrusor overactivity secondary to traumatic spinal cord injury. BJU 
Int 2006;98:77-82. 
17. 
A phase IIa, multicentre, double blind, single dose, parallel group, placebo controlled, 
clinical pilot study to assess the efficacy and safety of single dose, intra-detrusor 
injections of 750 units of Dysport® in subjects suffering from neurogenic detrusor 
overactivity following spinal cord injury or multiple sclerosis. Report Y-52-52120-155, 
03 October 2013. 
18. 
Kennelly M, Dmochowski R, Ethans K, et al. Long-term efficacy and safety of 
onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor 
overactivity: an interim analysis. Urology 2013;81(3):491-7. 
19. 
Krassioukov A, Warburton DE, Teasell R, Eng JJ. A Systematic review of the 
management of autonomic dysreflexia after spinal cord injury. Arch Phys Med Rehabil 
2009;90:682-95. 
20. 
ICS guidelines EAU Guidelines on Neurogenic Lower Urinary Tract Dysfunction 
European Urology Volume 56, Issue 1, July 2009, Pages 81-88. 
21. 
Patrick DL, Martin ML, Bushnell DM, et al. Quality of life of women with urinary 
incontinence: further development of the incontinence quality of life instrument (I-QOL). 
Urology 1999;53(1):71-76. Erratum in: Urology 1999;53(5):1072. 
22. 
Patrick DL, Martin ML, Bushnell DM, et al. Cultural adaptation of a quality-of-life 
measure for urinary incontinence. Eur Urol 1999;36(5):427-35. 
23. 
Bushnell DM, Martin ML, Summers KH, et al. Quality of life of women with urinary 
incontinence: cross-cultural performance of 15 language versions of the I-QOL. Qual 
Life Res 2005;14(8):1901-13. 
24. 
Wagner TH, Patrick DL, Bavendam TG, et al. Quality of life in persons with urinary 
incontinence: development of a new measure. Urology 1996;47:67 72. 
25. 
Polman CH, Reingold SC, Banwell B. Diagnostic criteria for multiple sclerosis: 2010 
revisions to the McDonald criteria. Ann Neurol 2011;69:292 302. 

SAP_001.pdf: 
COVANCE INC. CONFIDENTIAL 
Page 1 of 75 
ST-AD-008 version 03 
 
Ipsen Innovation 
Protocol No.: D-FR-52120-223 
A PHASE III, MULTICENTER, RANDOMISED, DOUBLE-BLIND, PARALLEL GROUP, 
PLACEBO CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF 
ONE OR MORE INTRADETRUSOR TREATMENTS OF 600 OR 800 UNITS OF 
DYSPORT FOR THE TREATMENT OF URINARY INCONTINENCE IN SUBJECTS 
WITH NEUROGENIC DETRUSOR OVERACTIVITY DUE TO SPINAL CORD INJURY 
OR MULTIPLE SCLEROSIS 
Covance Study ID: 000000146513 
STATISTICAL ANALYSIS PLAN 
Version: Final v1.0 
Date of Issue: 21-September-2018 
Author: 
 
 
Ipsen Innovation 
Ipsen Group 
5 Avenue du Canada 
91940 Les Ulis Cedex, France 
Tel: +33 (0)1 60 92 20 00 
Fax: 
 
 
Covance Clinical Development Services 
Osprey House,  
1 Maidenhead Office Park,  
Westacott Way,  
Maidenhead,  
SL6 3QH 
UK 
Tel: 01628 548 000 
 
 
 
PPD
PPD








Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 3 of 75 
ST-AD-008 version 02 
REVIEWERS 
The following reviews of the SAP were conducted: 
 
VERSION HISTORY 
Version Number 
Version Date 
Pre-Final 
16-March-2018 
Pre-Final 2  
24-May-2018 
Pre-Final 3 
01-July-2018 
Pre-Final 4 
30-July-2018 
Final v1.0 
21-September-2018 
 
Name and Title  
 Role 
Last Version  
Reviewed 
Company/ 
Organisation 
 
 
 
Pre-final 4 
Covance 
 
 
 
Pre-final 4 
Covance 
 
 
 
Pre-final 4 
Covance 
 
 
 
Pre-final 4 
IPSEN 
 
 
 
Pre-final 4 
IPSEN 
 
 
 
Pre-final 4 
IPSEN 
(Consultant) 
 
 
Pre-final 4 
IPSEN 
 
 
 
Pre-final 4 
IPSEN 
 
 
 
Pre-final 4 
IPSEN 
 
 
 
 
Pre-final 4 
IPSEN 
i
 
 
 
 
Pre-final 4 
IPSEN 
 
 
 
Pre-final 4 
IPSEN 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
P


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 4 of 75 
ST-AD-008 version 02 
TABLE OF CONTENTS 
APPROVALS ........................................................................................................................... 2 
REVIEWERS ........................................................................................................................... 3 
VERSION HISTORY .............................................................................................................. 3 
GLOSSARY OF ABBREVIATIONS ..................................................................................... 6 
1 SOURCE DOCUMENTS .................................................................................................. 8 
2 PROTOCOL DETAILS .................................................................................................... 8 
2.1 Study Objectives ........................................................................................................ 8 
2.2 Overall Study Design ................................................................................................ 9 
2.3 Sample Size and Power ........................................................................................... 12 
3 EFFICACY AND SAFETY VARIABLES .................................................................... 12 
3.1 Primary Efficacy Endpoint .................................................................................... 13 
3.2 Secondary Efficacy Endpoints ............................................................................... 13 
Bladder diary measures: ............................................................................................ 13 
Urodynamic filling cystometry measures (urodynamic subset only): ...................... 13 
Patient-reported outcome questionnaires: ................................................................. 14 
Duration of effect following the first and subsequent treatments ............................. 14 
3.2.1 Hierarchical Analysis of Selected Secondary Endpoints ..................................... 14 
3.3 Safety Variables ....................................................................................................... 14 
4 PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES ............................. 15 
5 ANALYSIS POPULATIONS .......................................................................................... 15 
5.1 Screened Population ................................................................................................ 15 
5.2 Randomised Population .......................................................................................... 15 
5.3 Safety Population ..................................................................................................... 15 
5.4 Modified Intention-to-Treat Population ............................................................... 15 
5.5 Per Protocol Population .......................................................................................... 15 
5.5.1 Protocol Deviations ................................................................................................. 15 
5.6 Urodynamic Population .......................................................................................... 16 
6 DATA HANDLING .......................................................................................................... 16 
6.1 Time points and Visit Windows ............................................................................. 16 
6.2 Handling of Dropouts or Missing Data ................................................................. 17 
6.2.1 Analysis Endpoints .................................................................................................. 17 
6.2.2 Missing or Partial Date ........................................................................................... 18 
7 STATISTICAL METHODS............................................................................................ 19 
7.1 General Principles ................................................................................................... 19 
7.2 Subject Disposition and Data Sets Analysed ......................................................... 21 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 5 of 75 
ST-AD-008 version 02 
7.3 Protocol Deviations ................................................................................................. 21 
7.4 Demographics and Other Baseline Characteristics ............................................. 21 
7.4.1 UTI Prior to First IMP Administration ................................................................ 22 
7.4.2 Medical History ....................................................................................................... 22 
7.4.3 Prior and Concomitant Medications ..................................................................... 23 
7.5 Treatment Exposure ............................................................................................... 23 
7.6 Efficacy ..................................................................................................................... 24 
7.6.1 Significance Testing and Estimations .................................................................... 24 
7.6.2 Multiplicity Adjustment ......................................................................................... 24 
7.6.3 Primary Efficacy Analysis ...................................................................................... 25 
7.6.4 Sensitivity Analyses for the Primary Efficacy Endpoint ..................................... 26 
7.6.5 Hierarchical Analysis of Secondary Efficacy Endpoints ..................................... 28 
7.6.6 Other Analysis of Secondary Efficacy Endpoints ................................................ 29 
7.6.7 Subgroup Analysis................................................................................................... 33 
7.7 Safety ........................................................................................................................ 33 
7.7.1 Adverse Events ........................................................................................................ 33 
7.7.2 Laboratory Evaluations .......................................................................................... 35 
7.7.3 Antibody Test ........................................................................................................... 36 
7.7.4 Vital Signs ................................................................................................................ 36 
7.7.5 Electrocardiograms ................................................................................................. 37 
7.7.6 Other Safety Variables ............................................................................................ 37 
7.8 Primary Analysis of the Study ............................................................................... 37 
8 CHANGES IN PLANNED ANALYSES ........................................................................ 37 
9 DATA ISSUES .................................................................................................................. 38 
10 REFERENCES ................................................................................................................. 38 
11 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 6 of 75 
ST-AD-008 version 02 
GLOSSARY OF ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ANCOVA 
Analysis of Covariance 
ASIA 
American Spinal Injury Association  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body mass index 
BTX 
Botulinum Toxin 
BTX-A 
Botulinum Toxin Type A 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CIC 
Clean intermittent catheterisation 
Cm 
centimetre 
CS 
Compound symmetry 
CSR 
Clinical Study Report 
DBPC 
Double-blind placebo-controlled 
DC 
Detrusor compliance 
ECG 
Electrocardiogram 
EFP 
End fill pressure 
EOS 
End of study 
EQ-5D-5L 
EuroQol 5-dimension 5-level 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GLMM 
Generalised Linear Mixed Model 
Ho 
Null hypothesis 
Ha 
Alternative hypothesis 
ICH 
International Conference on Harmonisation  
IDC 
Involuntary detrusor contraction 
IMP 
Investigational medicinal product 
I-QoL 
Incontinence quality of life 
IVRS 
Interactive Voice Response System 
Kg 
kilogram 
LOCF 
Last observation carried forward 
LPLV 
Last patient last visit 
LSMEANS 
Least square means 
n 
Number of subjects 
NA 
Not applicable 
MAR 
Missing at random 
MCC 
Maximum cystometric capacity 
MDP 
Maximum detrusor pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed model repeated measures  
mPGI-I 
Modified patient global impression – improvement 
mITT: 
Modified Intention-To-Treat 
MS 
Multiple sclerosis 
NDO 
Neurogenic detrusor overactivity 
PdetMax@1stIDC 
Maximum detrusor pressure at first involuntary detrusor 
contraction 
PP 
Per-protocol 
PT 
Preferred Term 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 7 of 75 
ST-AD-008 version 02 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System® 
SCI 
Spinal Cord Injury 
SD 
Standard Deviation 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures and Listings 
U 
Units 
UTI 
Urinary tract infection 
UI 
Urinary incontinence 
VC 
Variance components 
vs 
Versus 
Vol@1stIDC 
Volume at first involuntary detrusor contraction 
WHO 
World Health Organisation 




Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 9 of 75 
ST-AD-008 version 02 
 To assess the efficacy of two Dysport doses (600 U and 800 U) in improving bladder 
diary measures and patient-reported efficacy endpoints following retreatment IMP 
administrations, including assessing duration of effect. 
 To assess the safety of two Dysport doses (600 U and 800 U) for the treatment of UI due 
to neurogenic detrusor overactivity (NDO). 
2.2 Overall Study Design 
This is a Phase III, multicenter, randomised, double-blind, parallel group, placebo controlled 
study to assess the efficacy and safety of two Dysport doses (600 U and 800 U) administered 
to the bladder of adult subjects with NDO due to spinal cord injury (SCI) or multiple sclerosis 
(MS). 
The target population is subjects with UI caused by NDO due to either SCI or MS, who have 
not been adequately managed with oral medication and who routinely require clean 
intermittent catheterisation (CIC) to manage their bladder function. 
 
The study will include two treatment periods.  
 
A double-blind placebo controlled (DBPC) treatment, i.e. following Treatment 1 on 
Day 1 during which subjects receive a single IMP treatment administration of either 
 Dysport 600 U  
 Dysport 800 U  
 Placebo. 
DBPC Cycle will run from randomisation and treatment on Day 1 to the 
administration of Treatment 2. The length of the DBPC period will depend on 
when the patient receives Treatment 2. 
 
A subsequent double-blind active treatment period, during which subjects can receive 
multiple active IMP retreatment administrations of either; 
 Dysport 600 U  
 Dysport 800 U. 
Subjects who were randomised to receive Dysport at Treatment 1 (600 U or 800 U) 
will continue to receive the same dose for all subsequent treatments and those who 
were initially randomised to placebo will receive either 600 U or 800 U, depending 
on their allocated randomisation sequence (see next section). 
The study contains two subsets: 
•Urodynamic subset (planned ≥ 200 subjects) 
o All subjects in this subset must have standardised urodynamics (as described in the 
Study Specific Urodynamic Manual) during Screening and at Week 6 following each 
study treatment 
o Screening standardised urodynamics must confirm the presence of NDO 
•Non-Urodynamic subset 
o All subjects in this subset must have documented urodynamic proven NDO in the 12 
months prior to Screening. If not, then urodynamics must be performed per local 
practice during Screening to confirm the diagnosis of NDO 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 10 of 75 
ST-AD-008 version 02 
o Urodynamics will not be performed in the post-screening period in this subset 
Screening  
Screening period will last for up to 30 days, but can be extended in certain circumstances to 
obtain an appropriately and fully completed bladder diary or to obtain a valid bladder diary. 
Furthermore, where a urinary tract infection (UTI) occurs after completion of the bladder 
diary and impacts the ability to perform urodynamics, the time to Screening Visit 2 can be 
extended until the UTI is resolved. During the screening period, informed consent will be 
obtained and eligibility for study participation will be assessed. Subjects will complete a 7-
day bladder diary, urodynamic assessment, patient-reported outcome questionnaires and have 
blood and urine samples taken.  
Randomisation/treatment 
The Treatment Visit (Day 1) should occur up to 14 days after the screening period, but can be 
extended until the UTI is resolved (where a UTI has occurred and impacts the ability to 
perform IMP administration). At the Treatment 1 visit on Day 1, subjects who meet all the 
eligibility criteria will be randomised (in a 2:2:1:1 ratio) to one of four treatment sequences: 
 
Sequence             Subjects                   1st 
Treatment 
in 
DBPC Cycle 
Subsequent 
retreatment(s) 
in Dysport Cycles (Dysport 
Cycle 1, Dysport Cycle 2, 
etc) 
1 
110 subjects 
Dysport 600 U  
Dysport 600 U  
2 
110 subjects 
Dysport 800 U  
Dysport 800 U  
3 
55 subjects 
Placebo 
Dysport 600 U  
4 
55 subjects 
Placebo 
Dysport 800 U  
 
During the analysis of DBPC cycle, the two placebo containing sequences will be pooled into 
a single arm. 
Randomisation will be stratified by; 
 Aetiology of NDO (SCI or MS)  
 Previous intradetrusor botulinum toxin type A (BTX-A) usage (BTX-A naïve vs. BTX-A 
non-naïve). 
Follow-up (after IMP administration in DBPC cycle): 
 Week 1 (Day 8) (telephone) 
 Week 2 (Day 15) (clinic visit) 
 Week 4 (Day 29) (telephone) 
 Week 6 (Day 43) (clinic visit; primary timepoint) 
 Week 12 (Day 85) (clinic visit; the retreatment could be requested by subject from this 
visit) 
 Every 12 weeks (telephone visits; until retreatment received or end of study (EOS) at 
Weeks 104 to 116). 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 11 of 75 
ST-AD-008 version 02 
Details of the procedures performed at each visit following the first treatment are shown in the 
schedule of assessments, Appendix V. 
Retreatment assessment 
A subject may request retreatment with IMP at any time Ӌ12 weeks after their most recent 
study treatment. 
The retreatment criteria are as follows: 
1)      Retreatment requested by subject; 
2)      More than 12 weeks (84 days) since the previous IMP administration; 
3)      
 
 
      
 
 
; 
5)      In the investigator’s opinion it is safe and appropriate to provide retreatment. 
 
A patient may only be retreated if eligible based on the study retreatment criteria. The bladder 
diary device/portal may provide an indication that the patient is within 30% of their Baseline 
(Screening) UI level, however to confirm eligibility a manual calculation can be performed by 
multiplying the weekly number of UI episodes on the screening bladder diary by 0.7. If the 
subject has a current number of weekly UI episodes greater than this calculated number then 
the subject is within 30% of their Baseline UI level and meets the retreatment criterion #3. 
 
Example calculation: 
͌Study Baseline (Screening) number of weekly UI episodes = 28 episodes 
28 episodes x 0.7 = 19.6 (rounded up to 20) 
͌Subject is therefore eligible for retreatment if current weekly UI episodes are 20 or more.  
 
Retreatment should ideally occur within 14 days of confirmation of eligibility for retreatment 
and can occur up to and including Week 104 following the first IMP administration of the 
first period. 
Retreatment follow-up 
Follow-up after each retreatment follows the same schedule as the first IMP administration 
(Treatment 1).  
 Week 1 (Day 8) (telephone) 
 Week 2 (Day 15) (clinic visit) 
 Week 4 (Day 29) (telephone) 
 Week 6 (Day 43) (clinic visit) 
 Week 12 (Day 85) (clinic visit; the retreatment could be requested by subject from this 
visit) 
 Every 12 weeks (telephone visits; until retreatment received or EOS at Weeks 104 to 116). 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 12 of 75 
ST-AD-008 version 02 
Details of the procedures performed at each Retreatment Follow-up Visit in the Dysport cycle 
are contained in Appendix V. 
End of Study Visit 
The EOS Visit will take place between 104 and 116 weeks after the first IMP administration 
on Day 1. Subjects may receive study retreatment up to and including Week 104 and a 
minimum of 12 weeks of follow-up is required after each IMP administration. For those 
subjects completing the study, the EOS Visit will occur: 
 
At Week 104 after the first IMP administration, if it has been more than 12 weeks since 
the previous IMP administration. 
 
At Week 12 Retreatment Follow-up Visit, if the subject received their most recent IMP 
administration between Week 92 and Week 104 following their first IMP administration. 
Early discontinuation 
A subject who discontinues the study early should, if at all possible, be followed-up for at 
least 12 weeks following their most recent IMP administration and should attend the EOS 
Visit. 
Duration of subject participation 
104 weeks (24 months) to 116 weeks depending on the timing of final IMP administration. 
2.3 Sample Size and Power 
The sample size is based on the ability to detect a statistically significant treatment difference 
in the weekly number of UI episodes at Week 6 following the first IMP administration in the 
two Dysport arms (600 U and 800 U) compared to the placebo arm. 
Assuming a weekly decrease of 21 UI episodes in each Dysport arm and a weekly decrease of 
12 UI episodes in the placebo arm, with a common standard deviation of 20 UI episodes, 80% 
power, and an alpha of 0.025 (as testing of both the 600 U and 800 U doses vs. the placebo 
dose will be performed simultaneously), a sample size of 96 subjects per dose group (a total 
of 288 subjects) is needed. Dropout between randomisation and Week 6 (primary efficacy 
timepoint) is expected to be 10%, and thus a total of 318 subjects would be needed to be 
enrolled. However, in order to ensure that the development program will deliver adequate 
Dysport exposure data to meet ICH E1 guideline recommendations, a total of 330 subjects are 
planned to be randomised. Subjects who leave the study early will not be replaced. 
Sample size calculations were performed in SAS Studio 3.6. 
3 
EFFICACY AND SAFETY VARIABLES 
For the purpose of all analysis, the study baseline is defined as the last value available during 
screening or day of treatment visit prior to the first study IMP treatment administration 
(Treatment 1) i.e. prior to the DBPC Cycle. This study baseline will be used in analysis of the 
efficacy endpoints and the safety endpoints for all treatment cycles.  
 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 13 of 75 
ST-AD-008 version 02 
3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from study baseline in weekly number of 
UI episodes at Week 6 after the first IMP administration (Treatment 1). 
3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are divided into those that relate to parameters measured in 
the bladder diary, those measured by urodynamic filling cystometry and those that are quality 
of life measures. From these secondary measures, there are two that have been selected to be 
analysed as part of a hierarchal testing scheme  see Section 3.2.1. 
Bladder diary measures: 
Mean change from study baseline to post-treatment timepoints in the following 
variables: 
 
weekly number of UI episodes (except for week 6 after Treatment 1 which is 
the primary efficacy endpoint) 
 
total daily urinary frequency (spontaneous void and CIC) 
 
daily spontaneous voiding frequency  
 
daily CIC frequency  
 
total 24-hour voided volume (spontaneous void and CIC) 
 
24-hour voided volume (spontaneous void only) 
 
24-hour voided volume (CIC only) 
 
total volume per void (spontaneous void and CIC) 
 
volume per void (spontaneous void only) 
 
volume per void (CIC only) 
Proportion of subjects with: 
 
no episodes of UI (i.e. 100% improvement where continence is achieved) 
 
UI response at several levels (i.e. ≥30% improvement, ≥50% improvement, 
≥75% improvement)  
Urodynamic filling cystometry measures (urodynamic subset only): 
Mean change from study baseline to week 6 after Treatment 1 in the following 
variables: 
 
MCC 
 
MDP during storage 
 
Vol@1stIDC (subjects without a post-treatment IDC will have their 
Vol@1stIDC imputed from their MCC) 
 
maximum detrusor pressure at first involuntary detrusor contraction 
(PdetMax@1stIDC) 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 14 of 75 
ST-AD-008 version 02 
 
end fill pressure (EFP) 
 
detrusor compliance (DC) 
Proportion of subjects with: 
 
No IDCs (i.e. urodynamic cure is achieved) 
Patient-reported outcome questionnaires: 
Mean change from study baseline to post-treatment timepoints in the following 
variables: 
 
I-QoL total summary score 
 
I-QoL Score of domain: Avoidance and limiting behaviour 
 
I-QoL Score of domain: Psychosocial impact 
 
I-QoL Score of domain: Social embarrassment 
 
EuroQol 5-dimension 5-level (EQ-5D-5L): Total descriptive score  
 
EQ-5D-5L: self-rated health (VAS) 
 
modified patient global impression - improvement (mPGI-I) score (to be 
assessed at each timepoint without comparison to baseline) 
Duration of effect following the first and subsequent treatments  
 
time to request retreatment 
 
time to eligibility for retreatment 
 
time between treatments. 
Detailed definitions of all efficacy endpoints are presented in Appendix II. 
 
3.2.1 Hierarchical Analysis of Selected Secondary Endpoints 
 
A hierarchical analysis will be performed in the order listed for the following secondary 
efficacy endpoints at Week 6 after Treatment 1: 
1) 
Proportion of subjects with no episodes of UI (i.e. continence is achieved): 
 
measured by 7-day bladder diary. 
2) 
Mean change from study Baseline (assessed at Screening) in the I-QoL total summary 
score: 
 
measured by patient-reported questionnaire. 
 
3.3 Safety Variables 
Safety will be assessed throughout the study by evaluating: 
 Treatment Emergent Adverse Events (TEAEs) 
 Adverse events of special interest (AESI) 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 15 of 75 
ST-AD-008 version 02 
 Adverse events (AEs) related to toxin spread 
 AEs related to hypersensitivity 
 
Other protocol defined TEAEs 
 Urinary Tract Infections (UTI) 
 Vital signs (heart rate, respiratory rate, blood pressure and body temperature) 
 Laboratory blood parameters (haematology and serum chemistry) 
 Laboratory urine parameters (laboratory urinalysis/microscopy, culture and sensitivity) 
 Development of BTX-A antibodies (neutralizing) 
 Usage of concomitant medications and therapies. 
Timepoints for safety evaluations are detailed in Appendix V. 
4 
PHARMACOKINETIC/PHARMACODYNAMIC VARIABLES 
Not applicable. 
5 
ANALYSIS POPULATIONS 
5.1 Screened Population 
Screened population includes all subjects screened (enrolled); these are subjects who have 
signed the informed consent.  
5.2 Randomised Population 
All subjects assigned a randomisation number. Randomised subjects will be analysed 
according to their randomised treatment. 
5.3 Safety Population 
All subjects who received at least one IMP administration (including only partial 
administration) of the IMP. Safety subjects will be analysed according to their actual 
treatment received. 
5.4 Modified Intention-to-Treat Population 
All randomised subjects who received at least one IMP administration. Modified intention-to-
treat (mITT) subjects will be analysed according to randomised treatment. 
5.5 Per Protocol Population 
All subjects in the mITT population who have no important protocol deviations that could 
potentially affect the primary efficacy endpoint outcome for the subject. Per Protocol (PP) 
subjects will be analysed according to the randomised treatment. 
5.5.1 Protocol Deviations 
Protocol deviations are defined as any change, divergence, or departure from the study design 
or procedures defined in the study protocol. Important protocol deviations are a subset of 
protocol deviations that may significantly impact the correctness, accuracy, and/or reliability 
of the study data or that may significantly affect a subject’s rights, safety, or well-being. A 
detailed list of protocol deviations that will be mapped to protocol deviation coded term based 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 16 of 75 
ST-AD-008 version 02 
on Ipsen SDTM+ User Guide are contained in the separate document titled “Ipsen 222 and 
223: Protocol Deviations”; this will be standalone working document which will be finalised 
prior to database lock. 
5.5.1.1 
Important Protocol Deviations Leading to Exclusion from the PP Analysis 
Only those important protocol deviations considered to have a major effect on primary 
efficacy analysis will lead to complete exclusion of the patient from the PP population. The 
majority of the important protocol deviations leading to exclusion from the PP population will 
be determined programmatically from the data.  Those criteria which require clinical or 
medical monitoring interpretation will be reviewed prior to database lock  these will be 
outlined in the “Ipsen 222 and 223: Protocol Deviations” document. 
5.5.1.2 
Handling of Stratification Factors 
Stratification errors (e.g. previous intradetrusor BTX-A usage) discovered after randomisation 
cannot be changed in the IVRS system and subjects will be analysed according to their eCRF 
recorded strata (i.e. correct strata) for the primary analysis of efficacy.  
 
Mis-stratifications will be documented as a protocol deviation, and the incorrect stratification 
recorded in Interactive Voice Response System (IVRS) (NDO medical history for aetiology 
of NDO [SCI or MS], and prior medications for previous intradetrusor BTX-A usage for UI 
[BTX-A naïve or BTX-A non-naïve] in the bladder) will be used to perform a sensitivity 
analysis on the primary endpoint. A listing with the eCRF versus IVRS recorded 
stratifications will be displayed for the randomised subjects.  
5.6 
Urodynamic Population 
All subjects in the mITT population included in the urodynamic subset at randomisation. 
6 
DATA HANDLING 
6.1 Time points and Visit Windows 
Day 1 is defined as the day of the first IMP administration.  Relative days after Day 1 are 
calculated as (assessment date  Day 1 date) + 1.  Relative days prior to Day 1 are calculated 
as (assessment date  Day 1 date).  The day prior to Day 1 is Day -1.  
Generally, all analysis will be performed using data at nominal visits (see Table 1). Only if 
the data is missing, the unscheduled visits (or early withdrawal visit) within the visit window 
will be used in analysis of efficacy endpoints.  For the 7-day bladder diary, the entire 7-day 
duration need not be included in the entire visit window for it to be assigned to that visit e.g. 
if a patient has start date of the 7-day bladder diary on Day 61, then the 7th day would fall on 
Day 67, and would be assigned to Week 6 diary data. 
If multiple unscheduled visits occur within a single visit, then the unscheduled visit closest to 
the target day of the visit window will be used in the analysis.  If there is a tie, the later 
unscheduled visit will be used in the analysis. Similarly, if there are both scheduled and 
unscheduled visits prior to Treatment 1 then the last assessment prior to the Treatment 1 will 
be used as baseline in analysis of efficacy endpoints. 
 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 17 of 75 
ST-AD-008 version 02 
Table 1 Definition of Visit Windows 
Visit 
Target Day of 
Visita 
Acceptable visit window 
mITT/PP/urodynamic analyses 
Screening 
Day –30 
NA 
Treatment visit of DBPC cycle 
Day 1 
NA 
Week 2 
Day 15 
Days 8 to 22 (Day 15±7 days) 
Week 6 
Day 43 
Days 23 to 63 (Day 43±20 days) 
Week 12 
Day 85 
Days 64 to 106 (Day 85±21 days) 
Week 24 
Day 169 
Days 107 to 211 (Day 169-62 days and +42 
days) 
Week 36 
Day 253 
Days 212 to 295 (Day 253-41 days and 
+42days) 
Routine visit every 12 weeks until 
retreatment occurs or EOS 
Day x + 84 
Day x-41 days and Day x +42days) 
 
 
 
End of Studyb (Week 104) 
Day X 
Day X±14 days 
 
 
 
Retreatment Assessment Visit 
 
Within 14 days of request 
Retreatment Visit of treatment cycle 
2c  
Day 1 
Within 14 days of confirmed eligibility.   
Week 2 
Day 15 
Days 8 to 22 (Day 15±7 days) 
Week 6 
Day 43 
Days 23 to 63 (Day 43±20 days) 
Week 12 
Day 85 
Days 64 to 106 (Day 85±21 days) 
Week 24 
Day 169 
Days 107 to 211 (Day 169-62 days and +42 
days) 
Week 36 
Day 253 
Days 212 to 295 (Day 253-41 days and 
+42days) 
Routine visit every 12 weeks until 
retreatment occurs or EOS 
Day x + 84 
Day x-41 days and Day x +42days) 
 
 
 
 
 
 
End of Studyb (Week 104 to Week 
116) 
Day X 
Day X ±14 days 
 
 
 
a Relative to the date of the first IMP administration (Day 1) of DBPC Cycle  
b The EOS visit will occur at Week 104 for subjects who had their most recent IMP administration at Week 92 or 
earlier. 
c The visit window from treatment cycle 3, 4, 5, etc. is the same as treatment cycle 2. 
 
6.2 Handling of Dropouts or Missing Data 
6.2.1 Analysis Endpoints 
6.2.1.1 Efficacy Endpoints 
Refer to Section 3.1 and 3.2 for the list of primary and secondary efficacy endpoints and 
Section 3.2.1 for the list of secondary endpoints used in the hierarchal analysis. 
Bladder diary: For data collected from the 7-day bladder diary, if there is 1 or 2 days with no 
data, the arithmetic means recorded (on the 5 or 6 days that do have events recorded) from the 
bladder diary parameters will be used for the days with no recorded bladder diary data. If 
there are more than 2 days of missing data, then the 7-day bladder diary data will be 
considered invalid.  


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 18 of 75 
ST-AD-008 version 02 
Primary efficacy endpoint: No imputation is planned for the primary analysis of the primary 
endpoint. A sensitivity analysis of the primary efficacy endpoint will be performed using 
multiple imputations (MI) for missing or invalid data (see Section 7.6.4.3).  
Urodynamic secondary efficacy endpoints: All urodynamic data will be reviewed by 
independent central reviewers to determine the final values for the urodynamic parameters. 
Only the central reader urodynamic values will be used for analysis purposes. For the 
secondary efficacy endpoint of Vol@1stIDC, subjects who do not exhibit a post-treatment 
IDC after the first IMP administration will have Vol@1stIDC imputed using the recorded 
corrected MCC volume at that post-treatment visit. 
Quality of life secondary endpoints: For I-QoL total summary score, in accordance with the I-
QoL User’s Manual (US English version, March 2013), if no more than three items are 
omitted, a normal arithmetic mean substitution will be computed for these omitted items and 
imputed to calculate the total summary score. If more than three items are omitted, then there 
will be no more imputation for those omitted items, and the total summary score will be 
missing. Similarly, this rule will be applied for each of the domain scores (avoiding and 
limiting behavior, psychosocial impact, and social embarrassment). These derived scores will 
be used for analysis, and the investigator recorded eCRF I-QoL total summary score, and each 
recorded domain score will only be listed.  
The formula for the derived scale scores is as follows: 
Scale Score = {(the sum of the items  lowest possible score) / possible raw score range} * 
100 
For continuous endpoints analysed by mean or mean change values, inference will be done 
using mixed-models repeated measures, which assumes that missing outcomes are missing at 
random (MAR). 
6.2.1.2 Safety Endpoints 
In general, all available data from subjects who have prematurely discontinued from the study 
will be used for analysis. For AEs with missing information for the intensity and causality, it 
will be represented as a missing category.  
 
6.2.2 Missing or Partial Date 
In all listings, missing or incomplete dates will be left as they have been recorded. However, 
for calculation / sorting / assignation based on dates, the following methods will be used: 
(1) If the onset date of an AE/concomitant medication is missing / incomplete, it is assumed 
to have occurred during the study treatment phase (i.e. a treatment-emergent adverse 
event (TEAE) for AEs) except if the partial onset date or stop date indicates differently. 
(2) A missing / incomplete date of medical history or disease diagnosis will be assumed to 
have occurred before any study treatment. For calculation purposes, if only the year is 
available, then the first day of January will be used to impute, if only the day is missing 
then the first day of the month will be used to impute. 
(3) An AE could be assigned to several possible treatment cycles according to its partial 
onset date and stop date. If only the AE start day is missing, then the AE will be assigned 
to that treatment cycle that includes the first day of that month.  If the AE start date has a 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 19 of 75 
ST-AD-008 version 02 
missing month, then January will be used. An AE with missing start date will be assigned 
to each treatment cycle before its end date.  The Analysis Data Model programming 
specifications will outline the rules in more detail. During the study, examples of date 
imputations will be shared with the team to ensure AE assignment to treatment cycles are 
in agreement with the team.    
(4) In calculations with date of the first IMP administration, if missing, the date of 
randomisation will be used. 
7 
STATISTICAL METHODS 
7.1 General Principles 
All data processing, summarisation and analyses will be performed using the SAS 
Environment / Version 9.4 (or later) of the SAS statistical software package. 
All data collected during the study will be presented in listings without any imputation by 
treatment group, subject, assessment and visit (where applicable), unless otherwise specified.  
Data will be presented in summary tables by treatment group (as described below), 
assessment and visit (where applicable).  
Overall, the analysis strategy is to evaluate efficacy and safety data from the initial DBPC 
Cycle and to evaluate efficacy and safety over repeated Dysport treatments, using analyses by 
Dysport Cycle (Dysport Cycle 1, 2…etc.), as illustrated in schematic diagram later in this 
section. In general, tables associated with the DBPC Cycle will be separate from the tables 
assessing repeat treatment with Dysport which are presented by Dysport Cycle:  
¾ During analysis of the DBPC (DBPC cycle), data will be displayed using the following 
treatment group labels, in the order presented: 
 Placebo 
 Dysport 600 U 
 Dysport 800 U 
 All Dysport 
¾ During analysis by Dysport Cycle, data will be displayed by number of Dysport 
treatments (see diagram below) using the following treatment group labels: 
 Dysport Cycle 1 
o Dysport 600U 
o Dysport 800U 
o All Dysport 
 Dysport Cycle 2 
o Dysport 600U 
o Dysport 800U 
o All Dysport 
  Dysport Cycle X 




Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 21 of 75 
ST-AD-008 version 02 
7.2 Subject Disposition and Data Sets Analysed 
Subjects randomised will be summarised by country and site, and also summarised by 
aetiology of NDO (SCI or MS), and previous BTX-A usage (BTX-A naïve vs. BTX-A non-
naïve in the bladder) for the Randomised population. 
The number of subjects screened but not randomised (screen failures) will be tabulated by 
country. The reasons for screen failures will be listed. 
The randomisation details will be displayed in a listing for the Randomised population.  
The number and percentages of enrolled subjects included in analysis populations 
(Randomised, Safety, mITT, PP and urodynamic) will be summarised by treatment group and 
overall. The reason for subject exclusion from each of the populations will be tabulated and 
listed. 
In addition, the number and percentage of subjects who completed the study, prematurely 
discontinued the study with primary reasons will be tabulated by treatment group in the 
Randomised population.  The number of subjects entering, prematurely withdrawing with 
primary reasons will be tabulated by treatment group in the Randomised population for the 
DBPC Cycle and by Dysport Cycle. Subject disposition data, including retreatments after the 
first IMP administration, and study discontinuation will be listed. 
7.3 Protocol Deviations 
All protocol deviations will be listed for the Randomised population.   
The protocol deviations, including defining those leading to exclusion from the PP population, 
will be identified before data are unblinded. 
7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarised for the mITT 
population.  
Standard descriptive statistics including 95% confidence interval (CI) will be presented for 
the continuous variables of: 
 Age (years)  
 Weight (kg); 
 Height (cm); 
 Body mass index (BMI) (kg/m2) calculated as [weight(kg)/(height(cm)/100)^2 ] 
The total counts and percentages of subjects will be presented for the categorical variables of: 
 Age groups [≥18 and ≤ 40, >40 and ≤ 65, > 65 years (further categorising to >65 and 
≤ 75, and >75 years)) 
 Sex (Male, Female); 
 Race (Asian, Black or African American, White, Native Hawaiian or Other Pacific 
Islander, American Indian or Alaska Native and Other); 
 Ethnicity (Hispanic/Latino, Not Hispanic/Latino); 
 Stratification variables: 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 22 of 75 
ST-AD-008 version 02 
o aetiology of NDO (SCI, MS)  
o previous intradetrusor BTX-A usage (BTX-A bladder naïve, BTX-A 
bladder non-naïve).  
 Other baseline characteristics: 
o prior NDO oral medications (Yes, No) 
o concomitant NDO oral medications at time of first IMP administration 
(Yes, No) 
o prior treatment of anticholinergics (Yes, No) 
o concomitant treatment of anticholinergics at time of first IMP 
administration (Yes, No) 
o prior beta-3 agonists (Yes, No) 
o concomitant beta-3 agonists at time of first IMP administration (Yes, No) 
o daily CIC frequency at baseline  
o history of UTI in the 6 months prior to study (Yes, No) 
o using a wheelchair regularly in subjects with MS (Yes, No) 
No formal tests of statistical significance will be performed on the demographic and baseline 
data. Other baseline data not only measured at screening will be summarised by treatment 
group with the post-baseline measurements. 
The demographics and baseline characteristics data will also be summarised by aetiology of 
NDO (SCI, MS) for the mITT population.  
Pregnancy test will be listed only. 
7.4.1 UTI Prior to First IMP Administration 
The counts and percentages of the following categories will be summarised for the mITT 
population: 
 
- Overall subjects with UTI prior to first IMP administration 
- Subjects with a medical history of UTI 
- Subjects with a medical history of UTI within 6 months prior to screening 
  - Subjects with a recorded AE of UTI between informed consent and first IMP 
administration  
 
7.4.2 Medical History 
Medical History (significant medical or surgical history, NDO medical history for SCI and 
MS subjects) will be coded by Sponsor using the Medical Dictionary for Regulatory 
Activities [MedDRA v21.0 (March 2018); latest version if updated during the study).  All 
medical history will be listed, and the number and percentage of subjects with any medical 
history will be summarised for the mITT population by system organ class (SOC) and 
preferred term (PT) for each treatment group and overall.   


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 23 of 75 
ST-AD-008 version 02 
NDO Medical History will be summarised by aetiology of NDO (SCI, MS). Duration of NDO 
will be calculated as (informed consent date 
 date of development of NDO 
symptoms)*12/365.25 and reported as whole months, and presented using standard 
descriptive statistics. 
For SCI history, percentage of neurological level of stable SCI, cause of stable SCI, American 
Spinal Injury Association (ASIA) Grade and neurological syndrome will be summarised. 
Duration of SCI will be calculated as (date of the first IMP administration  date of stable 
SCI)*12/365.25 and reported as whole months, and presented using standard descriptive 
statistics.  
For MS history, the percentage of level of mobility, classification of MS will be summarised. 
Duration of MS will be calculated as (date of the first IMP administration  date of initial 
diagnosis)*12/365.25 and reported as whole months, and presented using standard descriptive 
statistics.  Duration of onset of symptoms will be calculated as (date of the first IMP 
administration  date of onset of symptoms)*12/365.25 and reported as whole months, and 
presented using standard descriptive statistics. 
7.4.3 Prior and Concomitant Medications 
Medications received prior to or concomitantly with treatment will be coded by Sponsor using 
World Health Organisation Drug Dictionary (WHO Drug Dictionary; Version B2-BDE 
March 2016 or a later version if updated during the study), and will be summarised by 
treatment group and overall with the number and percentage of subjects, by therapeutic class 
(the Anatomic Therapeutic Chemical [ATC] Classification codes) and preferred term. The 
concomitant medications and therapies will be summarised separately for the DBPC Cycle 
and by Dysport Cycle (Dysport Cycle 1, 2, etc). 
Prior medications and concomitant medications are defined as follows: 
Prior medications/non-drug therapies are those taken within 30 days prior to screening with a 
stop date prior to the date of the first IMP administration. Prior medications or therapies for 
NDO are those with both start date and stop date prior to the date of the first IMP 
administration. 
Concomitant medications are those with a start date on or after the date of the first IMP 
administration, or those with a start date before the date of the first IMP administration and a 
stop date on or after the date of the first IMP administration (or ongoing). 
Prior medications and concomitant medications will be listed together and summarised 
separately for the mITT population. Similarly, this will be listed and summarised for the prior 
and concomitant medications for NDO, and for prophylactic antibiotic for initial treatment, 
retreatments and urodynamic assessments. 
Concomitant Surgical Procedures will be summarised by SOC and PT for the mITT 
population. 
7.5 Treatment Exposure  
Treatment exposure will be summarised descriptively by treatment group (placebo, Dysport 
600 U, Dysport 800 U, All Dysport) in the Safety population. IMP administration data will be 
listed for the Safety population. 
The treatment exposure will be summarised by number and percentage of subjects treated in 
each treatment cycle (DBPC cycle, Dysport Cycle 1, Dysport Cycle 2, etc), the number of 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 24 of 75 
ST-AD-008 version 02 
Dysport Cycles will be displayed descriptively using summary statistics for the Safety 
population.  
The treatment exposure in weeks will be summarised by treatment group as below: 
For overall study (irrespective of number of treatments) 
 Total IMP exposure across the study will be calculated as (Last attended visit date in 
the study  first IMP administration date + 1) / 7. Data will be presented in weeks for 
placebo, 600 U Dysport, 800 U Dysport, All Dysport groups. 
 The number of subjects cumulatively exposed to IMP for at least 12 weeks, 24 weeks, 
52 weeks, 78 weeks and 104 weeks will be summarised for placebo, 600 U Dysport, 
800 U Dysport and All Dysport groups. 
 Total Dysport exposure across the study will be calculated as (Last attended visit date 
in the study  first Dysport injection date + 1) / 7. Data will be presented in weeks for 
600 U, 800 U and All Dysport groups. 
 The number of subjects cumulatively exposed to Dysport at least 12 weeks, 24 weeks, 
52 weeks, 78 weeks and 104 weeks will be summarised. Data will be presented in 
weeks for 600 U, 800 U and All Dysport groups  
For Dysport Cycles 
 The total number of subjects who received 1, 2, 3, …etc and at least 1, 2, 3…etc 
Dysport treatments at 600 U, 800 U and All Dysport will be summarised . 
7.6 Efficacy 
The primary analysis based on the primary efficacy endpoint (mean change from study 
baseline in weekly number of UI episodes at Week 6 after the first IMP administration) will 
be performed on the mITT population.  
The analysis for urodynamic parameters will be performed on the urodynamic population. 
7.6.1 Significance Testing and Estimations 
The primary efficacy hypotheses are as follows: 
1) Ho: There is no difference between treatment with Dysport 600 U or Dysport 800 U and 
treatment with placebo with respect to the change from baseline to Week 6 after the first 
study treatment in the number of UI episodes per week. 
2) Ha: There is a difference between treatment with Dysport 600 U or Dysport 800 U and 
treatment with placebo with respect to the change from baseline to Week 6 after the first 
study treatment in the number of UI episodes per week. 
7.6.2 Multiplicity Adjustment 
For the primary endpoint, due to multiple pairwise comparisons of each Dysport dose group 
versus placebo, a Hochberg correction will be applied to control the type one error at 5% 
significance level. The p-values from the two pairwise tests are ordered in magnitude from 
largest to smallest.  
If both p-values for the two primary tests (the test of 600 U vs. placebo and the test of 800 U 
vs. placebo) are lower than 0.05, both will be declared statistically significant. If one of the 
primary tests has a p-value greater or equal to 0.05, then the other test will be declared 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 25 of 75 
ST-AD-008 version 02 
statistically significant if its p-value is lower than 0.025 (and thus half of the overall 
experiment wise alpha of 0.05). 
The two ordered secondary endpoints will be tested for both doses at the 0.05 level (using a 
hierarchical methodology) if, for both doses, the two primary tests achieve a p-value lower 
than 0.05. If one of the primary tests has a p-value greater or equal to 0.05, and the other has a 
p-value lower than 0.025, secondary endpoints will be assessed (using hierarchical 
methodology) for the dose group with p-value lower than 0.025, at the 0.025 significance 
level. 
In order to control the family-wise type one error, the following hierarchical testing procedure 
will be applied for the testing of the superiority of both Dysport doses to placebo for the 
primary and selected secondary endpoints (ordered as described in Section 7.6.5): 
 Step 1: The Dysport 600 U and Dysport 800 U will be compared to placebo on the 
primary endpoint. If the p-values associated with both doses are <0.05 then both doses 
will be declared statistically significant and the testing will proceed at the 0.05 level 
from step 2 onwards. If one dose has p≥0.05 but the other has p<0.025 (significant 
dose) then testing will proceed at the 0.025 level from step 2 onwards on the 
significant dose only. If both dose groups have p≥0.05 or one dose group has p≥0.05 
and the other dose group has p≥0.025, the testing procedure will be stopped. 
 Step 2: The Dysport 600 U and Dysport 800 U will be compared to placebo for the 
first hierarchical secondary endpoint. Testing will be at the significance level defined 
in step 1 (0.05 or 0.025). If the p-value associated with this test is lower than the 
significance level defined in step 1 then it will be considered significant and testing 
will proceed to step 3. Otherwise the testing procedure will be stopped. 
 Step 3: The Dysport 600 U and Dysport 800 U will be compared to placebo for the 
second hierarchical secondary endpoint. Testing will be at the significance level 
defined in step 2 (0.05 or 0.025). If the p-value associated with this test is lower than 
the significance level defined in step 2 then it will be considered significant. 
The above testing rules ensure that the hierarchical procedure controls the experiment-wise 
type one error (i.e. over the three tests) at the 0.05 level for relevant secondary endpoints. 
In the event the hierarchical testing procedure is stopped at the end of any particular step, the 
testing of the following steps will be considered descriptive only and no formal statistical 
conclusion will be drawn. 
Each other secondary endpoint not included within the hierarchical testing procedure will be 
analysed for exploratory purposes only to compare each Dysport dose to placebo at a 0.05 
type one error rate. 
7.6.3 Primary Efficacy Analysis 
The primary efficacy endpoint is mean change in the weekly number of UI episodes from 
study baseline to Week 6 after the first treatment. Seven-day bladder diaries that contain data 
recorded on at least 5 days will be included in the analysis.  
As all subjects should have visits up to and including week 12, but thereafter visits are 
dependent on whether the subject receives retreatment, statistical testing between treatment 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 26 of 75 
ST-AD-008 version 02 
groups will be performed only up to Week 12, inclusive. Descriptive statistics table will 
present any timepoint. 
Weekly number of UI episodes and the mean change from study baseline will be presented for 
the DBPC Cycle. The mixed model repeated measures (MMRM) analysis will be conducted 
with the change of the weekly number of UI episodes from study baseline as response 
variable. Fixed effect variables include treatment group, visit (Week 2, Week 6 and Week 12), 
treatment-by-visit interaction, stratification variables [the aetiology of NDO and prior 
intradetrusor BTX-A usage for UI] and study baseline value of weekly number of UI episodes. 
Random effect will include the subject effect.  An unstructured covariance matrix will be 
specified in the mixed model to account for within subject correlation. If model fails to 
converge, the structure of first order autoregressive AR (1), compound symmetry (CS) or 
variance components (VC) will be used. 
The least square means (LSMEANS) of the change of weekly number of UI at each visit in 
each group with standard error, the difference of mean between the two treatment groups at 
each visit, the 95% CI of the difference and the p-value for treatment group will be presented. 
The comparison of main interest will be treatment difference at Week 6. 
The SAS codes of MMRM for reference are below. 
 
    
 
    
 
    
 
    
 
 
 
 
 
 
 
 
 
The validity of the model assumptions of normality will be investigated using residual plots. 
The LS means of change from study baseline for weekly UI in the DBPC and Dysport Cycles 
will be presented in line plots by treatment groups. 
7.6.4 Sensitivity Analyses for the Primary Efficacy Endpoint 
7.6.4.1 Using PP Population 
Primary efficacy analysis will be conducted on the PP population as a supportive analysis. 
7.6.4.2 Using ANCOVA 
The analysis of covariance (ANCOVA) will be conducted for the two primary tests (Dysport 
600 U vs. placebo, and Dysport 800 U vs. placebo), with the change of the weekly number of 
UI episodes from study baseline as response variable, including treatment group, stratification 
variables [the aetiology of NDO (SCI or MS) and prior intradetrusor BTX-A usage for UI 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 27 of 75 
ST-AD-008 version 02 
(BTX-naïve or BTX-non-naïve)] and study baseline value of weekly number of UI episodes 
as covariates.  
The least square means (LSMEANS) of the change of weekly number of UI at Week 6 in 
each group with standard error, the difference of mean between the treatment groups, the 95% 
CI of the difference and the p-value for treatment group will be presented.  
The SAS codes of ANCOVA for reference are below. 
 
    
 
    
 
    
 
 
 
 
 
 
 
. 
 
7.6.4.3 Using MI 
In presence of missing data in the primary efficacy endpoint, a multiple imputation approach 
for handling missing data will be undertaken on the mITT population. 
 
 
 
 
 
 
 
    
 
    
  
    
 
 
 
   
 
 
    
 
    
 
    
 
 
 
 
 
 
                           
 
CCI
CCI
CCI
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 28 of 75 
ST-AD-008 version 02 
 
   
 
   
  
   
  
 
 
In above codes, the variables are defined as: 
 
 
7.6.4.4 Using Mis-Stratification Factors 
As discussed in Section 5.6.2, the primary endpoint will be analysed with the MMRM using 
the incorrect stratification factors as recorded in IVRS for the mITT population. 
7.6.5 Hierarchical Analysis of Secondary Efficacy Endpoints 
As specified in Section 7.6.12, a hierarchical analysis will be performed in the order listed for 
the following two secondary efficacy endpoints at Week 6 after the first IMP administration: 
1) 
Proportion of subjects with no episodes of UI (i.e. continence is achieved) 
2) 
Mean change from study Baseline in the I-QoL total summary score 
The Derivation rules are specified in Section 3.2 and Appendix II. 
 
For 1), a logistic generalised linear mixed model (GLMM) for repeated measures will be 
fitted for UI responses using repeated measurements at Week 2, Week 6, and Week 12. The 
“proportion of subjects with no episodes of UI” will be analysed as a response variable, the 
model will include treatment group, stratification variables, study baseline value, visit (week 2, 
week 6 and week 12), study baseline*visit and treatment*visit interactions as fixed effect. The 
study baseline value will be weekly number of UI episodes. The logistic GLMM is fitted 
using the logit link and the binomial distribution. Odds ratios, 95% CIs of odds ratio, and p-
values for treatment group comparisons at each visit (week 2, week 6 and week 12) will be 
presented. 
The SAS codes of GLMM for reference are below. 
 
  
 
 
 
 
  
  
 
 
In above codes, the variables are defined as: 
 
 
CCI
CCI
CCI
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 29 of 75 
ST-AD-008 version 02 
 
 
 
 
For 2), MMRM model will be fitted using the “mean change” endpoint, as the response 
variable to obtain the p-value of treatment groups. The model will be the same as primary 
analysis model in section 7.6.3. The least square means of change at Week 6 in each group 
with standard error, the mean difference of pairwise comparison, the 95% CI of the difference 
and the p-value for the treatment groups will be presented for each model.  
If the testing procedure is stopped at the end of any particular step, the outcomes of the 
following steps will be presented and used for description only and no formal statistical 
conclusion will be drawn.  
 
7.6.6 Other Analysis of Secondary Efficacy Endpoints 
The analysis of efficacy of the above-mentioned endpoints (primary endpoint and secondary 
endpoints included in the hierarchical analysis) will be conducted at timepoints other than 
Week 6 in the DBPC Cycle and is described below (except urodynamic endpoints as only 
performed at Week 6). The analysis of other secondary endpoints (see Section 3.2) is also 
described below.  
Descriptive summaries will be performed for the DBPC Cycle and by Dysport Cycles (i.e. 
Dysport Cycle 1, Dysport cycle 2 …), see the schematic diagram in Section 7.1.  
Statistical comparison analyses are only applicable for the DBPC treatment cycle. Analyses 
between treatment groups, Dysport 600 U vs. Placebo, and Dysport 800 U vs. Placebo will be 
performed accordingly using GLMM and MMRM as mentioned below for each endpoint. As 
all subjects should have visits up to and including week 12, but thereafter visits are dependent 
on whether the subject receives retreatment, statistical testing between treatment groups will 
be performed only up to Week 12, inclusive. All secondary endpoints not included in the 
hierarchical analysis are considered as exploratory endpoints and will therefore be analysed 
for exploratory purposes only to compare each Dysport dose to placebo, alpha at 0.05 level. 
 
7.6.6.1 Diary Parameters 
Refer to Section 3.2 for details of diary parameter endpoints. 
 
7.6.6.1.1 
Weekly Number of UI Episodes 
Mean change from study baseline 
For both the DBPC Cycle and the Dysport Cycles, summary tables for mean values in each 
assessment visit and the mean change from study baseline will be presented using descriptive 
statistics  
For the DBPC treatment cycle, mean change from study baseline to Week 2, and Week 12, 
will also be analysed using MMRM, using data from Week 2, 6 and 12, as in the primary 
efficacy analysis in section 7.6.3. 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 30 of 75 
ST-AD-008 version 02 
Thresholds of reduction 
For both the DBPC Cycle and the Dysport Cycles, the number and percentage of subjects 
with UI will be summarised by improvement levels from study baseline (≥30% improvement, 
≥50% improvement, ≥75% improvement, 100% improvement (no episodes of UI)) for each 
assessment visit. 
Bar charts will also be plotted. For the DBPC treatment cycle, the GLMM for repeated 
measures will be fitted for UI responses using repeated measurements at Week 2, Week 6, 
Week 12. Each UI response level compared to study baseline (≥30% improvement, ≥50% 
improvement, ≥75% improvement or 100%) will be analysed as a response variable in each 
model, as described for the proportion of subjects with no UI episodes in section 7.6.5. 
 
7.6.6.1.2 
Daily Urinary Frequency and Voided Volume 
For both the DBPC Cycle and by Dysport Cycles, the summary tables for mean values in each 
assessment visit and the mean change from study baseline will be presented using descriptive 
statistics. 
For the DBPC treatment cycle, mean change from study baseline to Week 2, Week 6, and 
Week 12 will be analysed using MMRM, as in the primary efficacy analysis presented in 
Section 7.6.4.2.  
 
7.6.6.2 Urodynamic Filling Cystometry Parameters 
See Section 3.2 for list of urodynamic endpoints.  
The summary tables for mean values at Week 6 and the mean change from study baseline for 
the DBPC cycle, and for the Dysport Cycles (i.e. Dysport Cycle 1, Dysport cycle 2 …) will be 
presented using descriptive statistics for continuous endpoints.  For each of the “mean change” 
at Week 6 urodynamic parameters, an ANCOVA model will be fitted using the “mean change” 
endpoint, as the response variable to obtain the p-value of treatment groups. The model will 
be the same as the sensitivity analyses for the primary efficacy endpoint in 7.6.4.2. The 
LSMEANS of the mean change from study baseline at Week 6 in each group with standard 
error, the difference of mean between the two treatment groups, the 95% CI of the difference 
and the p-value for treatment group will be presented. 
 
Number and percentage of subjects with no IDC will be also summarised. A logistic 
regression model will be performed with “proportion of subjects” as the response variable. 
The model will include treatment group, and stratification variables.  
 
Odds ratio, 95% CI of odds ratio, and p-value will be presented.  
The SAS codes of logistic regression for reference are below. 
 
    
 
 
 
In above codes, the variables are defined as: 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 31 of 75 
ST-AD-008 version 02 
 
 
 
 
Line plots of the LS means of changes will be plotted for MCC, MDP, Vol@1stIDC.  In 
addition, a bar chart for the proportion of subjects with no IDC at Week 6 will be plotted. 
 
7.6.6.3 Patient Reported Outcome Questionnaires  
This includes the I-QOL, EQ-5D-5L and mPGI-I endpoints (see Section 3.2). 
EQ-5D-5L comprises of the descriptive system for 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression, where each dimension has 5 levels 
(1=indicating no problem, 2=indicating slight problems, 3=indicating moderate problems, 
4=indicating severe problems, 5=indicating extreme problems).  It also includes a self-rated 
health which is numbered from 0 (worst health you can imagine) to 100 (best health you can 
imagine): 
  
Level Mobility 
Self-care 
Usual 
Activities 
Pain/Discomfort Anxiety/Depression 
1 
I have no 
problems 
walking,  
I have no 
problems 
washing or 
dressing 
myself  
I 
have 
no 
problems 
doing 
my 
usual 
activities  
I have no pain 
or discomfort  
I am not anxious or 
depressed  
2 
I have slight 
problems 
walking,  
I have slight 
problems 
washing or 
dressing 
myself  
I have slight 
problems 
doing 
my 
usual 
activities 
I 
have 
slight  
pain 
or 
discomfort 
I 
am 
slightly 
anxious 
or 
depressed  
3 
I have 
moderate 
problems 
walking,  
I 
have 
moderate 
problems 
washing or 
dressing 
myself 
I 
have 
moderate 
problems 
doing 
my 
usual 
activities 
I have moderate 
pain 
or 
discomfort 
I am moderately 
anxious 
or 
depressed  
4 
I have severe 
problems 
walking,  
I 
have 
severe 
problems 
washing or 
dressing 
myself 
I have severe 
problems 
doing 
my 
usual 
activities 
I have severe 
pain 
or 
discomfort 
I 
am 
severely 
anxious 
or 
depressed  
5 
I am unable 
to walk  
I am unable 
to wash or 
dress 
myself 
I am unable to 
do my usual 
activities 
I have extreme 
pain 
or 
discomfort  
I 
am 
extremely 
anxious 
or 
depressed  
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 32 of 75 
ST-AD-008 version 02 
 
The EQ-5D-5L descriptive system will be added numerically e.g. mobility=2, self-care=3, 
usual activities=2, pain/discomfort=3, anxiety/depression=2 gives a state=23232 i.e. slight 
problems with mobility, moderate problems with washing or dressing, slight problems with 
doing usual activities, moderate pain or discomfort, and slightly anxious or depressed. 
Missing values will be coded as a 9. The arithmetic score for the EQ-5D-5L score will be 
taken as 2+3+2+3+2=12.   
 
For both the DBPC Cycle and by the Dysport Cycles, the summary tables for mean values in 
each assessment visit and the mean change from study baseline will be presented using 
descriptive statistics.  
For the DBPC Cycle for I-QOL and EQ-5D-5L, mean change from study baseline to Week 6 
and Week 12, will be analysed using MMRM, similar to the primary efficacy analysis. Mean 
mPGI-I score at Week 2, Week 6, Week 12 will be analysed as a response variable, using 
MMRM as in the supportive primary analysis, without baseline factor for mPGI-I. 
The LS means of change from study baseline in DBPC cycle for I-QoL total summary score 
at all timepoints will be presented in a line plot by treatment groups up to Week 12. 
  
7.6.6.4 Retreatment intervals  
For both the DBPC Cycle and by the Dysport Cycles, summary statistics will be displayed for 
time between treatments received, time to request and time to eligibility for retreatment. For 
the DBPC Cycle the number and percentage of patients receiving retreatment: ≥ Week 12 to < 
Week 16, ≥ Week 16 to < Week 20 weeks and then every 4 weeks will be presented.  
The following formal statistics will be performed only for the time between treatments 
received endpoint. For both the DBPC Cycle and by the Dysport Cycles, median number of 
days together with the 25th and 75th percentiles and their 95% CI will be determined based on 
the Kaplan-Meier method. Patients with no retreatment will be censored at the last visit. The 
survival curves will be presented by treatment group as well.  
For the DBPC and Dysport treatment cycles, the log-rank tests will be performed to compare 
survival curves between treatment groups, by providing p-values.  
The SAS codes of survival analysis for reference are below. 
 
 
 
 
 
 
 
 
 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 33 of 75 
ST-AD-008 version 02 
7.6.7 Subgroup Analysis 
1) For the primary endpoint (DBPC Cycle at Week 6), the following baseline subgroups will 
be assessed for the mITT population:  
 Aetiology of NDO (SCI or MS)  
 Prior intradetrusor BTX-A usage (BTX-A bladder naïve or BTX-A bladder  
non-naïve)  
 Age groups (≥18 to ≤ 40, >40 to ≤ 65, > 65 years) 
 Sex (Male or Female) 
 Concomitant use of anticholinergics and/or beta-3 agonists (Yes or No) 
 
2) For the secondary efficacy endpoints included in the hierarchical analysis (DBPC Cycle at 
Week 6), the following baseline subgroup will be assessed for the mITT population: 
 Aetiology of NDO (SCI or MS)  
 
 
For 1) and 2) descriptive statistics and statistical analysis will be performed for each subgroup 
as detailed in section 7.6.3 and 7.6.5, with subgroup*treat interaction included in the analysis 
model. The subgroup analysis will be omitted if the subcategories have fewer than 30 subjects 
counts.    
For 1), the treatment differences and 95% CI will be presented for each subgroup (e.g. 
Aetiology of NDO: SCI and MS) on a forest plot.  
 
7.7 Safety 
All safety data will be included in the subject data listings. Summary tables will be based 
upon the safety population. 
7.7.1 Adverse Events 
All AEs will be coded by Sponsor using MedDRA v21.0 (March 2018); (the latest version if 
updated during the study), and will be classified by MedDRA preferred term and system 
organ class. 
A TEAE is defined as any AE with start date/and time at or after the date/and time of the first 
dose of IMP, or any AE with start date/and time prior to the date/and time of the first dose of 
IMP whose intensity worsens at or after the date/time of the first dose of IMP. The Pre-
treatment AE is defined as any AE with start date/and time prior to the first dose of IMP 
administration in DBPC Cycle, and after the date of informed consent. 
All TEAEs will be assigned to either DBPC Cycle and/or Dysport Cycle X based on the start 
date and time, or intensity increase date. For example, for presentation of TEAEs by Dysport 
Cycle, if the start time/intensity increase time of TEAE is at or after the time of treatment 
administration of Dysport Cycle X, Day 1 and prior to the time of treatment administration of 
Dysport Cycle X+1, Day 1, the TEAEs will be assigned to Dysport Cycle X.  
In this study, an AESIs for Dysport is TEAEs that suggest a possible remote spread of effect 
of the toxin or events suggestive of hypersensitivity like reactions. TEAEs due to possible 
remote spread of the effects of Dysport will be identified using the list of MedDRA PTs 
compatible with the mechanism of action of BTX-A and based on the recommendations from 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 34 of 75 
ST-AD-008 version 02 
the Committee for Medicinal Products for Human Use (CHMP) and the Food and Drug 
Administration (FDA). TEAEs potentially representing hypersensitivity reactions will be 
identified using the Standardised MedDRA Query (SMQ) (narrow search query) for 
hypersensitivity reactions. A list of MedDRA preferred terms, used to identify any potential 
AESI, is provided in Appendix IV. 
All TEAEs identified using the search strategy described above will be medically evaluated 
during the study, before the database lock and unblinding, by the sponsor to identify events 
which could possibly represent ‘remote spread of effect of toxin’, or which are suggestive of 
‘hypersensitivity reactions’ due to study treatment administration. Cases will be excluded if 
they are confounded by presence of alternative clinical etiologies (medical history, 
concomitant medication or diagnosis which could account for the symptoms); if they are 
considered to be local effects instead of distant spread as judged by the site of injection; the 
time period between the last study treatment administration and event onset is not in 
accordance 
with 
the 
expected 
mechanism 
of 
action; 
or 
due 
to 
insufficient 
information/evidence to make an assessment. 
In the TFLs, only the final list of AESIs confirmed by the sponsor as “a possible remote 
spread event” or “hypersensitivity reactions” will be taken into account. 
All AEs (with TEAEs flagged) reported during the study will be presented in a listing which 
will be sorted by treatment group in the respective assigned treatment cycle for that AE, 
subject ID, AE start date and time, primary system organ class (SOC), preferred term (PT), 
and verbatim text. The treatment cycle where the TEAE onset or intensity increased will be 
presented in the listing as well. Separate listings of all TEAEs, serious TEAEs, IMP-related 
TEAEs, TEAE of special interest, other protocol defined TEAEs, TEAEs leading to early 
withdrawal and TEAEs leading to death reported during the study will also be presented. 
Overview 
tables 
will 
be 
produced 
for 
DBPC 
Cycle, 
Dysport 
Cycles                        
and overall for the number and percentage of subjects with at least one of the following 
TEAEs, where subjects with more than one TEAE in a particular category are counted only 
once in that category. The number of TEAE occurrences will be provided as well. Note that 
for TEAEs that could only occur in the MS population (e.g. MS exacerbation), the 
denominator for the percentage calculation will relate to the number of MS patients; these 
TEAEs will be identified in the tables. 
 
any TEAE  
 intensity of TEAE (mild, moderate, severe) 
 Any IMP related TEAE 
 Any TEAE leading to withdrawal 
 
any serious TEAE 
 any IMP related serious TEAE  
 any serious TEAE leading to withdrawal  
 
any TEAE of special interest by type of AESI 
 any AESI leading to withdrawal 
 any serious AESI 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 35 of 75 
ST-AD-008 version 02 
 
any UTI TEAEs 
 UTI TEAEs leading to withdrawal 
 serious UTI TEAEs  
 
TEAE leading to death 
In view of the anticipated difference in duration of the Dysport and placebo treatment cycles, 
this overview table will also be provided including only TEAEs occurring up to 12 weeks 
after first IMP treatment administration. 
A similar overview table will be produced for the number and percentage of subjects with at 
least one of the following events occurred pre-treatment for randomised subjects. The number 
of occurrences of the following events will be presented as well. 
 
any AE  
 Intensity of AE (mild, moderate, severe) 
 
any SAE 
 any SAEs leading to withdrawal 
 
AE leading to death 
TEAEs will be summarised overall, for DPBC cycle, and Dysport Cycles with the number 
and percentage of subjects with TEAEs presented by primary SOC and PT. In addition, this 
table will be provided including only TEAEs occurring any time after first dose of IMP until 
up to 12 weeks after first IMP treatment administration. This will also be summarised by 
aetiology of NDO.  
For AESIs, summary tables may also be produced following medical review of available 
information. 
The same summaries for overall, for DBPC Cycle, and Dysport Cycles with the number and 
percentage of subjects with TEAEs presented by primary SOC and PT will be presented for 
serious TEAEs, IMP-related TEAEs, TEAEs leading to withdrawal, TEAEs of special 
interest, and other protocol defined TEAEs. TEAEs with PTs observed in ≥1%, ≥2%, and 
≥5% of subjects and IMP-related TEAEs with PTs observed in ≥1%, ≥2%, and ≥5% of 
subjects will be summarised as well. 
Additionally, TEAEs will be tabulated by decreasing overall PT frequency and intensity in 
each SOC and PT category.  
The above will also be presented for SAEs. 
7.7.2 Laboratory Evaluations 
Clinical laboratory data from the central laboratory (haematology, biochemistry and urinalysis, 
and urine culture and sensitivity) will be listed in Standard International (SI) units. Any 
unscheduled laboratory assessments will be included in the listings. For post-baseline, only 
data from scheduled visits will be included in the summary tables.  
Haematology parameters: 
 Red blood cell count 
 Haemoglobin 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 36 of 75 
ST-AD-008 version 02 
 Haematocrit 
 Mean corpuscular volume 
 Mean corpuscular hemoglobin 
 Mean corpuscular hemoglobin concentration 
 White blood cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and others) 
 Platelet count. 
 
Serum Chemistry parameters: 
 Urea, creatinine, total bilirubin, conjugated bilirubin 
 Chloride, bicarbonate, sodium, potassium, calcium, inorganic phosphate 
 Alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma 
glutamyl transferase 
 Albumin, total protein, total cholesterol, triglycerides, fasting glucose. 
 
Urinalysis parameters: 
 pH, protein, ketones, bilirubin, blood, urobilinogen, nitrites, leukocytes, glucose and 
specific gravity 
 
Laboratory results will be classified as low, normal, or high at each visit according to the 
laboratory supplied reference ranges. Abnormal values will be flagged (High [H], Low [L]) in 
the data listings. A list of clinically significant abnormal values will be presented by treatment 
group and subject ID. 
Descriptive statistics will be presented for actual values and changes from study baseline at 
each scheduled assessment by treatment group. 
The number and percentage of subjects will be summarised for clinical significance of each 
abnormal value.  
For each scheduled post-baseline assessment visit, shift from study baseline tables of the 
number and percentage of subjects with low, normal or high values will be presented. 
7.7.3 Antibody Test 
Antibody testing results will be presented in a data listing. The listings for subjects with at 
least one positive neutralising (baseline or post baseline) will be provided separately. 
The number and percentage of subjects with the presence of neutralising BTX-A antibodies at 
study baseline, and post-baseline visits will be presented in the shift tables. The number of 
neutralising BTX-A antibodies seroconverters (subjects having a negative result at study 
baseline and at least one positive result at one post-treatment time point) and the time by 
when the subjects seroconverted will be reported. 
 
7.7.4 Vital Signs 
The normal ranges for the vital signs are displayed in Table 2 below: 
Table 2 Vital Signs Normal Ranges 
Parameter 
Low 
Normal 
High 


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 37 of 75 
ST-AD-008 version 02 
Diastolic 
Blood 
Pressure (mmHg) 
<40 
40-110 
>110 
Systolic 
Blood 
Pressure (mmHg) 
<60 
60-190 
>190 
Heart Rate (bpm) 
<50 
50-130 
>130 
Height (cm) 
<120 
120-200 
>200 
Weight (kg) 
<35 
35-120 
>120 
 
Vital signs data will be presented in a listing by treatment group and subject. Any 
unscheduled vital signs assessment will be presented in the listings. Vital signs include blood 
pressure (systolic/diastolic), heart rate, respiratory rate and temperature. 
Summary statistics will be presented for actual values and changes from study baseline at 
each scheduled assessment by treatment group. 
The number and percentage of subjects with abnormal values (Low and High) will be 
presented by treatment group. 
For the DBPC period and each Dysport Cycle, shift from study baseline tables of the number 
and percentage of subjects with low, normal or high values will be presented. 
7.7.5 Electrocardiograms 
Not applicable. 
7.7.6 Other Safety Variables 
Pregnancy test, urinary tract ultrasound and physical examination data will be presented in 
data listings. 
7.8 Primary Analysis of the Study 
 
 
 
 
 
 The analysis 
will consist of all tables, figures and listings for the study described in this statistical analysis 
plan using all available data up to the cut-off date and a clinical study report will be written. 
A final analysis will occur when all subjects have completed the study (or at other timepoints 
if required to support regulatory agency submissions). 
8 
CHANGES IN PLANNED ANALYSES 
Not applicable. 
9 
DATA ISSUES 
Not applicable. 
CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
September-2018 
Ipsen Protocol No. D-FR-52120-223                                                                            Covance Study ID: 
000000146513 
 
COVANCE INC. CONFIDENTIAL 
Page 38 of 75 
ST-AD-008 version 02 
10 REFERENCES 
1 
ICH. Statistical Principles for Clinical Trials, Guideline E9, 1998.  
2 
CHMP. Consider on Adjustment for Baseline Covariates. EMEA: London, 2013 
3 
Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika 1988;75:800-802. 
4 
ICH E3 Implementation Working Group. ICH E3 Guideline: Structure and Content 
of Clinical Study Reports Questions & Answers (R1), 6 July 2012 
5 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: 
John Wiley & Sons. 
 
 


CCI


CCI


CCI


CCI


CCI


CCI


CCI


Statistical Analysis Plan  
Version: Final v1.0                                                                                                      Date of Issue: 21-
CCI