Long-term Extension Study of BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity in Patients 5 to 17 Years of Age
Phase: PHASE3
Conditions: Urinary Incontinence
Sponsor: Allergan

 
NCT01852058 
 
Study ID: 191622-121 
 
Title: Long-term Extension Study of BOTOX® in the Treatment of Urinary Incontinence Due to 
Neurogenic Detrusor Overactivity in Patients 
5 to 17 Years of Age 
 
Protocol Amendment 2 Date: 14-Apr-2016 

 
 
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Allergan Confidential 
Protocol 191622-121 Amendment 2 
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The following information can be found on FDA
 Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and emergency telephone 
numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; US 21 CFR 312.23 
section 6(iii)b. 
 

 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
 
I have read this protocol in its entirety and I agree to all aspects. 
 
  
  
Investigator Printed Name  
  Signature 
  Date 
 
 

 
 
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Table of Contents 
Table of Contents 
...................................................................................................................... 4
 
List of Tables 
............................................................................................................................. 8
 
List of Figures 
........................................................................................................................... 8
 
Protocol Summary .................................................................................................................... 9
 
1. Background and Clinical Rationale 
................................................................................. 16 
2. Study Objectives and Clinical Hypotheses 
...................................................................... 20 
2.1  Study Objectives 
.................................................................................................... 20 
2.2  Clinical Hypotheses ............................................................................................... 20 
3. Study Design 
.................................................................................................................... 21
 
3.1  Data Review Committee 
........................................................................................ 21 
4. Study Population and Entry Criteria 
................................................................................ 22 
4.1  Number of Patients 
................................................................................................. 22 
4.2  Study Population Characteristics 
........................................................................... 22 
4.3  Inclusion Criteria 
.................................................................................................... 22 
4.4  Exclusion Criteria................................................................................................... 23 
4.5  Permissible and Prohibited Medications/Treatments 
............................................. 24 
4.5.1 Permissible Medications/Treatments ......................................................... 24 
4.5.1.1 Definition of Females of Childbearing Potential and Acceptable 
Contraceptive Methods 
..................................................................... 25 
4.5.2 Prohibited Medications/Treatments ........................................................... 25 
5. Study Treatments 
............................................................................................................. 26 
5.1  Study Treatments and Formulations ...................................................................... 26 
5.2  Control Treatment 
.................................................................................................. 27 
5.3  Methods for Blinding 
............................................................................................. 27 
5.4  Treatment Allocation Ratio and Stratification ....................................................... 27 
5.5  Method for Assignment to Treatment Groups/Randomization 
.............................. 27 
5.6  Treatment Regimen and Dosing 
............................................................................. 29 
5.7  Storage of Study Medications/Treatments 
............................................................. 29 
5.8  Preparation of Study Medications/Treatments 
....................................................... 29 

 
 
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5.9  Treatment Administration ...................................................................................... 30 
5.9.1 Day of Treatment Criteria 
.......................................................................... 30 
5.9.2 Prophylactic Antibiotics 
............................................................................. 30 
5.9.3 Use of Anesthesia 
....................................................................................... 31 
5.9.4 Treatment Procedure 
.................................................................................. 32 
5.9.5 Autonomic Dysreflexia 
.............................................................................. 33 
5.10 Retreatment 
............................................................................................................ 33 
5.10.1 Qualification for Retreatment Criteria 
....................................................... 33 
6. Response Measures and Summary of Data Collection Methods 
..................................... 34
 
6.1  Efficacy Measures 
.................................................................................................. 34 
6.1.1 Bladder Diary Measures 
............................................................................. 34 
6.1.2 Health Outcomes Measures........................................................................ 34 
 
 
6.1.4 Duration of Effect Measures 
...................................................................... 35 
6.2  Safety Measures 
..................................................................................................... 35 
6.3  Examination Procedures, Tests, Equipment, and Techniques 
................................ 36 
6.3.1 Latex Sensitivity or Allergy 
....................................................................... 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.12 Health Outcome Measures 
......................................................................... 40 
 
6.4  Other Study Supplies ............................................................................................. 41 
6.5  Summary of Methods of Data Collection 
.............................................................. 42 
7. Statistical Procedures 
....................................................................................................... 42 
7.1  Analysis Populations 
.............................................................................................. 42 
7.2  Collection and Derivation of Efficacy Assessments 
.............................................. 43 
7.2.1 Efficacy Variables ...................................................................................... 43 

 
 
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7.3  Hypothesis and Methods of Analysis 
..................................................................... 45 
7.3.1 Efficacy Analyses 
....................................................................................... 45 
7.3.1.1 Efficacy Analyses for Daytime Urinary Incontinence Episodes 
...... 45 
7.3.1.2 Efficacy Analyses for the Average Urine Volume at First Morning 
Catheterization 
.................................................................................. 46 
7.3.1.3 Efficacy Analyses for the Presence or Absence of Night Time 
Urinary Incontinence 
........................................................................ 46 
7.3.1.4 Health Outcomes Parameters ........................................................... 46 
 
7.3.1.6 Dose-response 
................................................................................... 47 
7.3.1.7 Duration of Effect 
............................................................................. 47 
7.4  Safety Analyses 
...................................................................................................... 47 
7.5  Subgroup Analyses 
................................................................................................. 48 
7.6  Sample Size Calculation ........................................................................................ 48 
7.7  Interim Analyses..................................................................................................... 48 
 
 
8.1  Patient Entry Procedures 
........................................................................................ 48 
8.1.1 Overview of Entry Procedures 
................................................................... 48 
8.1.2 Informed Consent and Patient Privacy 
....................................................... 49 
8.1.3 Procedures for Final Study Entry 
............................................................... 49 
 
 
8.3  Instructions for the Patients 
.................................................................................... 50 
8.4  Unscheduled Visits 
................................................................................................. 50 
8.5  Compliance with Protocol 
...................................................................................... 51 
8.6  Early Discontinuation of Patients .......................................................................... 51 
8.7  Withdrawal Criteria 
................................................................................................ 51 
8.8  Study Termination 
.................................................................................................. 52 
9. Adverse Events 
................................................................................................................ 52
 
9.1  Definitions 
.............................................................................................................. 52 
9.1.1 Adverse Event 
............................................................................................ 52 
9.1.2 Definition of Adverse Events of Urinary Tract Infection and Urinary 
Retention 
.................................................................................................... 53 
9.1.3 Serious Adverse Event 
............................................................................... 53 
9.1.4 Severity ...................................................................................................... 54 
9.1.5 Relationship to Study Drug or Study Procedure 
........................................ 54 

 
 
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9.2  Procedures for Reporting Adverse Events 
............................................................. 54 
9.3  Procedures for Reporting a Serious Adverse Event 
............................................... 55 
9.4  Procedures for Unblinding of Study Medication 
................................................... 55 
10. Administrative Items ....................................................................................................... 56 
10.1 Protection of Human Subjects 
................................................................................ 56 
10.1.1 Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations 
................................................................... 56 
10.1.2 Compliance With IRB or IEC Regulations 
................................................ 56 
10.1.3 Compliance With Good Clinical Practice 
.................................................. 56 
10.1.4 Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) 
.................................................................................. 57 
10.2 Changes to the Protocol ......................................................................................... 57 
10.3 Patient Confidentiality ........................................................................................... 57 
10.3.1 Patient Privacy ........................................................................................... 57 
10.4 Documentation 
....................................................................................................... 58 
10.4.1 Source Documents ..................................................................................... 58 
10.4.2 Case Report Form Completion................................................................... 59 
10.4.3 Study Summary 
.......................................................................................... 59 
10.4.4 Retention of Documentation 
...................................................................... 60 
10.5 Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 60 
10.5.1 Labeling/Packaging 
.................................................................................... 60 
10.5.2 Clinical Supply Inventory 
.......................................................................... 60 
10.5.3 Return or Disposal of Study Medications/Treatments and/or Supplies 
..... 61 
10.6 Monitoring by the Sponsor .................................................................................... 61 
10.7 Handling of Biological Specimens......................................................................... 61 
10.8 Publications 
............................................................................................................ 61 
10.9 Coordinating Investigator ...................................................................................... 61 
11. References 
........................................................................................................................ 62
 
12. Attachments 
..................................................................................................................... 64
 
12.1 Preparation of Study Medication ........................................................................... 65 
12.1.1 BOTOX 50 U (not to exceed 6 U/kg) 
........................................................ 66 
12.1.2 BOTOX 100 U (not to exceed 6 U/kg) 
...................................................... 66 
12.1.3 BOTOX 200 U (not to exceed 6 U/kg) 
...................................................... 67 
12.2 Study Treatment Injection Pattern 
.......................................................................... 68 

 
 
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12.4 Health Outcomes Questionnaire Descriptions and Instruction
Q and Modified 
TBS) 
....................................................................................................................... 78 
12.5 Glossary of Abbreviations 
...................................................................................... 81 
12.6 Protocol Amendment 1 Summary 
.......................................................................... 83 
12.7 Protocol Amendment 2 Summary 
.......................................................................... 86 
 
List of Tables 
 
 
 
List of Figures 
 
 
 
 

 
 
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Protocol Summary 
 
Study Compound:  BOTOX® (Botulinum Toxin Type A) Purified Neurotoxin Complex (US Adopted Name is 
OnabotulinumtoxinA) 
Phase:  3 
Study Objective:  To evaluate the long-term safety and efficacy of BOTOX for the treatment of urinary 
incontinence due to neurogenic detrusor overactivity (NDO) in patients 5 to 17 years of age who have not been 
adequately managed with anticholinergic therapy. 
Clinical Hypotheses:  BOTOX (one or more treatment groups) has an acceptable long-term safety and efficacy 
profile when injected into the detrusor of patients 5 to 17 years of age with NDO. 
Study Design 
Structure:  Multicenter, double-blind, long-term follow-up 
Duration:  Patients will participate in the study for at least 48 weeks following entry into the study and should 
have at least 12 weeks follow-up since the last treatment prior to exiting the study.  The minimum duration is 
therefore 48 weeks, and the maximum duration is approximately 60 weeks (for patients who received their last 
treatment at week 48 with 12 weeks posttreatment follow-up). 
Study Treatment Groups:  There will be 3 dose options in this study:  50 U BOTOX (not to exceed 6 U/kg), 
100 U BOTOX (not to exceed 6 U/kg), and 200 U BOTOX (not to exceed 6 U/kg).  At each retreatment, the 
investigator can elect to keep the dose the same or increase the dose one level; if it is deemed that a dose 
reduction would be warranted then the patient should be exited from the study. (see Section 5.5 for further 
details).  The dose decision will be based on the response to the previous treatment (for the first retreatment the 
reference treatment will be the initial treatment received in the preceding study).  Both the preceding and 
subsequent dose will remain blinded until the interim analysis has been reported (see Section 7.7).  The dosing 
options will depend on the investigator’s decision as summarized below: 
• Elect to keep the same dose as received at the previous treatment (dose not to exceed 6 U/kg) 
• Elect to increase the dose compared to the previous treatment (dose not to exceed 6 U/kg):  
o if the patient received 50 U at the previous treatment, they would receive 100 U  
o if the patient received 100 U at the previous treatment, they would receive 200 U  
o if the patient received 200 U at the previous treatment, they would remain at 200 U  
However, if the investigator requests a repeat dose escalation despite the patient having received 2 doses of 
200 U, the patient will be exited prior to receiving any further treatments and will be followed-up for a 
minimum of 12 weeks since their last treatment.  In addition, if the investigator assesses that the patient should 
not be retreated with the current dose and that a dose reduction would be warranted, the patient should be exited 
from the study as a reduction of dose in this study is not an option.  In such cases, the patient will be followed 
up for a minimum of 12 weeks since their last treatment.   
Controls:  None 
Dosage/Dose Regimen:  Multiple treatments may be administered in this study.  Request for retreatment can 
occur at scheduled clinic visits, scheduled telephone visits, or between scheduled visits.  If the request is made 
at a scheduled clinic visit, then that visit will also become the qualification for retreatment visit, otherwise a 
qualification for retreatment clinic visit should be conducted within approximately 1 to 2 weeks of the 
patient/parent/caregiver request.  (Note that those patients who qualified for retreatment in the preceding study 
191622-120, at which point they exited, do not need to be requalified to receive their first retreatment in this 
study).  

 
 
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Safety: 
• adverse events  
• serious adverse events 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
General Statistical Methods and Types of Analyses: 
One analysis population will be used in the statistical analysis of this study:  the BOTOX-treated population.  
Data from the patients’ participation in this extension study (191622-121) will be integrated with the 
corresponding patients’ data from the preceding study (191622-120).  Thus, the BOTOX-treated population will 
include all patients enrolled into the extension study who have received at least 1 BOTOX treatment over the 
course of the total evaluation period.   
All efficacy and safety analyses will be based on the treatment actually received in each treatment cycle.  
Patients will be grouped to the nearest dose group (50, 100, or 200 U BOTOX) based on the dose actually 
received. 
There will be no hypothesis testing in this long-term extension study.  All data will be summarized with 
descriptive statistics and/or frequency tables. 
For efficacy analysis, week 6 after each treatment will be the timepoint of main interest and the efficacy 
variable of key focus is change from baseline in the daily average frequency of daytime urinary incontinence 
episodes.  Data will be presented by BOTOX treatment cycle according to the dose received at that treatment 
cycle (grouped to the nearest dose group, ie, 50, 100, or 200 U BOTOX), as well as by an overall BOTOX
 
group (ie, regardless of dose).  For each BOTOX treatment cycle, descriptive statistics will be provided for the 
daily average frequency of daytime urinary incontinence episodes at baseline and each posttreatment visit.  The 
change from baseline (arithmetic mean and least-squares [LS] mean) and the 95% confidence intervals (CI) of 
the arithmetic and LS mean change will be provided.   
Other efficacy analyses will include the proportions of patients achieving ≥ 50%, ≥ 75%, ≥ 90%, and 100% 
reduction from baseline in daytime urinary incontinence. 
Duration of effect will be evaluated as time from study drug administration to request for retreatment, and 
dose-response analyses will include a nonparametric area under the curve (AUC) analysis of daily average 
frequency of daytime urinary incontinence episodes.  
For other efficacy and health outcomes variables, descriptive statistics will be provided.   
For safety variables, all safety analyses will be conducted on the BOTOX-treated population and data will be 
presented by BOTOX treatment cycle according to the dose received at that treatment cycle, with all patients 
allocated to the nearest dose group (50, 100, or 200 U BOTOX), as well as by an overall BOTOX
 group 
(ie, regardless of dose). 

 
 
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Sample Size Calculation:   
For this extension study, no formal sample size calculation was used.  Approximately 100 patients are 
anticipated to roll over into this study, which is assuming approximately 76% of patients randomized into 
Study 191622-120 will be available and willing to participate in this study. 

 
 
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1. 
Background and Clinical Rationale  
Neurogenic Detrusor Overactivity in Pediatric Patients 
The urinary bladder has 2 principal functions, to adequately store urine (storage phase), and 
to efficiently empty urine (voiding phase).  Coordination of these functions is accomplished 
through a complex interaction between the peripheral innervations of the lower urinary tract 
and the micturition centers of the central nervous system. 
Attainment of voluntary bladder control occurs once the appropriate coordinated neurological 
development has occurred, which usually starts from approximately 2 to 3 years of age.  
However, if there is a spinal cord lesion, an interruption of the spinal pathways and higher 
central nervous system micturition centers that control bladder function occurs.  In children, 
this is most commonly due to incomplete neural tube closure during embryonic development 
with traumatic or neoplastic lesions of the spinal cord being less common.  The most 
common form of incomplete neural tube closure is spina bifida whereby some vertebrae 
overlying the spinal cord are not fully formed and remain unfused and open.  
Myelomeningocele is the most commonly presenting form of spina bifida in which there is a 
protrusion of both the meninges that cover the spinal cord and the spinal cord itself through 
the unfused vertebrae; the meningeal membranes usually form a sac enclosing the spinal 
elements.  In meningocele, an uncommon form of spina bifida, the vertebrae have developed 
more normally; however, the meninges have been forced into the gaps of the vertebrae.  In 
the mildest form, spina bifida occulta, the gap in the vertebrae is so small that there is no 
protrusion of spinal cord or meninges and it often remains undetected.  To avoid further 
nerve damage and infection in spina bifida patients, early surgical intervention usually occurs 
in order to put any protruding spinal cord and its nerve roots back inside the spine, which is 
then covered with meninges.  This can lead to a subsequent complication during growth 
whereby the scar tissue at the site of the meningocele closure causes a tethering of the spinal 
cord. 
A
 tethered cord can also occur through congenital malformations such as presence of a spur 
of bony tissue in the spinal canal (split cord syndrome), growth of fatty tissue at the base of 
the developing spinal cord that entangles it (lipomeningomyelocele), an incomplete 
involution of the distal spinal cord leading to a thickened filum terminale (tight filum 
terminale syndrome), or it may be due to an injury in later life.  However, the common 
feature shared among tethered cord disorders is that the spinal cord is attached to the spinal 
column rather than hanging free in the canal.  Since the spinal cord grows more slowly than 

 
 
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the spinal column, a tethered spinal cord becomes stretched and stressed over time, causing 
neurological damage in the cord. 
Less commonly in the pediatric population, a spinal cord lesion can be caused by a direct 
spinal insult/injury
, or due to  a demyelination of the nerves (transverse myelitis); the latter 
may have various potential causes (eg, viral infection, immune disorder). 
Regardless of the source of the spinal cord lesion, it commonly results in a neurogenic 
bladder, which often exhibits detrusor overactivity; since there is a known neurological cause 
this is termed neurogenic detrusor overactivity (NDO).  Detrusor overactivity is defined as an 
involuntary detrusor contraction (IDC) during filling cystometry (Abrams et al, 2002), so this 
mainly affects the storage phase of the bladder
.  At bladder fill volumes which would 
normally be accommodated by the bladder, detrusor muscle contractions occur through 
efferent neuronal activity via the spinal micturition centers to the detrusor muscle.  This 
abnormal efferent activity may be a consequence of the abnormal neuronal input to the 
detrusor as well as a malfunction of the afferent signals from the bladder
.  Essentially
, the 
bladder has an inability to appropriately store urine resulting in uninhibited detrusor 
contractions that frequently result in uncontrolled urinary incontinence. 
In addition to urinary incontinence, patients with NDO, frequently suffer from a low capacity 
bladder and high intravesical pressures with uncoordinated bladder sphincter activity 
(Van Gool et al, 2001).  This can put at risk the upper urinary tract due to vesico-ureteric 
reflux, particularly when uncontrolled bladder contractions occur against a closed bladder 
outlet.  This has been clearly demonstrated in pediatric patients (McGuire et al, 1981; 
Bauer et al, 1984; Gerridzen et al, 1992). 
Currently Available Treatments for Neurogenic Detrusor Overactivity 
Early intervention with clean intermittent catheterization (CIC) is the principal intervention 
for pediatric patients with NDO.  The regular mechanical emptying of the bladder by CIC 
should not only reduce the degree of urinary incontinence, but also very importantly decrease 
the risk of upper urinary tract damage (Tekgül et al, 2012).  CIC is recommended to be 
started as early as possible to make it easier for the procedure to be mastered and for children 
to accept it as they grow older (Joseph et al, 1989; Tekgül et al, 2012).  Anticholinergic 
therapy is also commonly used in conjunction with CIC.  The addition of anticholinergics 
may provide some additional relief; however their use can also be associated with 
problematic side effects.  Other therapies are invasive, including surgically implanted 
neuromodulation devices, surgical augmentation of the bladder, and urinary diversion.  

 
 
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However, these approaches also have efficacy limitations and an inherent risk associated with 
the surgery so are frequently considered a last resort. 
Mechanism of Action of BOTOX for Neurogenic Detrusor Overactivity 
BOTOX inhibits synaptic vesicle-mediated neurotransmission through the cleavage of 
SNAP-25 (synaptosomal protein of molecular weight 25 kDa) in the nerve terminal.  This is 
a protein component of the SNARE complex (soluble NSF [N-ethylmaleimide-sensitive 
factor] Attachment Protein Receptor) that is responsible for the successful docking and fusion 
of synaptic vesicles to the nerve terminal membrane.  This process also provides a delivery 
mechanism for receptors such as TRPV1 (transient receptor potential vanilloid 1) to the nerve 
terminal as the receptors are embedded in the vesicle membrane and consequently exposed at 
the nerve terminal once the vesicle fuses with the nerve terminal membrane.  BOTOX thus 
prevents both the release of neurotransmitters from within synaptic vesicles and the 
expression of certain receptors at the nerve terminal (Apostolidis et al, 2006). 
There are several targets in the bladder that can be inhibited following injection of BOTOX 
into the bladder wall.  A
 direct inhibition of detrusor contraction through inhibition of 
acetylcholine is a clear efferent pathway target (Coelho et al, 2010).  In addition, modulation 
of various afferent pathways which also contribute to the condition have been proposed.  
BOTOX has been shown to inhibit various sensory neurotransmitters including substance P
, 
calcitonin gene-related peptide, and adenosine triphosphate (Chancellor et al, 2008).  It is 
also suggested from studies in humans that BOTOX may result in a reduction in certain 
sensory receptors that are thought to be upregulated in patients with detrusor overactivity
, ie, 
TRPV1 and ionotropic purinergic receptor type 3 (P2X
3) receptors (Apostolidis et al, 2005; 
Apostolidis et al, 2006; Chancellor et al, 2008). 
The inhibition of these various pathways through intradetrusor BOTOX injections therefore 
results in improvement in bladder function and patient symptoms. 
BOTOX Development Program in Adult Neurogenic Detrusor Overactivity Patients 
Allergan has completed a clinical development program for the use of BOTOX in adult 
patients with urinary incontinence due to NDO and it is licensed for use in many countries.  
Where registered, the licensed dose in adults is 200 U. 
The adult development program and brief summary of results is provided below
, however 
further details can be found in the BOTOX Investigator’s Brochure. 

 
 
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The adult program was initiated with a phase 2 study (191622-511) that evaluated a single 
treatment of 200 and 300 U BOTOX versus placebo (N = 59).  This study demonstrated 
clinically and statistically significant improvements with BOTOX compared to placebo in 
urinary incontinence and urodynamic parameters as well as an improvement in 
patient-reported health-related quality of life (HRQOL).  Two pivotal phase 3 studies were 
subsequently conducted in spinal cord injury and multiple sclerosis patients who were not 
adequately managed with anticholinergic therapy (Study 191622-515, N = 416 and 
Study 191622-516, N = 275).  Patients in both studies received 200 U BOTOX, 
300 U BOTOX, or placebo administered as intradetrusor injections via cystoscopy
.  Patients 
could receive an additional treatment if prespecified retreatment criteria were fulfilled; 
patients received active treatment with BOTOX for this retreatment (200 or 300 U BOTOX).  
Patients were to remain in the studies for at least 48 weeks, and those receiving a second 
treatment were to be followed for at least 12 weeks post-treatment 2.  In addition, patients 
could enter a long-term extension study (191622-094, 3 years duration) in which they could 
receive multiple treatments of BOTOX
 (initially of 200 or 300 U BOTOX but subsequently 
amended to only 200 U).  At this time, the study is still ongoing; however data from an 
interim analysis are available. 
Both pivotal phase 3 studies achieved the primary efficacy endpoint of significant reductions 
in urinary incontinence at week 6; reductions of approximately 20 episodes per week were 
observed in both BOTOX treatment groups compared to approximately 10 episodes per week 
in the placebo groups (Cruz et al, 2011; Ginsberg et al, 2012).  Efficacy was further 
supported by achievement of the urodynamic secondary endpoints of a significant increase in 
maximum cystometric capacity (MCC) and a significant decrease in maximum detrusor 
pressure during the first involuntary detrusor contraction.  Again, no clinically relevant 
difference was observed between the 200 and 300 U doses.  The patient perception of benefit 
was reflected in the achievement of the HRQOL endpoint in both pivotal studies.  The 
duration of effect of BOTOX was approximately 9 to 10 months. 
With respect to safety
, adverse events were primarily limited to local adverse events related 
to the urinary tract, in particular urinary retention and urinary tract infection (UTI).  In 
patients not using CIC prior to treatment, a dose-dependent increase in post-void residual 
urine volume was observed post-treatment.  A
 proportion of patients, both in the placebo and 
active dose groups, initiated CIC that was also dose-dependent. 
A
 consistent efficacy and safety profile has been demonstrated with repeat treatment. The 
reductions from baseline in urinary incontinence episodes remained similar over repeated 

 
 
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BOTOX treatments as did the improvement in HRQOL. The most common adverse events 
remained urological eg, urinary tract infection and urinary retention, and the incidence of 
such adverse events did not increase with repeated BOTOX treatments. 
Since there was no additional efficacy or benefit with the 300 U BOTOX dose compared to 
the 200 U BOTOX dose, and given that the 200 U BOTOX dose displayed a better safety 
profile, 200 U BOTOX was submitted for licensing registration, and approval has 
subsequently been granted in many countries at this dose.   
Use of BOTOX in Pediatric Neurogenic Detrusor Overactivity Patients 
Following the development of BOTOX for use in adults with urinary incontinence due to 
NDO, the efficacy and safety in the pediatric NDO population is being evaluated in 
Study 191622-120.  This current study
, 191622-121, is an extension of the initial pediatric 
study to enable an evaluation of long-term data over repeated treatments.  The doses of 
BOTOX available for use in this extension study remain the same as those in the preceding 
study (ie, 50, 100, and 200 U with no dose to exceed 6 U/kg).  However, in this extension 
study
, at each retreatment the investigator has the option to change the dose of the patient’s 
next BOTOX treatment based on the patient’s response to their previous treatment.  In 
addition, following further discussion with the US FDA, it was agreed that the minimum age 
requirement could be decreased from 8 years old to 5 years old at entry into the main study
, 
191622-120.  Since NDO due to spina bifida is a congenital disease with lifelong 
consequences, the primary goal of treatment is early intervention in order to prevent 
worsening bladder pressures and preserve renal function, thereby halting the progression of 
kidney disease. 
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
The objectives of this study are to evaluate the long-term safety and efficacy of BOTOX for 
the treatment of urinary incontinence due to NDO in patients 5 to 17 years of age who have 
not been adequately managed with anticholinergic therapy
. 
2.2 
Clinical Hypotheses 
BOTOX (one or more of the treatment groups) has an acceptable long-term safety and 
efficacy profile when injected into the detrusor of patients 5 to 17 years of age with NDO. 

 
 
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3. 
Study Design 
This is a multicenter, double-blind, long-term extension study to the preceding study
, 
191622-120.  Patients will roll over directly from the preceding study; the exit visit of study 
191622-120 is also the entry visit (day 1) for Study 191622-121 (patients exit 
Study 191622-120 once they have qualified for retreatment, or at week 48 if they never 
qualified).   
Patients can receive multiple double-blind treatments of 50, 100, or 200 U BOTOX (not to 
exceed 6 U/kg) in the extension study once they qualify for retreatment (for the first 
retreatment this qualification may have occurred in the preceding study).  The dose received 
at any given treatment will be determined by the investigator based on the response to the 
preceding blinded treatment.  The investigator can elect to keep the dose the same or increase 
the dose compared to the preceding treatment (if it is deemed a decrease in dose is warranted, 
the patient would be exited from the study).  The actual dose received remains blinded 
(unless the patient is requested to exit the study via the IVRS, as described at the end of 
Section 5.5, or until the interim analysis has been reported as described in Section 7.7).  The 
study medication will be administered via cystoscopy as 20 evenly spaced intradetrusor 
injections of 0.5 mL each, sparing the trigone.  
Following any treatment, patients will have posttreatment follow-up clinic visits at weeks 2, 
6, and 12, and then alternating telephone and clinic visits every 6 weeks thereafter until they 
qualify for further retreatment or exit the study.  Request for retreatment can occur at any 
scheduled clinic or telephone visit, or between scheduled visits.  If a request occurs at a 
scheduled clinic visit, this then becomes a qualification for retreatment visit, otherwise a 
qualification for retreatment clinic visit should occur within approximately 1 to 2 weeks of 
request.  Patients exit the study once 48 weeks have elapsed since entry on day 1 and at least 
12 weeks follow-up since their last study treatment has occurred (exit will therefore be 
between 48 and 60 weeks since study entry on day 1; the latter being for patients who 
received retreatment at week 48). 
The efficacy measure of key interest is daytime urinary incontinence episodes, and the key 
timepoint is week 6 after each treatment.  
3.1 
Data Review Committee 
An independent Data Review Committee (DRC) will be used for this study to review safety 
data.  It will be composed of at least a study-independent non-Allergan physician and a 
study-independent Allergan statistician.  Additional members may be included and ad hoc 

 
 
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members may also be invited depending on the safety findings and required scope of 
expertise.    
Details regarding the DRC are included in the DRC charter, including committee 
membership, data review procedures, frequency of review
, and communication between the 
DRC and others. 
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 100 patients are anticipated to roll over into this study
, which  assumes that 
approximately 76% of patients randomized into Study 191622-120 will be available and 
willing to participate in this study
. 
4.2 
Study Population Characteristics 
This study will include patients who, at the time of consent in the preceding study 
(191622-120), were 5 to 17 years of age, have urinary incontinence due to NDO, and had not 
been adequately managed with anticholinergics. 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
1. patient was aged ≥ 5 years to ≤ 17 years of age at the time of informed consent for the 
preceding study
, 191622-120  
2. patient has participated in Study 191622-120 and fulfilled that study’s exit criteria 
(completed the qualification for retreatment/exit visit or the week 48/exit visit if they 
never qualified for retreatment) 
 
 
 
 
 
 
 
 

 
 
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5. patient must be regularly using CIC to empty the bladder (CIC can be performed by 
either the patient or the parent/caregiver) 
 
 
 
 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
 
 
 
 
 
  
 
 
5. patient has any newly diagnosed medical condition that may put them at increased risk 
with exposure to BOTOX including myasthenia gravis, Eaton-Lambert syndrome, or 
amyotrophic lateral sclerosis 
6. patient currently uses or plans to use a baclofen pump 
7. patient currently uses or plans to use an implantable or nonimplantable 
electrostimulation/neuromodulation device for the treatment of NDO  
8. patient currently uses or plans to use an indwelling catheter, rather than CIC, for 
treatment of NDO (NOTE:  an indwelling catheter can be used if needed overnight as 
long as it is not used during the diary collection periods) 
 
 
 

 
 
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11. patient has had previous botulinum toxin therapy of any serotype for any urological 
condition (other than the study medication) or for any nonurological condition since 
entry into the preceding study
, 191622-120 
 
 
 
 
 
  
 
 
 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Therapy considered necessary for the patient’s welfare may be given at the discretion of the 
investigator
.  Patients should be instructed to maintain a stable dose during the study
, 
whenever possible.  All medications and adjunct therapies should be recorded on the 
appropriate electronic case report form (eCRF).  If the permissibility of a specific 
medication/treatment is in question, please contact Allergan. 
For those patients who were taking anticholinergics at entry into the preceding study
, 
191622-120, they can continue to be taken during this study
.  In addition, the dose can be 
modified or their use discontinued; the reason for dose modification or discontinuation 
should be documented by the investigator
.  However, intravesical anticholinergics are 
prohibited throughout the study
, as is the initiation of anticholinergic therapy
. 
Refer to Section 5.9.3 for information on permitted study treatment anesthesia. 

 
 
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4.5.1.1 
Definition of Females of Childbearing Potential and Acceptable 
Contraceptive Methods 
For females of childbearing potential (ie, females who are postmenarche), the following 
methods of contraception, if properly used, are generally considered reliable:  oral 
contraceptives, patch contraceptives, injection contraceptives, implantable contraceptives, 
male condom with intravaginal spermicide, diaphragm or cervical cap with spermicide, 
vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral tubal ligation), 
vasectomized partner, or sexual abstinence (when this is the lifestyle of the patient). 
If a postmenarche female patient is sexually active, the investigator and each patient (and her 
parent/legally authorized representative, in accordance with local laws and IRB/IEC 
requirements) will determine the appropriate method of contraception to be used during the 
study
. 
If a female becomes pregnant during the study
, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow-up, which should be at least 12 weeks since study treatment.  
The investigator will:  (1) notify the patient’s physician that the patient has been treated with 
BOTOX, and (2) follow the progress of the pregnancy
.  The investigator should document 
the outcome of the pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan should be notified 
before the prohibited medication/treatment is administered. 
The use of intravesical anticholinergic therapy is prohibited throughout the study
.  The 
initiation of anticholinergic therapy is also prohibited during the study (eg, those patients 
who were not using anticholinergic therapy during the preceding study
, 191622-120, are not 
permitted to start anticholinergic therapy in this study).  The use of other medications or 
therapies, other than anticholinergics, to treat the symptoms of NDO is also prohibited during 
the study
. 
Botulinum toxin treatment of any serotype other than study drug is prohibited for any 
indication.  Immunization to any botulinum toxin serotype is also prohibited during the study
. 
Administration of intravesical capsaicin or resiniferatoxin is prohibited during the study
. 

 
 
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Use of electrical stimulation and neuromodulation devices (implanted and external) for the 
treatment of overactive bladder (OAB) are prohibited during study participation (if a patient 
is enrolled into the study with a device still implanted, it must be inactive for the duration of 
the study). 
Use of baclofen pumps are prohibited during the study
. 
Use of aminoglycoside antibiotic therapy is not permitted during study treatment 
administration.  If a patient requires aminoglycoside antibiotic therapy during the trial, any 
study treatment administration must be delayed until the aminoglycoside antibiotic therapy is 
completed.  Use of aminoglycoside antibiotics should also be avoided for 8 weeks after study 
treatment.  Examples of such medications are:  amikacin sulfate, gentamicin sulfate, 
kanamycin, tobramycin, netilimicin sulfate, streptomycin.  
Anticoagulant medications (eg, warfarin and other coumadin derivatives), antiplatelet 
medications (eg, clopidogrel and aspirin [including low dose]) and any other medications 
with anticoagulative effects (eg, nonsteroidal anti-inflammatory drugs) are prohibited for a 
minimum of 3 days (or longer according to the clinical judgment of the investigator) prior to 
any study treatment, and must not be recommenced until the day following treatment(s). 
Neuromuscular blocking agents may not be administered at the same time as the study 
treatment. 
Indwelling catheters cannot be used to replace CIC and are prohibited during the study
, 
except if needed overnight.  However, an indwelling catheter cannot be used during the diary 
collection periods. 
5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
BOTOX 
Each vial of BOTOX (Botulinum Toxin Type A) purified neurotoxin complex,  
 
(US Adopted Name is OnabotulinumtoxinA), contains:  100 units (U) of 
Clostridium botulinum toxin Type A, 0.5 mg albumin (human), and 0.9 mg sodium chloride 
in a sterile, vacuum-dried form without a preservative.  One unit corresponds to the 
calculated median lethal intraperitoneal dose (LD
50) in mice.  The study medication will be 
reconstituted with 0.9% sodium chloride (preservative-free). 

 
 
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5.2 
Control Treatment 
There is no control treatment in this study
. 
5.3 
Methods for Blinding 
Both patients and investigators will remain blinded to BOTOX dosage (unless the patient is 
requested to exit the study via the IVRS, as described at the end of Section 5.5, or until the 
interim analysis has been reported as described in Section 7.7). 
The study medication will be packaged and labeled in identically appearing vials and 
reconstituted by an independent drug reconstitutor (IDR).  The study medication will be 
identified as an investigational compound and the carton will also be labeled with the study 
number and kit number
. 
5.4 
Treatment Allocation Ratio and Stratification 
Treatment allocation will be as described in Section 5.5 with no stratification. 
5.5 
Method for Assignment to Treatment Groups/Randomization 
There will be no randomization in this long-term extension study
.   
All patients who receive treatment in this study will receive BOTOX.  The blinded dose 
received (50, 100, or 200 U BOTOX, not exceeding 6 U/kg) will be dependent on the 
assessment of the clinical response (efficacy and safety) to the previous blinded study 
treatment (which will have been 50, 100, or 200 U BOTOX, not exceeding 6 U/kg).  The 
patient/parent/caregiver will be questioned on their treatment response to establish if, in their 
opinion, the current treatment response is adequate or if there was little or no treatment 
benefit and whether they would be willing/want to have a higher dose.  They will also be 
questioned on whether the patient is experiencing side effects.  Using this information, the 
investigator will use his/her own clinical assessment of the patient and apply the following 
criteria for the retreatment dose request:  
• if the benefit/risk balance is evaluated by the investigator to be appropriate at the current 
dose, then the same dose would be requested 
• if the investigator assessed that, although the preceding dose was well tolerated, the 
response received was insufficient and warrants a higher dose, then a dose increase would 
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• if the investigator assessed that there were side effects that would warrant a lower dose, 
the patient would be exited from the study 
Compared to the previous treatment, the investigator therefore has the following options:  
• elect to keep the same dose as received at the previous treatment (not to exceed 6 U/kg) 
• elect to increase the dose compared to the previous treatment (not to exceed 6 U/kg):  
o if the patient received 50 U BOTOX at the previous treatment, they would receive 100 U 
BOTOX 
o if the patient received 100 U BOTOX at the previous treatment, they 
would receive 200 U BOTOX 
o if the patient received 200 U BOTOX at the previous treatment, they 
would remain at 200 U BOTOX (after 2 requests to increase the dose from 
200 U the patient will be exited; see below)  
At the qualification for retreatment visit the investigator or designee will contact the 
IVRS/IWRS and indicate the treatment option for the patient.  IVRS/IWRS options will be 
either to remain at the same dose or to increase the dose since patients will be exited from the 
study if the investigator assessed that a lower dose was warranted (see below). 
In the following 2 scenarios patients will be exited once a minimum of 12 weeks follow-up 
since their last treatment has occurred: 
• if the investigator requests a dose increase on 2 occasions for a patient already 
receiving 200 U, the IVRS/IWRS will indicate upon the second request that the 
patient must be exited from the study and further retreatment will therefore not be 
received. 
• if the investigator assesses that the patient should not be retreated with the current 
dose but that a dose reduction would be warranted, the patient should be exited from 
the study as a reduction of dose in this study is not an option. 
Once all “day of treatment criteria” have been met at the day of treatment visit, the study 
medication will be allocated via IVRS/IWRS.  Study medication will be labeled with 
medication kit numbers and the IVRS/IWRS will provide the IDR with a specific medication 
kit number and treatment group assignment for the patient. 
The patient number used in Study 191622-121 will be the same as that allocated to the 
patient in the preceding study
, 191622-120. 

 
 
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5.6 
Treatment Regimen and Dosing 
Patients can receive multiple retreatments in this study
.  
All patients eligible for retreatment will receive either 50 U BOTOX (not to exceed 6 U/kg), 
100 U BOTOX (not to exceed 6 U/kg), or 200 U BOTOX (not to exceed 6 U/kg).  The 
dosage used at each retreatment will be determined as described in Section 5.5. 
To qualify for retreatment a patient must fulfill the qualification for retreatment criteria 
(see Section 5.10.1 for details).   
Each retreatment will also require all the day of treatment criteria to be fulfilled 
(see Section 5.9.1 for details). 
5.7 
Storage of Study Medications/Treatments 
The study medication must be stored in a secure area and administered only to patients 
entered into the clinical study
, at no cost to the patient, in accordance with the conditions 
specified in this protocol. 
 
 
  
 
 
 
 
 
 
 
5.8 
Preparation of Study Medications/Treatments 
Study medication should be prepared once all the “day of treatment criteria” have been 
fulfilled, and the IVRS/IWRS has been contacted.  It will be prepared in accordance with the 
instructions for reconstitution and preparation of study medication provided in the Pharmacy 
Manual.  
An IDR must prepare the study medication.  The IDR must be trained and have the skills 
necessary to prepare the study medication (eg, pharmacist,  nurse, study coordinator).  This 
person must not be associated or involved with a study patient’s care or study assessments, 
with the exception of study medication preparation. 

 
 
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5.9 
Treatment
 Administration
 
5.9.1 
Day of Treatment Criteria 
Treatment will be administered within 4 weeks of qualification for retreatment (see 
Section 5.10.1 for qualification for retreatment criteria), but no later than 48 weeks since 
study enrollment on day 1 of this study
.  The following “day of treatment criteria” must be 
fulfilled prior to each administration of study medication: 
• patient does not have a UTI, in the opinion of the investigator (taking into account patient 
symptoms, presence of significant leukocyturia at screening (e.g. ≥ 30 WBC/HPF), urine 
culture results, need for antibiotic treatment,etc)  
• appropriate prophylactic antibiotics have been initiated (see Section 5.9.2) 
• antiplatelet or anticoagulant therapy or medications with anticoagulative effects have 
been discontinued at least 3 days prior to treatment 
• negative urine pregnancy result (for postmenarche females) 
• investigator continues to deem treatment is appropriate and no condition or situation 
exists which, in the investigators opinion, puts the patient at significant risk from 
receiving retreatment 
Note:  If a patient does not fulfill the “day of treatment criteria”, they would still be 
considered qualified for retreatment (ie, qualification for retreatment or any associated 
procedures are not to be repeated).  The treatment administration visit would be rescheduled 
for as soon as possible (if applicable), and the day of treatment criteria would need to be 
fulfilled prior to treatment administration. 
5.9.2 
Prophylactic
 Antibiotics
 
All patients must receive prophylactic antibiotics prior to each treatment administration.  The 
approach is dependent upon the clinical judgment of the investigator, but could include either 
an intravenous (IV) dose of antibiotics prior to treatment administration on day 1 or oral 
antibiotics for at least 1 to 3 days prior to treatment and on the day of treatment.  Antibiotics 
could also be continued for 1 to 3 days posttreatment (or longer). 
Note:  Independent from the above description for prophylactic antibiotics, if a UTI is 
identified from the urinalysis/culture obtained during the qualification for retreatment period, 
the UTI must be treated with an antibiotic to which the identified bacteria is sensitive per 

 
 
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local site practice. As per the day of treatment criteria described in Section 5.9.1, the patient 
must not have a UTI on the day of treatment, in the opinion of the investigator
. 
5.9.3 
Use of Anesthesia 
Anesthesia will be used for all patients during the treatment administration.  The type of 
anesthesia is dependent upon the age of the patient as described below
. 
Precautions for latex sensitivity or allergy will be taken in accordance with local site practice.  
Appropriate precautions should also be taken for patients with a history of malignant 
hyperthermia.  
• for all patients < 12 years of age: 
o general anesthesia (which could include conscious sedation) will be used.  
It will be administered per local site practice; however, the use of 
neuromuscular blocking agents is not permitted. 
• for patients ≥ 12 years of age, either general anesthesia or the instillation of local 
anesthesia will be used: 
o general anesthesia (which could include conscious sedation) will be 
administered per local site practice; however, the use of neuromuscular 
blocking agents is not permitted 
o local anesthesia to the bladder wall (with or without sedation) will be via 
instillation into the bladder of 1 to 2% lidocaine (or similar acting local 
anesthetic) prior to the procedure.  The instillation solution should remain 
in the bladder for at least 15 minutes in order to achieve sufficient 
anesthesia.  The bladder will then be drained of lidocaine, rinsed with 
saline, and drained again. 
In addition, sedatives may be used if deemed medically necessary; their administration will 
be according to local site practice 
The following are permitted to facilitate the insertion/removal of the cystoscope: 
• lubricating gel 
• local anesthesia to the urethra:  intraurethral lidocaine gel (or similar local anesthetic gel) 

 
 
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5.9.4 
Treatment Procedure 
Precautions for latex sensitivity or allergy will be taken in accordance with local site practice. 
A
 rigid or flexible cystoscope may be used for study treatment administration.  As described 
above, lubricating gel and intraurethral lidocaine (or similar) can be used to facilitate 
cystoscope insertion.  The bladder should be instilled with a sufficient amount of saline in 
order to achieve adequate visualization for the study injections.  
The injection of study medication must not occur if bladder stones were identified during the 
qualification for retreatment visit from the bladder scan/ultrasound.  
The investigator will receive one 10 mL syringe prefilled with 10 mL of study medication 
and one 1 mL syringe prefilled with saline. 
The 10 mL of study medication will be administered as 20 injections each of 0.5 mL.  Under 
direct cystoscopic visualization, injections should be distributed evenly across the detrusor 
wall and spaced approximately 1 cm apart.  To avoid injecting the trigone, the injections 
should be at least 1 cm above the trigone (see the Study Treatment Injection Pattern diagram 
in Attachment 12.2).  The injection needle should be filled (primed) with approximately 1 mL 
of reconstituted study medication prior to the start of injections (depending on needle length) 
to remove any air
.  The injection needle should be inserted approximately 2 mm into the 
detrusor for each injection.  For the final injection site, a sufficient amount of saline (from the 
prefilled 1 mL syringe) will be flushed through the injection needle to deliver the small 
amount of study medication remaining in the needle.  This will ensure that the entire volume 
of study medication is administered to the patient. 
After the injections are given, the saline used for visualization should be drained from the 
bladder
.  Patients should remain in the clinic under observation for at least 30 minutes, or 
longer according to local site practice.  Safety monitoring and assessments are to be done 
according to local site practice (eg, monitoring of blood pressure, pulse rate).  Prior to 
leaving the study clinic, patients/parents/ caregivers will be instructed to contact the study 
site if they experience any adverse events posttreatment. 
The investigator, or designee, will be required to document on the study treatment eCRF 
whether the study drug administration was performed as indicated above.  In addition, details 
on equipment used (eg, rigid or flexible cystoscope) will be recorded. 

 
 
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5.9.5 
Autonomic Dysreflexia 
Patients with a spinal injury at thoracic level T5/6 or above or known history of autonomic 
dysreflexia should have their heart rate monitored during the treatment procedure and for a 
minimum of 30 minutes posttreatment.  Should autonomic dysreflexia develop in a patient, 
the condition should be immediately handled according to local site practice.  An occurrence 
of autonomic dysreflexia will be reported as an adverse event. 
5.10 
Retreatment 
Patients can receive multiple retreatments in this study
.  For each retreatment, patients must 
fulfill the qualification for retreatment criteria described in Section 5.10.1.  In addition, prior 
to treatment administration the day of treatment criteria must be fulfilled, as described in 
Section 5.10.1. 
5.10.1 
Qualification for Retreatment Criteria 
At each follow-up clinic visit and telephone contact from week 12 onward, the patient’s 
treatment response will be discussed with the patient/parent/caregiver
. 
Patients/parents/caregivers can request retreatment at any scheduled clinic or telephone visit, 
or between scheduled visits.  If a request is made at a scheduled clinic visit and all 
“qualification for retreatment criteria” are fulfilled, that clinic visit then becomes the 
qualification for retreatment visit and the additional procedures will be performed, otherwise 
a qualification for retreatment clinic visit should be conducted within approximately 1 to 
2 weeks of the request for retreatment and the “qualification for retreatment criteria” should 
be assessed prior to performing any other procedures.  The reason for the request will be 
collected.  (Note that patients who qualified for retreatment in the preceding study
, 
191622-120, at which point they exited, do not need to be requalified to receive their first 
retreatment in this study). 
In order to qualify for retreatment, the criteria listed below must be fulfilled: 
• patient/parent/caregiver requests retreatment 
• patient has a total of at least 2 daytime urinary incontinence episodes over the 2-day diary 
collection period 
• at least 12 weeks has elapsed since previous study treatment 
• patient has not experienced a serious treatment-related adverse event at any time 

 
 
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Once these criteria are fulfilled, the patient is considered qualified for retreatment; this does 
not need to be repeated (or any of the associated qualification for retreatment procedures) if 
the patient does not get treated at the subsequent treatment visit or the treatment visit is 
delayed. 
6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Bladder Diary Measures 
The efficacy measure of main interest is the number of daytime urinary incontinence 
episodes as recorded in the 2-day bladder diary during the week preceding each study visit.  
The timepoint of main focus is week 6 after each treatment. 
In addition, volume of urine at first morning catheterization and the occurrence of night time 
urinary incontinence will also be efficacy measures collected using the bladder diary
. 
Please refer to Section 6.3.5 for further details regarding the bladder diary
. 
6.1.2 
Health Outcomes Measures 
Two questionnaires will be utilized in this extension study: 
 
 
• Modified Treatment Benefit Scale (Modified TBS) 
o the proportions of patients whose condition is rated as either ‘greatly 
improved’
 or ‘improved’
 will be determined 
Please refer to Attachment 12.4 for further details regarding these questionnaires. 
 
 
 
 
 
 
 

 
 
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6.1.4 
Duration of Effect Measures 
The following 2 measures of duration of effect will be determined: 
• time to patient request for retreatment 
• time to patient qualification for retreatment 
6.2 
Safety Measures 
• adverse events  
• serious adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6.3 
Examination Procedures, Tests, Equipment, and Techniques  
Once the parental/legal guardian consent, minor assent, and data authorization/protection 
forms have been obtained, and all the required inclusion and exclusion criteria at have been 
met, the patient will be considered enrolled in the study
. 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  If it is not possible to use the same evaluator to follow the patient, then it is 
preferable to have the evaluations overlap (examine the patient together and discuss findings) 
for at least one visit. 
6.3.1 
Latex Sensitivity or Allergy 
Precautions for latex sensitivity or allergy will be taken in accordance with local site practice 
for any applicable procedures eg, urodynamics, blood sampling, as well as for the study 
treatment procedures. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
 
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6.3.12 
Health Outcome Measures 
The  
and the Modified TBS are both completed at weeks 6 and 12 after each treatment 
and at the qualification for retreatment visit (if the patient qualifies). 
Questionnaires should be administered prior to the patient undergoing any procedure for any 
study visit and prior to study treatment and will be completed as described in 
Attachment 12.4.  The same person(s) (patient or parent(s)/caregiver) should complete the 
questionnaires throughout the study where possible.  For example, if the patient is able to 
complete the questionnaires themselves, they should complete all questionnaires themselves 
throughout the study
.  If a parent or caregiver will assist or complete on the patient’s behalf, 
then this should be done throughout the study
. 
The versions of the questionnaires provided in the protocol (Attachment 12.4) are samples 
and will be replaced with the local language questionnaire for the country where the 
questionnaire will be administered. 
 
 
 
 
 
   
 
 
 
 
 

 
 
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6.4 
Other Study Supplies 
The following will be provided by Allergan: 
• all supplies needed for urine pregnancy testing, blood and urine sampling (supplies for 
central laboratory urine analysis and urine culture and sensitivity) 
• patient bladder diaries 
• containers to measure volume of urine at first morning catheterization 
The study sites will be responsible for providing the following supplies: 
• prophylactic antibiotics required prior to study treatment 
• sedatives and anesthesia for use during study treatment administration 
• sterile saline (or other appropriate sterile fluid) for bladder visualization during 
cystoscopic procedures, and for reconstitution of study medication 
• needles and syringes for reconstitution of study medication  

 
 
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• all necessary equipment to measure the required urodynamic parameters 
• flexible or rigid cystoscope with injection port and needles for injection 
• ultrasound for kidney and bladder assessment 
• refrigerator to store dry/reconstituted study medication at a temperature of 2 to 8
oC, 
monitored by a calibrated temperature recorder  
• freezer (nonfrost free) to store immunogenicity serum samples at -20 ±5oC or below
, 
monitored by a calibrated temperature recorder 
• internet connection (high-speed connection) for eCRF completion 
6.5 
Summary of Methods of Data Collection 
An IVRS/IWRS will be used to manage study medication inventory
.  Data will be collected 
using eCRFs via a validated electronic data capture system (EDC).  Source documents will 
be used and stored at the sites, and may include a patient’s medical records, hospital charts, 
clinical charts, patient chart, copy of the EDC file, as well as the results of diagnostic tests 
such as laboratory tests, ultrasounds, and urodynamics (if performed).  A
 central laboratory 
will be used for the analysis of all blood and urine samples (only storage for immunogenicity 
samples).  The data will be transferred via secure server to Allergan. 
7. 
Statistical Procedures 
The final statistical analysis will be conducted when all patients have completed or exited the 
study
.  On completion and analysis of the preceding study (191622-120), an interim analysis 
of this study is planned; sites may be unblinded upon completion of the interim analysis.  
A
 detailed statistical analysis plan will be finalized prior to the first study database lock. 
7.1 
Analysis Populations 
One analysis population will be used in the statistical analysis of this study:  the 
BOTOX-treated population. 
Data from the patients’ participation in this extension study (191622-121) will be integrated 
with the corresponding patients’ data from the preceding study (191622-120).  Thus, the 
BOTOX-treated population will include all patients enrolled into the extension study who 
have received at least 1 BOTOX treatment over the course of the total evaluation period. 

 
 
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All efficacy and safety analyses will be based on the treatment actually received in each 
treatment cycle.  Patients will be grouped to the nearest dose group (50, 100, or 
200 U BOTOX) based on the dose actually received. 
7.2 
Collection and Derivation of Efficacy Assessments 
The key efficacy measure is the number of daytime urinary incontinence episodes recorded in 
the bladder diary
.  The diary data will be collected by the patient/parent/caregiver over 
2 consecutive days in the week prior to clinic visits. 
In addition, the bladder diary will be used to record the urine volume at first morning 
catheterization and the occurrence of night time incontinence. 
Two questionnaires will be utilized in this extension study: 
• 
  
• Modified TBS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2.1 
Efficacy Variables 
The following efficacy variables are being assessed in this long-term extension study: 
• change from baseline in daily average frequency of daytime urinary incontinence 
episodes 
• change from baseline in average urine volume at first morning catheterization (mL) 

 
 
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• presence or absence of night time urinary incontinence 
• 
 
• proportion of patients with a positive treatment response on the Modified TBS (ie, rating 
their condition “greatly improved” or “improved”) 
 
 
 
 
 
 
 
 
 
 
 
 
The key efficacy variable is the change from baseline in daily average frequency of daytime 
urinary incontinence episodes (daytime is defined as the time between waking up to start the 
day and going to bed to sleep for the night).  The daily average frequency of daytime urinary 
incontinence episodes is obtained using the total number of daytime urinary incontinence 
episodes recorded in a 2-day bladder diary divided by 2.  Baseline is defined as the daily 
average frequency of episodes of daytime urinary incontinence prior to the initial study 
treatment in the preceding study
, 191620-120.  Each daytime period recorded in the bladder 
diary is normalized to represent a 12-hour period to account for differing durations of the 
daytime period.  The daily average frequency of daytime urinary incontinence episodes will 
be adjusted by the normalized daytime period. 
The timepoint of main interest is week 6 after each BOTOX treatment. 
For the baseline and posttreatment data, a patient must have at least 1 day of diary data 
(defined as a day where there is 1 or more urinary episodes [eg, incontinence, catheterization, 
or voluntary void] during the daytime collection period [between waking to start the day and 
going to bed to sleep at night]).  In the case of patients who partially complete their diary
, 
providing that at least 1 valid diary day out of 2 is available, the 2-day frequency of daytime 
urinary incontinence will be prorated with the value from the valid diary day
.  If less than 
1 diary day out of 2 has been completed, the frequency of daytime urinary incontinence will 
be considered as missing. 

 
 
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7.3 
Hypothesis and Methods of Analysis 
There will be no hypothesis testing in this long-term extension study.  All data will be 
summarized with descriptive statistics and/or frequency tables. 
7.3.1 
Efficacy
 Analyses
 
The efficacy analysis will be based on the BOTOX-treated population.  Week 6 after each 
treatment will be the timepoint of main interest and the efficacy variable of key focus is 
change from baseline in the daily average frequency of daytime urinary incontinence 
episodes.  Data will be presented by BOTOX treatment cycle according to the dose received 
at that treatment cycle (grouped to the nearest dose group, ie, 50, 100 or 200 U BOTOX), as 
well as by an overall BOTOX group (ie, regardless of dose). 
7.3.1.1 
Efficacy Analyses for Daytime Urinary Incontinence Episodes 
For each BOTOX treatment cycle, descriptive statistics will be provided for the daily average 
frequency of daytime urinary incontinence episodes at baseline and posttreatment visits.  The 
change from baseline (arithmetic mean and least-squares [LS] mean) and the 95% confidence 
intervals (CI) of the arithmetic and LS mean change will be provided.   
A responder analysis for daytime urinary incontinence will be performed using different 
thresholds of reduction from baseline.  A patient will be considered a treatment responder if 
they have at least a 50% reduction from baseline in daytime urinary incontinence, however 
other thresholds will also be evaluated.  The proportion of patients with ≥ 50%, ≥ 75%, 
≥ 90%, and 100% reduction from baseline in daytime urinary incontinence will be presented 
by BOTOX treatment cycle for each posttreatment visit. 
In addition the change from baseline and responder analyses will be performed using the 
normalized daily average frequency of daytime urinary incontinence episodes; these analyses 
will also be conducted without the normalization of the variable to a 12 hour daytime period. 

 
 
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7.3.1.2 
Efficacy Analyses for the Average Urine Volume at First 
Morning Catheterization 
For each BOTOX treatment cycle, descriptive statistics will be provided for the average urine 
volume at first morning catheterization at baseline and posttreatment visits as described in 
Section 7.3.1.1. 
7.3.1.3 
Efficacy Analyses for the Presence or Absence of Night Time 
Urinary Incontinence 
For each BOTOX treatment cycle, the number and proportion of patients who experienced 
night time urinary incontinence on 0, 1, or 2 nights will be presented for baseline and 
posttreatment visits. 
7.3.1.4 
Health Outcomes Parameters 
Health outcomes questionnaires and measures will be analyzed according to scoring 
algorithms described in the detailed statistical analysis plan. 
 
 
 
 
For the Modified TBS, the proportion of patients with a positive treatment response (defined 
as their condition being either “greatly improved” or “improved”) will be presented and its 
95% CI will be provided for each BOTOX treatment cycle at baseline and posttreatment 
visits. 
 
 
 
 
   
 
 
 

 
 
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7.3.1.6 
Dose-response 
Exploratory analysis may be performed to study dose-response based on the daily average 
frequency of daytime urinary incontinence episodes.  Details for any dose-response analysis 
will be provided in the statistical analysis plan. 
7.3.1.7 
Duration of Effect 
Duration of treatment effect will be assessed as time from each study drug administration to 
request for retreatment.  The time from the day of each BOTOX treatment to the request for 
the subsequent treatment will be estimated using the Kaplan-Meier survival method for each 
treatment group for each BOTOX treatment cycle.  For those patients who did not request 
retreatment, their data will be censored using the date of their last study visit.  The 
proportions of patients/parents/caregivers requesting retreatment in each BOTOX treatment 
cycle will also be presented. 
In addition, time to qualification for retreatment will be presented and analyzed as described 
above for time to request for retreatment. 
7.4 
Safety
 Analyses
 
All safety analyses will be conducted on the BOTOX-treated population.  Safety variables 
are adverse events, serious adverse events, physical examination, vital signs, laboratory tests 
(urinalysis, hematology and clinical chemistry), renal function, kidney and bladder 
ultrasound, concomitant medications, concurrent procedures, and pregnancy test for females 
who are postmenarche.  
Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code 
adverse events.  For each adverse event reported, the number and percent of patients will be 
tabulated based on the preferred term.  The tables will be generated by relationship to 
treatment as well as by primary system organ class and severity. 
Data will be presented by BOTOX treatment cycle and grouped according to the actual dose 
received at that treatment cycle (grouped to the nearest dose group [50, 100, or 
200 U BOTOX]), as well as by an overall BOTOX group (ie, regardless of dose). 

 
 
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7.5 
Subgroup
 Analyses
 
For each BOTOX treatment cycle, descriptive statistics will be provided for the daily average 
frequency of daytime urinary incontinence episodes as described in Section 7.3.1.1 by 
investigator site, as well as by key demographic or baseline characteristics, including 
concurrent anticholinergic therapy (eg, use and nonuse), baseline daytime urinary 
incontinence episodes (≤ 6 episodes or > 6 episodes over the 2-day diary collection period), 
age (< 12 years or ≥ 12 years), race, and sex. 
7.6 
Sample Size Calculation 
The sample size calculation for this study is determined empirically
.  Approximately 
100 patients are anticipated to roll over into this study, which is assuming approximately 
76% of patients randomized into Study 191622-120 will be available and willing to 
participate in this study. 
7.7 
Interim
 Analyses
 
An interim analysis is planned to coincide with the completion and subsequent database lock 
of the main study
, 191622-120.  On completion of this interim analysis, the study will be 
unblinded to Allergan personnel.  Study sites will be unblinded upon finalization of the 
interim clinical study report.  Additional interim analyses may also be conducted.  Further 
details of the interim analysis will be provided in the analysis plan. 
 
 
 
 
 
8.1 
Patient Entry Procedures 
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (Inclusion/Exclusion 
Criteria) will be considered for entry into this study
.  Patients will roll over directly into this 

 
 
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study from the preceding study
, 191622-120 (the exit visit of the preceding study will be the 
same as the entry visit for this extension study).  
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient/legally authorized representative and a patient 
wishing to participate or his/her legally authorized representative must give informed consent 
and, when applicable, minor assent prior to any study-related procedures or change in 
treatment.  The patient/legally authorized representative must also give authorization (US 
only), data protection consent (Europe only), and other written documentation in accordance 
with the relevant country and local privacy requirements (where applicable) prior to any 
study-related activities or procedures. 
As patients directly roll over from Study 191622-120 to this extension study
, consent will 
have been obtained prior to the patient exiting the preceding study
, 191622-120. 
Further information is provided in Section 10.1. 
Each patient who provides informed consent and/or assent will continue to use their 
IVRS/IWRS-assigned patient number from Study 191622-120 and this will be used on 
patient documentation throughout the study
. 
8.1.3 
Procedures for Final Study Entry 
Final study eligibility will be determined at the day 1 visit to confirm that the patient fulfills 
all the inclusion criteria without any exclusion criteria as specified in Sections 4.3 and 4.4 of 
the protocol.  
Entry into this study is directly from the exit visit from the preceding study
, 191622-120 
(exit visit of Study 191622-120 equals day 1 for Study 191622-121), therefore procedures 
associated with the exit visit of the preceding study do not need to be repeated for entry into 
this study
.  Similarly
, if a patient entered this extension study having qualified for retreatment 
in the preceding study
, the qualification procedures do not need to be repeated in this study
. 
A
 patient is considered to have entered (ie, enrolled) into the study when they have met the 
study entry criteria. 

 
 
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8.3 
Instructions for the Patients 
Patients/parents/caregivers will be instructed on the following: 
• to strictly follow the study visit schedule and report any changes in condition to the 
investigative site 
• to maintain the dose of any concurrent medication and anticholinergic medication 
during the study whenever possible (except anticholinergic medication which can be 
modified as described in Section 4.5.1) 
• to remain on the same CIC regimen 
• to change wet pads/diapers/underwear as soon as possible during diary collection 
periods in order to accurately capture episodes of incontinence   
• to call the study site if they are experiencing any difficulties following study 
treatment administration or study procedures  
• to contact the study site to report any hospitalizations 
• to call the study site as soon as possible in order to reschedule, if the patient cannot 
make their next scheduled study visit 
• diaries should be completed and brought to the study site at each scheduled clinic 
study visit 
8.4 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise and at the discretion of the 
investigator
.  Additional examinations may be performed as necessary to ensure the safety 

 
 
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and well being of patients during the study
.  eCRFs will be completed for each unscheduled 
visit.   
8.5 
Compliance with Protocol 
Participating patients (or parents/caregivers) should be able to adhere to the diary completion 
and testing parameters as described in this protocol. 
Data will be recorded on the appropriate eCRF supported by appropriate source 
documentation.  At each visit, patients/parents/caregivers should be asked if any concomitant 
medications had been used, if they had undergone any concurrent procedures (non-study 
procedures), and their compliance with the protocol since the previous visit. 
8.6 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time.  Patient discontinuation from 
the study and the reason for early discontinuation will be clearly documented on the 
appropriate eCRF
.  Patients who agree to follow-up will be followed for a minimum of 
12 weeks after study treatment for safety as per the protocol.  If a patient exits the study prior 
to study completion, all assessments for that visit should be performed in addition to any 
other exit visit assessments.   
8.7 
Withdrawal Criteria  
Patients have the right to withdraw from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or the institution.  The 
investigator and Allergan also have the right to withdraw a patient from the study at any time 
for any reason. 
Patients should be discontinued from the study if any of the following criteria are met.  
Where possible, the decision to withdraw a patient from study treatment or the study should 
be discussed with Allergan. 
• patient develops (or has an exacerbation of) any medical condition that, in the opinion 
of the investigator, would put the patient at an unacceptable medical risk or 
compromises the patient’s ability to participate in the study 
• patient becomes pregnant (see Section 4.5.1.1 Definition of Females of Childbearing 
Potential and Acceptable Contraceptive Methods) 

 
 
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• patient/parent/caregiver is unwilling or unable to continue to comply with study 
procedures 
• investigator requests a dose increase after the patient has received 2 treatments with 
200 U BOTOX 
• investigator assesses that the patient should not be retreated with the current dose, but 
that a dose reduction would be warranted 
8.8 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator
.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification. 
9. 
Adverse Events 
Throughout the course of the study
, all adverse events will be monitored and reported on an 
adverse event case report form, including seriousness, severity
, action taken, and relationship 
to study drug or injection procedure.  If adverse events occur, the first concern will be the 
safety of the study participants. 
Any adverse event that is recorded as ongoing at exit from the preceding study (191622-120) 
that is still ongoing at entry into this study will be recorded. 
9.1 
Definitions 
9.1.1 
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment.  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Progression of NDO, including new or worsening of anticipated clinical signs or symptoms, 
which are collected as clinical efficacy variables and assessed as unequivocally associated 
with the disease progression and /or lack of efficacy
, should not be reported as adverse events 
unless the disease progression is greater than anticipated in the natural course of the disease. 

 
 
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Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent/assent has been obtained).  At each visit, the investigator will 
begin by querying for adverse events by asking each patient or parent/caregiver a general, 
non-directed question such as “How have you been feeling since the last visit?”  Directed 
questioning and examination will then be done as appropriate.  All reported adverse events 
will be documented on the appropriate eCRF
.   
9.1.2 
Definition of Adverse Events of Urinary Tract Infection and 
Urinary Retention 
Study-specific definitions for the adverse events of UTI and urinary retention are provided 
below
. 
Adverse Event of Urinary Tract Infection 
An adverse event of UTI is defined as being a symptomatic UTI that requires treatment in the 
opinion of the investigator
. 
Note:  If urinalysis/culture results are reported which, in the opinion of the investigator, are 
considered clinically significant but do not fulfill the above definition of a UTI, the findings 
should be recorded as adverse events (eg, bacteriuria, leukocyturia). 
Adverse Event of Urinary Retention 
Urinary retention should only be reported in patients who had the ability to spontaneously 
void between catheterizations prior to study treatment.  It is defined in these patients as the 
inability to spontaneously void for at least 24 hours, which is not in conjunction with the 
patient experiencing constipation. 
9.1.3 
Serious
 Adverse
 Event
 
A
 serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity
, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition (see Section 9.3 for procedures for reporting a serious adverse event). 

 
 
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Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or non spontaneous) as a serious adverse event. 
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any preplanned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study
.  If it has not been documented at the time of the patient’s entry into the study
, then it 
should be documented as a serious adverse event and reported to Allergan. 
9.1.4 
Severity 
A
 clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate  
Discomfort enough to cause interference with usual activity
. 
Severe  
Incapacitating with inability to work or do usual activity
. 
Not applicable  
In some cases, an adverse event may be an ‘all or nothing’
 finding 
which cannot be graded. 
9.1.5 
Relationship to Study Drug or Study Procedure 
A
 determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A
 causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.   
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF
. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator’s Brochure) must be reported to the governing IRB/IEC as required by 
the IRB/IEC, local regulations, and the governing health authorities.  Any adverse event that 
is marked ‘ongoing’
 at the exit visit must be followed-up as appropriate. 

 
 
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9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent/assent and until study exit or early termination) and for at least 12 weeks after the 
last dose of study drug must be immediately reported but no later than 24 hours after learning 
of a serious adverse event.  Serious adverse events must be reported to Allergan (or agent of 
Allergan) as listed on the Allergan Study Contacts Page and recorded on the Serious Adverse 
Event form.  All patients with a serious adverse event must be followed up and the outcomes 
reported.  The investigator must supply Allergan and the IRB/IEC with any additional 
requested information (eg, autopsy reports and discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. notify Allergan immediately by fax or e-mail using the Serious Adverse Event form 
(contact details can be found on page 1 of the Serious Adverse Event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of this 
protocol and the Study Contacts Page. 
2. obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
patient 
3. provide Allergan with a complete, written description of the adverse event(s) on the 
Serious Adverse Event form describing the event chronologically
, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course, and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality
, which includes a statement as 
to whether the event was or was not related to the use of the investigational drug 
4. promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities 
9.4 
Procedures for Unblinding of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unblind the patient’s treatment assignment to determine which dosage of BOTOX has been 
assigned and institute appropriate follow-up care.  When possible, the Allergan Medical 
Safety Physician should be notified prior to unblinding study medication.  The investigator 
should inform the Allergan Medical Safety Physician of the unblinding if there is no 
notification prior to the unblinding.   

 
 
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The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 
10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
guideline on GCP
. 
10.1 
Protection of Human Subjects 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent/assent is to be obtained from each patient and/or from the patient’s 
legally authorized representative prior to initiating any study-related activity or procedure.  If 
the patient is under the legal age of consent, the consent form must be signed by the legally 
authorized representative in accordance with the relevant country and local regulatory 
requirements. 
Written parental/legal guardian informed consent in addition to a separate written minor 
consent and/or assent (in accordance with any applicable state and local laws/regulations) are 
required for each minor study patient prior to study enrollment or any study-related 
procedures in the study
. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually
.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  

 
 
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10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A
 report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
subject’s name will not be disclosed in these documents.  The patient’s name may be 
disclosed to the Sponsor of the study
, Allergan, or the governing health authorities or the US 
Food and Drug Administration (FDA) if they inspect the study records.  Appropriate 
precautions will be taken to maintain confidentiality of medical records and personal 
information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to and study-related procedure, 
and/or from the patient’s legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA
 requirements, additional purposes of this study may include the 
publishing of anonymous patient data from the study
. 
 

 
 
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10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient’s medical records, hospital charts, clinic charts, the 
investigator’s patient study files, as well as the results of diagnostic tests such as x-rays, 
laboratory tests, ultrasounds, and electrocardiograms.  The investigator’s copy of the eCRF 
serves as part of the investigator’s record of a patient’s study-related data.   
The following information should be included in the patient’s medical record: 
• patient’s name 
• patient’s contact information 
• a statement that informed consent and/or assent was obtained (including the date).  A
 
statement that written authorization (US sites only), data protection consent (EU sites 
only), or other country and local patient privacy required documentation for this study 
has been obtained (including the date) 
• date that the patient entered the study and patient number 
• study title and/or the protocol number of the study
, and the name of Allergan 
• dates of all patient visits 
• date and details of study treatment administration 
• date(s) of patient request for retreatment 
• reason for dose option 
• medical and surgical history (including prior medications for treatment of NDO) 
• all concurrent medications (list all prescription and non-prescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded). 
• occurrence and status of any adverse events (including any procedure-related adverse 
events) 
• date the patient exited the study
, and a notation as to whether the patient completed 
the study or reason for discontinuation 
• results of laboratory tests performed by the central laboratory  

 
 
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• the results of laboratory tests performed by the site (eg, urine pregnancy test) 
• urodynamic tracings, if urodynamic assessment performed  
• results of bladder and kidney ultrasound  
• concurrent procedures performed during the study 
• vital signs and physical examination findings 
• height and weight 
The responses to the following questionnaires/assessments entered directly onto the 
appropriate form will be considered source data: 
• bladder diary 
• primary reason for requesting retreatment 
• 
 
• Modified TBS 
In addition, study drug accountability and reconstitution records (stored separately with the 
IDR in order to maintain blinding status for site staff with direct contact with patient and/or 
data) will be retained as source documentation. 
10.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient’s 
eCRF and related documents in a timely manner
.  An investigator who has signed the 
protocol signature page should electronically sign for the eCRFs (as indicated in the eCRFs) 
to ensure that the observations and findings are recorded on the eCRFs correctly and 
completely
.  The eCRFs are to be submitted to Allergan in a timely manner, or as otherwise 
specified by Allergan, and will be maintained in a central data repository
. 
10.4.3 
Study Summary 
An investigator’s summary will be provided to Allergan within a short time after the 
completion of the study
, or as designated by Allergan.  A
 summary is also to be provided to 
the responsible IRB/IEC. 

 
 
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10.4.4 
Retention of Documentation 
All study related correspondence, patient records (ie, source documents listed in 
Section 10.4.1), consent forms, patient privacy documentation, records of the distribution and 
use of all investigational products, bladder diaries, questionnaires, correspondence with the 
IRB/IEC, and other essential documents should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Allergan-specific essential 
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 contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s), or if needed by Allergan. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
The investigational materials will be packaged and labeled in identically appearing vials.  
The study treatment will be identified as an investigational compound.  The study number 
and kit number will be identified on the carton. 
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
(ie, number of vials) received from Allergan, dispensed to the patients, the number of units 
returned to the Allergan or Allergan designee during and at the completion of the study
.  
A
 detailed inventory must be completed for the study medication.  The study medication 
must be reconstituted and administered only by appropriately qualified persons to patients in 
the study
.  The medication is to be used in accordance with the protocol under the direct 
supervision of an investigator
. 

 
 
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10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction, or destroyed at the site as specified in writing by Allergan. 
10.6 
Monitoring by the Sponsor 
A
 representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity
, blinding, size, and endpoints of the study
. 
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review
, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Handling of Biological Specimens 
Samples of blood and urine, for evaluation of hematology
, chemistries, and urinalysis, will be 
analyzed at a centralized clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology or Clinical Laboratory Improvement 
Amendments certification).  
The central laboratory manual provides details regarding laboratory collection and shipment 
procedures for blood and urine samples in this study
. 
Allergan shall have full ownership rights to any biological samples derived from the study
. 
10.8 
Publications 
Allergan as the sponsor has proprietary interest in this study
.  Authorship and manuscript 
composition will reflect joint cooperation between the investigators and Allergan personnel.  
Authorship will be established prior to the writing of the manuscript.  As this study involves 
multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with Allergan. 
10.9 
Coordinating Investigator 
A
 signatory coordinating investigator will be designated prior to the writing of the clinical 
study report. 

 
 
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11. 
References 
Abrams P
, Cardozo L, Fall M, Griffiths D, Rosier P
, Ulmsten U, et al.  The standardisation of 
terminology of lower urinary tract function:  report from the standardisation sub-committee 
of the International Continence Society
.  Neurourology and Urodynamics.  2002;21:167-178. 
Apostolidis A, Popat R, Yiangou Y
, Cockayne D, Ford AP
, Davis JB, et al.  Decreased 
sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor 
injections of botulinum toxin for human detrusor overactivity
.  J Urol.  2005;174:977-983. 
Apostolidis A, Dasgupta P
, Fowler CJ.  Proposed mechanism for the efficacy of injected 
botulinum toxin in the treatment of human detrusor overactivity
.  Eur Urol.  
2006;49:644-650. 
Bachmann C, Lehr D, Janhsen E, Steuber C, Gäbel E, von Gontard A, et al.  German version 
of the pediatric incontinence questionnaire for urinary incontinence health related quality of 
life.  J Urol.  2009;182:1993-1999. 
Bauer SB, Hallet M, Khoshbin S, Lebowitz RL, Winston KR, Gibson S et al.  The predictive 
value of urodynamic evaluation in newborns with myelodysplasia.  JAMA.  
1984;152:650-652. 
Bower WF
, Sit FKY
, Bluyssen N, Wong EMC, Yeung CK.  PinQ:  A
 valid, reliable and 
reproducible quality-of-life measure in children with bladder dysfunction.  J Pediatr Urol.  
2006;2:185-189. 
Chancellor MB, Fowler CJ, Apostolidis A, de Groat WC, Smith CP
, Somogyi GT
, et al.  Drug 
insight:  biological effects of botulinum toxin A
 in the lower urinary tract.  Nat Clin Pract 
Urol.  2008:5;319-328. 
Coelho A, Dinis P
, Ointo R, Gorgal T
, Silva C, Silva A, et al.  Distribution of the high-affinity 
binding site and intracellular target of botulinum toxin type A
 in the human bladder
.  Eur 
Urol.  2010:57;884-890. 
Colman S, Chapple C, Nitti V
, Haag-Molkenteller C, Hastedt C, Massow U.  Validation of 
treatment benefit scale for assessing subjective outcomes in treatment of overactive bladder
.  
Urology
.  2008;72:803-807. 
Cruz F
, Herschorn S, Aliotta P
, Brin M, Thompson C, Lam W
, et al.  Efficacy and safety of 
onabotulinumtoxinA
 in patients with urinary incontinence due to neurogenic detrusor 

 
 
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overactivity:  a randomised, double-blind, placebo-controlled trial.  Eur Urol.  
2011;60:742-750. 
Gerridzen RG, Thijssen AM, Dehoux E.  Risk factors for upper tract deterioration in chronic 
spinal cord injury patients.  J Urol.  1992;147:416-418. 
Ginsberg D, Gousse A, Keppenne V
, Sievert KD, Thompson C, Lam W
, et al.  Phase 3 
efficacy and tolerability study of onabotulinumtoxinA
 in patients with urinary incontinence 
resulting from neurogenic detrusor overactivity
.  J Urol.  2012;187:2131-2139. 
Joseph DB, Bauer SB, Colodny AH, Mandell J, Retik AB.  Clean intermittent catheterization 
of infants with neurogenic bladder
.  Pediatrics.  1989;84:78-82. 
McGuire EJ, Woodside JR, Borden TA, Weiss RM.  Prognostic value of urodynamic testing 
in myelodysplastic patients.  J Urol.  1981;126:205-209. 
Nevéus T
, von Gontard A, Hoebeke P
, Hjälmås K, Bauer S, Bower W
, et al.  The 
standardization of terminology of lower urinary tract function in children and adolescents:  
report from the standardisation committee of the international children’s continence society
.  
J Urol.  2006;176:314-324. 
Schwartz GJ, Work DF
.  Measurement and estimation of GFR in children and adolescents.  
Clin J Am Soc Nephrol.  2009;4:1832-1843. 
Tekgül S, Riedmiller H, Dogan HS, Gerharz E, Hoebeke P
, Kocvara R, et al.  Guidelines on 
pediatric urology
.  Uroweb 2012.  Available at 
http://www
.uroweb.org/gls/pdf/21_Paediatric_Urology_LR_August%202012.pdf.  Accessed 
14 January 2013. 
van Gool JD, Dik P
, de Jong TPVM.  Bladder-sphincter dysfunction in myelomeningocele.  
Eur J Pediatr
.  2001;160:414-420. 
 

 
 
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12. 
Attachments 
 
 
12.2  Study Treatment 
 
 
12.4  Health Outcomes Questionnaire Descriptions and Instructions 
12.5  Glossary of Abbreviations 
12.6  Protocol Amendment 1 Summary 
12.7  Protocol Amendment 2 Summary 
 

 
 
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12.1 
Preparation of Study Medication 
Study medication vials will be reconstituted for the 50, 100, and 200 U BOTOX dose groups 
(not to exceed 6 U/kg) based on the tables in the following sections. 
When reconstituting study medication for each patient, sterile, preservative-free, normal 
saline (diluent) should be added to the BOTOX vial with a new 10-mL syringe.  The vacuum 
within the vial will draw in the diluent.  Do not use the vial if a vacuum is not observed.  
Instead, contact IVRS/IWRS to allocate a replacement kit and notify Allergan personnel of 
the situation. 
Once the diluent has been drawn into the vial, the vial should be rotated gently to mix the 
contents.  The reconstituted study medication should be clear, colorless and free of 
particulate matter
. 
A
 new 10-mL syringe should be used to withdraw the required solution from the study 
medication vial.  This will be the dosing syringe.  The reconstitution is completed by adding 
to the dosing syringe, the additional amount of saline required to make the final 
concentration.  A
 detailed step-by-step process for study medication reconstitution will be 
provided in a Pharmacy Manual. 
 

 
 
 
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12.2 
Study Treatment Injection Pattern 
 
 
Copyright 2005 Allergan, Inc. 
All rights reserved. 
 
 

 
 
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12.4 
Health Outcomes Questionnaire Descriptions and Instructions 
( 
and Modified TBS) 
Patient questionnaires will be:  
• administered to all patients in the study prior to having any study procedure performed 
• completed by the patient (parent or caregiver can also complete) using a black, ballpoint 
pen on a firm writing surface.  The same person(s), (patient or parent(s)/caregiver), 
should complete the questionnaires throughout the study where possible. 
• administered in a quiet place with ample time for the patient to complete the 
questionnaire 
• filled out completely (every question must be answered) 
• initialed and dated on the last page by the patient/parent/caregiver who completed the 
questionnaire 
• completed only at protocol-specified study visits (no attempt should be made at any 
subsequent visit to administer missed questionnaires) 
• a source document; please do not make or use any photocopies of the forms 

 
 
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• checked for completeness, and not content, in the patient’s presence - study site personnel 
should not change responses on the questionnaires 
The versions of the questionnaires provided in the protocol are samples and will be replaced 
with a translation of the questionnaire in the local language for the country where the 
questionnaire will be administered. 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
 
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Modified Treatment Benefit Scale 
The TBS is single-item scale designed to assess the change in the patient’s OAB condition 
following treatment (Colman et al, 2008).  The patients current condition (urinary problems, 
urinary incontinence) is compared to their condition prior to receipt of any study treatment.  
The TBS was modified for this study based on parent/caregiver and patient input on the 
Pediatric Diary to adapt it for use in a pediatric population.  The questionnaire can be 
completed by patients, parents, or caregivers, and this will be indicated on the questionnaire. 
Patients/parents/caregivers respond to the following: 
Please write down what you think about how much you leak urine (pee) now compared to 
how much you leaked urine (pee) before you had any study treatment in the PREVIOUS 
trial. 
  
Leaking urine (pee) has 
 greatly improved 
 improved 
 not changed 
 worsened  
since I had any study treatment 

 
 
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12.5 
Glossary of Abbreviations 
Term/Abbreviation
 Definition
 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AUC 
area under the curve 
BOTOX® 
Botulinum Toxin Type A
 Purified Neurotoxin Complex  
(US adopted name onabotulinumtoxinA), referred to as BOTOX 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIC 
clean intermittent catheterization 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
DLPP 
detrusor leak point pressure 
DRC 
Data Review Committee 
EBC 
expected bladder capacity 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme linked immunosorbent assay 
EU 
European Union 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HEENT 
head, eyes, ears, nose, throat 
HIPAA 
Health Insurance Portability and Accountability Act 
HRQOL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
IDC 
involuntary detrusor contraction 
IDR 
independent drug reconstitutor 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 

 
 
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LS 
least squares 
MCC 
maximum cystometric capacity 
mITT 
modified intent-to-treat 
NDO 
neurogenic detrusor overactivity 
OAB 
overactive bladder 
 
 
 
 
 
 
PP 
per protocol 
RBC 
red blood cell 
SD 
standard deviation 
SNAP-25 
synaptosomal protein of molecular weight 25 kDa 
SNARE 
soluble NSF [N-ethylmaleimide-sensitive factor] attachment 
protein receptor 
T1 
thoracic vertebra level 1 
TBS 
Treatment Benefit Scale 
TRPV1 
transient receptor potential vanilloid 1 
UDS 
urodynamic studies 
US 
United States (of America) 
UTI 
urinary tract infection 
WBC 
white blood cell 
 

 
 
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Date (DD/MMM/YYYY)/Time (PT) Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 191622-121 Amendment 2