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

NCT01852045 
 
Study ID: 191622-120 
 
Title: BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor 
Overactivity in Patients 5 to 17 Years of Age 
 
Protocol Amendment 3 Date: 27 September 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
27-Sep-2017
Allergan Confidential 
Protocol 191622-120 Amendment 3 
BOTOX® 
 
 
 
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GDD-TA-T-004 v2012.9 
 
Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
STUDY TITLE 
BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor Overactivity 
in Patients 5 to 17 Years of Age 
 
Protocol Number:   
191622-120 Amendment 3 
EudraCT Number: 
2012‐004877‐26 
Phase: 
3 
Name of Investigational Product: 
BOTOX® 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California, USA 
92612 
+1-714-246-4500 
+1-800-347-4500 
Allergan Ltd. 
1st Floor, Marlow 
International, The Parkway, 
Marlow Buckinghamshire 
SL7 1YL United Kingdom 
Tel: +44 (0) 1628 494444 
Fax: +44 (0) 1628 494449 

 
 
Approval Date: 
 
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Allergan Confidential 
Protocol 191622-120 Amendment 3 
BOTOX® 
 
 
 
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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. 
 

 
 
Approval Date: 
 
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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 
 
 

 
 
Approval 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 ................................................................................. 17 
2 
Study Objectives and Clinical Hypotheses ...................................................................... 22 
2.1 
Study Objectives .................................................................................................... 22 
2.2 
Clinical Hypotheses ............................................................................................... 22 
3 
Study Design .................................................................................................................... 22 
3.1 
Data Review Committee ........................................................................................ 23 
4 
Study Population and Entry Criteria ................................................................................ 23 
4.1 
Number of Patients ................................................................................................. 23 
4.2 
Study Population Characteristics ........................................................................... 23 
4.3 
Inclusion Criteria .................................................................................................... 23 
4.4 
Exclusion Criteria .................................................................................................. 25 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 27 
4.5.1  Permissible Medications/Treatments ......................................................... 27 
4.5.1.1 
Definition of Females of Childbearing Potential and Acceptable 
Contraceptive Methods .............................................................. 28 
4.5.2  Prohibited Medications/Treatments ........................................................... 28 
5 
Study Treatments ............................................................................................................. 29 
5.1 
Study Treatments and Formulations ...................................................................... 29 
5.2 
Control Treatment .................................................................................................. 30 
5.3 
Methods for Blinding ............................................................................................. 30 
5.4 
Treatment Allocation Ratio and Stratification ....................................................... 30 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 30 
5.6 
Treatment Regimen and Dosing ............................................................................. 30 
 
 
5.8 
Preparation of Study Medications/Treatments ....................................................... 31 
5.9 
Treatment Administration ...................................................................................... 31 

 
 
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5.9.1  Day of Treatment Criteria .......................................................................... 31 
5.9.2  Prophylactic Antibiotics ............................................................................. 32 
5.9.3  Use of Anesthesia ....................................................................................... 32 
5.9.4  Treatment Procedure .................................................................................. 33 
5.9.5  Autonomic Dysreflexia .............................................................................. 34 
5.10  Retreatment ............................................................................................................ 34 
5.10.1  Qualification for Retreatment Criteria ....................................................... 35 
6 
Response Measures and Summary of Data Collection Methods ..................................... 35 
6.1 
Efficacy Measures .................................................................................................. 35 
6.1.1  Primary Efficacy Measure .......................................................................... 35 
6.1.2  Secondary Efficacy Measures .................................................................... 36 
 
 
6.2 
Safety Measures ..................................................................................................... 36 
6.3 
Examination Procedures, Tests, Equipment, and Techniques ................................ 37 
6.3.1  Latex Sensitivity or Allergy ....................................................................... 37 
6.3.2  Medical History .......................................................................................... 37 
6.3.3  Physical Examination ................................................................................. 38 
6.3.4  Weight and Height ...................................................................................... 38 
6.3.5  Vital Signs .................................................................................................. 38 
6.3.6  Bladder Diary ............................................................................................. 39 
6.3.7  Urodynamic Testing ................................................................................... 39 
6.3.8  Bladder and Kidney Ultrasound ................................................................. 40 
 
 
6.3.10  Hematology and Clinical Chemistry .......................................................... 41 
6.3.11  Renal Function Testing............................................................................... 42 
6.3.12  Immunogenicity Testing ............................................................................. 42 
6.3.13  Pregnancy Test ........................................................................................... 43 
6.3.14  Health Outcome Measures ......................................................................... 43 
6.4 
Other Study Supplies ............................................................................................. 43 
6.5 
Summary of Methods of Data Collection .............................................................. 44 
7 
Statistical Procedures ....................................................................................................... 44 
7.1 
Analysis Populations .............................................................................................. 44 
7.2 
Collection and Derivation of Primary and Secondary Efficacy Assessments ........ 45 
7.2.1  Primary Efficacy Variable .......................................................................... 46 
7.2.2  Secondary Efficacy Variables ..................................................................... 46 

 
 
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7.3 
Hypothesis and Methods of Analysis ..................................................................... 47 
7.3.1  Primary Efficacy Analyses ......................................................................... 47 
7.3.2  Secondary Efficacy Analyses ..................................................................... 48 
 
 
7.3.2.2 
Efficacy Analyses for the Secondary Efficacy Variables ........... 49 
 
 
 
 
 
 
 
 
 
 
7.4 
Safety Analyses ...................................................................................................... 51 
7.5 
Sensitivity Analysis ................................................................................................ 52 
7.6 
Subgroup Analyses ................................................................................................. 52 
7.7 
Sample Size Calculation ........................................................................................ 52 
7.8 
Interim Analyses .................................................................................................... 53 
8 
Study Visit Schedule and Procedures .............................................................................. 53 
8.1 
Patient Entry Procedures ........................................................................................ 53 
8.1.1  Overview of Entry Procedures ................................................................... 53 
8.1.2  Informed Consent and Patient Privacy ....................................................... 53 
8.2 
Procedures for Final Study Entry ........................................................................... 54 
8.3 
Visits and Associated Procedures ........................................................................... 54 
8.4 
Instructions for the Patients .................................................................................... 54 
8.5 
Unscheduled Visits ................................................................................................. 55 
8.6 
Compliance with Protocol ...................................................................................... 55 
8.7 
Early Discontinuation of Patients .......................................................................... 55 
8.8 
Withdrawal Criteria ................................................................................................ 56 
8.9 
Study Termination .................................................................................................. 56 
9 
Adverse Events ................................................................................................................ 56 
9.1 
Definitions .............................................................................................................. 56 
9.1.1  Adverse Event ............................................................................................ 56 
9.1.2  Definition of Adverse Events of Urinary Tract Infection and Urinary 
Retention .................................................................................................... 57 
9.1.3  Serious Adverse Event ............................................................................... 58 
9.1.4  Severity ...................................................................................................... 58 

 
 
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9.1.5  Relationship to Study Drug or Study Procedure ........................................ 59 
9.2 
Procedures for Reporting Adverse Events ............................................................. 59 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 59 
9.4 
Procedures for Unblinding of Study Medication ................................................... 60 
10  Administrative Items ....................................................................................................... 60 
10.1  Protection of Human Subjects ................................................................................ 60 
10.1.1  Compliance with Informed Consent Regulations (US 21 CFR Part 50) 
and Relevant Country Regulations ............................................................ 60 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 61 
10.1.3  Compliance With Good Clinical Practice .................................................. 61 
10.1.4  Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) .............................................................. 61 
10.2  Changes to the Protocol ......................................................................................... 61 
10.3  Patient Confidentiality ........................................................................................... 61 
10.3.1  Patient Privacy ........................................................................................... 62 
10.4  Documentation ....................................................................................................... 62 
10.4.1  Source Documents ..................................................................................... 62 
10.4.2  Case Report Form Completion................................................................... 63 
10.4.3  Study Summary .......................................................................................... 64 
10.4.4  Retention of Documentation ...................................................................... 64 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 64 
 
10.5.2  Clinical Supply Inventory .......................................................................... 65 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 65 
10.6  Monitoring by the Sponsor .................................................................................... 65 
10.7  Handling of Biological Specimens ........................................................................ 65 
10.8  Publications ............................................................................................................ 66 
10.9  Coordinating Investigator ...................................................................................... 66 
11  References ........................................................................................................................ 67 
12  Attachments ..................................................................................................................... 70 
12.1  Preparation of Study Medication ........................................................................... 71 
12.1.1  BOTOX 50 U (not to exceed 6 U/kg) ........................................................ 72 
12.1.2  BOTOX 100 U (not to exceed 6 U/kg) ...................................................... 72 
12.1.3  BOTOX 200 U (not to exceed 6 U/kg) ...................................................... 73 

 
 
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12.2  Study Treatment Injection Pattern .......................................................................... 74 
12.3  Urodynamic Procedure .......................................................................................... 75 
12.3.1  Overview .................................................................................................... 75 
12.3.2  Central Reviewer Process .......................................................................... 75 
12.3.3  Site Urodynamic Qualification .................................................................. 75 
 
12.3.5  Urodynamic Annotations ........................................................................... 77 
 
 
 
 
 
12.5  Glossary of Abbreviations ...................................................................................... 89 
12.6  Protocol Amendment 1 Summary .......................................................................... 92 
12.7  Protocol Amendment 2 Summary .......................................................................... 96 
12.8  Protocol Amendment 3 Summary .......................................................................... 97 
 
List of Tables 
 
 
 
List of Figures 
 
 
Figure 2 
Examples of AUC for Urinary Episode Change ............................................. 51 
 
 

 
 
Approval Date: 
 
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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 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 of the treatment groups) has an acceptable safety profile when 
injected into the detrusor of patients 5 to 17 years of age with NDO.  BOTOX (one or more of the treatment 
groups) improves the symptoms of NDO as measured by a reduction from baseline in daytime urinary 
incontinence episodes. 
Study Design 
Structure:  Multicenter, randomized, double-blind, parallel group 
Duration:  Patients will participate in the study until one of the following exit criteria is met, whichever occurs 
sooner: 
• 
patient has qualified for retreatment (retreatment to occur in the extension study, for patients who elect and 
qualify to enroll), or 
• 
patient has completed 48 weeks after randomization/day 1, if never qualifies for retreatment (ie, completes 
the 48 week visit) 
Study Treatment Groups:  There will be 3 treatment groups: 
 
• 
50 U BOTOX (not to exceed 6 U/kg) 
• 
100 U BOTOX (not to exceed 6 U/kg) 
• 
200 U BOTOX (not to exceed 6 U/kg) 
Controls:  None 
Dosage/Dose Regimen:  A single treatment will be administered on day 1 once all “day of treatment criteria” 
are fulfilled (see Section 5.9.1).  Treatment will be administered via cystoscopy (rigid or flexible cystoscope) as 
20 intradetrusor injections of 0.5 mL each evenly distributed, sparing the trigone.  Administration will be under 
general anesthesia (see Section 5.9.3 for details) for all patients < 12 years of age.  For patients 12 years and 
older, administration can be under local anesthesia (with or without sedation), or general anesthesia.  
Precautions for latex sensitivity or allergy will be taken, in accordance with local site practice. 
Qualification for retreatment can occur in this study (see Section 5.10); however, the patient will exit this study 
once qualified for retreatment and treatment administration will occur in the extension study (patients who 
never qualify for retreatment can also enroll into the extension study once they complete this study [ie, 
48 weeks from randomization/day 1]). 
Randomization/Stratification:  Patients will be randomized on day 1 to one of 3 treatment groups: 
• 
50 U BOTOX (not to exceed 6 U/kg)  
• 
100 U BOTOX (not to exceed 6 U/kg)  
• 
200 U BOTOX (not to exceed 6 U/kg)  
Patients will be centrally randomized and assigned a randomization number prior to treatment.  In order to 
ensure balance across treatment groups, patients will be stratified by age (< 12 years or ≥ 12 years), and 
baseline daytime urinary incontinence episodes (a total of ≤ 6 episodes or > 6 episodes over the 2-day diary 
collection period). 

 
 
Approval Date: 
 
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Study Population Characteristics 
Number of Patients:  Approximately 132 patients will be randomized at approximately 35 to 45 sites 
(40 patients per treatment group plus 10% dropout by the primary timepoint of week 6). 
Condition/Disease:  Urinary incontinence due to NDO 
Key Inclusion Criteria:   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
patient must be regularly using clean intermittent catheterization (CIC) to empty the bladder 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
Approval Date: 
 
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Key Exclusion Criteria:  
 
 
• 
patient has had surgery of the spinal cord within 6 months of screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
patient has cerebral palsy 
 
  
 
 
 
 
 
 
 
 
• 
patient currently uses or plans to use a baclofen pump 
• 
patient currently uses or plans to use an implantable or nonimplantable electrostimulation/neuromodulation 
device for treatment of NDO.  (If a nonimplantable device is used, it must be discontinued at least 7 days 
prior to the first screening procedure; if a device is implanted, it must be inactive for at least 4 weeks prior 
to the first screening procedure; neither should be used during the study). 
• 
patient uses 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) 
• 
patient has had previous or current: 
o 
botulinum toxin therapy of any serotype for any urological condition, or  
o 
treatment with botulinum toxin of any serotype within 3 months of randomization/day 1 
for any other condition or use  
 
  
 
 

 
 
Approval Date: 
 
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Response Measures 
Efficacy:  
Primary: 
• 
daytime urinary incontinence episodes 
Secondary: 
• 
maximum cystometric capacity (MCC) 
• 
presence/absence of an IDC 
• 
if an IDC is present, maximum detrusor pressure during the first IDC (PdetMax1stIDC) 
• 
maximum detrusor pressure during the storage phase (PdetMax) 
• 
if a leak occurs, detrusor leak point pressure (DLPP) 
• 
urine volume of first morning catheterization 
• 
presence/absence of night time urinary incontinence 
• 
time to patient request and time to qualification for retreatment 
Safety:   
• 
adverse events  
• 
serious adverse events 

 
 
Approval Date: 
 
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General Statistical Methods and Types of Analyses:  For efficacy variables, data will be analyzed using the 
modified intent-to-treat (mITT) population consisting of all randomized patients who receive treatment on 
randomization/day 1.  Patients will be analyzed using their randomized treatment assignment except for those 
patients who triggered the 6 U/kg limit who will be grouped according to the nearest dose group (50, 100, or 
200 U BOTOX) based on the dose actually received.  The primary efficacy variable is the change from baseline 
at week 6 posttreatment in the daily average frequency of daytime urinary incontinence episodes, with baseline 
frequency defined as the daily average frequency of daytime urinary incontinence episodes preceding the study 
treatment.  
For each of the BOTOX doses, descriptive statistics will be provided for the daily average frequency of daytime 
urinary incontinence episodes at baseline and week 6, including change from baseline.  The treatment difference 
in mean change from baseline for 200 versus 50 U BOTOX and 100 versus 50 U BOTOX will be calculated.  
Pairwise comparisons of 200 versus 50 U BOTOX and 100 versus 50 U  BOTOX at week 6, will be evaluated 
using an analysis of covariance (ANCOVA) model; a hierarchical analysis strategy to adjust for multiplicity 
will be used.  A similar analysis, without a hierarchal testing strategy, will be applied to other timepoints and to 
the secondary efficacy variables (pairwise comparisons will be done up to week 12). 
 
 
A preliminary estimate of duration of effect will be evaluated as time from treatment on day 1 to request for 
retreatment using a Kaplan-Meier survival analysis.  Dose-response analyses will include a nonparametric area 
under the curve (AUC) analysis of daily average frequency of daytime urinary incontinence episodes.  
The health outcomes parameters of PinQ and Modified TBS will be analyzed using either an analysis of 
variance (ANOVA) or ANCOVA for continuous variables, or using Pearson’s chi-square test, Fisher’s exact 
test (or CMH) for categorical variables as appropriate on the mITT population. 
For safety variables, data from all patients who received study drug will be included; data will be analyzed 
using the dose actually received, with all patients allocated to the nearest dose group (50, 100, or 
200 U BOTOX). 
Sample Size Calculation:  The sample size calculation for this study is determined empirically.  A total of 
34 patients per treatment group are to be randomized for the study (30 patients per treatment group plus 
additional patients to address patient attrition [estimated to be 10% by week 6]). 
The following table displays the estimated distance for treatment differences between 200 U BOTOX 
(maximum 6 U/kg) and 50 U BOTOX (maximum 6 U/kg) in mean daily average frequency of daytime episodes 
of urinary incontinence change from baseline at week 6 for a range of common standard deviations (SD).  All 
calculations assume 30 patients per treatment group and a 2-sided test significance level of 0.05.  The 
calculation was performed using the commercial software nQuery Advisor (procedure MTC0-1), version 6.01, 
and the confidence interval is based on the large sample z statistic. 
Standard Deviation 
Distance From Mean to the Limit 
2.0 
1.012 
2.5 
1.265 
3.0 
1.518 
3.5 
1.771 
4.0 
2.024 
 
Note:  The ranges of the SDs are determined based on the values from the adult pivotal phase 3 studies 
(191622-515 and 191622-516).  The estimate of the SD for the 200 U BOTOX treatment group is 3.44 for 
Study 191622-515, 2.58 for Study 191622-516, and 3.10 for the 2 studies combined. 

 
 
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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 (CNS). 
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 
CNS 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, where 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, where 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 shared 
common feature 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 the spinal column, a tethered 
spinal cord becomes stretched and stressed over time, causing neurological damage in the 
cord.  

 
 
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Less commonly in the pediatric population, a spinal cord lesion can be caused by a direct 
spinal insult/injury, or be 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.  
However, these approaches also have efficacy limitations and an inherent risk associated with 
the surgery, so are frequently considered a last resort. 

 
 
Approval Date: 
 
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Mechanism of Action of BOTOX® for Neurogenic Detrusor Overactivity 
BOTOX (Botulinum Toxin Type A purified neurotoxin complex [US adopted name 
onabotulinumtoxinA], referred to as 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.  Thus, BOTOX 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 [P2X3] 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 BOTOX. 
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).  Currently, Study 191622-094 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.  No clinically relevant difference 
was observed between the 200 and 300 U BOTOX 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 posttreatment.  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 BOTOX 
treatment.  The reductions from baseline in urinary incontinence episodes remained similar 

 
 
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over repeated 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 treatment. 
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 purpose of Study 191622-120 is to assess the safety and efficacy of BOTOX for 
the treatment of urinary incontinence in the NDO pediatric population.  On completion of 
this study, patients will also have the opportunity to roll-over into an extension study and 
receive retreatment (Study 191622-121).  
The pediatric population to be studied, following discussion with the United States Food and 
Drug Administration (US FDA), was defined as patients aged 8 to 17 years, as the age group 
needed to be sufficiently bothered by urinary incontinence to be in line with the adult 
indication of urinary incontinence due to NDO.  However, 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.  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. 
The doses selected in this pediatric study provide a sufficient range to assess dose-response 
while not exceeding the adult dose of 200 U BOTOX.  In addition, an upper cap of 
6 U/kg BOTOX is in place to ensure maintenance of a safety margin based on nonclinical 
studies.  There are data from published literature in which doses above those proposed in this 
study have been used in the pediatric population (eg, 300 U and 10 U/kg [Gamé et al, 2009; 
Sager et al, 2012]).  However, dose-ranging studies in the pediatric NDO population have not 
been conducted and it would not be appropriate to exceed the dose for the adult indication ie, 
200 U. 

 
 
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2 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
The objectives of this study are to evaluate the 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 (1 or more of the treatment groups) has an acceptable safety profile when injected 
into the detrusor of patients 5 to 17 years of age with NDO.  BOTOX (1 or more of the 
treatment groups) improves the symptoms of NDO as measured by a reduction from baseline 
in daytime urinary incontinence episodes. 
3 
Study Design 
This is a multicenter, randomized, double-blind, parallel group study to evaluate the efficacy 
and safety of BOTOX in patients with urinary incontinence due to NDO who are 5 to 17 
years of age.  Patients will be evaluated during a screening period for eligibility.  Eligible 
patients will be randomized and receive treatment on day 1.  Patients will be centrally 
randomized and assigned a randomization number prior to treatment in a 1:1:1 ratio to 
receive a single treatment of 50, 100, or 200 U BOTOX (not to exceed 6 U/kg).  
Randomization will be stratified by age (< 12 years or ≥ 12 years) and baseline daytime 
urinary incontinence episodes (a total of ≤ 6 episodes or > 6 episodes over the 2-day bladder 
diary collection period).  The study medication will be administered via cystoscopy as 
20 intradetrusor injections of 0.5 mL each, sparing the trigone.  
Patients will have posttreatment follow-up clinic visits at weeks 2, 6, and 12.  Thereafter, 
patients will have alternating telephone and clinic follow-up visits every 6 weeks until they 
exit the study.  Patients exit the study once they qualify for retreatment, or at week 48 if the 
patient never qualifies for retreatment.  Request for retreatment can occur at any scheduled 
clinic or telephone visit or between scheduled visits from week 12 onwards, and then that 
clinic visit will also become the qualification for retreatment visit.  If the patient qualifies for 
retreatment they will exit the study, so the visit at which the patient qualifies for retreatment 
will also become the exit visit.  In addition, request for retreatment can occur at a scheduled 
telephone visit or between scheduled visits after week 12; if this occurs a qualification for 
retreatment clinic visit should occur within 1 to 2 weeks (which then also becomes the exit 
visit if the patient qualifies for retreatment). 

 
 
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The primary efficacy measure is daytime urinary incontinence episodes, and the primary 
timepoint is week 6. 
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 
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 102 patients will be randomized at approximately 35 to 45 sites in order to 
have an estimated 90 patients (30 per treatment group) based on an anticipated dropout rate 
of 10% by the primary timepoint of week 6. 
4.2 
Study Population Characteristics 
This study will include patients 5 to 17 years of age with urinary incontinence due to NDO 
who have not been adequately managed with anticholinergics. 
4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
 
 
 
 
 
 
 
3. male or female, aged ≥ 5 years to ≤ 17 years of age at the time of informed consent 

 
 
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7. patient must be regularly using CIC to empty the bladder 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
 
 
2. patient has had surgery of the spinal cord within 6 months of screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. patient has cerebral palsy 

 
 
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8. patient currently uses or plans to use a baclofen pump 
9. patient currently uses or plans to use an implantable or nonimplantable 
electrostimulation/neuromodulation device for treatment of NDO.  (If a 
nonimplantable device is used, it must be discontinued at least 7 days prior to the first 
screening procedure; if a device is implanted, it must be inactive for at least 4 weeks 
prior to the first screening procedure; neither should be used during the study). 
10. patient uses 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) 
11. patient has had previous or current: 
• botulinum toxin therapy of any serotype for any urological condition, or  
• treatment with botulinum toxin of any serotype within 3 months of 
randomization/day 1 for any other condition or use 
 
 
 
 
 
 
 

 
 
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19. patient has any medical condition that may put them at increased risk with exposure to 
BOTOX including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or 
amyotrophic lateral sclerosis 
 
 
 
 
 
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. 
Patients who are using anticholinergic medication at baseline should continue to take their 
anticholinergic medication at the same dose throughout the study (except intravesical 
anticholinergics which are prohibited within 4 weeks of screening and throughout the study). 

 
 
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Refer to Section 5.9.3 for information on permitted study treatment anesthesia. 
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 must 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 must 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. 
Patients who were not using anticholinergic medication at baseline should not use 
anticholinergic medication for the duration of the study.  The use of intravesical 
anticholinergic therapy is prohibited within 4 weeks of the start of screening and throughout 
the study.  The use of other medications or therapies, other than anticholinergics, to treat the 
symptoms of NDO within 7 days of the start of the screening period procedures and during 
the study is also prohibited.  
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. 

 
 
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Administration of intravesical capsaicin or resiniferatoxin is prohibited during the study. 
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 at least 4 weeks 
prior to the first screening procedure; if a nonimplantable device is used, it must be 
discontinued at least 7 days prior to the first screening procedure. 
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 

 
 
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calculated median lethal intraperitoneal dose (LD50) in mice.  The study medication will be 
reconstituted with 0.9% sodium chloride (preservative-free). 
5.2 
Control Treatment 
There is no control treatment in this study. 
5.3 
Methods for Blinding 
The study medication will be packaged and labeled in identically appearing vials and 
reconstituted by an independent drug reconstitutor (IDR) who is not associated or involved 
with a study patient’s care or study assessments, with the exception of study medication 
preparation.  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 
Patients will be randomized centrally and assigned a randomization number prior to 
treatment.  In addition, patients will be stratified by age (< 12 years or ≥ 12 years) and by the 
number of daytime urinary incontinence episodes reported at baseline (a total of ≤ 6 or 
> 6 episodes over the 2-day diary).  One randomization number will be assigned to each 
patient prior to treatment and will be associated with 50, 100, or 200 U BOTOX in a 1:1:1 
ratio. 
5.5 
Method for Assignment to Treatment Groups/Randomization 
Following the screening period, patients who meet the study inclusion/exclusion criteria and 
the day of treatment criteria (see Section 5.9.1) will be assigned a randomization number 
through the interactive voice response system (IVRS)/interactive web response system 
(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. 
5.6 
Treatment Regimen and Dosing 
All eligible patients enrolled into the study will receive a double-blind treatment of 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). 
Treatment will be administered following randomization on day 1 and fulfillment of all the 
“day of treatment criteria” (see Section 5.9.1).  Patients will exit from the study once they 

 
 
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have qualified for retreatment (see Section 5.10.1 for details of qualification for retreatment 
criteria), and retreatment will be administered in the extension study (191622-121) for those 
patients who elect and qualify to enroll.  If patients do not qualify for retreatment during 
48 weeks following randomization/day 1, they will exit from the study; these patients may 
also enroll into the extension study at this visit. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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.  Instructions for the reconstitution and 
preparation of study medication are 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. 
5.9 
Treatment Administration 
5.9.1 
Day of Treatment Criteria 
The following “day of treatment criteria” must be fulfilled prior to the administration of 
study medication: 

 
 
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• 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 treatment 
5.9.2 
Prophylactic Antibiotics 
All patients must receive prophylactic antibiotics prior to treatment administration on 
randomization/day 1.   
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). 
 
 
  
 
 
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.  

 
 
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• 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 by an appropriately qualified 
anesthesiologist; 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 by an appropriately qualified 
anesthesiologist; however the use of neuromuscular blocking agents is not 
permitted 
o local anesthesia to the bladder wall (with or without sedation) will be via 
the 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) 
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 have been identified 
(eg, during the screening period or at the time of injection).  

 
 
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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 drug 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. 
5.9.5 
Autonomic Dysreflexia 
Patients with a spinal injury at thoracic level T5/6 or above or a 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 remain in the study until they qualify for retreatment.  Once patients have qualified 
for retreatment they will exit this study (so the clinic visit where they qualify for retreatment 
also becomes the exit visit).  Patients will have the opportunity to enter the extension study 

 
 
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where the retreatment administration will occur for patients who elect and qualify to enroll.  
Patients who never qualify for retreatment will exit the study at the week 48 visit, and will 
also have the opportunity to enter the extension study at this visit. 
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 parent/patient/caregiver. 
Patients/parents/caregivers can request retreatment at any scheduled clinic visit from week 12 
onwards, (ie, at a week 12, 24, 36, or 48 clinic visit), at a scheduled telephone visit (ie, at a 
week 18, 30, or 42 telephone visit), or between scheduled visits.  If the request is made at a 
scheduled clinic visit and all “qualification for retreatment criteria” are fulfilled, that visit 
then becomes a qualification for retreatment visit and the additional procedures will be 
performed.  If the request occurs at a scheduled telephone visit or between visits, a 
qualification for retreatment clinic visit should be conducted within approximately 1 to 
2 weeks of the request and the “qualification for retreatment criteria” should be assessed 
prior to performing any other procedures.  The reason for the request will be collected. 
In order to qualify for retreatment, the criteria listed below must be fulfilled at the 
qualification for retreatment visit: 
• Patient/parent/caregiver requests retreatment  
• patient has a total of at least 2 daytime urinary incontinence episodes over the 2-day 
bladder diary collection period 
• at least 12 weeks has elapsed since treatment 1 
• patient has not experienced a serious treatment-related adverse event at any time 
6 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
The primary efficacy measure is the number of daytime urinary incontinence episodes as 
recorded in the 2-day bladder diary during the week preceding each study visit.  The primary 
timepoint is week 6 after treatment. 

 
 
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6.1.2 
Secondary Efficacy Measures 
There are several urodynamic secondary efficacy measures; a central reviewer will determine 
the final value. 
• MCC (mL) 
o the MCC will also be presented as a proportion of the expected bladder 
capacity (EBC), where EBC is calculated as:  (30 + [age in years × 30]) 
for patients who have volumes below the adult volume of 500 mL (age is 
at the time of the assessment) (Nevéus et al, 2006) 
• presence or absence of an IDC 
• if an IDC is present, maximum detrusor pressure during the first IDC 
(PdetMax1stIDC) (cm H2O) 
• maximum detrusor pressure during the storage phase (PdetMax) (cm H2O) 
• if a leak occurs, detrusor leak point pressure (DLPP) (cm H2O) 
• urine volume at first morning catheterization (mL) 
• presence or absence of night time urinary incontinence 
In addition, the following duration of effect measures are considered secondary efficacy 
measures: 
• time to patient request and 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  
Screening procedures can commence once the parental/legal guardian consent, minor assent, 
and data authorization/protection forms have been obtained; screening will be considered to 
have started (eg, day -28) at the time of the first screening activity or procedure.  On 
completion of screening, when all the required inclusion/exclusion and “day of treatment 
criteria” have been met, the patient will be randomized (day 1) and 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). 
6.3.2 
Medical History 
The patient’s medical history (all history occurring in the past year and all other relevant 
history, in the investigator’s opinion), including diagnosis or symptom, date of onset, current 
status, and associated surgical procedures (including name of procedure and date of surgery) 
will be documented.  In addition, the presence or absence of the following baseline 

 
 
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characteristics will be collected:  detrusor sphincter dyssynergia, bladder sensation with 
filling, fecal incontinence, and ambulatory status. 
The number of UTIs in the 6 months prior to screening will be documented. 
6.3.3 
Physical Examination 
The physician or appropriately qualified designee will examine the patient for any physical 
abnormalities of the following body systems at screening and exit:  general appearance, 
HEENT (head, eyes, ears, nose, throat), heart/cardiovascular, lungs, abdomen, neurologic, 
extremities, back, musculoskeletal, lymphatic, skin, genitourinary, and other findings. 
6.3.4 
Weight and Height 
Weight and height should be measured using a calibrated scale and measuring tape/ruler 
according to local site practice.  Weight or height reported by the patient, parent, or legally 
authorized representative will not be acceptable.  
Weight and height will be measured during the screening period (which for this evaluation 
can include prior to randomization on day 1) and, if the patient qualifies for retreatment, at 
the qualification for retreatment clinic visit. 
For patients who do not enter the extension study, weight and height will be measured at the 
exit visit of the current study (191622-120). 
6.3.5 
Vital Signs 
Vital signs will be measured at each study clinic visit prior to any invasive procedures as 
outlined below.  The same procedure used for a patient should be used throughout the study. 
Pulse rate (beats per minute):  patients should be resting for at least 3 minutes.  Pulse rate is 
then counted over 30 seconds and multiplied by 2. 
Blood pressure (mm Hg):  the correct size blood pressure cuff for the size of the patient 
should be used.  Patients should be resting for at least 3 minutes.  Systolic/diastolic blood 
pressure is then measured with a sphygmomanometer. 
Respiration rate (breaths per minute):  patients should be resting for at least 3 minutes.  
Respiration rate is counted over 30 seconds and multiplied by 2. 

 
 
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Temperature (ºF or ºC):  patients should be rested and the body temperature taken according 
to local site practice (oral, axillary, or tympanic). 
Vital signs will be compared to age-appropriate normative values. 
6.3.6 
Bladder Diary 
Patients/parents/caregivers will collect bladder diary data 
 
 
 
.  For screening, the bladder diary can be completed
 
.  The same person(s) 
(patient or parent(s)/caregiver) should complete the bladder diary throughout the study where 
possible.  For example, if the patient is able to complete the bladder diary themselves during 
the screening period, they should complete it 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 bladder diary will capture the following information: 
• day/date, time, and type (urinary incontinence, catheterization, voluntary void) of each 
voiding episode during the daytime (time between waking up to start the day and going to 
bed to sleep for the night) 
• volume of urine on catheterization at morning wakening 
• time of night sleep and morning wakening 
• whether urinary incontinence occurred during the night 
More detailed instructions on the patient bladder diary will be provided to the patient and 
parent/caregiver. 
The diary data will be used to satisfy eligibility requirements for study entry, as well as for 
qualification for retreatment. 
6.3.7 
Urodynamic Testing 
Urodynamic testing will be standardized across all study sites (Attachment 12.3) and 
performed during the 
 
 

 
 
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Patient eligibility with regard to the presence of an IDC will be determined by the 
investigator from either the urodynamics procedure performed during the screening period or 
from a historical urodynamic evaluation. 
Urodynamic data will be reviewed by an independent central reviewer to determine final 
values for analysis purposes for the parameters listed below.  The principal investigator, 
subinvestigator, or trained technician will perform urodynamic procedures on each patient, 
then interpret and record the results on the calculation worksheet.  A copy of the worksheet, 
along with the printed tracings will be submitted to the central reviewer.  If the central 
reviewer’s interpretation of the results differs from that of the investigator, the central 
reviewer’s results will be used for final analysis.  Study sites will not typically be informed 
of any differences between their urodynamic values and the urodynamic values determined 
by the central reviewer.  However, study sites may receive feedback and/or retraining if data 
validity is uncertain, if persistent methodological issues arise, or if a data value needs to be 
rechecked/reconfirmed by the site. 
The following urodynamic parameters are to be measured: 
• MCC (mL) 
• presence or absence of an IDC 
• if an IDC is present, PdetMax1stIDC (cm H2O) 
• Pdetmax (cm H2O) during storage 
• if leak occurs, DLPP (cm H2O) 
Refer to Attachment 12.3 for the standardized urodynamic procedure.  Related forms will be 
provided in the Study Procedure Manual. 
6.3.8 
Bladder and Kidney Ultrasound 
Ultrasound of the bladder and kidneys 
 
  For the screening 
ultrasound only, bladder wall thickness will be determined.  For this measurement, the 
bladder will be filled to ≥ 50 to 90% of the age-expected bladder capacity, or the bladder 
capacity prior to leakage. 

 
 
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If the patient qualifies for retreatment, an ultrasound of the bladder and kidneys will also be 
performed at the qualification for retreatment clinic visit.  In addition, for patients who do not 
enter the extension study, a bladder and kidney ultrasound will be performed at the exit visit. 
In the case of unclear new findings suggestive of stones (kidney, ureter, or bladder), other 
diagnostic measures must be performed to confirm the presence of stones (eg, x-ray with or 
without contrast, urogram, computed tomography scan, magnetic resonance imaging, or 
cystoscopy).  Treatment should not be administered if bladder stones are identified. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
6.3.10 
Hematology and Clinical Chemistry 
A blood sample for hematology and nonfasting clinical chemistry assays by a central 
laboratory will be taken at the time the IV line is started for general anesthesia on day 1 prior 
to treatment administration (if no general anesthesia is to be administered a blood sample is 
taken prior to randomization/treatment).  A blood sample will also be taken 
 
.  
Analytes will be obtained as specified below, except for the week 12 sample where only 
complete blood count, blood urea nitrogen (BUN), and creatinine will be obtained: 
• hematology:  hemoglobin, hematocrit, RBC count, RBC morphology, WBC count, 
neutrophils, bands, lymphocytes, monocytes, basophils, eosinophils, and platelets 

 
 
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• blood chemistry:  glucose, creatinine, BUN, total bilirubin, aspartate aminotransferase/ 
serum glutamic oxaloacetic transaminase, alanine aminotransferase/serum glutamic 
pyruvic transaminase, alkaline phosphatase, uric acid, sodium, potassium, bicarbonate 
(carbon dioxide content), chloride, phosphorus, calcium, magnesium, and total protein 
Laboratory results will be compared to age-appropriate normative values. 
6.3.11 
Renal Function Testing 
Renal function will be monitored by Allergan from an estimate of the glomerular filtration 
rate (eGFR) determined from the serum creatinine levels 
 
 
The calculation of eGFR will be based on the formula of Schwartz and Work (2009) as 
follows: 
eGFR = 0.41 × height (cm)/serum creatinine (mg/dL) 
For eGFR 
the height values used in the calculation will be based 
on values collected at screening.  At study exit, the height values used in the calculation will 
be based on values collected at exit. 
6.3.12 
Immunogenicity Testing 
Blood samples for immunogenicity testing will be collected 
 
 
Serum samples will be collected and stored 
 
 
 
 
A 2-step process will be used for the detection of binding and neutralizing antibodies to 
BoNT/A.  In step 1, serum samples will be screened for reactivity using a validated 
enzyme-linked immunosorbent assay (ELISA) to determine the presence of toxin-binding 
antibodies.  In step 2, only samples from subjects which were considered positive for 
toxin-binding antibodies in the ELISA will be tested for neutralizing antibodies to BOTOX.  
This will be done using a validated mouse protection assay (MPA). 

 
 
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6.3.13 
Pregnancy Test 
Urine pregnancy testing will be performed during the screening period on females who are 
postmenarche, 
.  A negative 
result is required prior to receiving study medication. 
6.3.14 
Health Outcome Measures 
The PinQ is completed 
 
  The Modified TBS is completed at
 
  
Questionnaires should be completed prior to the patient undergoing any procedure for any 
study visit and prior to study treatment and will completed as detailed 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. 
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, urine culture and sensitivity) 
• containers to measure volume of urine at first morning catheterization  
• patient bladder diaries 
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 

 
 
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• 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 
• flexible or rigid cystoscope with injection port and needles for injection 
• all necessary equipment to measure the required urodynamic parameters 
• ultrasound for kidney and bladder assessment 
 
 
 
 
 
 
 
 
 
• internet connection (high-speed connection) for eCRF completion 
6.5 
Summary of Methods of Data Collection 
An IVRS/IWRS will be used to screen, randomize, and manage the 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.  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 statistical analysis will be conducted when all patients have completed or exited the 
study.  Throughout the entire study, both patients and investigators will remain blinded to 
treatment.  A detailed statistical analysis plan will be finalized prior to the study database 
lock. 
7.1 
Analysis Populations 
Two different populations will be defined for the statistical analysis:  safety and modified 
intent-to-treat (mITT). 
The safety population will include all patients who undergo the treatment procedure and 
receive study drug on randomization/day 1 and will be analyzed on an as-treated basis 

 
 
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(ie, using the dose actually received with all patients allocated to the nearest dose group 
[50, 100, or 200 U BOTOX]). 
The mITT population will include all randomized patients who received treatment on 
randomization/day 1 and will be analyzed on an as-randomized basis, except for patients who 
received less than their randomized dose due to the limit of 6 U/kg, as they will be grouped 
to the nearest dose group (50, 100, or 200 U BOTOX) based on the dose actually received.  
Demographics, baseline characteristics, and efficacy variables will be analyzed using the 
mITT population. 
 
7.2 
Collection and Derivation of Primary and Secondary Efficacy 
Assessments 
The primary 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 and during the screening period. 
In addition, the bladder diary will be used to record the following secondary efficacy 
assessments: 
• urine volume at first morning catheterization (mL) 
• presence or absence of night time urinary incontinence 
There are several urodynamic secondary efficacy assessments obtained from the 
urodynamics performed at week 6 and during the screening period; a central reviewer will 
determine the final value. 
• MCC (mL) 
• presence or absence of an IDC 
• if an IDC is present, PdetMax1stIDC (cm H2O) 
• PdetMax (cm H2O) during storage 
• if leak occurs, DLPP (cm H2O) 
Visit windows for the analysis at each timepoint will be defined in the statistical analysis 
plan. 

 
 
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7.2.1 
Primary Efficacy Variable  
The primary efficacy variable is the change from baseline posttreatment in the 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, and 
baseline frequency is defined as the daily average frequency of episodes of daytime urinary 
incontinence preceding the study treatment.  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 primary timepoint will be week 6 posttreatment. 
For the baseline and posttreatment data, a patient must have at least 1 valid diary day 
(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, then the frequency of daytime urinary 
incontinence will be considered as missing.  Missing frequency of episodes of daytime 
urinary incontinence at baseline will be imputed using the median of all nonmissing values at 
baseline within the same treatment group.  For the scheduled visits up to week 6 after the 
study treatment, missing frequencies of episodes of daytime urinary incontinence will be 
replaced using the last observation carried forward approach.  No imputation will be done for 
missing values on visits after the week 6 visit. 
7.2.2 
Secondary Efficacy Variables 
There are 7 secondary efficacy variables assessed at the week 6 primary timepoint: 
• change from baseline in MCC (mL) 
• presence or absence of an IDC 
• if an IDC is present, change from baseline in PdetMax1stIDC (cm H2O) 
• change from baseline in PdetMax (cm H2O) 

 
 
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• change from baseline in DLPP (cm H2O) 
• change from baseline in average urine volume at first morning catheterization (mL) 
• presence or absence on night time urinary incontinence 
No imputation will be done for the missing values of the secondary efficacy variables.  For 
the urodynamic secondary variables (MCC, presence/absence of an IDC, PdetMax1stIDC, 
PdetMax, and DLPP), the values provided by the central reviewer will be used.  
The average urine volume at first morning catheterization will be calculated from the values 
recorded in the bladder diary.  Similarly the presence/absence of night time urinary 
incontinence will be based on the response to the question asked each morning in the diary as 
to whether the patient had urinary incontinence during the night. 
7.3 
Hypothesis and Methods of Analysis 
All data will be summarized with descriptive statistics and/or frequency tables.  Categorical 
variables will be analyzed using Fisher’s exact test, Pearson’s chi-squared test, or 
Cochran-Mantel-Haenszel (CMH) methods, as appropriate.  Continuous variables will be 
analyzed using analysis of variance (ANOVA) or analysis of covariance (ANCOVA), as 
appropriate.  For the evaluation of efficacy analysis described below, a 2-sided test with a 
p-value ≤ 0.05, unadjusted for multiplicity, will be considered statistically significant, unless 
specified otherwise. 
7.3.1 
Primary Efficacy Analyses 
The primary efficacy analysis will be based on the mITT population, with imputation of 
missing values as described in Section 7.2.1.  The primary timepoint will be week 6 after 
treatment. 
For each of the BOTOX doses, descriptive statistics will be provided for the daily average 
frequency of daytime urinary incontinence episodes at baseline and week 6, together with the 
change from baseline (arithmetic mean and least-squares [LS] mean); the 95% confidence 
intervals (CI) of the arithmetic and LS mean change will be provided. 
For each of the BOTOX doses of 200 U and 100 U, the null hypothesis is that there is no 
difference between that dose group and the 50 U BOTOX dose group in mean change from 
baseline in daily average frequency of daytime urinary incontinence episodes at week 6.  The 
alternative hypothesis is that there is a difference in mean change from baseline in daily 

 
 
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average frequency of daytime urinary incontinence episodes between that BOTOX dose 
group and the 50 U dose group at week 6. 
The hypotheses will be tested using an ANCOVA model with baseline value as covariate and 
treatment group, age (< 12 years or ≥ 12 years), baseline daytime urinary incontinence 
episodes (a total of ≤ 6 episodes or > 6 episodes over the 2-day diary collection period), and 
concurrent anticholinergic therapy (use or nonuse) as factors. 
A hierarchical analysis strategy (Lubsen and Kirwan, 2002) will be used to control type I 
error due to the multiplicity issues related to the primary efficacy analyses for the primary 
efficacy variable.  In the order of (1) 200 U versus 50 U BOTOX, and (2) 100 U versus 
50 U BOTOX, treatment group differences will be tested at the 0.05 significance level in a 
fixed sequence fashion.  Results of hypothesis testing for 100 U versus 50 U BOTOX will be 
considered for statistical significance only if the treatment difference for 200 U versus 50 U 
BOTOX is shown to be statistically significant. 
The treatment difference in mean change from baseline for 200 U versus 50 U BOTOX and 
100 U versus 50 U BOTOX will be calculated, as well as the 95% CI of these differences. 
The treatment-by-investigator interaction will be assessed. 
7.3.2 
Secondary Efficacy Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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7.3.2.2 
Efficacy Analyses for the Secondary Efficacy Variables 
The analysis of MCC, PdetMax, and average urine volume at first morning catheterization at 
week 6 after treatment will generally be analyzed as described for the primary efficacy 
endpoint in Section 7.3.1, except that the hierarchal testing strategy will not be implemented.  
For the urodynamic variables, only the central reviewer’s interpretation will be analyzed. 
For analysis of MCC, data will also be presented as a proportion of the EBC, where 
EBC = (30 + [age in years × 30]) for volumes below the adult volume of 500 mL (age is at 
the time of the assessment). 
The proportions of patients with presence/absence of an IDC at week 6 will be presented and 
analyzed using the CMH method (200 versus 50 U BOTOX and 100 versus 50 U BOTOX) 
controlling for age (< 12 years or ≥ 12 years), baseline daytime urinary incontinence episodes 
(a total of ≤ 6 episodes or > 6 episodes over the 2-day diary collection period), and 
concurrent anticholinergic therapy (use or non-use). 
For the analysis of night time urinary incontinence, the numbers and proportions of patients 
who experienced night time urinary incontinence on 0, 1, or 2 nights will be presented. 
Analysis of time to patient request for retreatment and time to patient qualification for 
retreatment will be performed as described in Section 7.3.3.4 Duration of Effect. 

 
 
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AUC = area under the curve 
 
 
 
 
. 
7.3.3.4 
Duration of Effect 
A preliminary estimate of duration of treatment effect will be assessed on completion of this 
study (on completion of the extension study, a further estimate will be presented using data 
integrated across both studies).  Time from treatment on day 1 to request for retreatment will 
be estimated using the Kaplan-Meier survival method for each treatment group.  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 during 
the study and the median duration by days/weeks 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 safety population.  Safety variables are adverse 
events, serious adverse events,
 
 
 
  
 
 
 
 
 
 
   

 
 
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7.5 
Sensitivity Analysis 
Sensitivity analyses of the primary efficacy variable, using both the PP population and the 
median imputation method for the mITT population will be performed.  Missing values will 
be imputed by using the median of the nonmissing values within the same treatment group at 
the same timepoint. 
In addition, the change from baseline and responder analyses previously described using the 
normalized daily average frequency of daytime urinary incontinence episodes will also be 
conducted without the normalization of the variable to a 12-hour daytime period. 
7.6 
Subgroup Analyses 
The primary efficacy analysis will be presented by investigator site as well as by key 
demographic or baseline characteristics, including concurrent anticholinergic therapy (use 
and nonuse), baseline daytime urinary incontinence episodes (a total of ≤ 6 episodes or 
> 6 episodes over the 2-day diary collection period), age (< 12 years or ≥ 12 years), race, and 
sex. 
7.7 
Sample Size Calculation 
The sample size calculation for this study is determined empirically, while taking into 
account the treatment effect observed in the adult pivotal phase 3 studies, 191622-515 and 
191622-516.  The mean (standard deviation) of the change from baseline in daily urinary 
incontinence at week 6 was -3.1 (3.44) and -3.1 (2.58) in Studies 191622-515 
and 191622-516, respectively. 
Approximately 34 patients per treatment group are to be enrolled for the study.  This includes 
30 patients per treatment group and an increase to 34 per group in order to address patient 
attrition (estimated to be 10% by week 6)  
The following table displays estimates of the distance for treatment differences between 
BOTOX 200 U (maximum 6 U/kg) and 50 U (maximum 6 U/kg) in mean daily average 
frequency of daytime episodes of urinary incontinence change from baseline at week 6 for a 
range of common standard deviations (SD).  All calculations assume 30 patients per 
treatment group and a 2-sided test significance level of 0.05.  The calculation was performed 
using the commercial software nQuery Advisor (procedure MTC0-1), version 6.01, and the 
CI is based on the large sample z statistic. 

 
 
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Standard Deviation 
Distance From Mean to the Limit 
2.0 
1.012 
2.5 
1.265 
3.0 
1.518 
3.5 
1.771 
4.0 
2.024 
 
Note:  The ranges of the SDs are determined based on the values from the adult pivotal phase 
3 studies (191622-515 and 191622-516).  The estimate of the SD for the 200 U BOTOX 
treatment group is 3.44 for Study 191622-515, 2.58 for Study 191622-516, and 3.10 for the 
2 studies combined. 
7.8 
Interim Analyses 
No interim analysis is planned for this study. 
8 
Study Visit Schedule and Procedures 
Please see Table 1 for a schematic of the schedule of visits and procedures, Figure 1 for the 
visit flow chart, and Section 6.3 for detailed information on study procedures, tests, 
equipment, and techniques. 
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. 
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. 
Further information is provided in Section 10.1. 

 
 
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Each patient who provides informed consent and/or assent will be assigned a patient number 
via IVRS/IWRS that will be used on patient documentation throughout the study. 
8.2 
Procedures for Final Study Entry 
Final study eligibility will be determined at 
 to confirm that 
patient bladder diary records support protocol requirements for urinary incontinence.  In 
addition, prior to randomization, the investigator should confirm that the day of treatment 
criteria have been fulfilled (Section 5.9.1).  Patients should continue to meet other inclusion 
and exclusion criteria as specified in Sections 4.3 and 4.4 of the protocol. 
A patient is considered to have entered the study when they are randomized to treatment. 
See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.3 
Visits and Associated Procedures 
For a summary of the procedures to be performed, 
 
  A description of individual procedures is provided in Section 6.3.  The total 
number of clinic visits and study duration for each patient will depend on whether patients 
request and qualify for retreatment.  Evaluations should be performed by the same evaluator 
throughout the study whenever possible.  
 
 
8.4 
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 

 
 
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• 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 
8.5 
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 
and well being of patients during the study.  eCRFs will be completed for each unscheduled 
visit.   
8.6 
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 (nonstudy 
procedures), and their compliance with the protocol since the previous visit. 
8.7 
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 
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8.8 
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) 
• patient/parent/caregiver is unwilling or unable to continue to comply with study 
procedures 
8.9 
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. 
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) 

 
 
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product.  In addition, during the screening period, adverse events will be assessed regardless 
of the administration of a pharmaceutical 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. 
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. 
 
 
 
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. 

 
 
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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). 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) 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 
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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. 
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.

 
 
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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.   
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. 

 
 
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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.  
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 

 
 
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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 enrollment into the study, 
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. 
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 
(European sites only), or other country and local patient privacy required 
documentation for this study has been obtained (including the date) 
• date that the patient was randomized into the study, patient number, patient 
medication kit number, and date and details of study drug administration 
• study title and/or the protocol number of the study and the name of Allergan 
• dates of all patient visits and date of any request for retreatment 

 
 
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• 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  
• the results of laboratory tests performed by the site (eg, urine pregnancy test) 
• urodynamic tracings  
• 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 
 
 
 
 
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 

 
 
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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. 
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 
 
 
  
 
 

 
 
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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. 
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,
will be 
analyzed at a centralized clinical laboratory with certification from a recognized accreditation 
agency (eg, College of American Pathology [CAP] or Clinical Laboratory Improvement 
Amendments [CLIA] 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. 

 
 
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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(6);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(4):803-807. 

 
 
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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 
overactivity:  a randomised, double-blind, placebo-controlled trial.  Eur Urol.  2011;60(4): 
742-750. 
Gamé X, Mouracade P, Chartier-Kastler E, Viehweger E, Moog R, Amarenco G, et al.  
Botulinum toxin-A (Botox®) intradetrusor injections in children with neurogenic detrusor 
overactivity/neurogenic overactive bladder:  a systematic review.  J Pediatr Urol.  
2009;5:156-164. 
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(1):78-82. 
Lubsen J and Kirwan B-A.  Combined endpoints:  can we use them?  Statistics in Medicine.  
2002;21(19):2959–2970. 
McGuire EJ, Woodside JR, Borden TA, Weiss RM.  Prognostic value of urodynamic testing 
in myelodysplastic patients.  J Urol.  1981;126(2):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. 
Sager C, Burek C, Durán V, Corbetta JP, Weller S, Bortagaray J, et al.  Pharmacotherapy in 
pediatric neurogenic bladder intravesical botulinum toxin type A.  ISRN Urology.  2012; 
2012:article ID 763159, 6 pages. 
Schwartz GJ, Work DF.  Measurement and estimation of GFR in children and adolescents.  
Clin J Am Soc Nephrol.  2009;4:1832-1843. 

 
 
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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 
January 14, 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 
12.1 
Preparation of Study Medication 
12.2 
Study Treatment 
12.3 
Urodynamic Procedure 
 
 
12.5 
Glossary of Abbreviations 
12.6 
Protocol Amendment 1 Summary 
12.7 
Protocol Amendment 2 Summary 
12.8 
Protocol Amendment 3 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 the 191622-120 Pharmacy Manual. 
 

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

 
 
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12.3 
Urodynamic Procedure 
12.3.1 
Overview 
Urodynamic testing will be standardized across all participating study centers and 
consequently artifacts inherent in the procedure are minimized.  Urodynamics must be 
performed by the principal investigator, subinvestigator, or a trained technician, qualified to 
perform the procedure (ie, experienced in performing pressure/flow cystometry). 
The principal investigator, subinvestigator, or trained technician will perform the urodynamic 
procedure, then interpret and record the results on the calculation worksheet.  The worksheet 
should be completed to derive the values which are provided to the central reviewer.  The 
worksheet and the tracings must be signed and dated by the investigator or physician 
subinvestigator.   
12.3.2 
Central Reviewer Process 
A copy of the worksheet, along with the printed tracings will be submitted to the independent 
central reviewer.  The independent central reviewer will verify the results provided on the 
calculation worksheet.  If the central reviewer’s interpretation of the results differs from that 
received from the site, the central reviewer’s result will be used for final analysis.  Study sites 
will not be informed of any discrepancy between their determinations and the central 
reviewer’s determination.  However, study sites may receive feedback and/or retraining if 
data validity is uncertain or if persistent methodological issues arise. 
12.3.3 
Site Urodynamic Qualification 
To demonstrate that the urodynamic equipment and study site personnel are able to complete 
the urodynamic testing for central review as specified for this protocol, the tracing should be 
from a pediatric patient in a comparable age group (ie, 4 to 18 years old), using a 
tracing/graph showing detrusor overactivity and using the same annotation procedure as 
defined in this protocol.  This qualification tracing may be a tracing that the site has on file 
(after appropriate release has been obtained, if applicable, per local site practice) or may be a 
newly produced tracing, and should have anonymized patient identifiers.  The qualification 
tracing must be annotated 
In 
addition, an event summary, a completed calculation worksheet, and a transmittal form must 
be submitted with the sample tracing.  The central reviewer and Allergan will work with the 
sites to ensure the sample tracing is acceptable, and that applicable site personnel have 
received protocol-specific urodynamic training prior to the site being permitted to enroll 

 
 
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patients in the study.  Following approval of the sample tracing, subsequent urodynamic 
studies for this protocol must be performed in the same manner, using the same urodynamic 
equipment, and the submitted tracing should contain the same data points and annotations as 
the sample tracing (as applicable).  All efforts should be made for the same person to perform 
the urodynamics testing at a given site. 
If new urodynamics equipment is obtained and is intended to be used in this study a new site 
urodynamic qualification may need to be performed. 

 
 
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12.3.5 
Urodynamic Annotations 
All urodynamic parameters collected during pressure/flow cystometry must be annotated on 
the urodynamic tracing electronically so that the tracing is interpretable retrospectively by the 
independent central reviewer.  To ease interpretation, abbreviations should be standardized 
using the annotations below: 
Parameter 
Defined As: 
Standardized 
Tracing 
Annotation 
 
 
 
 
 
 
 
 
 
 
Maximum 
cystometric 
capacity  
Point when one of the following criteria is fulfilled: 
 
• 
First leakage is observed  
 
NOTE: 
o 
Annotate “MCC-IDC Leak” if occurs with an IDC 
o 
Annotate “MCC-DLPP” if occurs without an IDC 
 
• 
Patient indicates they can no longer delay micturition because 
of a strong desire to void, and is given the permission to void, 
OR patient indicates that they are too uncomfortable to 
continue the procedure (due to bladder filling) 
o 
NOTE:  The MCC will be considered to be the point 
at which the patient enters the voiding phase and is 
given permission to void.  It is also important to 
clearly annotate whether the void was volitional 
(voluntary void “VV”) 
 
• 
Precipitant void (terminal detrusor overactivity) is observed 
o 
NOTE:  If the patient has precipitant micturition ie, 
is about to leak (terminal detrusor overactivity), the 
MCC should be annotated at the start of the terminal 
contraction (this may need to be annotated 
retrospectively). 
 
• 
500 mL has been instilled into the bladder 
 
OR 
 
Infused volume is > 150% of expected bladder capacity 
(EBC), where EBC = (30 + [age in years × 30]) for volumes 
below the adult volume of 500 mL  
 
• 
In the opinion of the investigator, the patient’s safety is 
possibly compromised with further bladder filling (e.g., 
elevated bladder pressures, etc) 
 
MCC or 
MCC-IDC Leak, 
as applicable 

 
 
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Parameter 
Defined As: 
Standardized 
Tracing 
Annotation 
 
 
 
 
 
 
 
Maximum 
detrusor 
pressure during 
storage phase  
Point at which the maximum detrusor pressure in the Pdet channel is 
observed during the storage phase (eg, the greater of the amplitude of 
the strongest IDC, the terminal detrusor contraction, the pressure at the 
end of filling, or the highest pressure at any other time during the 
storage phase).   
o 
NOTE: If leakage occurs at PdetMax then this is MCC 
as well 
PdetMax 
Detrusor Leak 
Point Pressure 
The lowest detrusor pressure at which urine leakage occurs (if present) 
in the absence of either a detrusor contraction or increased abdominal 
pressure 
DLPP 
 
 
 
 

 
 
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12.3.7 
Urodynamic Procedure 
The procedure should be performed in accordance with the investigator’s usual practice and 
available equipment, while complying with the protocol requirements for the procedure and 
tracing.   
 
   

 
 
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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 
PdetMax1stIDC 
maximum detrusor pressure during the first IDC 
PdetMax 
maximum detrusor pressure during the storage phase 
PinQ 
Pediatric Incontinence Questionnaire 
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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12.6 
Protocol Amendment 1 Summary 
Title:  BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor 
Overactivity in Patients 8 to 17 Years of Age  
Protocol 191622-120 Amendment 1 
Date of Amendment:  October 2013 
Amendment Summary 
This summary includes changes made to Protocol 191622-120 (14 January 2013).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Protocol Title Page 
Removed emergency contact 
number 
This information is now included in a 
study specific contacts page. 
Investigator signature 
page 
Removed Study Location 
Added text indicating that the 
Investigator will ensure all 
participating personnel are 
adequately informed about the 
protocol 
Removed provision for multiple 
investigator signatures 
Global change to Allergan’s protocol 
template 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Section 
Revision 
Rationale 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
Clarified that indwelling 
catheters are permitted 
overnight if needed, but that 
indwelling catheterization is not 
permitted during diary 
collection periods 
 
 
 
 
 
The use of an indwelling catheter 
overnight is common practice in the 
patient population intended to be 
recruited to this study; therefore their 
use is allowed.  However, since the first 
morning catheterization urine volume is 
an efficacy parameter, as well as 
presence or absence of night time 
incontinence, indwelling catheters will 
not be allowed during diary collection 
periods. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Study Schedule 
(Table 1)/6.3.8  Bladder 
and Kidney Ultrasound  
Added requirement to measure 
bladder wall thickness by 
ultrasound at the screening visit 
Patients may have urinary bladder 
fibrosis which is linked with poor 
compliance.  Measurement of bladder 
wall thickness will allow for further 
characterization of the patient 
population being studied. 

 
 
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Section 
Revision 
Rationale 
4.5.1.1  Definition of 
Females of 
Childbearing Potential 
and Acceptable 
Contraceptive Methods 
Removed text relating to 
females becoming sexually 
active when postmenarche 
Females who are postmenarche are 
considered to be of childbearing 
potential in a biological context; 
therefore text removed 
5.9.4  Treatment 
Procedure 
Added text to clarify that 
patients should remain under 
observation at the clinic for 
longer than 30 minutes if local 
site practice requires this 
The protocol provides a minimum time 
period for observation after treatment; 
however, local site practice should take 
precedence if it requires a longer 
observation period. 
6.3.2  Medical History 
Clarified what relevant medical 
history should be collected and 
added a sentence to include the 
collection of the presence or 
absence of selected baseline 
characteristics 
This provides guidance for sites, and 
the collection of baseline characteristics 
will allow further characterization of 
the patient population being studied. 
6.3.4  Weight and 
Height 
Amended text to clarify when 
height and weight should be 
measured 
Clarifications provided to ensure that 
data are available when needed for 
certain calculations, eg, dose based on 
patient weight, estimate of glomerular 
filtration rate 
6.3.8  Bladder and 
Kidney Ultrasound 
Amended text to clarify when 
ultrasound is to be performed 
 
Clarification 
6.3.11  Renal Function 
Testing 
New section 
Renal function assessment (estimated 
glomerular filtration rate based on 
serum creatinine levels and patient 
height) was added based on Regulatory 
Agency feedback. 
7.4  Safety Analysis 
Addition of renal function 
assessment 
Renal function, as assessed by 
estimated glomerular filtration rate, is 
now a safety parameter. 
8.7  Early 
Discontinuation of 
Patients 
Clarification added in relation to 
follow up in patients who agree 
to follow-up after exiting the 
study early 
Clarification regarding time period of 
follow-up included based on 
Regulatory Agency feedback 
9.1.1  Adverse Event 
Additional text regarding the 
documentation of disease 
progression/lack of efficacy 
Global change to Allergan’s protocol 
template 
10.3.1  Patient Privacy 
and 10.4.2  Case Report 
Form Completion 
Amended wording 
To reflect global change to Allergan’s 
protocol template 

 
 
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Section 
Revision 
Rationale 
12.1.1  BOTOX 50 U 
12.1.2  BOTOX 100 U 
12.1.3  BOTOX 200 U 
Amended lower body weight 
range from 15 kg (33 lbs) to 
14 kg (31 lbs) 
Typographical error in original protocol 
12.3.3  Site 
Urodynamic 
Qualification 
Added clarification that the 
sample urodynamic tracing can 
be from a urodynamic 
assessment of a pediatric patient 
who is comparable in age to the 
age group of study participants 
and that traces will be 
anonymized 
To clarify sample tracing procedures 
and comply with patient privacy laws 
12.3.5  Urodynamic 
Annotation 
Added that first leakage can 
occur with or without an IDC 
and annotations should be 
reflected accordingly 
Clarification 
12.3.8  Parameters to be 
recorded on the 
worksheet 
Added volume at first IDC 
Additional measurement required for 
calculation worksheet 
12.5  Package Insert 
Removed section 
Global change to Allergan’s protocol 
template 
 
 
 

 
 
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12.7 
Protocol Amendment 2 Summary 
Title:  BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor 
Overactivity in Patients 5 to 17 Years of Age  
Protocol 191622-120 Amendment 2 
Date of Amendment:  April 2016 
Amendment Summary 
This summary includes changes made to Protocol 191622-120 (4 October 2013).   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Title and Study 
Population 
Changed minimum age to 5 
Updated patient inclusion criterion 
 
 
 
 
Inclusion criteria 
Reduced minimum age 
requirement from 8 years old to 
5 years old 
Expand age range for inclusion in the 
study. 
Section 5.9.1 
Day of Treatment Criteria:  
added “or presence of 
significant leukocyturia (e.g. ≥ 
30 WBC/HPF)” to the criteria 
which the investigator should 
consider when determining if 
the patient has a UTI 
 
To ensure patient safety, added that in 
addition to considering patient 
symptoms, urine culture results and the 
need for antibiotic treatment, the 
investigator should also consider the 
presence of clinically significant 
leukocyturia when determining if the 
patient has a UTI.  Also provided an 
example of clinically significant 
leukocyturia as ≥30 WBC/HPF. 
Section 5.9.3 
Use of Anesthesia:  added 
“which could include conscious 
sedation” 
For clarity 
Section 12.1 
Updated dosing table to add row 
for lower body weight 
To include dosing information for a 
younger patient population.  
 
 
 

 
 
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12.8 
Protocol Amendment 3 Summary 
Title:  BOTOX® in the Treatment of Urinary Incontinence Due to Neurogenic Detrusor 
Overactivity in Patients 5 to 17 Years of Age  
Protocol 191622-120 Amendment 3 
Date of Amendment:  September 2017 
Amendment Summary 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Sections 
Revision 
Rationale 
 
Synopsis 
Section 4.4: Number of 
Patients 
Section 7.7: Sample Size 
Calculation 
 
Decreased the sample size 
from N=132 to N=102 
Due to enrollment challenges, the 
sample size was recalculated.  While 
the revised sample size will provide a 
wider confidence interval than the 
current sample size, the proposed 
reduction should not negatively affect 
the clinical and scientific integrity of 
the study.  The FDA has concurred 
with this plan. 
 
Section 7.1: Analysis 
Populations 
Deleted Per-protocol 
population 
To reflect current company standard 
for not performing analyses on per-
protocol population for superiority 
trials. 
 
 

 
 
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