Clinical trial NCT01557244
Conditions: Urinary Bladder, Neurogenic
Keywords: neurogenic detrusor overactivity neurogenic bladder neuropathic bladder neurologic disease fesoterodine
Sponsor: Pfizer
Start date: 2012-07-02; Completion date: 2020-02-13
Enrollment: 181 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to find out if the medicine fesoterodine is a useful treatment in children with bladder muscle overactivity caused by a neurological condition. Children will be aged 6 to 17 years old. This is done by finding out how well it works, what the body does to fesoterodine, what side effects are experienced and the safety of fesoterodine. It will be compared with the medicine oxybutynin, which is already available for treating the condition.

Detailed description:

Arms: arm 1: Fesoterodine PR 4 mg for 12 weeks in active comparator period, followed by 12 weeks in safety extension period arm 2: Fesoterodine 8 mg for first week followed by 11 weeks at 8 mg in active control period, followed by 12 weeks in safety extension period. arm 3: Oxybutynin arm 4: Fesoterodine BIC 2 mg for 12 weeks in efficicay period, followed by 12 weeks in safety extension period. arm 5: Fesoterodine BIC 4 mg for first week followed by 11 weeks at 8 mg in the efficacy period, followed by 12 weeks in safety extension period.
Interventions: intervention 1: Fesoterodine PR 4 mg intervention 2: Fesoterodine PR 8 mg intervention 3: Fesoterodine PR 8 mg intervention 4: Oxybutynin intervention 5: Fesoterodine PR intervention 6: Fesoterodine BIC 2 mg intervention 7: Fesoterodine BIC 4 mg
Intervention descriptions: intervention 1: Fesoterodine 4 mg tablet once daily for 24 weeks intervention 2: Fesoterodine PR 8 mg tablet once daily for 24 weeks, the first week being 4 mg. intervention 3: Fesoterodine 8 mg tablet once daily for 24 weeks, the first week being 4 mg. intervention 4: Oxybutynin extended release tablets according to approved pediatric labeling for 12 weeks with dose titration phase for first 4 weeks to achieve dose optimisation. intervention 5: Fesoterodine 4 mg or 8 mg tablets once daily for 12 weeks after 12 weeks of oxybutinin. Those assigned to 8 mg will take 4 mg for the first week. intervention 6: Fesoterodine BIC 2 mg tablet once daily for 24 weeks. intervention 7: Fesoterodine BIC 4 mg tablet once daily for 24 weeks, with the first week being 2 mg.

Protocol documents:
Prot_000.pdf: 
Fesoterodine
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Protocol Amendment 5, 3 March 2014
Page 1
CLINICAL PROTOCOL
A 24-WEEK RANDOMIZED, OPEN-LABEL, STUDY TO EVALUATE THE 
SAFETY AND EFFICACY OF FESOTERODINE IN SUBJECTS AGED 6 TO 17
YEARS WITH SYMPTOMS OF DETRUSOR OVERACTIVITY ASSOCIATED 
WITH A NEUROLOGICAL CONDITION (NEUROGENIC DETRUSOR 
OVERACTIVITY)
Compound:
PF-00695838
Compound Name (if applicable):
Fesoterodine
US IND Number (if applicable):
European Clinical Trial Database 
(EudraCT) Number:
2010-022475-55
Protocol Number:
A0221047
Phase:
3
The name, title, address and telephone numbers of the sponsor’s medical expert for the trial 
is documented in the study contact list located on the web portal, 
(www.epharmasolutions.com/2326.html).
CCI


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Document History
Document
Version Date
Summary of Changes
Amendment 5
3 March 2014
To enroll subjects ≤25 kg as 
a separate cohort within the 
study who will be 
administered a beads-in-
capsule (BIC) formulation.
To specify a target of 
approximately 99 evaluable 
subjects at Week 12 for 
subjects > 25 kg.
To include the enrollment 
of subjects aged 17 years 
old.
To correct minor errors and 
update with current protocol 
template.
Amendment 4
02 October 2012 
Country-specific: France
(See Appendix 5)
The additional wording for the
exclusion criteria are:
The protocol will exclude 
patients who have had an 
endoscopic anti-reflux 
therapy in the previous 3 
months before Visit 2.
Patients who present with 
QTc interval prolongation, 
personal and family history 
of QTc interval 
prolongation, or pre-
existing and important 
cardiac diseases and present 
a risk of QT interval 
Prolongation (eg, 
hypokalemia) will be 
excluded.


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Protocol Amendment 5, 3 March 2014
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The additional specific
withdrawal criterion is:
That an endoscopic anti-
reflux therapy during the 
trial period is a criterion of 
premature exit from the trial
Minor QC/wording 
correction.
Amendment 3
11 January 2012
Rationale:
Update to various sections 
following new SOP CT02 
template, implemented 17 
November 2011.
PG sampling for oxybutynin 
subjects who continue into the 
safety extension phase.
Minor QC/wording corrections 
and updates.
Amendment 2
07 October 2011
Rationale:
Update to Section 15.1 
following new SOP CT02 
template, implemented 08 
September 2011.
Updates following FDA advice 
letter, including:  Vision testing, 
cognitive function testing, 
telephone call for all treatment 
groups at Week 1, Removal of 
PinQ, Laboratory evaluations at 
baseline, Week 12 and Week 24, 
PK sample collection at Week 4 
instead of Week 12.
Changes to wording for 
Oxybutynin supply and 
administration.
Various minor editorial changes.


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Protocol Amendment 5, 3 March 2014
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Amendment 1
27 April 2011
Rationale:
The protocol has been updated 
with the following:
Updates to SOP CT02 clinical 
protocol template, implemented 
08 November 2010 country 
feedback on the protocol (eg, 
acceptability of dose 
optimization assessments and 
standards of care) evaluation of 
risks related to study 
complexity, operationalizing and 
executing the protocol, in 
particular dose 
titration/optimization of the 
comparator (oxybutynin) 
decision to use electronic 
bladder diary and dosing log.
Updates made following review 
by FDA and Pfizer internal 
Technical Review Committee.
Administrative QC.
Original protocol
03 August 2010
N/A
These amendments incorporate all revisions to date, including amendments made at the 
request of country Health Authorities, IRB/IEC, etc.


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Protocol Amendment 5, 3 March 2014
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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures (Section 6) and Assessments (Section 7) for detailed information 
on each procedure and assessment required for compliance with the protocol.
Protocol Activity
Visit
1
Visit 
2
Phone 
Call 
all 
groups
q
Oxybutynin 
dose 
optimization
perioda,q
Visit 
3
Visit 
4q
Visit 
5b
Visit 
6q
Visit 
7c
Visit 
8
Screening Rand 
Phone Calls
Oxybutynin 
subjects
Feso 
PK & 
Fix 
Oxy 
dose
Phone 
call
Start of 
Extension
Phone 
Call
End of 
Treat-
ment 
Follow-up 
call
Day -30 
to 
Day -3
Day 1
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week
12
Week 
18
Week 24
Week 
26
Informed Consent & 
Assent
X
Demography
X
Medical History
X
Review Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
Child Behavior Check 
List (CBCL)
X
X
X
Grooved Pegboard test
X
X
X
Vital Signsd
X
X
X
X
X
Weight
X
X
X
X
Physical Examinationd
X
X
X
Visual acuity and 
accommodation
X
X
X
Post-void residual (PVR) 
urine volumee
X
X
X
X
X
Laboratoryf
Hematology
X
X
X
Blood Chemistry
X
X
X
Urinalysisg
X
X
X
X
Urine/Serum 
Pregnancy Testh
X
X
X
X
X
Pharmacokinetics (PK) 
blood samplingi
X
Pharmacogenomics (PG) 
blood samplingj
X
X
Urodynamic Studiesk
X
X
Dispense electronic data 
capture devicel
X
Collect/review electronic 
data capture devicem
X
X
X
X
Bladder diary 
Completion 
instructions
X


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Protocol Amendment 5, 3 March 2014
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Protocol Activity
Visit
1
Visit 
2
Phone 
Call 
all 
groups
q
Oxybutynin 
dose 
optimization
perioda,q
Visit 
3
Visit 
4q
Visit 
5b
Visit 
6q
Visit 
7c
Visit 
8
Screening Rand 
Phone Calls
Oxybutynin 
subjects
Feso 
PK & 
Fix 
Oxy 
dose
Phone 
call
Start of 
Extension
Phone 
Call
End of 
Treat-
ment 
Follow-up 
call
Day -30 
to 
Day -3
Day 1
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week
12
Week 
18
Week 24
Week 
26
Completion reminder 1
week before
X
X
Review bladder diaryn
X
X
Dosing log
Completion 
instructions
X
Review dosing logn,o
X
X
X
Xp
X
Xp
X
X
Study Medication 
Dispensed
X
X
X
Study Medication 
return/count
X
X
X
Assess Study Medication 
compliance
X
X
Oxybutynin dose 
adjustment a
X
X
X
Dispense appointment 
& dosing record card
X
Review and collect 
appointment & dosing 
record card
X


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Protocol Amendment 5, 3 March 2014
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Protocol Activity
Visit
1
Visit 
2
Phone 
Call 
all 
groups
q
Oxybutynin 
dose 
optimization
perioda,q
Visit 
3
Visit 
4q
Visit 
5b
Visit 
6q
Visit 
7c
Visit 
8
Screening Rand 
Phone Calls
Oxybutynin 
subjects
Feso 
PK & 
Fix 
Oxy 
dose
Phone 
call
Start of 
Extension
Phone 
Call
End of 
Treat-
ment 
Follow-up 
call
Day -30 
to 
Day -3
Day 1
Week 
1
Week 
2
Week 
3
Week 
4
Week 
8
Week
12
Week 
18
Week 24
Week 
26
a.
Subjects who are receiving oxybutynin (>25 kg subjects) will have additional contacts, by telephone or clinic visits, as deemed 
appropriate, at approximately weekly intervals for dose adjustment to optimize efficacy and tolerability.
b.
Or in the event of the subject withdrawing early from the active comparator treatment/efficacy phase.  Urodynamic assessment 
should only be performed in subjects who have been on a stable dose of study medication for at least 2 weeks, and who have not missed 
any doses in the 3 days prior to the visit.
c.
Or in the event of the subject withdrawing early from the safety extension phase.
d.
If vital signs or physical examinations show a clinically relevant change from baseline, then safety monitoring will occur at a 
minimum of monthly intervals, or more frequently as clinically appropriate, until the abnormality resolves.
e.
PVR only in subjects who are not performing intermittent catheterization  or in any subjects who have >1 urinary tract infection 
(UTI) during the study.
f.
Laboratory assessments may be repeated as needed to follow-up on significant findings.
g.
Urinalysis: Urine microscopy, culture, and sensitivity to be performed in the event of the presence of symptoms (eg, fever, flank 
pain), positive leucocytes and/or nitrites on urinalysis, or if the subject has a documented history of vesicoureteral reflux (VUR).
h.
Serum pregnancy test at Visit 1, urine pregnancy test at all other visits.  Only for female subjects of child-bearing potential. 
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
i.
PK blood sampling only in subjects randomized to treatment with fesoterodine during the active comparator/efficacy phase.  A 
maximum of three PK samples will be collected from each subject. Subjects randomized to treatment with oxybutynin (>25 kg subjects) 
will not be required to provide PK samples. In the event of subject withdrawing early from the active comparator/efficacy phase prior to 
Visit 3, PK samples should be obtained at the early termination visit.
j.
At Visit 3 PG samples only in subjects randomized to treatment with fesoterodine during the active comparator/efficacy phase, and 
who do not have prior laboratory documentation of their CYP2D6 genotype. At Visit 5 (or early withdrawal from the active 
comparator/efficacy phase), only subjects (>25 kg) who were on oxybutynin who will continue into the safety extension phase and who 
do not have prior laboratory documentation of their CYP2D6 genotype.
k.
Urodynamic studies: subjects who demonstrate a clinically relevant increased detrusor pressure or other urodynamic findings 
suggestive of worsening condition compared to baseline should not be allowed to continue into the safety extension phase.  Consideration 
should be given to imaging of upper urinary tract (for example, videourodynamics, or ultrasound) according to accepted local standard of 
care in subjects with VUR, or other conditions that predispose to upper urinary tract dysfunction or damage.
l.
Bladder diary and dosing log data will be recorded on the same electronic data capture device. The bladder diary will be completed 
for 3 days prior to Visits 2 and 5; the dosing log will be completed on a daily basis. Subjects and/or their caregivers should be re-educated 
and re-trained if review of data suggests that the bladder diary or dosing log are not being completed correctly.
m.
Electronic data capture device should be collected at Visit 2 for subjects who are not randomized, or at other visits if the subject 
discontinues.
n.
Assessment of the bladder diary or dosing log may be performed via remote electronic review.
o.
Review of dosing log should occur as indicated and also within 2 - 3 days following initiation in treatment or change in dose, 
tablet/capsule strength or treatment (oxybutynin) or as otherwise appropriate.
p.
At Visit 3, the time of last 3 doses should be recorded for fesoterodine, and at Visit 5 the time of last dose of fesoterodine or 
oxybutynin.
q.
Telephone calls may be substituted by a clinic visit at the discretion of the investigator and when indicated by local circumstances 
and/or regulatory requirements (eg for Japan, clinic visits should be the default option).


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TABLE OF CONTENTS
TABLES ..................................................................................................................................11
1. INTRODUCTION ...............................................................................................................13
1.1. Indication.................................................................................................................13
1.2. Background and Rationale ......................................................................................13
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
2.1. Objectives................................................................................................................17
2.1.1. Primary Objectives .....................................................................................17
2.1.2. Secondary Objectives .................................................................................17
2.2. Endpoints.................................................................................................................18
2.2.1. Primary Endpoint........................................................................................18
2.2.2. Secondary Endpoints ..................................................................................18
2.2.2.1. Efficacy Endpoints ....................................................................18
2.2.2.2. Safety Endpoints .......................................................................18
2.2.2.3. Pharmacokinetic Endpoints.......................................................19
3. STUDY DESIGN.................................................................................................................19
3.1. Study Visits .............................................................................................................21
4. SUBJECT SELECTION......................................................................................................22
4.1. Inclusion Criteria.....................................................................................................23
4.2. Exclusion Criteria....................................................................................................24
4.3. Continuation Criteria...............................................................................................27
4.4. Lifestyle Guidelines ................................................................................................27
4.5. Sponsor Qualified Medical Personnel.....................................................................27
5. STUDY TREATMENTS.....................................................................................................28
5.1. Fesoterodine ............................................................................................................28
5.2. Oxybutynin (Subjects >25 kg) ................................................................................28
5.3. Allocation to Treatment ..........................................................................................29
5.4. Drug Supplies..........................................................................................................30
5.4.1. Formulation and Packaging........................................................................30
5.4.2. Preparation and Dispensing........................................................................31
5.4.3. Administration............................................................................................31
5.4.4. Compliance.................................................................................................32


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5.5. Drug Storage and Drug Accountability...................................................................33
5.6. Concomitant Medication(s).....................................................................................34
5.6.1. Permitted Concomitant Therapies ..............................................................34
5.6.2. Prohibited Concomitant Therapies .............................................................34
6. STUDY PROCEDURES .....................................................................................................35
6.1. Visit 1 (Screening, Day -30 to Day -3) ...................................................................35
6.2. Visit 2 (Randomization/Baseline, Day 1) ...............................................................36
6.3. Week 1 Telephone Call (2 days)...........................................................................37
6.4. Dose Optimization of Oxybutynin (Weeks 1, 2 and 3, 2 days) (Subjects >25 
kg)..............................................................................................................................38
6.5. Visit 3 (Week 4, 14 days)......................................................................................39
6.6. Visit 4 (Week 8, 14 days)......................................................................................39
6.7. Visit 5 (Week 12, -7 days to +14 days)...................................................................40
6.8. Visit 6 (Week 18, 14 days)....................................................................................41
6.9. Visit 7 (Week 24, -7 days to +14 days)...................................................................41
6.10. Visit 8 (Follow-up, Week 26 +14 days)................................................................42
6.11. Additional Contacts...............................................................................................42
6.12. Subject Withdrawal...............................................................................................43
7. ASSESSMENTS..................................................................................................................44
7.1. Efficacy Assessments..............................................................................................44
7.1.1. Urodynamic Assessments...........................................................................44
7.1.2. Bladder Diary..............................................................................................45
7.2. Safety Assessments .................................................................................................46
7.2.1. Vital Signs ..................................................................................................46
7.2.2. Physical Examination .................................................................................46
7.2.3. Weight Measurements ................................................................................47
7.2.4. Visual Acuity and Accommodation............................................................47
7.2.5. Electrocardiogram.......................................................................................47
7.2.6. Post-Void Residual (PVR) Urine Volume..................................................48
7.2.7. Clinical Laboratory Evaluation...................................................................48
7.2.8. Childhood Behavior Checklist (CBCL) (Appendix 4)...............................49
7.2.9. Grooved Pegboard Test (GPT)...................................................................49


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7.2.10. Pregnancy Testing ....................................................................................49
7.3. Pharmacokinetic Assessments.................................................................................50
7.3.1. Plasma for Analysis of 5-HMT...................................................................50
7.3.2. Shipment of Pharmacokinetic Samples ......................................................50
7.4. Pharmacogenomics Evaluations..............................................................................51
7.4.1. Shipment of Pharmacogenomics Samples..................................................51
7.5. Dosing Log..............................................................................................................51
8. ADVERSE EVENT REPORTING......................................................................................51
8.1. Adverse Events........................................................................................................51
8.2. Reporting Period .....................................................................................................52
8.3. Definition of an Adverse Event...............................................................................52
8.4. Abnormal Test Findings..........................................................................................53
8.5. Serious Adverse Events...........................................................................................53
8.5.1. Protocol-Specified Serious Adverse Events...............................................54
8.5.2. Potential Cases of Drug-Induced Liver Injury............................................54
8.6. Hospitalization ........................................................................................................55
8.7. Severity Assessment................................................................................................56
8.8. Causality Assessment..............................................................................................57
8.9. Exposure During Pregnancy....................................................................................57
8.10. Withdrawal Due to Adverse Events (See section on Subject Withdrawal) ..........58
8.11. Eliciting Adverse Event Information ....................................................................59
8.12. Reporting Requirements........................................................................................59
8.12.1. Serious Adverse Event Reporting Requirements .....................................59
8.12.2. Non-Serious Adverse Event Reporting Requirements .............................59
8.12.3. Sponsor Reporting Requirements to Regulatory Authorities ...................60
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................60
9.1. Sample Size Determination.....................................................................................60
9.2. Efficacy Analysis ....................................................................................................61
9.2.1. Efficacy Analysis Sets................................................................................61
9.2.1.1. Full Analysis Set (FAS) ............................................................61
9.2.1.2. Per Protocol Analysis Set (PPAS).............................................61
9.2.2. Analysis of Primary Endpoint ....................................................................61


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9.2.2.1. Cohort 1 (>25 kg)......................................................................61
9.2.2.2. Cohort 2 (≤25 kg)......................................................................62
9.2.3. Analysis of Secondary Endpoints...............................................................63
9.2.4. Analysis of Other Endpoints.......................................................................63
9.3. Safety Analysis........................................................................................................64
9.4. Blinded Interim Analysis for Sample Size Re-estimation. .....................................64
9.5. External Data Monitoring Committee.....................................................................64
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................65
11. DATA HANDLING AND RECORD KEEPING .............................................................66
11.1. Case Report Forms / Electronic Data Record .......................................................66
11.2. Record Retention...................................................................................................66
12. ETHICS..............................................................................................................................67
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............67
12.2. Ethical Conduct of the Study ................................................................................67
12.3. Subject Information and Consent..........................................................................67
12.4. Subject Recruitment ..............................................................................................68
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................68
13. DEFINITION OF END OF TRIAL...................................................................................69
13.1. End of Trial in a Member State.............................................................................69
13.2. End of Trial in all Participating Countries ............................................................69
14. SPONSOR DISCONTINUATION CRITERIA ................................................................69
15. PUBLICATION OF STUDY RESULTS..........................................................................69
15.1. Communication of results by Pfizer:.....................................................................69
15.2. Publications by Investigators ................................................................................70
16. REFERENCES ..................................................................................................................71
TABLES
Table 1: Severity Assessment..................................................................................................56
APPENDICES
Appendix 1. Examples of CYP3A4 Inducers and Potent CYP3A4 Inhibitors .............72
Appendix 2. Total Volume of Trial-Related Blood Loss..............................................73
Appendix 3. Washout Times for Anticholinergic Medications.....................................75


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Appendix 4. Child behavior Checklist (CBCL) ............................................................76
Appendix 5. Country-specific amendment: France.......................................................80


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1. INTRODUCTION
1.1. Indication
Fesoterodine is an antimuscarinic drug that is being developed for the treatment of symptoms 
associated with a neurological condition (eg, spina bifida) in subjects aged 6-17 years, 
hereafter referred to as "neurogenic detrusor overactivity" or NDO.
1.2. Background and Rationale
At least 25% of clinical problems seen in pediatric urology are the result of neurogenic 
lesions that affect lower urinary tract function (Bauer, et al 2002).1  The principal causes may 
be classified as acquired or congenital in origin, with the vast majority of bladder dysfunction 
in children related to neural tube defects, most commonly myelomeningocele (Aslan & 
Kogan, 2002).2
Neurogenic detrusor overactivity is associated with involuntary contractions of the detrusor 
muscle, defined as detrusor overactivity, which occur as the bladder fills.  This can only be 
diagnosed with cystometric evaluation (Neveus, et al, 2006).3
The outcome of upper urinary tract function is related to detrusor and urethral sphincter 
function.  In dyssynergistic dysfunction, detrusor and urethral sphincter contraction is
uncoordinated (detrusor-sphincter dyssynergia) resulting in high intravesical pressures, 
vesicoureteric reflux, and ultimately renal damage (Coward & Saleem, 2001);4 (Aslan & 
Kogan, 2002).2  In children with myelodysplasia, the risk of upper urinary tract (UUT) 
deterioration and renal damage approaches 80% when no intervention is instituted (Bauer et 
al, 2002).1
In atonic dysfunction, although a lack of detrusor and (usually) sphincter activity results in a 
low pressure bladder generally protecting the urinary tract, incontinence then becomes a 
problem (Coward & Saleem, 2001);4 (Aslan &  Kogan, 2002).2
Treatment of NDO in children depends on presentation, underlying cause, and the risk of 
deterioration in function of both upper and lower urinary tract.  Clean intermittent 
catheterization (CIC) is first line therapy for bladder emptying in children with areflexic 
bladders and high postvoid residual urine volume, and may be combined with antimuscarinic 
therapy in specific populations, eg, patients with high pressure bladders as below (Aslan & 
Kogan, 2002);2 (Kennelly & DeVoe, 2008).5
Drug Development Rationale
Antimuscarinic drugs are the cornerstone of pharmacotherapy in the pediatric NDO 
population, and have been shown to improve intravesicular pressure, and decrease symptoms.  
Four antimuscarinic drugs (oxybutynin, trospium chloride, tolterodine and darifenacin) have 
documented results in the pediatric NDO population (Kennelly & DeVoe, 2008).5  Of these, 


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only oxybutynin is widely approved for use in children, and is available as a once a day 
extended release (XL) tablet, as well as an immediate release tablet. Although effective,
oxybutynin use has been limited by a side effect profile which may have particular relevance 
in the pediatric population where development (eg, physical, cognitive, psychosocial) is still 
ongoing.
A particular medication’s effectiveness is highly dependent on patient compliance which is 
itself dependent on tolerability.  Given individual differences in toleration and the limited 
choice available there is an unmet need for alternative treatments.
Children with NDO therefore represent a disease population with a need for an alternative 
effective, safe and well-tolerated therapy to help manage the overactive detrusor, reducing or 
preventing incontinence, as well as the high pressure bladder contractions that can result in 
UUT deterioration and renal damage.
Other treatments such as alpha blockers, anxiolytics, tricyclic antidepressants, intravesical 
oxybutynin, botulinum-A toxin, electrical stimulation and biofeedback, may also be used 
(Coward & Saleem, 2001)4 although safety and efficacy have not been reliably demonstrated.
Acetylcholine which interacts with muscarinic receptors at the detrusor is the predominant 
peripheral neurotransmitter responsible for bladder contraction.  Both fesoterodine and 
oxybutynin are muscarinic receptor antagonists and consequently have a role in mediating 
detrusor overactivity.
Fesoterodine is an antimuscarinic drug available as a prolonged release (PR) tablet 
formulation, and is approved in Europe and the USA at doses of 4 mg and 8 mg once daily 
for the treatment of overactive bladder (OAB) in adults; it is not approved for use in the 
pediatric population.
Fesoterodine functions as a prodrug of 5-hydroxymethyltolterodine (5-HMT).  After oral 
administration, fesoterodine cannot be detected in plasma, as it is rapidly and extensively 
hydrolyzed by nonspecific esterases to 5-HMT, which is the principal active moiety 
responsible for the antimuscarinic effects of fesoterodine.
Clinical Safety Data
Adverse effects characteristic of antimuscarinic drugs, eg, dry mouth, constipation, urinary 
retention, micturition difficulties, dry eyes, and dry throat were observed in Phase 1 studies 
with fesoterodine doses up to 28 mg once daily.  In a double-blind, randomized, parallel-
group, placebo- and positive-controlled (moxifloxacin 400 mg/day) thorough QT study with 
fesoterodine 4 mg and 28 mg/day doses, fesoterodine did not prolong the QTc interval.  
Fesoterodine PR has been evaluated in Phase 2 and Phase 3 controlled studies in 2859 OAB 
patients.  Of this total, 782 received fesoterodine 4 mg/day and 785 received fesoterodine 
8 mg/day for treatment periods of 8 or 12 weeks.  The most common adverse event in Phase 
3 was dry mouth, with a reported incidence of 19% with fesoterodine 4 mg and 35% with 
fesoterodine 8 mg, compared to 7% with placebo.  Most of the cases were mild to moderate 
and discontinuations due to dry mouth were less than 1%.  Constipation was the second most 


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common adverse event with a reported incidence of 4% with fesoterodine 4 mg and 6% with 
fesoterodine 8 mg compared to 2% with placebo.  There were no apparent trends in mean 
changes from baseline to the end of treatment or in shifts of clinical relevance over time in 
any hematology, clinical chemistry, or urinalysis parameters.  Among subjects treated with 
fesoterodine, no clinically relevant changes from baseline were observed for vital sign 
parameters, electrocardiogram (ECG) parameters, physical examination findings, or residual 
urine data.  In summary, fesoterodine is generally well-tolerated at doses of 4 mg and 8 mg 
once daily.
An 8-week open-label, uncontrolled pharmacokinetics and safety study was conducted in 21 
pediatric OAB patients, aged between 8-17 years, weighing >25 kg (A0221066). Each 
subject was to receive the initial study dose of 4 mg once daily for 4 weeks, which could be 
escalated to 8 mg once daily for the next 4 weeks based on patient’s tolerability and efficacy 
responses. The study included 10 idiopathic and 11 neurogenic patients. Patients with NDO 
did not appear to have any remarkable differences in 5-HMT pharmacokinetics (PK) when 
compared with patients with idiopathic OAB. Clearance of 5-HMT appears to be similar in 
pediatric patients compared to adults when allometrically scaled by patient weight. 
Administration of fesoterodine 4 and 8 mg once-daily doses to pediatric patients of ages 8-17 
yrs and body weight >25 kg provided steady-state plasma 5-HMT exposures similar to those 
in adults. There were no discontinuations due to AEs or deaths in this study; there was one 
serious adverse event (AE) of constipation while taking fesoterodine 8 mg, resulting in 
hospitalization and temporary discontinuation of study treatment. Based on the safety 
results, fesoterodine treatment was well tolerated by pediatric patients in Study A0221066 
and there were no significant safety issues. The 3-day bladder diaries were deemed feasible 
and useful for assessing the OAB symptoms in both idiopathic and neurogenic pediatric 
patients.
Study Rationale
The primary purpose of this study is to evaluate the safety and efficacy of fesoterodine 4 mg 
and 8 mg once daily in pediatric NDO subjects aged between 6-17 years and with a body 
weight >25 kg, and fesoterodine 2 mg and 4 mg in subjects ≤25 kg.  Additionally, the safety 
and efficacy of oxybutynin extended release (XL) will be evaluated in subjects >25 kg only.   
Sparse PK samples will also be obtained to determine the steady-state population 
pharmacokinetics of 5-HMT following fesoterodine treatment in pediatric NDO subjects.
The study will enroll two weight cohorts as follows:

Cohort 1
For subjects >25 kg, following 12 weeks of treatment with either fesoterodine 4 mg, 
8 mg or oxybutynin XL in an active comparator phase, subjects will then enter a 
safety extension phase receiving either 4 mg or 8 mg of fesoterodine for an additional 
12 weeks.  This cohort will include subjects 25.1 kg and above.


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
Cohort 2
For subjects ≤25 kg, following 12 weeks of treatment with either dose of fesoterodine 
(2 mg, 4 mg as a beads-in-capsule formulation) in an efficacy phase, subjects will 
then enter a safety extension phase receiving the same doses of fesoterodine for an 
additional 12 weeks. This cohort will include subjects 25.0 kg and below.
In the event that it is not possible to develop an age-appropriate formulation, then lighter 
subjects will not be dosed, and the end of the trial will be defined by the completion of the 
heavier >25 Kg cohort.
Dose Selection Rationale
Fesoterodine
Cohort 1 (Subjects >25 kg)
Pharmacokinetic (PK) simulations were conducted based on the adult 5-HMT population PK 
parameters and allometric scaling of the adult population parameters applied to a distribution 
of pediatric patients 6-17 years of age and body weights >25 kg.  The modeling and 
simulations (M&S) results along with the population PK results from the Phase 2 study 
A0221066 were used to confirm the pediatric doses for Study A0221047.
These M&S analyses predicted that following administration of fesoterodine 4 and 8 mg 
once-daily doses to children aged 6-17 years and weighing >25 kg body weight, the plasma 
5-HMT exposures would be to be similar to those in adults given the same doses.  The actual 
observed 5-HMT plasma concentrations from Study A0221066 are in agreement with the 
simulation results, and administration of fesoterodine 4 and 8 mg once-daily to pediatric 
patients was well tolerated and provides steady-state plasma 5-HMT exposures similar to 
those in adults.
Based on the PK results of Study A0221066, combined with modeling and simulations, 
fesoterodine 4 and 8 mg once-daily are selected as doses for this safety and efficacy Study 
A0221047 in NDO patients of ages 6-17 years and body weight >25 kg.  If subjects cannot 
tolerate the dose they are randomized to they should be withdrawn from the trial as a dose 
reduction is not permitted in this trial.
Cohort 2 (Subjects ≤25 kg)
Selection of doses is based on simulations and integrated observed data from 21 children 
aged 6 to 17 years and >25 kg in the prior fesoterodine Study A0221066, and 19 completed 
subjects in the currently on-going Study A0221047, as well as the PK and bioavailability of 
5-HMT following administration of the beads in the capsule formulation in adults (Study 
A0221068, A0221069).  Modelling and simulations have been used to confirm the selection 
of doses in subjects ≤25 kg, with the aim of achieving 5-HMT exposures similar to those 
identified as safe and efficacious in subjects >25 kg and not exceeding the exposures in 
adults given 4 mg and 8 mg doses of fesoterodine.


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The daily dose of fesoterodine in this study is 2 mg or 4 mg given once daily for subjects 
25 kg.  If subjects cannot tolerate the dose they are randomized to they should be withdrawn 
from the trial.
For both cohorts, the dose assigned at randomization (Day 1) will not be changed irrespective 
of any change in weight.
Oxybutynin
Subjects randomized to oxybutynin (only Cohort 1: subjects >25 kg) will receive oxybutynin 
extended release (XL) tablets at a starting dose in accordance with approved pediatric 
labeling, and accepted practice eg, oxybutynin XL 5 mg once a day. Dose optimization will 
be achieved by either up or down -titration in 5 mg increments on a weekly basis to achieve a 
balance of efficacy and tolerability.  The maximum dose used in this study will not exceed 
the recommended dose consistent with approved pediatric labeling, and accepted practice.  
Subjects who took oxybutynin XL prior to study entry and who are randomized to the 
oxybutynin treatment group may restart on their pre-study dose.  All subjects should achieve 
a minimum total daily dose of oxybutynin XL 10 mg by the end of the dose adjustment 
period at Week 4.  Subjects who are unable to tolerate a minimum total dose of oxybutynin 
XL 10 mg once daily should be withdrawn.  Dose adjustments after Week 4 are not 
permitted.
Single Reference Safety Document
Complete information for fesoterodine may be found in the Single Reference Safety 
Document, which for this study is the current Investigator Brochure. The Single Reference 
Safety Document for oxybutynin XL is the product label.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objectives

To determine the safety and efficacy of fesoterodine 4 mg and 8 mg following once daily 
treatment for 12 weeks in pediatric NDO subjects with weight >25 kg.

To determine the safety and efficacy of fesoterodine 2 mg and 4 mg following once daily
treatment for 12 weeks in pediatric NDO subjects with weight 25 kg.
2.1.2. Secondary Objectives
The secondary objectives of this study are to:

evaluate the safety and efficacy of fesoterodine versus oxybutynin in pediatric NDO 
subjects with weight >25 kg.


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
evaluate the safety of fesoterodine 4 mg and 8 mg once daily treatment for up to 
24 weeks in pediatric NDO subjects with weight >25 kg.

evaluate the safety of fesoterodine 2 mg and 4 mg once daily treatment for up to 24 
weeks in pediatric NDO subjects with weight ≤25 kg.

determine the steady-state population pharmacokinetics of 5-HMT following fesoterodine 
4 mg and 8 mg once daily treatment in pediatric NDO subjects with weight >25 kg.

determine the steady-state population pharmacokinetics of 5-HMT following treatment 
with two doses of fesoterodine 2 mg and 4 mg once daily in pediatric NDO subjects.
2.2. Endpoints
2.2.1. Primary Endpoint

Maximum cystometric bladder capacity defined as maximal tolerable cystometric 
capacity or until voiding/leaking begins or at 40 cm H2O.
2.2.2. Secondary Endpoints
2.2.2.1. Efficacy Endpoints

Detrusor pressure at maximum bladder capacity.

Presence of involuntary detrusor contractions (IDC).

Bladder volume at first IDC.

Bladder compliance.

Mean number of micturitions and/or catheterizations/24 hrs.

Mean number of incontinence episodes/24 hrs.

Mean urgency episodes/24 hrs if applicable (only for sensate subjects).

Mean volume voided per micturition or mean volume per catheterization.
2.2.2.2. Safety Endpoints

Adverse events, including monitoring of targeted events including, but not limited to:

Anticholinergic effects such as dry mouth, dry eyes and constipation.

CNS effects such as behavioral changes (eg, aggression), decreased cognitive 
function, headache, seizures, somnolence.


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
Visual effects such as accommodation disorder, blurred vision, and amblyopia.

Visual acuity and accommodation tests.

Cognitive function by the Child Behavior Check List and Grooved Pegboard Test.

Vital Signs, including heart rate in the context of age-appropriate norms.

Urinary Tract Infection, as evidenced by urinalysis, urine microscopy, culture and 
sensitivity.

Clinical Laboratory Evaluations in the context of age-appropriate norms, with particular 
reference to liver function tests and renal chemistry.

Post-void residual volume (PVR) in subjects not performing CIC, or with >1 urinary tract 
infection (UTI) during the study.
2.2.2.3. Pharmacokinetic Endpoints

Model-based pharmacokinetic parameter estimates for absorption rate constant (Ka), 
apparent oral clearance (CL/F) and volumes of distribution (Vd) to predict the area under 
the curve (AUC), maximum concentration (Cmax), time to reach Cmax (Tmax) and half-life 
of 5-HMT.
3. STUDY DESIGN
The study was designed to be in line with clinical practice and to minimize disruption, 
discomfort and inconvenience for subjects whilst maintaining scientific integrity.
Cohort 1 (Subjects >25 kg)
For this cohort this is a randomized, open label, active comparator parallel group study with 
three treatment arms.


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Note: The first week of the fesoterodine 8 mg group will be at a dose of 4 mg each day, for the active 
comparator phase and for those subjects changing from oxybutynin to the safety extension phase.
The study consists of two parts: a 12 week three arm phase with an active comparator 
(oxybutynin XL), followed by a 12 week two arm extension phase without the active 
comparator.
There is a variable screening period (minimum 3 days) prior to the baseline visit, the duration 
of which is principally determined by the prior medication subjects may need to washout
(Appendix 3).  At baseline, subjects will be randomized to one of three arms: 4 mg or 
8 mg/day of fesoterodine or oxybutynin XL.  Subjects will be randomized to each arm in a 
1:1:1 ratio.
After 12 weeks (or earlier if appropriate), subjects in the oxybutynin arm of the study will be 
allocated by the investigator to fesoterodine at either 4 mg or 8 mg/day.
A sufficient number of subjects will be randomized into Cohort 1 to ensure a total of 
approximately 99 subjects (approximately 33 evaluable subjects per arm) are evaluable for 
the primary efficacy and safety analyses at Week 12, after which screening to Cohort 1 will 
be closed.


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Cohort 2 (Subjects ≤25 kg)
Note: The first week of the fesoterodine 4 mg group will be at a dose of 2 mg each day, for the efficacy phase.
For this cohort the study consists of two parts: a 12 week two arm efficacy phase, followed 
by a 12 week two arm safety extension phase.
There is a variable screening period (minimum 3 days) prior to the baseline visit, the duration 
of which is principally determined by the prior medication subjects may need to washout 
(Appendix 3).
At baseline, subjects will be randomized to one of two fesoterodine treatment arms: doses 
2 mg and 4 mg/day). Subjects will be randomized to each arm in a 1:1 ratio. Once allocated 
subjects will remain on that dose for the 12 week efficacy phase, and will continue at the 
same dose during the 12 week safety extension phase.
It is planned that a sufficient number of subjects will be randomized into this cohort to ensure 
a total of approximately 50 subjects (approximately 25 evaluable subjects per arm) are 
evaluable for the primary efficacy and safety analyses at Week 12, after which screening to 
Cohort 2 will be closed.
The dosing of lighter subjects is dependent on the availability of an age-appropriate Beads-
in-Capsule formulation. In the event that it is not possible to develop an age-appropriate 
formulation, then lighter subjects will not be dosed, and the end of the trial will be defined by 
the completion of the heavier >25 Kg cohort.
3.1. Study Visits
Following Screening (V1), there are 4 additional clinic visits: 


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
Randomization (Day 1, V2),

Week 4 (V3), 

Week 12 (V5) and 

Week 24 (V7).
There will also be a minimum of 3 telephone calls (or clinic visits) to subjects to identify any 
new adverse events, review concomitant medication usage and the dosing log at:

Week 1

Week 8 (V4), 

Week 18 (V6)
and a further telephone call (or clinic visit) at:

Week 26 (V8).  To review ongoing or new adverse events, review concomitant 
medications for subjects 2 weeks after completing study treatment.  It will also be 
completed for all subjects who withdraw early from the study and take at least 1 dose of 
study medication.
In addition, subjects >25 kg randomized to treatment with oxybutynin XL may receive a 
minimum of 3 contacts at approximately weekly intervals between V2 and V3 for dose 
adjustment to achieve a balance of efficacy and tolerability up to the maximum 
recommended dose.  The contacts may be telephone calls or clinic visits as deemed 
appropriate by the investigator.
Other contacts (for example, telephone calls or unscheduled clinic visits) may also be made, 
as appropriate, to verify study medication dose, and to provide reminders to the subject to 
complete the bladder diary and, if needed, daily dosing log.
After the end of the trial, continued access to fesoterodine may be provided, if it is 
demonstrated that fesoterodine may provide a therapeutic benefit that cannot be obtained 
from available marketed treatments, and it is appropriate, feasible, and allowed according to 
SOPs and local regulations. In this case, fesoterodine will be provided until commercially 
available or 30 June 2017 or until subject discontinues such continued access treatment, 
whichever is earlier.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether this protocol is suitable for a particular subject.


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4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male or female subjects aged 6-17 years 11 months (age at time of first dose); that is 
subjects who have passed their sixth birthday but not reached their eighteenth birthday.
2. Subjects with stable neurological disease and clinically- or urodynamically-demonstrated 
NDO, confirmed urodynamically at Visit 2, by detrusor overactivity or decreased bladder 
compliance, with decreased maximum cystometric bladder capacity.
NOTE: Subjects with hypocontractile bladder, detrusor underactivity, or a 'flaccid' 
bladder should not be included.
3. Evidence of a personally signed and dated informed consent document indicating that the 
subject (or a legal representative) has been informed of all pertinent aspects of the study. 
In addition, an assent from the subject will be obtained when appropriate, and when the 
potential subject is capable of providing assent.
4. Female subjects who are of child-bearing potential (defined as 9 years old or have 
experienced menarche, whichever is earlier) must not be intending to become pregnant, 
currently pregnant, or lactating. The following conditions apply:
a.
Subjects of childbearing potential must have a confirmed negative pregnancy test 
prior to randomization.
b. Subjects of child-bearing potential must agree to use effective contraception during 
the period of the trial and for at least 28 days after completion of treatment.  Effective 
contraception includes abstinence.
c.
Sexually active male subjects must agree to use effective contraception during the 
period of the trial and for at least 28 days after completion of treatment.
Further details of the definition of child-bearing potential and effective contraception 
may be found in Section 4.4.
5. Swallowing:
a.
Subjects >25 kg must already have the ability to swallow tablets whole, without 
chewing or crushing.  The first dose of medication will be given in clinic under 
observation, and any subject not able to swallow tablets will be excluded from the 
study.


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b. Subjects ≤25 kg can either swallow the capsules whole or sprinkle on food.
6. Subjects and their caregivers/parents who are willing and able to comply with scheduled 
visits, treatment plan, laboratory tests, and other study procedures.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
In France, see Appendix 5.
1. Any condition known to affect drug absorption (eg, gastrectomy).
2. History of surgical procedures that could confound study results or increase the risk to 
subjects, including but not limited to: sphincterotomy, artificial sphincter, implantable 
stent, bladder augmentation procedures, urinary diversion procedures.  Continent 
diversion procedures eg, Mitrofanoff are permitted.
3. A history of indwelling urinary catheter within 4 weeks of participation in this study. 
Intermittent catheterization is permitted.
4. Any comorbid condition that, in the opinion of the investigator, would confound study 
results or increase the risk to subjects eg, current history of bladder calculus.
5. A history of autonomic dysreflexia eg, increased blood pressure with bladder filling or 
other stimuli.
6. Subjects with clinically relevant out-of-range values for hematology or serum chemistry 
as confirmed by blood tests performed at Visit 1, and which require the subject’s 
exclusion in the opinion of the investigator.
7. A 12-lead ECG at screening with clinically significant abnormality.
8. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol.
9. Subjects required to take or expected to initiate concomitant medications that can interact 
with the pharmacokinetics and/or pharmacodynamics of fesoterodine or oxybutynin, such 
as:

Potent CYP3A4 inhibitors within 3 weeks prior to Visit 2 (baseline), or the 
expectation to start such a treatment during the trial (Appendix 1).

Medications capable of inducing CYP3A4 enzyme metabolism (Appendix 1).

Drugs for the treatment of overactive bladder (eg, darifenacin, oxybutynin (including 
intravesical), propiverine, tolterodine, fesoterodine, solifenacin and trospium).

Treatment with botulinum toxin A within 9 months prior to Visit 2 (baseline).


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
Drugs with antispasmodic, parasympathetic, or cholinergic effects.  Stable use of 
desmopressin for enuresis is allowed if established for at least 3 months.
Previous treatment with these medications does not exclude subjects.  However, prohibited 
concomitant medications must have a minimum washout appropriate to the drug so any 
clinical effect is at a minimum prior to beginning the bladder diary, and baseline urodynamic 
evaluations (Section 5.6).
10. Intermittent or unstable use of diuretics or alpha blockers, tricyclic antidepressants or any 
other treatment that may confound the results of the study, within 2 weeks or an 
appropriate washout period (whichever is longer) prior to starting the bladder diary or 
during the course of the study.  Stable usage/dosage is allowed if established for at least 
3 months.
11. Electrostimulation therapy or bladder retraining if started within 30 days of Visit 1 or are 
expected to start such therapy during the study period.  Subjects who are on an 
established regimen may remain on this for the duration of the study.
12. Subjects with a clinically significant urinary tract infection (UTI) at screening.
Urine microscopy, culture and sensitivity testing will be performed in the event of:

presence of symptoms (eg, fever, flank pain), or

positive leucocytes and/or nitrites on urinalysis, or

if subject has a documented history of vesicoureteral reflux (VUR).
A clinically significant UTI is defined as:

positive urine culture with a uropathogen (defined as ≥105 CFU/ml) and the presence 
of symptoms, or

pyuria (defined as >50 white blood cells (WBC)/hpf) and the presence of symptoms, 
or

positive urine culture with a uropathogen (defined as ≥105 CFU/ml) with or without 
symptoms in a subject with a documented history of VUR.
Subjects who are found to have an active UTI during screening may continue 
screening activities on resolution of symptoms or treatment of the UTI to the 
satisfaction of the treating physician.
13. Subjects not requiring intermittent catheterization who have a post-void residual volume 
greater than 20 ml as determined by transabdominal ultrasound (eg, bladder scan) 
immediately after urination.  If at screening, the PVR is found to be greater than 20 ml
the subject will be asked to void again.  Repeat PVR assessment should be made as soon 


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as possible, and no more than 5 minutes, after the second void.  Subjects found to have a 
persistently elevated PVR >20 ml at this visit will be excluded from the study.
14. Subjects with any history of malignancy.
15. Subjects with any condition or at risk of any condition that would contraindicate or 
warrant precautions for the use of fesoterodine or oxybutynin, including:

Hypersensitivity to fesoterodine, tolterodine or oxybutynin.

Known history of hypersensitivity to peanut or soya or any of the excipients of the 
fesoterodine or oxybutynin formulation.

Gastric retention.

Severely decreased gastrointestinal motility (not under active management).

Uncontrolled narrow angle glaucoma.

Gastrointestinal obstructive disorders.

Myasthenia gravis.

Severe hepatic impairment (Child Pugh C).

Severe ulcerative colitis.

Toxic megacolon.
16. Previously received any investigational drug within 4 weeks or 5 half-lives (whichever is 
longer) prior to Visit 1.  Participation in other studies within 4 weeks before the current 
study begins or during study participation.
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
18. Subjects who are investigational site staff members or relatives of those site staff 
members or subjects who are Pfizer employees directly involved in the conduct of the 
trial.


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4.3. Continuation Criteria
There must be no urodynamic evidence of clinically relevant increased detrusor pressure or 
other urodynamic findings suggestive of worsening condition compared to baseline, prior to 
continuation in the Safety Extension period.
4.4. Lifestyle Guidelines
Subjects should maintain their normal daily routine, and changes in lifestyle during the 
course of the study should be avoided.
Subjects should avoid the consumption of grapefruit juice as it interferes with the metabolism 
of fesoterodine.
Female subjects of childbearing potential
Childbearing potential is defined as female subjects 9 years old or have experienced
menarche, whichever is earlier, and who are anatomically and functionally able to conceive.
Subjects of childbearing potential must have a confirmed negative pregnancy test prior to 
randomization.
Female subjects must agree to use effective contraception during the period of the trial and 
for at least 28 days after completion of treatment.  Male subjects must agree to use effective 
contraception during the period of the trial and for at least 28 days after completion of 
treatment.
Acceptable effective forms of contraception include:

Abstinence;

Barrier method, eg, condom with spermicidal foam/gel/film/cream/suppository;

Hormonal contraceptives: (oral, injected, intrauterine, transdermal or implanted) provided 
the subject remains on the treatment throughout the entire study and has been using 
hormonal contraceptives for an adequate period of time to ensure effectiveness.
Where there is uncertainty over contraceptive requirements, or an unusual method is being 
used for this population (such as an intrauterine device) the Pfizer medical expert must be 
contacted to determine if the subject is suitable for study participation.
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the study portal.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 


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at a minimum, protocol and investigational compound identifiers, patient study number, 
contact information for the investigational site and contact details for a help desk in the event 
that the investigational site staff cannot be reached to provide advice on a medical question 
or problem originating from another healthcare professional not involved in the subjects 
participation in the study. The help desk number can also be used by investigational staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the investigational site and 
the study team are not available. It is therefore intended to augment, but not replace the 
established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study. The help desk 
number is not intended for use by the subject directly and if a subject calls that number they 
will be directed back to the investigational site.
5. STUDY TREATMENTS
5.1. Fesoterodine
Cohort 1 (Subjects >25 kg)
Subjects randomized to fesoterodine will receive either 4 mg or 8 mg fesoterodine PR tablets 
once daily throughout the initial 12 weeks of the active comparator phase and will continue 
at the same dose during the 12 week safety extension phase. All those assigned to the 
fesoterodine 8 mg arm will start at 4 mg daily for one week, and will then escalate to 8 mg 
daily. If subjects cannot tolerate the dose they are randomized to they should be withdrawn 
from the trial as a dose reduction is not permitted in this trial.
Cohort 2 (Subjects ≤25 kg)
Subjects will be randomized to either 2 mg or 4 mg fesoterodine BIC capsules once daily 
throughout the initial 12 weeks of the efficacy phase and will continue at the same dose 
during the 12 week safety extension phase.  All those assigned to the fesoterodine 4 mg arm 
will start at 2 mg daily for one week and will then escalate to 4 mg daily.  If subjects cannot 
tolerate the doses they are randomized to, they should be withdrawn from the trial as a dose 
reduction is not permitted on this trial.
For both cohorts, it is expected that all subjects will also complete the extension phase 
unless, in the judgment of the investigator, this is not appropriate.  Subjects can withdraw 
from the study at any time.
5.2. Oxybutynin (Subjects >25 kg)
Subjects in Cohort 1 (weight >25 kg) randomized to oxybutynin will receive oxybutynin 
extended release (XL) tablets at a starting dose in accordance with approved pediatric 
labeling, and accepted practice eg, oxybutynin XL 5 mg once a day. Dose optimization will 
be achieved by either up or down titration in 5 mg increments on an approximately weekly 
basis to achieve a balance of efficacy and tolerability.  All subjects should achieve a 
minimum total daily dose of oxybutynin XL 10 mg by the end of the dose adjustment period 


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at Week 4.  The maximum dose used in this study will not exceed the recommended dose 
consistent with approved pediatric labeling, and accepted practice.  Subjects who were on 
oxybutynin prior to study entry and who are randomized to the oxybutynin XL treatment 
group may, at the discretion of the investigator, restart at the equivalent pre-study total daily 
dose.
After Week 4, subjects taking oxybutynin XL should remain on the same dose for the 
subsequent 8 weeks of the study, and no further dose adjustments should be permitted. 
Subjects who are unable to tolerate a minimum total dose of oxybutynin XL 10 mg once 
daily should be withdrawn. Subjects who withdraw from the oxybutynin treatment arm for 
reasons of toleration, and who fulfill all continuation criteria, may be directly allocated by the 
investigator to fesoterodine treatment at either 4 mg or 8 mg/day for the remaining 12 week 
safety extension period. All those assigned to the fesoterodine 8 mg arm will start at 4 mg 
daily for one week, and will then escalate to 8 mg daily. All subsequent study visits should 
be scheduled relative to the start of the extension phase.
At Visit 5 (or earlier if appropriate), subjects in the oxybutynin arm of the study will be 
allocated by the investigator to fesoterodine at either 4 mg or 8 mg/day. Subjects should 
undergo a minimum 2 day washout period from oxybutynin prior to starting treatment with 
Fesoterodine.  All those assigned to the fesoterodine 8 mg arm will start at 4 mg daily for one 
week, and will then escalate to 8 mg daily. Once allocated the dose will remain fixed for the 
period of the extension; if treatment is inadequate or the subject cannot tolerate the dose, 
consideration should be given to withdrawal.
5.3. Allocation to Treatment
This is an open label study.  The study will use an automated telerandomization system 
incorporating a central randomization scheme; however separate randomization schedules 
will be maintained for Cohort 1 and Cohort 2.  At Visit 2, randomization, subjects will be 
randomly assigned to their treatment group according to a computer generated pseudorandom 
code using the method of random permuted blocks.  At Visit 5, start of extension period, 
subjects in the oxybutynin group in Cohort 1 (>25 kg) will be allocated to fesoterodine 4 mg 
or 8 mg, according to the investigator's judgment.
For Cohort 1 (subjects >25 kg), in order to ensure an appropriate balance of subjects in each 
treatment group across the whole body weight spectrum, subjects will be stratified at 
randomization into two groups dependent on their body weight.  The lower weight group 
within Cohort 1 will include all those with a weight of 50 kg or less and the higher weight 
group within Cohort 1 will include all those above 50 kg.
Cohort 2 (subjects ≤25 kg) will not be stratified.
As this is an open-label study, drug supply will not be blinded, however due to the central 
randomization and automated telerandomization system, the investigator’s knowledge of the 
treatment assigned to each subject should not influence the decision to enroll a particular 
subject or affect the order in which subjects are enrolled.


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5.4. Drug Supplies
5.4.1. Formulation and Packaging
Fesoterodine
For Cohort 1 (subjects >25 kg), fesoterodine PR 4 mg and 8 mg will be provided by Pfizer as 
tablets.  The tablets will be packaged by Pfizer according to applicable regulatory 
requirements.  Both the 4 mg and 8 mg dosage forms are tablets designed for oral 
administration.  The tablets should be taken orally with water without chewing. The study 
medication is a blue, oval tablet. The subject will take one tablet daily as a single dose.
At Visit 2, subjects will be provided study medication for 4 weeks.  At Visit 3, subjects will 
be provided study medication for 8 weeks.  At Visit 5 (beginning of the safety extension 
phase), subjects will be provided study medication for 12 weeks.
For Cohort 2 (subjects ≤25 kg), subjects will be randomized to one of the two arms of the 
study, fesoterodine 2 mg or 4 mg once daily per the randomization schedule for this cohort.
Fesoterodine 2 mg and 4 mg once daily will be provided by Pfizer as a beads-in-capsule 
(BIC) formulation.  The BIC will be packaged by Pfizer according to applicable regulatory 
requirements.  Both dosage forms are capsules designed for oral administration.  The 
capsules should be taken orally with water without chewing.  For subjects who cannot 
swallow whole capsules, the capsule may be opened and the beads sprinkled on a suitable 
medium (eg, apple sauce) as directed by the Investigator or approved representative (eg, 
pharmacist).
At Visit 2, the subjects will be provided study medication for 4 weeks.  At Visit 3, subjects 
will be provided study medication for 8 weeks.  At Visit 5 (beginning of the Safety Extension 
Phase), subjects will be provided study medication for 12 weeks.  The subject will take one 
capsule daily as a single dose.
Subjects >25 kg (Cohort 1) who cannot swallow tablets are not permitted to take the BIC 
formulation and are excluded from the study.
Oxybutynin (Subjects >25 kg)
Commercially available oxybutynin XL 5 mg and 10 mg tablets will be sourced by Pfizer, 
labeled in accordance with applicable regulatory requirements, and provided to the trial sites.
Both the 5 mg and 10 mg dosage forms are tablets designed for oral administration.  Subjects 
will take oxybutynin in accordance with manufacturer and investigator or an approved 
representative (eg, pharmacist) instruction.  In exceptional circumstances and for countries 
where oxybutynin XL is locally approved, supplies may be obtained by the investigator or an 
approved representative (eg, pharmacist) to cover for unforeseen interruptions in the Pfizer 
central supply.  The tablets will be provided to subjects by the trial site according to 
applicable regulatory requirements.


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Oxybutynin will only be dosed during the active comparator phase (Cohort 1), and will be 
used according to approved pediatric labeling and accepted practice.  At Visit 2, the subjects 
will be provided study medication for 4 weeks according to investigator judgment.  At Visit 
3, subjects will be provided study medication for 8 weeks according to investigator 
judgment.
5.4.2. Preparation and Dispensing
Pfizer will provide sufficient amounts of the fesoterodine and oxybutynin XL study 
medications to the investigator.
The investigator, or an approved representative (eg, pharmacist) must ensure that deliveries 
of investigational product from the Sponsor are correctly received by a responsible person 
(eg, pharmacist), that all receipts are recorded in writing and that the products are stored in a 
secure area under recommended storage conditions.  It is also the responsibility of the 
investigator or designated personnel to ensure that the integrity of the packaged study 
product not be jeopardized prior to dispensing.  Each individual subject container must be 
dispensed as provided by Pfizer with no further repackaging or labeling done at the trial site.
Oxybutynin XL (subjects > 25 kg) will only be dispensed at one dosage strength (eg 5 mg) to 
avoid mis-dosing errors during the titration phase of the study.  If a subject is up-titrated to a 
dose level where the 10 mg tablet would be more convenient, then they must visit the site to 
return their 5 mg tablet supply and be dispensed 10 mg tablets.  When a subject has 
previously taken Oxybutynin XL where an established combination of dosage strengths have 
been used, they may continue with this regimen and be dispensed the appropriate 
combination.  The investigator or an approved representative (eg, pharmacist) will dispense 
the study medications in accordance with this protocol, and applicable regulatory 
requirements and regulations. The investigator or approved representative (eg, pharmacist) 
will administer/dispense the study medication only to subjects included in this study 
following the procedures set out in the study protocol.  The investigator or an approved 
representative (eg, pharmacist) is responsible for assuring retrieval of all study supplies from 
the subjects.
The investigator or approved representative (eg, pharmacist) must maintain accurate and
adequate records including date of receipt and return of drug shipments, lot number and 
quantities received/returned from/to Pfizer or CRO designee, and dates and amounts 
dispensed to and returned by the study subjects.  All full, partial full and empty drug 
containers must be returned to Pfizer or the CRO designee for drug accountability.
5.4.3. Administration
Study drug will be prepared in an open-label fashion.
Cohort 1 (subjects >25 kg)


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Subjects will be instructed to take study medication according to this protocol.  Subjects must 
take their first dose of study medication in clinic, to ensure correct dosing and tablet 
swallowing ability.
For fesoterodine 4 mg and 8 mg, subjects will swallow one tablet each day without chewing.  
For oxybutynin XL, subjects will take the medication as directed by the investigator or an 
approved representative (eg, pharmacist) per the dosing instructions described in Section 5.2.
Cohort 2 (subjects ≤25 kg)
Subjects will be instructed to take study medication according to instructions which will be 
supplied separately.  Subjects will take one capsule per day without chewing.  For subjects
who cannot swallow whole capsules, the capsule may be opened and the beads sprinkled on a 
suitable medium (eg, apple sauce).  Subjects must take their first dose of study medication in 
clinic, to ensure correct dosing.
Both cohorts
Subjects will also be asked to complete a daily dosing log (Section 7.5).  If information from 
the dosing log indicates that the subject has not taken study drug in accordance with dosing 
instructions, the subject and their legal representative(s) will be re-instructed on how to take 
the study medication, and followed-up as appropriate by the investigator or approved 
representative to ensure understanding and compliance.
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the CRFs and on the SAE form when appropriate.  In the event of medication 
dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error and, if applicable, any associated adverse event(s) is 
captured on an adverse event (AE) CRF page (refer to Adverse Event Reporting (Section 8)
for further details).
5.4.4. Compliance
If the tablet/capsule count from the returned study medication, or information from the daily 
dosing log, indicates the subject has not taken all prescribed study drug, the subject and their 


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legally acceptable representative(s) will be counseled about the importance of compliance 
and how to take the study medication.
Compliance with the study medication will be calculated for each subject using the following 
formula:
     
Total number of tablets/capsules used 
x 100
   Total number of tablets/capsules supposed to be taken in each treatment period
It is assumed that a subject takes or returns all of the study medication provided.  The 
denominator will be either the total number of tablets/capsules supposed to be taken prior to 
discontinuation or the total number of tablets/capsules supposed to be taken until the end of 
the study period for early termination and completed subjects, respectively.
Subject compliance for study medication should meet at least 80% of ideal compliance at the 
end of each study period (Week 12 and Week 24, or early termination).  If the subject’s 
compliance is below this for any study period, this will be recorded as a protocol deviation.  
If the subject's compliance is greater than 120%, then they should be counseled on proper 
dosing of study medication, and recorded as a protocol deviation. In either case, subjects 
with evidence of continued poor study compliance should be withdrawn. Additionally, 
compliance with dosing will be assessed for at least 3 days prior to PK sampling at Visit 3 
and one day prior to urodynamic evaluation at Visit 5.
5.5. Drug Storage and Drug Accountability
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product  is stored in a securely locked area accessible only to authorized 
personnel, under recommended storage conditions, and in accordance with applicable 
regulatory requirements and the manufacturer’s instructions.  Study drug supplies must be 
stored separately from normal hospital/practice stocks.  Fesoterodine PR 4 mg and 8 mg 
tablets and oxybutynin XL should be stored according to the product label. The storage 
conditions stated in the Investigator Brochure may be superseded by the storage conditions 
indicated on the label. It is the responsibility of the investigator/site to properly store and 
monitor drug supplies and to report any deviations immediately.
The BIC product (2 and 4 mg) should be stored at 2°-8°C (36°- 46°F). Fesoterodine PR
tablets should be stored at room temperature (15°- 25°C, [59°- 77°F]).
The investigator or an approved representative (eg, pharmacist) must maintain adequate 
records documenting the receipt, use, loss or other disposition of the investigational 
product(s).  Pfizer may supply drug accountability forms that must be used or may approve 
the use of standard institution forms.  In either case, the forms must identify the 
investigational product, including batch or code numbers, and account for its disposition on a 


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subject-by-subject basis, including specific dates and quantities.  The forms must be signed 
by the individual who dispensed the drug, and copies must be provided to Pfizer.
At Visits 3, 5 and 7, subjects must return all unused study medication and packaging (eg,
bottles) to the investigator or an approved representative (eg, pharmacist). This includes all 
study medications (fesoterodine and oxybutynin) and packaging (eg, bottles), whether 
provided by Pfizer or obtained commercially.
At the end of the trial, Pfizer will provide instructions as to disposition of any unused 
investigational product, including packaging (eg, bottles).  If Pfizer authorizes destruction at 
the trial site, the investigator or an approved representative (eg, pharmacist) must ensure that 
the materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer.  Destruction must be 
adequately documented.
If oxybutynin XL (subjects >25 kg) is locally sourced (in exceptional circumstances, see 
Section 5.4.1), it should be sourced, stored and disposed of in accordance with label 
instructions and applicable regulatory requirements and regulations.
5.6. Concomitant Medication(s)
Prior and concomitant medication information will be collected for all subjects for a period 
of 30 days prior to screening and during the study.  Information collected must include 
medication, total daily dose, start date, stop date (if applicable), and primary reason for use.
5.6.1. Permitted Concomitant Therapies
The following concomitant therapies are permitted:

Stable usage/dosage of diuretics, alpha blockers, or tricyclic antidepressants is allowed if 
established for at least 3 months.

Stable use of desmopressin for enuresis is allowed if established for at least 3 months.

Subjects who are on an established regimen of electrostimulation therapy or bladder 
retraining (for at least 30 days prior to Visit 1) may remain on this for the duration of the 
study.
5.6.2. Prohibited Concomitant Therapies
The following concomitant therapies are not permitted:

Potent CYP3A4 inhibitors within 3 weeks prior to Visit 2 (baseline), or the expectation to 
start such a treatment during the trial (Appendix 1).

Medications capable of inducing CYP3A4 enzyme metabolism (Appendix 1).


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
Drugs for treatment of overactive bladder, (eg, darifenacin, oxybutynin (including 
intravesical), propiverine, tolterodine, fesoterodine, solifenacin and trospium).

Treatment with botulinum toxin A within 9 months prior to Visit 2 (baseline).

Drugs with antispasmodic, parasympathetic, or cholinergic effects.

Intermittent or unstable use of diuretics or alpha blockers, tricyclic antidepressants or any 
other treatment that may confound the results of the study, within 2 weeks or an 
appropriate washout period (whichever is longer) prior to starting the bladder diary or 
during the course of the study.

Electrostimulation therapy or bladder retraining if started within 30 days of Visit 1 or 
started during the study period.  Subjects who are on an established regimen may remain 
on this for the duration of the study.

Treatment with an investigational drug within 4 weeks or 5 half-lives (whichever is the 
longer) preceding study entry.
Previous treatment with these medications does not exclude subjects.  However, prohibited
concomitant medications must have a minimum washout appropriate to the drug so any 
clinical effect is at a minimum prior to beginning the bladder diary, and baseline urodynamic 
evaluations eg, 3 day minimum washout for oxybutynin, 7 day minimum washout for 
darifenacin and solifenacin. (Appendix 3).
Subjects should avoid the consumption of grapefruit juice as it interferes with the metabolism 
of fesoterodine.
The agreement of the subject and their legally-acceptable representative(s) should be gained 
before withdrawal of any therapies.
6. STUDY PROCEDURES
6.1. Visit 1 (Screening, Day -30 to Day -3)
The screening visit may be conducted over separate days, if required.  The following 
assessments will be performed:

Informed consent and subject assent prior to any screening assessments.

Obtain subject demographic details.

Evaluation of subject’s eligibility based on inclusion and exclusion criteria.

Perform medical history, including whether the subject is sensate (ie, physically able to 
experience the sensation of urgency).


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
Perform concomitant medication review.

Perform electrocardiogram.

Measure vital signs (blood pressure, heart rate, temperature) after the subject has been in 
a sitting/resting position for at least 5 minutes.

Perform physical examination and weight measurement. Note that weight determines 
formulation assignment at the Randomization Visit 2.

In subjects who are not performing intermittent catheterization, perform post-void 
residual (PVR) urine volume assessment using trans-abdominal ultrasound (eg, bladder 
scan) immediately after urination.  PVR assessment is not required in subjects who empty 
their bladder using intermittent catheterization unless otherwise indicated (Section 7.2.6).

Clinical laboratory testing (approximately 5.5 ml of blood; see Appendix 2) including:

Hematology.

Blood chemistry.

Serum pregnancy test for all female subjects of childbearing potential.

Urinalysis and urine microscopy, culture and sensitivity if indicated.

Dispense electronic data capture device and instruction booklet.

Train subject and their caregiver on use of bladder diary in the electronic data capture 
device.
Subjects who are found to have an active UTI during screening may continue screening 
activities on resolution of symptoms or treatment of the UTI to the satisfaction of the treating 
physician.  Screening assessments which have already been performed do not need to be 
repeated, unless otherwise indicated, or if they will be >30 days before Day 1 
(Randomization).
6.2. Visit 2 (Randomization/Baseline, Day 1)
The following assessments will be performed at the Randomization visit which can be over 
separate days:

Evaluation of subject’s eligibility based on inclusion and exclusion criteria.

Perform concomitant medication review.

Perform review of adverse events occurring after signing the informed consent document.


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
Complete Child Behavior Checklist (CBCL).

Complete Grooved Pegboard Test.

Review bladder diary for completeness and check subject understanding of completion.

Measure vital signs (blood pressure, heart rate, temperature) after the subject has been in 
a sitting/resting position for at least 5 minutes.

In subjects who are not performing intermittent catheterization, perform post-void 
residual (PVR) urine volume assessment using trans-abdominal ultrasound (eg, bladder 
scan) immediately after urination.  PVR assessment is not required in subjects who empty 
their bladder using intermittent catheterization unless otherwise indicated (Section 7.2.6).

Visual acuity and accommodation assessment.

Urine pregnancy test for all female subjects of childbearing potential.

Perform urodynamic assessment.

Train subject and their caregiver on use of electronic dosing log and check they still have 
the instruction booklet dispensed at Visit 1.

Dispense appointment & dosing record card (for oxybutynin subjects only).

Dispense study medication, administer and observe first dose.
The electronic data capture device should be collected at this visit if the subject is not 
subsequently randomized.
6.3. Week 1 Telephone Call (2 days)
The following assessments will be performed at Week 1 by telephone or clinic visit:

Concomitant medication review.

Review of adverse events.

Review dosing log and remind subjects randomized to fesoterodine 8 mg(Cohort 1), that 
they will need to change from the 4 mg dose to the 8 mg dose, and those randomized to 
fesoterodine 4 mg (in Cohort 2), that they will need to change from the 2 mg dose to the 
4 mg dose.

Dose optimization review for oxybutynin group subjects (see Section 6.4, not applicable 
to Cohort 2).


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6.4. Dose Optimization of Oxybutynin (Weeks 1, 2 and 3, 2 days) (Subjects >25 kg)
Subjects randomized to oxybutynin will have their dose adjusted at weekly intervals during 
the first 4 weeks of the study. Only oxybutynin tablets of one dosage strength will be 
dispensed at Visit 2.  There should be a minimum of 3 contacts between V2 and V3 to assess
efficacy and tolerability. The contacts with the subject's parent/guardian (caregiver) may be 
by telephone calls or clinic visits as considered clinically appropriate following assessment 
by the investigator. The investigator will record dose adjustments in the medical records and 
CRF, and the caregiver will keep a telephone appointment and dosing log, to record the 
instructions they have been given.  In addition, within a few days of any change in 
oxybutynin dose, there should be verification that caregivers have correctly understood the 
change in the subject's dose regimen eg, by telephone contact, or by confirmation of dosing 
information captured in the subject's dosing log.
Subjects randomized to oxybutynin will receive oxybutynin extended release (XL) tablets at 
a starting dose in accordance with approved pediatric labeling, and accepted practice eg, 
oxybutynin XL 5 mg once a day. Dose optimization will be achieved by either up- or down-
titration in 5 mg increments on an approximately weekly basis to achieve a balance of 
efficacy and tolerability.  Subjects who were on oxybutynin prior to study entry and who are 
randomized to the oxybutynin XL treatment group may, at the discretion of the investigator, 
restart at the equivalent pre-study total daily dose.
Subject's caregivers should receive a contact approximately 1 week after starting oxybutynin 
to assess efficacy and tolerability, and to adjust the dose as appropriate.  Healthcare 
professionals deciding the dose adjustments must be medically-qualified and have 
prescribing authority, eg, MD. Qualifications of delegates will be reviewed and agreed with 
the Pfizer study team as part of the standard site pre-trial assessment procedure, and prior to 
any subject enrollment.
Two additional contacts should be made, approximately 1 week apart, and the oxybutynin 
dose adjusted to optimum efficacy and tolerability up to the maximum recommended dose 
consistent with approved pediatric labeling, and accepted practice.  All subjects should 
achieve a minimum total daily dose of oxybutynin XL 10 mg by the end of the dose 
adjustment period at Week 4.  After Week 4, subjects taking oxybutynin XL should remain 
on the same dose for the subsequent 8 weeks of the study, and no further dose adjustments 
should be made. Subjects who are unable to tolerate a minimum total daily dose of 
oxybutynin XL 10 mg should be withdrawn.
Subjects who withdraw from the oxybutynin treatment arm for reasons of toleration, and who 
fulfill all continuation criteria, may be directly allocated by the investigator to fesoterodine 
treatment at either 4 mg or 8 (initially 4) mg/day for the remaining 12 week safety extension 
period if deemed appropriate during which dose reductions will not be permitted; if the 
fesoterodine is not tolerated then the subject will be withdrawn.  All subsequent study visits 
should be scheduled relative to the start of the extension phase.
The following assessments will also be performed:


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
Concomitant medication review;

Review of adverse events;

Review dosing log.
6.5. Visit 3 (Week 4, 14 days)
The following assessments will be performed at Visit 3:

Concomitant medication review;

Review of adverse events;

Measure weight and vital signs (blood pressure, heart rate, temperature) after the subject 
has been in a sitting/resting position for at least 5 minutes;

Urinalysis and urine microscopy, culture and sensitivity if indicated;

In subjects who are not performing intermittent catheterization, perform post-void 
residual (PVR) urine volume assessment using trans-abdominal ultrasound (eg, bladder 
scan) immediately after urination.  PVR assessment is not required in subjects who empty 
their bladder using intermittent catheterization unless otherwise indicated (Section 7.2.6).

For fesoterodine arms only, pharmacokinetic blood samples taken (maximum of 3 
samples, approximately 2 ml of blood per sample; (Appendix 2).

For fesoterodine arms only, pharmacogenomic blood sample taken (one sample, 
approximately 2 ml of blood; (Appendix 2) if the subject does not have prior laboratory 
documentation of CYP2D6 genotype.

Urine pregnancy test for all female subjects of childbearing potential.

Review dosing log and record time of last 3 doses of fesoterodine and re-train if 
necessary, and review electronic capture device.

Study medication return/count.

Dispense study medication.
6.6. Visit 4 (Week 8, 14 days) 
The following assessments will be performed at Visit 4 by telephone or clinic visit:

Concomitant medication review.

Review of adverse events.


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
Review dosing log.
6.7. Visit 5 (Week 12, -7 days to +14 days)
Visit 5 may be performed over 2 separate days if required.  The following assessments will 
be performed:

Perform concomitant medication review.

Perform review of adverse events.

Complete Child Behavior Checklist (CBCL).

Complete Grooved Pegboard Test.

Review bladder diary for completeness and check subject understanding of completion.

Perform physical examination and weight measurement.
Measure vital signs (blood pressure, heart rate, temperature) after the subject has been in 
a sitting/resting position for at least 5 minutes.

In subjects who are not performing intermittent catheterization, perform post-void 
residual (PVR) urine volume assessment using trans-abdominal ultrasound (eg, bladder 
scan) immediately after urination.  PVR assessment is not required in subjects who empty 
their bladder using intermittent catheterization unless otherwise indicated (Section 7.2.6).

Visual acuity and accommodation assessment.

Clinical laboratory testing (approximately 5.5 ml of blood; see Appendix 2) including:

Hematology.

Blood chemistry.

Urine pregnancy test for all female subjects of childbearing potential.

Urinalysis and urine microscopy, culture and sensitivity if indicated.

For subjects who had oxybutynin during the active comparator phase (Cohort 1, subjects 
>25 kg), pharmacogenomic blood sample taken (one sample, approximately 2 ml of 
blood; (Appendix 2) if the subject does not have prior laboratory documentation of 
CYP2D6 genotype and they are to continue in the safety extension).

Perform urodynamic assessment including imaging of upper urinary tract if appropriate.  
Subjects who demonstrate a clinically relevant increased detrusor pressure compared to 


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baseline pressure or other urodynamic findings suggestive of worsening condition should 
not be allowed to continue into the safety extension phase.

Review dosing log, and record details of time of last dose of fesoterodine or oxybutynin, 
and review electronic capture device.

Collect appointment & dosing record card (for oxybutynin subjects only).

Study medication return/count; assess compliance with study medication regimen.

Dispense study medication.
6.8. Visit 6 (Week 18, 14 days)
The following assessments will be performed at Visit 6 by telephone or clinic visit:

Concomitant medication review;

Review of adverse events;

Review dosing log.
6.9. Visit 7 (Week 24, -7 days to +14 days)
The following assessments will be performed at Visit 7:

Concomitant medication review.

Review of adverse events.

Complete Child Behavior Checklist (CBCL).

Complete Grooved Pegboard Test.

Perform physical examination and weight measurement.

Measure vital signs (blood pressure, heart rate, temperature) after the subject has been in 
a sitting/resting position for at least 5 minutes.

Visual acuity and accommodation assessment.

Clinical laboratory testing (approximately 5.5 ml of blood; see Appendix 2) including:

Hematology.

Blood chemistry.


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
Urine pregnancy test for all female subjects of childbearing potential.

Urinalysis and urine microscopy, culture and sensitivity if indicated.

In subjects who are not performing intermittent catheterization, perform post-void 
residual (PVR) urine volume assessment using trans-abdominal ultrasound (eg, bladder 
scan) immediately after urination.  PVR assessment is not required in subjects who empty 
their bladder using intermittent catheterization unless otherwise indicated (Section 7.2.6).

Review dosing log.

Collect electronic data capture device.

Study medication return/count; assess compliance with study medication regimen.
6.10. Visit 8 (Follow-up, Week 26 +14 days)
The following assessments will be performed at Visit 8 by telephone or clinic visit:

Concomitant medication review;

Review of adverse events.
Subjects who withdraw early from the study and who have taken at least 1 dose of study 
medication should be contacted by telephone approximately 2 weeks after stopping study 
medication.
6.11. Additional Contacts
Other contacts may also be made, as appropriate, to verify changes in dose, and to provide 
reminders to the subject to complete the bladder diary and daily dosing log. Contacts may 
take the form of telephone calls. Subjects should be contacted:

At Week 1 to verify that they have correctly understood their dose regimen and if 
necessary to remind the subject to complete their daily dosing log.  Subjects randomized 
to fesoterodine 8 mg, who have started at 4 mg should be reminded to start taking the 
8 mg dose. Subjects randomized to fesoterodine 4 mg in Cohort 2 (≤25 kg), who have 
started at 2 mg should be reminded to start taking the 4 mg dose.

1 week after Visit 5, to verify that subjects previously taking oxybutynin have correctly 
understood their dosing regimen, and a reminder for those allocated to the 8 mg dose that 
they need to change from the initial 4 mg to the 8 mg dose.

Approximately 1 week prior to Visit 2 (unless the randomization visit occurs within 
1 week of Screening (V1)) and prior to Visit 5, to remind the subject to complete the 
bladder diary and to review instructions on proper completion if needed. Subjects and/or 


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their caregivers should be re-educated and re-trained if review of data suggests that the 
bladder diary or dosing log are not being correctly completed.
6.12. Subject Withdrawal
In France, see Appendix 5.
If treatment is inadequate or the subject cannot tolerate the dose of fesoterodine or 
oxybutynin, consideration should be given to withdrawal.
Subjects who withdraw from the oxybutynin treatment arm (Cohort 1, >25 kg) for reasons of 
toleration, and who fulfill all continuation criteria, may be directly allocated by the 
investigator to fesoterodine treatment at either 4 mg or 8 mg/day for the remaining 12 week 
safety extension period if appropriate.  All subsequent study visits should be scheduled 
relative to the start of the extension phase.
Subjects may withdraw from the study at any time at their own, or their legal 
representative(s) request, or they may be withdrawn at any time at the discretion of the 
investigator or sponsor for safety or behavioral reasons, or the inability of the subject to 
comply with the protocol required schedule of study visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject 
to return all unused investigational product(s) and electronic diary equipment, request the 
subject to return for a final visit, if applicable, and follow-up with the subject regarding any 
unresolved adverse events (AEs).
Subjects in the fesoterodine groups who withdraw prior to Week 4 should have PK samples 
obtained as per Visit 3.
If a subject withdraws from the study prior to Visit 5 (Week 12), the same assessments as at 
Visit 5 should be performed if possible. Urodynamic assessment should only be performed 
in subjects who have been on a stable dose of study medication for at least 2 weeks, and who 
have not missed any doses in the 3 days prior to the visit.
If a subject withdraws from the study after Visit 5, the same assessments as at Visit 7 (Week 
24) should be performed if possible.
Subjects who withdraw early from the study and who have taken at least 1 dose of study 
medication should also be contacted by telephone approximately 2 weeks after stopping 
study medication, and have the same assessments performed as at Visit 8 (Week 26).
If the subject withdraws from the study, and they or their legal representative(s) also 
withdraw consent for disclosure of future information, no further evaluations should be 
performed, and no additional data should be collected.  The sponsor may retain and continue 
to use any data collected before such withdrawal of consent.


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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, that may make the test unfeasible to 
perform.  In these cases the investigator will take all steps necessary to ensure the safety and 
well being of the subject.  When a protocol required test cannot be performed the investigator 
will document the reason for this and any corrective and preventive actions which they have
taken to ensure that normal processes are adhered to as soon as possible.  The study team will 
be informed of these incidents in a timely fashion.
7.1. Efficacy Assessments
7.1.1. Urodynamic Assessments
Urodynamic assessment will be performed by persons qualified to perform pediatric 
urodynamics by education, training and experience, in accordance with International 
Children’s Continence Society standards at Visit 2 (baseline) and Visit 5 (Week 12),
(Neveus, et al, 2006).3 It should be performed with the subject awake, or if necessary under 
sedation, but general anesthesia is not permitted under this protocol.  At Visit 2, previous 
treatment with prohibited concomitant medications must have a minimum washout 
appropriate to the drug so any clinical effect is at a minimum prior to baseline urodynamic 
evaluations eg, 3 day minimum washout for oxybutynin, 7 day minimum washout for 
darifenacin and solifenacin.  At Visit 5 (Week 12), the time of the last dose of study 
medication (fesoterodine 2 mg, fesoterodine 4 mg, fesoterodine 8 mg or oxybutynin XL) 
prior to the urodynamic assessment should be recorded, and when possible urodynamic 
assessments should be completed approximately 4-6 hours post-dose.  Typically a 
multichannel technique through a dual-lumen urodynamic catheter should be used. The 
bladder will be filled at a constant fill rate with test medium warmed to body temperature, 
until maximum cystometric capacity is reached as defined below, or in the judgement of the 
investigator, filling should be stopped.
Expected bladder capacity for age (mL) = [30 + (child’s age in years x 30)] mL up to the age 
of 12 years.  From the age of 12 years onwards EBC is relatively constant at 390 ml.
The infusion rate should be based on 5% of expected bladder capacity per minute and will be 
recorded on the CRF.
The following will be evaluated:

Maximum cystometric capacity, defined as maximal tolerable cystometric capacity, until 
voiding or leaking begins, or at a pressure of 40 cm H20.

Detrusor pressure at maximum bladder capacity.

Maximum detrusor pressure.


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
Presence of involuntary detrusor contractions (IDC).

Bladder volume at first IDC, if present.

Bladder wall compliance (ml/cm H2O), defined as volume/pressure during that change 
in bladder volume.

Presence of subtraction test (eg cough) on urodynamic trace.
Where possible, both V2 and V5 urodynamic assessments for a subject should be performed 
by the same person.  For all subjects, eligibility for study entry or continuation on the basis of 
urodynamic criteria will be verified by a central reader. Only the central reader’s assessment 
of the urodynamic evaluation should be recorded in the CRF.
Prophylactic antimicrobial treatment may be administered at the discretion of the investigator 
and in line with local practice.
Attempts should be made to perform a urodynamic assessment in subjects who withdraw 
prior to Visit 5 (Week 12) and after a minimum of 2 weeks on a stable dose of study 
medication, provided that they have not missed any doses in the three days prior to the visit.
At Visit 5 (or end of active comparator/efficacy phase), subjects who demonstrate a clinically 
relevant increased detrusor pressure, or other urodynamic findings suggestive of worsening 
condition compared to baseline, should not be allowed to continue into the safety extension 
phase.  In this case, consideration should be given to imaging of upper urinary tract (for 
example, videourodynamics or ultrasound) according to accepted local standard of care in 
subjects with VUR, or other conditions that predispose to upper urinary tract dysfunction or 
damage.
Full technical details are provided separately.
7.1.2. Bladder Diary
A bladder diary will be completed for 3 consecutive days (with a minimum of 2 days) during 
the week prior to Visit 2 (baseline) and Visit 5 (Week 12), using an electronic capture device.  
The bladder diary may be completed over a weekend, if this is more convenient for the 
subject.  Completion of the bladder diary prior to Visit 2 (baseline) should be begun only 
after previous treatment with prohibited concomitant medications has undergone a minimum 
washout appropriate to the drug so any clinical effect is at a minimum eg, 3 day minimum 
washout for oxybutynin, 7 day minimum washout for darifenacin and solifenacin. Daily 
micturition or catheterization frequency, volume of urine from each micturition or 
catheterization (for one of the days), incontinence episodes and urgency episodes (if 
appropriate) will be recorded.  Urinary urgency is defined according to the International 
Children’s Continence Society standards as the sudden and unexpected experience of an 
immediate need to void (Neveus, et al, 2006).3


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A proxy (eg, parent or teacher) may assist with completion of the diary if necessary. Contact 
should be made approximately 1 week prior to Visit 2 (unless the randomization visit occurs 
within 1 week of screening (V1)) and also prior to Visit 5, to remind the subject to complete 
the bladder diary and to review instructions on proper completion.  Bladder diary completion 
may be verified via remote review of electronic data.
7.2. Safety Assessments
7.2.1. Vital Signs
Blood pressure, temperature and pulse rate should be measured at Visit 1, Visit 2, Visit 3, 
Visit 5 and Visit 7. This schedule of measurements should provide adequate indication of 
any clinically relevant changes.  However, if vital signs show a clinically relevant change 
from baseline, then safety monitoring will occur at a minimum of monthly intervals, or more 
frequently as clinically appropriate, until the abnormality resolves.  The measured results will 
be assessed in the context of age appropriate norms.
Temperature may be taken via oral, tympanic or axillary routes as per local accepted practice.
Digital devices are permitted; however, mercury thermometers should not be used.  The same 
method should be used for the subject throughout the study.
Blood pressure should be measured using a pediatric or appropriately sized 
sphygmomanometer in the sitting/resting position with the subject’s arm supported at the 
level of the heart, and recorded to the nearest mmHg.  The same arm (preferably the 
dominant arm) will be used throughout the study.
The same size blood pressure cuff, which has been properly sized and calibrated, will be used 
to measure blood pressure each time.  The use of automated devices for measuring BP and 
pulse rate are acceptable, although, when done manually, pulse rate will be measured in the 
brachial/radial artery for at least 30 seconds.
7.2.2. Physical Examination
A physical examination will be performed at V1/Screening, and will include the following 
systems:

General appearance (including weight);

Skin;

Head, eyes, ears, nose, and throat; including visual acuity and accommodation (see 
Section 7.2.4).

Respiratory;

Cardiovascular;


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
Gastrointestinal;

Musculoskeletal;

Neurological.
If physical examinations show a clinically relevant change from baseline, then safety 
monitoring will occur at a minimum of monthly intervals, or more frequently as clinically 
appropriate, until the abnormality resolves.  Any clinically significant negative changes from 
the entry examination will be recorded as adverse events.
7.2.3. Weight Measurements
Weight will be recorded at Screening and used to assess eligibility, to determine which 
cohort the subject should be enrolled into and for stratification purposes (for Cohort 1, >25 
Kg only).  Subsequently weight will be recorded at Visit 3, Visit 5, and Visit 7.  All weight 
measurements should be standardized using the same equipment and measuring technique for 
an individual subject.  Any clinically significant change in weight should be reported as an 
adverse event.
7.2.4. Visual Acuity and Accommodation
Visual acuity will be assessed for each eye using the Snellen method, using an optotype that 
is appropriate to the child’s intellectual development at Visit 2, Visit 5, and Visit 7.
Amplitude of accommodation will be assessed by the push up test to assess minimum 
focusing distance at Visit 2, Visit 5, and Visit 7. The subject will focus on a single letter of 
the 20/40 line of an eye chart (appropriate optotype) and this will be moved slowly toward 
the subject until it blurs. At this point the distance from eye to letter will be measured. An 
attempt will be made to record 3 measurements and entered in the eCRF.
For both visual acuity and accommodation assessments the same optotype will be used for a 
specific subject throughout the study to ensure standardization and validity.
7.2.5. Electrocardiogram
ECGs should be performed after the subject has rested quietly for at least 10 minutes. A 
single 12-lead ECG will be obtained on all subjects at screening (V1).
The ECG at the screening visit should have no clinically significant abnormalities for the 
subject to be included in the study.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve consistent ECG recordings.  The ECG will be 
reviewed by a central reader for any clinically significant abnormality.


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7.2.6. Post-Void Residual (PVR) Urine Volume 
PVR urine volume in subjects not performing CIC will be assessed using trans-abdominal 
ultrasound (eg, bladder scan) immediately after urination.  If at screening, the measured 
volume is higher than 20 ml (see exclusion criterion 13), this should be confirmed by one 
repeated reading.  The subject will be asked to void again.  Repeat PVR assessment should 
be made as soon as possible and no more than 5 minutes, after the second void.  If the 
volume present in the bladder is still above the limit the subject should not be included.
Assessment of PVR in subjects performing CIC should also be carried out in the event that 
they experience >1 UTI during the study.
PVR measurements should be performed at V1 (Screening), V2 (Baseline), V3 (W4), V5 
(W12), and V7 (W24).
7.2.7. Clinical Laboratory Evaluation
Safety laboratory tests will be performed at Visit 1 (Screening) and additional visits as 
below, or as needed to follow-up on significant findings (Section 8.5.2).
Safety Laboratory (see Appendix 2)
Hematology – V1, V5, V7
Chemistry - V1, V5, V7
Urinalysis – V1, V3, V5, 
V7
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count with 
differential as below:
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
GOT (AST)
GPT (ALT)
GGT
Total and direct bilirubin
Alkaline phosphatase
LDH
CPK
BUN
Creatininec
Uric acid
Total protein 
Sodium
Potassium
Chloride
Albumin
Corrected calcium
Bicarbonate
Phosphorus
Glucose (non fasting) 
Urine will be tested for 
the following using a 
urine dipstick:
pH
Specific gravity
Leukocyte esterase
Nitrites
Glucose
Protein
Blood
Ketones
Urine microscopy, 
culture and sensitivitya
Pregnancy Testb (serum 
V1, urine at subsequent 
Visits, 2, 3, 5, and 7)
Unanonymized 
pharmacogenomic 
sample (V3 and V5)d
PK sample (V3 only)d


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a Urine microscopy, culture and sensitivity to be performed in the event of the presence of symptoms (eg, fever, flank 
pain), positive leucocytes and/or nitrites on urinalysis, or if the subject has a documented history of vesicoureteral 
reflux (VUR).
Subjects who are found to have an active UTI during screening as defined in exclusion criterion 12 may continue 
screening activities on resolution of symptoms or treatment of the UTI to the satisfaction of the treating physician.
b Females of childbearing potential only (9 years old or have experienced menarche, whichever is earlier). Pregnancy 
tests may also be repeated as per request of IRB/IECs or if required by local regulations.
cWhen indicated, the investigator may request calculation of an estimated GFR using the Schwartz equation GFR = (k x 
H)/Cr where k = constant, H =  Height (length) and Cr = Creatinine. In this case, the laboratory will need to be 
provided with the subject's height in cm.
d At V3 PG and PK samples are for fesoterodine group subjects only. At V5 (or early withdrawal from the active 
comparator/efficacy phase), only subjects who were on oxybutynin who will continue into the safety extension phase
and who do not have prior laboratory documentation of their CYP2D6 genotype (PG).
7.2.8. Childhood Behavior Checklist (CBCL) (Appendix 4)
The CBCL is a questionnaire by which a child's problem behaviors and competencies can be 
assessed.  This instrument will be completed by the parent or caregiver.  The CBCL can also 
be used to measure a child's change in behavior over time or following a treatment.  The first 
section of this questionnaire consists of 20 competence items and the second section consists 
of 120 items on behavior or emotional problems.  For the purpose of this trial, the parent or 
caregiver, should preferably be the same person at each visit, and will be asked to complete 
113 items on behavior and emotional problems. The parent or caregiver will be asked to 
describe their child as of ‘now’.
The CBCL will be completed at Visit 2, Visit 5 and Visit 7.
7.2.9. Grooved Pegboard Test (GPT)
The Grooved Pegboard Test is a manipulative dexterity test that assesses psychomotor speed, 
fine motor control, and rapid-visual motor coordination. It consists of a small board of 25 
holes with randomly positioned slots.  Pegs with a key along one side must be rotated to 
match the hole before they can be inserted. Time to completion, number of pegs dropped, 
and number of pegs placed correctly are scored.
The GPT will be assessed at Visit 2, Visit 5 and Visit 7.
7.2.10. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at screening, before investigational product 
administration at the baseline visit and at the end of treatment visit (both urine).  A negative 
pregnancy result is required before the subject may receive the investigational product.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected), repeated at Visits 3 
and 5, and 7 at the end of the treatment to confirm the subject has not become pregnant 
during the study.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.


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7.3. Pharmacokinetic Assessments
The study drug dose on the day of Visit 3 is to be administered at the clinic, when possible.  
Subjects will be asked to maintain consistency of dosing and to record the dosing times of 
fesoterodine on the 3 days prior to Visit 3.  The actual dates and times of blood sample 
collection as well as the last three doses of fesoterodine will be recorded in the CRF.  
Subjects randomized to treatment with oxybutynin (in Cohort 1, >25 kg) will not be required 
to provide blood samples for pharmacokinetic assessment.
7.3.1. Plasma for Analysis of 5-HMT
At Visit 3 (Week 4), blood samples (2 ml each) to provide approximately 1 mL of plasma for 
the analysis of 5-HMT will be collected into appropriately labeled tubes containing sodium 
heparin as anticoagulant.  Samples will be centrifuged at approximately 1700 g for about 10 
minutes at 4C.  The plasma will be stored in appropriately labeled screw-capped 
polypropylene tubes at approximately -20C or lower within 1 hour of collection.
A maximum of three (3) pharmacokinetic blood samples will be collected from each subject 
assigned to receive fesoterodine treatment.  Sampling times for the PK samples will be 
determined on an individual subject basis, using the following general guidance:

If the dose is administered at the clinic, a blood sample will be obtained just prior to dose 
administration.

If the dose is taken up to 3 hours before coming to the clinic, a blood sample will be 
obtained just after arrival at the clinic.

One blood sample will be obtained from each subject at about 5 hours (4-6 hrs) post-
dose.

When it is possible for a subject to remain at the clinic, a blood sample may be drawn 
8-10 hours after dose administration.
Samples may be used for future metabolite identification and/or further evaluation of the 
bioanalytical method, such as assay reproducibility. No additional samples are required for 
this testing, and all samples will be discarded following analysis. These data will be used for 
internal exploratory purposes and will not be included in the clinical report.
Samples will be analyzed for 5-HMT (also referred to as SPM7605) using a validated liquid 
chromatography/tandem mass spectrometry (LC/MS/MS) method in compliance with Pfizer 
standard operating procedures.
7.3.2. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.


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7.4. Pharmacogenomics Evaluations
Variation in the CYP2D6 gene plays a role in metabolism of active metabolite (5-HMT) of 
fesoterodine.  The alleles which will be genotyped are *3, *4, *5, *6, *7, *8, *10, *14, *17, 
*18, *21, *36, *41 and duplication.  Homozygous or heterozygous combinations of *3, *4, 
*5, *6, *7, *8, *14, *17, *18, and *21 will be classified as poor metabolizer (PM) of 
CYP2D6.  Other genotypes will be classified as extensive metabolizer (EM).
For those subjects who are randomized to fesoterodine and who do not have sufficient 
laboratory documentation, a 2-ml whole blood sample will be collected for CYP2D6 
genotype analysis.  All samples will be discarded following analysis.  Subjects who have 
prior laboratory documentation of their CYP2D6 genotype will not be required to submit a 
blood sample for pharmacogenomics.  Subjects randomized to treatment with oxybutynin 
will also not be required to provide a sample for pharmacogenomic assessment, unless they 
continue in the fesoterodine safety extension.
7.4.1. Shipment of Pharmacogenomics Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.5. Dosing Log
A dosing log should be completed by the subject or proxy, and the total number of 
tablets/capsules taken, time of dose, for subjects ≤ 25 kg whether the dose of fesoterodine 
was swallowed or sprinkled, as well as the reason for any change, recorded on a daily basis, 
using an electronic capture device. The dosing log should be completed every day.  A proxy 
(eg, parent) may assist with completion of the dosing log if necessary.
Contact should be made with the subject's parent/guardian (caregiver) at Week 1 to verify 
that they have correctly understood their dose regimen and to remind them to complete their 
daily dosing log if needed.  Evaluation of the dosing log may be performed via remote 
electronic review. The device will need to be reset at Visits 2 and 5, or in the event of early 
termination from oxybutynin treatment (in Cohort 1, >25 kg only), this will need to be reset
at start of the fesoterodine dosing in the safety extension phase.
The time of the last three doses of fesoterodine prior to V3, and the time of the last dose of 
fesoterodine and oxybutynin prior to V5 should be captured on the CRF.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.


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For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
trial.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides their assent and the legal representative provides their 
informed consent, which is obtained prior to the subject’s participation in the study, ie, prior 
to undergoing any study-related procedure and/or receiving investigational product, through 
and including 28 calendar days after the last administration of the investigational product.  
Serious adverse events occurring to a subject after the active reporting period has ended 
should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, 
all serious adverse events that the investigator believes have at least a reasonable possibility 
of being related to study drug are to be reported to the Sponsor.

Adverse events (serious and non-serious) should be recorded on the CRF from the time 
the subject has taken at least one dose of study treatment through last subject visit.
8.3. Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage.  Examples of adverse events include but are not 
limited to:

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;


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
Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure via breast-feeding;

Medication error;

Occupational exposure.
8.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows:

Test result is associated with accompanying symptoms, and/or;

Test result requires additional diagnostic testing or medical/surgical intervention, and/or;

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy, and/or;

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death.


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
Is life-threatening (immediate risk of death).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions).

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.5.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section on Serious Adverse Event Reporting Requirements).
8.5.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
concurrent with abnormal elevations in total bilirubin that meet the criteria outlined below in 
the absence of other causes of liver injury are considered potential cases of drug-induced 
liver injury (potential Hy’s Law cases) and should always be considered important medical 
events.
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions. Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range
who subsequently present with AST or ALT 3 times the upper limit of normal (X ULN) 
concurrent with a total bilirubin 2 X ULN with no evidence of hemolysis and an 
alkaline phosphatase 2 X ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition mentioned 
above:


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
For subjects with pre-existing AST or ALT baseline values above the normal range:
AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN (whichever 
is smaller).
Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: Total 
bilirubin increased by one time the upper limit of normal or ≥3 times the upper limit of 
normal (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. In addition to repeating 
AST and ALT, laboratory tests should include albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/INR and 
alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
subject, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected. Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted. All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for LFT abnormalities identified at the 
time should be considered potential Hy’s Law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs. Such 
potential Hy’s Law cases should be reported as serious adverse events.
8.6. Hospitalization
Adverse events reported from studies associated with hospitalization or prolongations of 
hospitalization are considered serious.  Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria.  Admission also includes transfer within the hospital 
to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit).
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;


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
Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include:

Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (eg, for work-up 
of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.7. Severity Assessment
TABLE 1: SEVERITY ASSESSMENT
If required on the adverse event case report forms, the investigator will use the 
adjectives MILD, MODERATE, or SEVERE to describe the maximum intensity of the 
adverse event.  For purposes of consistency, these intensity grades are defined as 
follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.


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Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided.  If the investigator does not know whether or not the
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (Reporting 
Requirements, Section 8.12). If the investigator's causality assessment is "unknown but not 
related to investigational product", this should be clearly documented on study records.
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 
CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
8.9. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy (also 
referred to as in-utero [EIU]) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or being exposed 
(eg, due to treatment or environmental exposure) after discontinuing or having been
directly exposed to the investigational product.
2. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed during 
his partner’s pregnancy.
If any study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer Drug Safety Unit on a Serious Adverse Event Form and Exposure 
in Utero (EIU) Supplemental Form, regardless of whether an SAE has occurred. In addition, 
the investigator must submit information regarding environmental exposure to a Pfizer 
product in a pregnant woman (eg, a subject reports that she is pregnant and has been exposed 
to a cytotoxic product by inhalation or spillage) using the EIU Form.  This must be done 
irrespective of whether an adverse event has occurred and within 24 hours of awareness of 
the exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).


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Follow-up is conducted to obtain pregnancy outcome information on all EIU reports with an 
unknown outcome.  The investigator will follow the pregnancy until completion or until 
pregnancy termination and notify Pfizer of the outcome as a follow up to the initial EIU
Form.
In the case of a live birth, the structural integrity of the neonate can be assessed at the time of 
birth.  In the event of a termination, the reason(s) for termination should be specified and, if 
clinically possible, the structural integrity of the terminated fetus should be assessed by gross 
visual inspection (unless pre-procedure test findings are conclusive for a congenital anomaly 
and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are classified as serious adverse 
events follows:

“Spontaneous abortion” includes miscarriage and missed abortion.

All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events.  In addition, any infant death after 1 month should 
be reported as SAEs when the investigator assesses the infant death as related or possibly 
related to the exposure to investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Exposure in Utero Pregnant 
Partner Release of Information Form to deliver to his partner.  The Investigator must 
document on the Exposure in Utero Form that the subject was given this letter to provide to 
his partner.
8.10. Withdrawal Due to Adverse Events (See section on Subject Withdrawal)
Withdrawal due to adverse event should be distinguished from withdrawal due to insufficient 
response, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event CRF page.
When a subject withdraws due to a serious adverse event, the serious adverse event must be 
reported in accordance with the reporting requirements defined below.


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8.11. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be 
questioned about adverse events.
8.12. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
8.12.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator
awareness of the event.  In particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available 
adverse event information.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event reports as well as to the initial and 
follow-up reporting of exposure during pregnancy and exposure via breast-feeding cases.
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Information on 
other possible causes of the event, such as concomitant medications and illnesses must be 
provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative.
8.12.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the CRFs as well as 
on the form for collection of serious adverse event information.


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8.12.3. Sponsor Reporting Requirements to Regulatory Authorities
Adverse events reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan, which will be dated and maintained by the 
Sponsor.  This document may modify the plans outlined in the protocol; however, any major
modifications of the primary endpoint definition and/or its analysis will also be reflected in a
protocol amendment.
As the dosing of lighter subjects is dependent on the availability of an age-appropriate Beads-
in-Capsule formulation, in the event that it is not possible to develop an age-appropriate 
formulation, then lighter subjects will not be dosed; the end of the trial will be defined by the 
completion of the heavier >25 Kg cohort and the analyses specified below for the lighter 
cohort (Cohort 2) will not be performed.
9.1. Sample Size Determination
Cohort 1 (>25 kg)
A sample size of 33 evaluable subjects per group is sufficient to give a power of at least 90% 
to detect a change from baseline of 70 mL in the primary endpoint, maximum cystometric 
capacity (MCC), when the standard deviation of the change from baseline is 120 mL.  This 
calculation assumes the testing will be performed at a two-sided 5% significance level and is 
based on results observed from the two highest dose periods (each 4 weeks) in previous 
tolterodine neurogenic bladder studies 583E-URO-0581-001, 583E-URO-0581-002 and 
583-URO-0581-003, as well as published data from studies of oral oxybutynin in neurogenic 
bladder subjects.  An oxybutynin active comparator arm will enable comparisons between 
fesoterodine and oxybutynin to be made; therefore a sufficient number of subjects will be 
randomized into Cohort 1 to ensure a total of approximately 99 subjects (33 evaluable 
subjects per arm) are evaluable at Week 12.
This sample size will also provide a 2-sided 95% confidence interval for the change from 
baseline in MCC of approximately ± 70 mL around the point estimate for the difference 
between each fesoterodine arm and oxybutynin, with 90% coverage probability.  Using this 
estimation approach, these confidence intervals will be used to assess the comparability of 
each fesoterodine dose and oxybutynin.
Cohort 2 (≤25 kg)
A sample size of approximately 25 evaluable subjects per arm will provide a 2-sided 95% 
confidence interval for the change from baseline in maximum cystometric capacity (MCC) of 
approximately ± 55 mL around the point estimate for the mean, with 80% coverage 
probability. This assumes a standard deviation of 120 mL. This is based on results observed 


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from the two highest dose periods (each 4 weeks) in previous tolterodine neurogenic bladder
studies 583E-URO-0581-001, 583E-URO-0581-002 and 583-URO-0581-003, as well as 
published data from studies of oral oxybutynin in neurogenic OAB patients.  It is planned 
that a sufficient number of subjects will be randomized into this cohort to ensure a total of 
approximately 50 subjects (25 evaluable subjects per arm) are evaluable at Week 12.
9.2. Efficacy Analysis
9.2.1. Efficacy Analysis Sets
The following efficacy analysis sets will be determined separately for each cohort.
9.2.1.1. Full Analysis Set (FAS)
The Full Analysis Set for each cohort will include all subjects who have been randomized 
and received at least one dose of study medication and have provided baseline primary 
endpoint data.
9.2.1.2. Per Protocol Analysis Set (PPAS)
The Per Protocol Analysis Set for each cohort will include all subjects who have completed 
the active comparative phase of the study, and who have not violated any of the 
inclusion/exclusion criteria or deviated from the protocol in a way that could affect the 
efficacy outcome of the study.
The PPAS for each cohort will be defined prior to unblinding the study.
9.2.2. Analysis of Primary Endpoint
9.2.2.1. Cohort 1 (>25 kg)
Change from baseline to Week 12 in the primary endpoint will be analysed using an 
ANCOVA including terms for treatment group, baseline (for the endpoint being analyzed) 
and weight.  The Least Squares mean change from baseline for each treatment group, 
standard error, 95% confidence intervals and p-values associated with the Least Squares 
mean changes from baseline will be presented.
All endpoints will also be summarized descriptively for each treatment group, by timepoint, 
using: N, mean, standard deviation, median, minimum and maximum.  Should any of the 
assumptions of the analysis methods not be adequately met, alternative procedures will be 
used and fully documented.
The following primary comparisons of interest will be assessed:

Change from Baseline to Week 12 for fesoterodine 4 mg.

Change from Baseline to Week 12 for fesoterodine 8 mg.


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The Least Squares means and 95% confidence intervals for the difference between each 
fesoterodine dose group and oxybutynin will also be calculated.
The following secondary comparisons will be assessed using 95% confidence intervals for 
the difference between treatment means (for the change from baseline to Week 12):

Fesoterodine 4 mg vs Oxybutynin.

Fesoterodine 8 mg vs Oxybutynin.
As these secondary comparisons are based on an estimation approach, no formal statistical 
hypothesis testing will be performed.  Conclusions will be based on point estimates and 
confidence intervals.
The primary analysis will be based on the Cohort 1 Full Analysis Set (FAS1).  The secondary 
analysis set will be the Cohort 1 Per Protocol Analysis Set (PPAS1).
For the PPAS analysis no imputation techniques for missing data will be employed.  For the 
FAS analysis a Baseline Observation Carried Forward (BOCF) and a Last Observation 
Carried Forward (LOCF) algorithm will be used for missing data.
Data from the active comparator phase for this cohort may be summarised, analysed and 
reported after all subjects in this cohort have either completed or withdrawn prior to the 
Week 12 visit (ie, prior to formal completion of the study).  The results of these analyses will 
be available to limited members of the study team as a management tool in order to aid 
decision making, and may also be shared with regulators in order to facilitate timely 
discussion of the overall program; they will not be used to stop or modify the design of the 
study.
9.2.2.2. Cohort 2 (≤25 kg)
Change from baseline to Week 12 in the primary endpoint will be analyzed using an 
ANCOVA including terms for treatment group and baseline (for the endpoint being 
analyzed).  The Least Squares mean change from baseline for each treatment group, standard 
error and 95% confidence intervals associated with the Least Squares mean changes from 
baseline will be presented.
All endpoints will also be summarized descriptively for each treatment group, by timepoint, 
using: N, mean, standard deviation, median, minimum and maximum.  Should any of the 
assumptions of the analysis methods not be adequately met, alternative procedures will be 
used and fully documented.
The following primary comparisons of interest will be assessed:

Change from Baseline to Week 12 for fesoterodine 2 mg.

Change from Baseline to Week 12 for fesoterodine 4 mg.


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As these comparisons are based on an estimation approach, no formal statistical hypothesis 
testing will be performed.  Conclusions will be based on point estimates and confidence 
intervals.
The primary analysis will be based on the Cohort 2 Full Analysis Set (FAS2).  The secondary 
analysis set will be the Cohort 2 Per Protocol Analysis Set (PPAS2).
For the PPAS analysis no imputation techniques for missing data will be employed.  For the 
FAS analysis a Baseline Observation Carried Forward (BOCF) and a Last Observation 
Carried Forward (LOCF) algorithm will be used for missing data.
Data from the efficacy phase for this cohort may be summarized, analyzed and reported after 
all patients in this cohort have either completed or withdrawn prior to the Week 12 visit (ie,
prior to formal completion of the study). The results of these analyses will be available to 
limited members of the study team as a management tool in order to aid decision making, 
and may also be shared with regulators in order to facilitate timely discussion of the overall 
program; they will not be used to stop or modify the design of the study.
9.2.3. Analysis of Secondary Endpoints
All secondary endpoints will be analysed using the same methods as the primary endpoint for 
each cohort.
9.2.4. Analysis of Other Endpoints
Plasma concentrations of 5-HMT will be listed and summarized using descriptive statistics, 
by timepoint and treatment group.
The population PK modeling approach will be used to analyze the plasma concentration-time 
data following fesoterodine administration for the estimation of population PK parameters 
(CL/F, Ka and Vd) of 5-HMT in pediatric subjects in this study.  Confidence intervals will be 
computed for means and variances of estimates.  Using NONMEM, the first-order or first 
order conditional estimation methods will be employed for all model building.  Individual 
estimates of PK parameters will be obtained using POSTHOC, an empirical Bayesian 
Estimation Method.  Population mean estimates for the pharmacokinetic parameters will be 
obtained by fitting the pharmacokinetic and variance models to the whole data set of all 
individuals.  The inter-subject variability will be estimated and 95% confidence intervals will 
be reported for all population parameter estimates.  For the residual variability, various 
models will be fitted, including but not restricted to additive and proportional models.  
Adequacy of model fitting will be judged by the objective function as well as goodness of fit 
plots and parameter precision estimates.  Exploratory analyses will be performed to 
investigate the effect of covariates including, but not limited to age, weight, CYP2D6 status, 
and sex.  An analysis plan describing the details of the model building, covariate assessment 
and model validation will be provided separately.


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9.3. Safety Analysis
The Safety Analysis Set will be defined separately for each cohort and consists of all 
randomized subjects who have received at least one dose of study medication in the relevant 
phase of the study.
For each cohort, results from the safety assessments and any adverse events will be presented 
in tabular and/or graphical format adhering to current Pfizer Data Standards.  These 
presentations will be split by treatment group, and produced separately for the active 
comparator/efficacy phase and the safety extension phase.  Safety endpoints such as vital 
signs, laboratory evaluations, weight, PVR, vision testing and CBCL/GPT results will be 
presented descriptively by treatment group. Adverse event incidence rates will be compared 
descriptively between treatment arms.  An evaluation of withdrawal rates and time to 
withdrawal will be performed.
9.4. Blinded Interim Analysis for Sample Size Re-estimation.
A blinded interim analysis may be performed after approximately 50% of randomized 
subjects in Cohort 1 have completed the active comparator phase of the study and provided 
data for the primary endpoint (including the corresponding baseline value) as a tool to 
reassess the sample size.  The sample size will be recalculated based on the variability of the 
primary endpoint obtained from this analysis. Even though this is an open label study, data 
utilized in this interim analysis will remain blinded to treatment allocation to minimize bias.  
Based on this, the study statistician and clinician will assess whether an adjustment to the 
sample size is required.
These results will not be used to modify the design of the study, other than a potential 
adjustment to the sample size.  No adjustment will be made to the nominal p-values to 
account for this analysis.  The results of this analysis will not be made available to the 
investigator and site staff, other than to inform them of any adjustment to the sample size that 
is recommended. A similar blinded interim analysis may be performed after approximately 
50% of randomized subjects in Cohort 2 have completed the efficacy phase of the study.
9.5. External Data Monitoring Committee
This study will use an External Data Monitoring Committee (EDMC) for the purpose of 
protecting the safety of subjects by regular independent assessment of risk/benefit during the 
conduct of the study (for each cohort separately as well as combined). The recommendations 
made by the EDMC to alter the conduct of the study will be forwarded to Pfizer for final 
decision.  Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data which are not endpoints, to regulatory 
authorities, as appropriate.
The EDMC will meet at specified intervals during the study to assess its progress including 
the safety data and/or critical efficacy endpoints. Safety data will include assessment of 
adverse events, vision testing, CBCL/GPT assessments, vital signs including heart rate, 
incidence of urinary tract infection (as evidenced by urinalysis, urine microscopy and 


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culture), clinical laboratory evaluations in the context of age-appropriate norms, with 
particular reference to liver function tests and renal chemistry, and post-void residual volume 
(PVR) in subjects not performing CIC, or with >1 urinary tract infection (UTI) during the 
study.
Assessment of adverse events of particular interest will include, but not be limited to, 
anticholinergic effects such as dry mouth, dry eyes and constipation, CNS effects such as 
behavioral changes (eg, aggression), decreased cognitive function, headache, seizures, 
somnolence and visual effects such as accommodation disorder, blurred vision, and 
amblyopia.
The remit of the EDMC will be to recommend whether to continue or modify the study. In 
the event that a negative benefit-risk is determined, the EDMC may recommend that the 
study (or recruitment to a particular cohort) be terminated. The EDMC will be advisory to 
the sponsor, Pfizer Inc. The sponsor will promptly review the EDMC recommendations, and 
will make decisions regarding accepting, modifying or rejecting those recommendations. 
The final decisions regarding trial continuation, modification or termination will be made by 
the sponsor.
Full technical details for the EDMC, including its primary responsibilities, relationship with 
other trial components, membership, timing of meetings, and rules will be provided in the 
EDMC Charter, which will be drawn up by the sponsor study team and agreed to by the 
EDMC. All members included in an EDMC must have acceptable conflict of interest status 
and a contract should be in place before the work commences.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and GCPs are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs is accurate.  The investigator and institution will 
allow Pfizer monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification.
The study site may be subject to review by the institutional review board (IRB)/independent 
ethics committee (IEC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms / Electronic Data Record
As used in this protocol, the term case report form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts.
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent forms, copies of all CRFs, safety reporting forms, source documents, and detailed 
records of treatment disposition, and adequate documentation of relevant correspondence (eg, 
letters, meeting minutes, telephone calls reports).  The records should be retained by the 
investigator according to International Conference on Harmonization (ICH), local 
regulations, or as specified in the Clinical Study Agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association, 1996 and 
2008).
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation guideline on Good Clinical Practice, and applicable local 
regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws.
Subject names, address, birth date and other identifiable data will be replaced by an alpha-
numerical code consisting of a numbering system provided by Pfizer in order to de-identify 
the trial subject. In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of subject personal data.
The informed consent form must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements.
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the IRB/IEC and Pfizer before use.


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The investigator must ensure that each study subject, or his/her legal representative, are fully 
informed about the nature and objectives of the study and possible risks associated with 
participation.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legal representative, and subject assent when 
appropriate, before any study-specific activity is performed.  The investigator will retain the 
original of each subject's or the subject's legal representative signed consent document.
Informed consent should be obtained from the parent(s) or legal representative before assent 
is sought.
An assent from the subject will be obtained in addition to the consent when appropriate, and 
when the potential subject is capable of providing assent.  The determination of 
appropriateness and capacity is made by the investigator and/or the relevant IRB or IEC, and 
should take into account the age, maturity, and psychological state of the potential subject.
Assent is not required if the investigator and/or the IRB/IEC determine that the capability of 
the child or adolescent subject is so limited that they cannot provide assent.
When applicable, full informed consent from “emancipated minors” is both necessary and 
sufficient, rather than assent plus the consent of a legally acceptable representative or 
representatives.
If a minor becomes of age following assent and enrolment in the study, a consent must be 
signed once the subject turns legal age, based on local requirements.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures.  Other methods, for example, increasing awareness of the study 
through patient associations, may be used as appropriate, and subject to approval by ethics 
committees.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately.
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application (CTA)) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision,
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of fesoterodine at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within a time period set by Pfizer.  As directed by 
Pfizer, all study materials must be collected and all CRFs completed to the greatest extent 
possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of results by Pfizer:
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of this study on www.clinicaltrials.gov (ClinicalTrials.gov).  Pfizer registers study 
protocols and posts Basic Results on ClincialTrials.gov for Pfizer-sponsored interventional 
studies in human subjects that evaluate the safety and/or efficacy of a Pfizer product
The results are posted in a tabular format called Basic Results.
For studies involving a Pfizer product, the timing of the posting depends on whether the 
Pfizer product is approved for marketing in any country at the time the study is completed:

For studies involving products applicable under the US Food and Drug Administration 
Amendments Act of 2007 (FDAAA), ie, FDA-approved products, Pfizer posts results 
within one year of the primary completion date (PCD). For studies involving products 
approved in any country, but not FDA approved, Pfizer posts results one year from last 
subject, last visit (LSLV).


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
For studies involving products that are not yet approved in any country, Pfizer posts the 
results of already-completed studies within 30 days of US regulatory approval, or one 
year after the first ex-US regulatory approval of the product (if only submitted for 
approval ex-US);

For studies involving products whose drug development is discontinued before approval, 
Pfizer posts the results within one year of discontinuation of the program (if there are no 
plans for outlicensing or within two years if outlicensing plans have not completed).
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical trial concluded according to the pre-specified protocol or was 
terminated.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed.  If any 
patent action is required to protect intellectual property rights, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the study results themselves) before disclosure.
If the study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the study at all 
participating sites, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Bauer SB, Koff SA, Jayanthi VR. Voiding dysfunction in children: neurogenic and 
nonneurogenic. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, editors. Campbell’s 
Urology. 8th ed. Saunders; 2002: p. 2231-61.
2.
Aslan AR, Kogan BA. Conservative management in neurogenic bladder dysfunction. 
Curr Opin Urol 2002; 12: 473-77.
3.
Neveus T, von Gontard A, Hoebeke P, 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-
24.
4.
Coward RJM, Saleem MA. The neuropathic bladder of childhood. Current Paediatrics
2001;11:135-42.
5.
Kennelly MJ, DeVoe WB. Overactive bladder: pharmacologic treatments in the 
neurogenic population. Rev Urol 2008; 10(3):182-91


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Appendix 1. Examples of CYP3A4 Inducers and Potent CYP3A4 Inhibitors
Potent CYP3A4 inhibitors within 3 weeks prior to Visit 2 (baseline), or the expectation to 
start such a treatment during the trial, as well as medications capable of inducing CYP3A4 
enzyme metabolism are prohibited.
The following table provides examples of such medications.  The lists are provided for your 
reference only and are not intended to be all-inclusive.  Please consult a member of the study 
team for further clarification if necessary.
CYP3A4 Inducers
Potent CYP3A4 Inhibitors
efavirenz
nevirapine
barbiturates
carbamazepine
glucocorticoids
modafinil
oxcarbazepine
phenobarbital
phenytoin
pioglitazone
rifabutin
rifampin
St. John's wort
Troglitazone
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
ketoconazole
nefazodone
saquinavir
telithromycin


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Appendix 2. Total Volume of Trial-Related Blood Loss
BLOOD TEST
FESOTERODINE
2, 4 or 8 mg
OXYBUTYNIN
Volume of whole blood
Volume of whole blood
Test panel
Test
Visit 1
Screening
Week 0
Visit 3
Week 
4
Visit 
5
Week 
12
Visit 7 
Week 
24
Visit 1
Screening
Visit 5
Week 12
Hematology
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count with 
differential of total 
neutrophils, 
eosinophils, 
monocytes,  
basophils, 
lymphocytes
2 ml
N/A
2 mL
2 mL
2 ml
2 ml
Chemistry
GOT (AST)
GPT (ALT)
GGT
Total and direct 
bilirubin
Alkaline phosphatase
Lactate 
dehydrogenase 
(LDH)
Creatine 
phosphokinase (CPK)
Blood urea nitrogen 
(BUN)
Creatinine
Uric acid
Total protein
Albumin
Sodium
Potassium
Chloride
Bicarbonate
Phosphorus
Corrected calcium
Glucose (non-fasting)
Serum pregnancy test 
(in females of 
childbearing potential 
only)a
3.5 ml
N/A
3.5 
mL
3.5 mL
3.5 ml
3.5 ml
Pharmacokinetic
5-HMT
N/A
6 mL
N/A
N/A
N/A
N/A
Pharmacogenomic
CYP2D6
N/A
2 mL
N/A
N/A
N/A
2 mL
Total blood 
volume
Total volume per visit
5.5 ml
8 mL
5.5 
mlb
5.5 mL
5.5 ml
7.5 ml
Total volume over 
study
24.5 mLb
13 mL
N/A - not applicable. Additional blood samples may be taken as needed to follow-up on significant findings, or as 
clinically indicated. The total volume does not include discarded blood from predraws used to remove fluid from 
flushed catheters at Visit 3. The discarded volume is not anticipated to exceed 1.65 ml based on 3 draws using winged 
infusion (butterfly) set with a priming volume of 0.55 ml  (23G, ¾ inch, 12 inch tubing).
a Serum pregnancy test at Screening (Visit 1) only (urine testing at subsequent visits)


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b For fesoterodine treatment groups, if no PG sample is required (due to prior genotyping), total blood volume at Visit 
3 = 6 ml, total blood volume over the study = 22.5 mL.
Guidelinesa
A0221047 blood loss volume 
(volume including discarded 
bloodd)
Maximum total volume at a single time
20 mlb
13.5 ml (16.25 ml)
Maximum total volume in a 4 week period
60 mlc
13.5 ml (16.25 ml)
Maximum possible total volume in a 4 week period 
(assuming subject withdraws prior to Visit 5, and 
within 4 weeks of Screening at Visit 1)
60 ml
19 ml (22.3 ml)
a As per Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric Population 
(Section 13.2) http://ec.europa.eu/health/files/eudralex/vol-10/ethical_considerations_en.pdf. Accessed 24 Nov 2010: 
Per individual, the trial-related blood loss (including any losses in the manoeuvre) should not exceed 3 % of the total 
blood volume during a period of four weeks and should not exceed 1% at any single time. Subjects weighing less than 
17 kg will be very unusual, especially for this population, and the breach of maximum guidelines volume is minor if it 
does happen, and it should be possible to stay within guideline limits by a very minor reduction in draw volume that 
does not affect ability to analyse.
b 1 % is 0.8 ml/kg = 0.8 ml x 25 kg = 20 ml at single time assuming minimum body weight of 25 kg and total volume 
of blood of 80 ml/kg body weight; for a 17 kg subject the volume is 13.6 mL,
c 3% is 2.4 ml/kg = 2.4 ml x 25 kg = 60 ml in a 4 week period assuming minimum body weight of 25 kg and total 
volume of blood of 80 ml/kg body weight;for a 17 kg subject the volume is 40.8 mL
d Assuming that predraws (to remove fluid from flushed catheters) are performed between each sample taken and 
based on a winged infusion (butterfly) set with a priming volume of 0.55 ml  (23G, ¾ inch, 12 inch tubing).


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Appendix 3. Washout Times for Anticholinergic Medications
Generic name
Example Trade
names
Elimination 
half life*
Minimum recommended 
washout period
Tolterodine IR
Detrol/Detrusitol
EMs: ~2 hrs
PMs: ~10 hrs
3 days
Tolterodine XL
Detrol/Detrusitol 
EMs: ~7 hrs
PMs: ~18 hrs
3 days
Oxybutynin IR
Cystrin
2-3 hrs
3 days
Oxybutynin XL
Lyrinel XL
Ditropan XL (US)
12-13 hr
3 days
Darifenacin 
Emselex
13 - 19 hrs
7 days
Solifenacin
Vesicare
45 - 68 hrs
7 days
Fesoterodine
Toviaz
~7 hrs
3 days
Propiverine 
Detrunorm
20 hrs
7 days
Trospium IR
Sanctura
18 hrs
3 days
Trospium SR
Sanctura XR
36 hrs
7 days
*Data from the respective drug labels


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Appendix 4. Child behavior Checklist (CBCL)
Please print. Be sure to answer all items.
Below is a list of items that describe children and youths. For each item that describes your child now, please circle the 2 
if the item is very true or often true of your child. Circle the 1 if the item is somewhat or sometimes true of your child. 
If the item is not true of your child, circle the 0. Please answer all items as well as you can, even if some do not seem to 
apply to your child.
0 = Not True (as far as you know)
1 = Somewhat or Sometimes True
2 = Very True or Often True
0 1
2
1. Acts too young for his/her age
0
1
2
17. Daydreams or gets lost in 
his/her thoughts
0 1
2
2. Drinks alcohol without parents' approval 
(describe):____________
____________________________
0
1
2
18. Deliberately harms self or 
attempts suicide
0 1
2
3. Argues a lot
0
1
2
19. Demands a lot of attention
0 1
2
4. Fails to finish things he/she starts
0
1
2
20. Destroys his/her own things
0 1
2
5. There is very little he/she enjoys
0
1
2
21. Destroys things belonging to his/her 
family or others
0 1
2
6. Bowel movements outside toilet
0
1
2
22. Disobedient at home
0 1
2
7. Bragging, boasting
0
1
2
23. Disobedient at school
0 1
2
8. Can't concentrate, can't pay attention for 
long
0
1
2
24. Doesn't eat well
0 1
2
9. Can’t get his/her mind off certain 
thoughts; obsessions (describe):
________________________________
__________________________
0
1
2
25. Doesn't get along with other kids
0 1
2
10. Can’t sit still, restless, or hyperactive
0
1
2
26. Doesn't seem to feel guilty 
after misbehaving
0 1
2
11. Clings to adults or too dependent
0
1
2
27. Easily jealous
0 1
2
12. Complains of loneliness
0
1
2
28. Breaks rules at home, school, 
or elsewhere
0 1
2
13. Confused or seems to be in a fog
0
1
2
29. Fears certain animals, situations, or 
places, other than school 
(describe):_____________________
___________________________
0 1
2
14. Cries a lot
0
1
2
30. Fears going to school
0
1
2
31. Fears he/she might think or do 
something bad
0 1
2
15. Cruel to animals
0
1
2
32. Feels he/she has to be perfect
0 1
2
16. Cruelty, bullying, or meanness to others
0
1
2
33. Feels or complains that no one loves 
him/her


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Please print. Be sure to answer all items.
0 = Not True (as far as you know)
1 = Somewhat or Sometimes True
2 = Very True or Often True
0
1
2
34. Feels others are out to get him/her
0
1
2
56. Physical problems without known
medical cause:
0
1
2
35. Feels worthless or inferior
0
1
2
a. Aches or pains (not stomach 
or headaches)
0
1
2
36. Gets hurt a lot, accident–prone
0
1
2
b. Headaches
0
1
2
37. Gets in many fights
0
1
2
c. Nausea, feels sick
0
1
2
38. Gets teased a lot
0
1
2
d. Problems with eyes (not if corrected by 
glasses) 
(describe):____________________
____________________________
0
1
2
39. Hangs around with others who get 
in trouble
0
1
2
e. Rashes or other skin problems
0
1
2
40. Hears sound or voices that aren’t there
(describe):________________
_____________________________
0
1
2
f. Stomachaches
0
1
2
41. Impulsive or acts without thinking
0
1
2
g. Vomiting, throwing up
0
1
2
42. Would rather be alone than with others
0
1
2
h. Other (describe):______________
____________________________
0
1
2
43. Lying or cheating
0
1
2
57. Physically attacks people
0
1
2
44. Bites fingernails
0
1
2
58. Picks nose, skin, or other parts of body 
(describe): _______________
____________________________
0
1
2
45. Nervous, highstrung, or tense
0
1
2
59. Plays with own sex parts in public
0
1
2
46. Nervous movements or twitching
(describe):_____________________ 
_____________________________
_____________________________
0
1
2
60. Plays with own sex parts too much
0
1
2
47. Nightmares
0
1
2
61. Poor school work
0
1
2
48. Not liked by other kids
0
1
2
62. Poorly coordinated or clumsy
0
1
2
49. Constipated, doesn't move bowels
0
1
2
63. Prefers being with older kids
0
1
2
50. Too fearful or anxious
0
1
2
64. Prefers being with younger kids
0
1
2
51. Feels dizzy or lightheaded
0
1
2
65. Refuses to talk
0
1
2
52. Feels too guilty
0
1
2
66. Repeats certain acts over and over; 
compulsions describe):__________
____________________________
0
1
2
53. Overeating
0
1
2
67. Runs away from home
0
1
2
54. Overtired without good reason
0
1
2
68. Screams a lot
0
1
2
55. Overweight
0
1
2
69. Secretive, keeps things to self


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Please print. Be sure to answer all items.
0 = Not True (as far as you know)
1 = Somewhat or Sometimes True
2 = Very True or Often True
0
1
2
70. Sees things that aren’t there 
(describe):____________________
_____________________________
0
1
2
87. Sudden changes in mood or feelings
0
1
2
71. Self-conscious or easily embarrassed
0
1
2
88. Sulks a lot
0
1
2
72. Sets fires
0
1
2
89. Suspicious
0
1
2
73. Sexual problems 
(describe):________________________
________________________________
______________________
0
1
2
90. Swearing or obscene language
0
1
2
74. Showing off or clowning
0
1
2
91. Talks about killing self
0
1
2
75. Too shy or timid
0
1
2
92. Talks or walks in sleep (describe): 
____________________________
____________________________
0
1
2
76. Sleeps less than most kids
0
1
2
93. Talks too much
0
1
2
77. Sleeps more than most kids during day 
and/or night (describe):______
____________________________
0
1
2
94. Teases a lot
0
1
2
78. Inattentive or easily distracted
0
1
2
95. Temper tantrums or hot temper
0
1
2
79. Speech problem (describe):_____
____________________________
0
1
2
96. Thinks about sex too much
0
1
2
80. Stares blankly
0
1
2
97. Threatens people
0
1
2
81. Steals at home
0
1
2
98. Thumb-sucking
0
1
2
82. Steals outside the home
0
1
2
99. Smokes, chews, or sniffs tobacco
0
1
2
83. Stores up too many things he/she doesn’t 
need (describe):_________
____________________________
____________________________
0
1
2
100. Trouble sleeping (describe):
________________________________
________________________
0
1
2
84. Strange behavior (describe): 
________________________________
________________________
0
1
2
101. Truancy, skips school
0
1
2
85. Strange ideas (describe): 
________________________________
________________________
0
1
2
102. Underactive, slow moving, or lacks 
energy
0
1
2
86. Stubborn, sullen, or irritable
0
1
2
103. Unhappy, sad, or depressed


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Please print. Be sure to answer all items.
0 = Not True (as far as you know)
1 = Somewhat or Sometimes True
2 = Very True or Often True
0
1
2
104.Unusually loud
0
1
2
111. Withdrawn, doesn't get involved with 
others
0
1
2
105. Uses drugs for nonmedical purposes 
(don't include alcohol or tobacco) 
(describe):_____________________ 
_____________________________
0
1
2
112. Worries
0
1
2
106.Vandalism
113. Please write in any problems your child 
has that were not listed above:
0
1
2
107.Wets self during the day
0
1
2
____________________________
0
1
2
108.Wets the bed
0
1
2
____________________________
0
1
2
109. Whining
0
1
2
____________________________
0
1
2
110.Wishes to be of opposite sex


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Appendix 5. Country-specific amendment: France
In France, the following amendments apply:
4.2 Exclusion criteria
Subjects presenting with any of the following will not be included in the study:
1. Any condition known to affect drug absorption (eg, gastrectomy).
2. History of surgical procedures that could confound study results or increase the risk 
to subjects, including but not limited to: sphincterotomy, artificial sphincter, 
implantable stent, bladder augmentation procedures, urinary diversion procedures.  
Continent diversion procedures eg, Mitrofanoff are permitted.
3. A history of indwelling urinary catheter within 4 weeks of participation in this study. 
Intermittent catheterization is permitted.
4. Any comorbid condition that, in the opinion of the investigator, would confound 
study results or increase the risk to subjects eg, current history of bladder calculus.
5. A history of autonomic dysreflexia eg, increased blood pressure with bladder filling 
or other stimuli.
6. Subjects who have had an endoscopic anti-reflux procedure in the previous 3 months 
before Visit 2.
7. Subjects with clinically relevant out-of-range values for hematology or serum 
chemistry as confirmed by blood tests performed at Visit 1, and which require the 
subject’s exclusion in the opinion of the investigator.
8. A 12-lead ECG at screening with clinically significant abnormality.
9. Subjects who present with QTc interval prolongation, personal and family history of
QTc interval prolongation, or pre-existing and important cardiac diseases and present 
a risk of QT interval prolongation (eg, hypokalemia).
10. Unwilling or unable to comply with the Lifestyle guidelines described in this 
protocol.
11. Subjects required to take or expected to initiate concomitant medications that can 
interact with the pharmacokinetics and/or pharmacodynamics of fesoterodine or 
oxybutynin, such as:

Potent CYP3A4 inhibitors within 3 weeks prior to Visit 2 (baseline), or the 
expectation to start such a treatment during the trial (Appendix 1).

Medications capable of inducing CYP3A4 enzyme metabolism (Appendix 1).


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
Drugs for the treatment of overactive bladder (eg, darifenacin, oxybutynin 
(including intravesical), propiverine, tolterodine, fesoterodine, solifenacin and 
trospium).

Treatment with botulinum toxin A within 9 months prior to Visit 2 (baseline).

Drugs with antispasmodic, parasympathetic, or cholinergic effects.  Stable use of 
desmopressin for enuresis is allowed if established for at least 3 months.
Previous treatment with these medications does not exclude subjects.  However, prohibited 
concomitant medications must have a minimum washout appropriate to the drug so any 
clinical effect is at a minimum prior to beginning the bladder diary, and baseline urodynamic 
evaluations (Section 5.6).
12. Intermittent or unstable use of diuretics or alpha blockers, tricyclic antidepressants or 
any other treatment that may confound the results of the study, within 2 weeks or an 
appropriate washout period (whichever is longer) prior to starting the bladder diary or 
during the course of the study.  Stable usage/dosage is allowed if established for at 
least 3 months.
13. Electrostimulation therapy or bladder retraining if started within 30 days of Visit 1 or 
are expected to start such therapy during the study period.  Subjects who are on an 
established regimen may remain on this for the duration of the study.
14. Subjects with a clinically significant urinary tract infection (UTI) at screening.
Urine microscopy, culture and sensitivity testing will be performed in the event of:

presence of symptoms (eg, fever, flank pain), or

positive leucocytes and/or nitrites on urinalysis, or

if subject has a documented history of vesicoureteral reflux (VUR).
A clinically significant UTI is defined as:

positive urine culture with a uropathogen (defined as ≥105 CFU/ml) and the 
presence of symptoms, or

pyuria (defined as >50 white blood cells (WBC)/hpf) and the presence of 
symptoms, or

positive urine culture with a uropathogen (defined as ≥105 CFU/ml) with or 
without symptoms in a subject with a documented history of VUR.


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Subjects who are found to have an active UTI during screening may continue 
screening activities on resolution of symptoms or treatment of the UTI to the 
satisfaction of the treating physician.
15. Subjects not requiring intermittent catheterization who have a post-void residual 
volume greater than 20 ml as determined by transabdominal ultrasound (eg, bladder 
scan) immediately after urination.  If at screening, the PVR is found to be greater than 
20 ml the subject will be asked to void again.  Repeat PVR assessment should be 
made as soon as possible, and no more than 5 minutes, after the second void.  
Subjects found to have a persistently elevated PVR >20 ml at this visit will be 
excluded from the study.
16. Subjects with any history of malignancy.
17. Subjects with any condition or at risk of any condition that would contraindicate or 
warrant precautions for the use of fesoterodine or oxybutynin, including:

Hypersensitivity to fesoterodine, tolterodine or oxybutynin.

Known history of hypersensitivity to peanut or soya or any of the excipients of the 
fesoterodine or oxybutynin formulation.

Gastric retention.

Severely decreased gastrointestinal motility (not under active management).

Uncontrolled narrow angle glaucoma.

Gastrointestinal obstructive disorders.

Myasthenia gravis.

Severe hepatic impairment (Child Pugh C).

Severe ulcerative colitis.

Toxic megacolon.
18. Previously received any investigational drug within 4 weeks or 5 half-lives 
(whichever is longer) prior to Visit 1.  Participation in other studies within 4 weeks 
before the current study begins or during study participation.
19. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.


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20. Subjects who are investigational site staff members or relatives of those site staff 
members or subjects who are Pfizer employees directly involved in the conduct of the 
trial.
6.12 Subject withdrawal
If treatment is inadequate or the subject cannot tolerate the dose of fesoterodine or 
oxybutynin, consideration should be given to withdrawal.
Subjects who undergo an endoscopic anti-reflux therapy during the study will be withdrawn.
Subjects who withdraw from the oxybutynin treatment arm (Cohort 1, > 25kg) for reasons of 
toleration, and who fulfill all continuation criteria, may be directly allocated by the 
investigator to fesoterodine treatment at either 4 mg or 8 mg/day for the remaining 12 week 
safety extension period if appropriate.  All subsequent study visits should be scheduled 
relative to the start of the extension phase.
Subjects may withdraw from the study at any time at their own, or their legal 
representative(s) request, or they may be withdrawn at any time at the discretion of the 
investigator or sponsor for safety or behavioral reasons, or the inability of the subject to 
comply with the protocol required schedule of study visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject 
to return all unused investigational product(s) and electronic diary equipment, request the 
subject to return for a final visit, if applicable, and follow-up with the subject regarding any 
unresolved adverse events (AEs).
Subjects in the fesoterodine groups who withdraw prior to Week 4 should have PK samples 
obtained as per Visit 3.
If a subject withdraws from the study prior to Visit 5 (Week 12), the same assessments as at 
Visit 5 should be performed if possible. Urodynamic assessment should only be performed 
in subjects who have been on a stable dose of study medication for at least 2 weeks, and who 
have not missed any doses in the 3 days prior to the visit.
If a subject withdraws from the study after Visit 5, the same assessments as at Visit 7 (Week 
24) should be performed if possible.
Subjects who withdraw early from the study and who have taken at least 1 dose of study 
medication should also be contacted by telephone approximately 2 weeks after stopping 
study medication, and have the same assessments performed as at Visit 8 (Week 26).
If the subject withdraws from the study, and they or their legal representative(s) also 
withdraw consent for disclosure of future information, no further evaluations should be 


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performed, and no additional data should be collected.  The sponsor may retain and continue 
to use any data collected before such withdrawal of consent.

SAP_001.pdf: 
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Protocol A0221047
A 24-WEEK RANDOMIZED, OPEN-LABEL, STUDY TO EVALUATE THE SAFETY 
AND EFFICACY OF FESOTERODINE IN SUBJECTS AGED 6 TO 17 YEARS WITH 
SYMPTOMS OF DETRUSOR OVERACTIVITY ASSOCIATED WITH A 
NEUROLOGICAL CONDITION (NEUROGENIC DETRUSOR OVERACTIVITY)
Statistical Analysis Plan 
(SAP)
Version: Version 2.0
Author: 
(All versions, GBDM)
Date: 25 February 2020
PPD


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TABLE OF CONTENTS
LIST OF TABLES.................................................................................................................... 3
1. AMENDMENTS FROM PREVIOUS VERSION(S) .......................................................... 4
2. INTRODUCTION ................................................................................................................ 6
2.1. Study Design ............................................................................................................ 7
2.2. Study Objectives..................................................................................................... 10
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING............................... 10
4. HYPOTHESES AND DECISION RULES........................................................................ 11
4.1. Statistical Hypotheses............................................................................................. 11
4.2. Statistical Decision Rules....................................................................................... 12
5. ANALYSIS SETS .............................................................................................................. 12
5.1. Full Analysis Set .................................................................................................... 13
5.2. Per Protocol Analysis Set....................................................................................... 13
5.2.1. Deviations assessed prior to randomization .............................................. 13
5.2.2. Deviations assessed post-randomization ................................................... 13
5.3. Safety Analysis Set................................................................................................. 13
5.4. Pharmacokinetic (PK) Analysis Set ....................................................................... 15
5.5. Treatment Misallocations....................................................................................... 15
5.6. Protocol Deviations................................................................................................ 15
5.6.1. Deviations assessed prior to randomization .............................................. 15
5.6.2. Deviations assessed post-randomization ................................................... 15
6. ENDPOINTS AND COVARIATES .................................................................................. 15
6.1. Efficacy Endpoint(s)............................................................................................... 15
6.1.1. Primary Endpoint....................................................................................... 15
6.1.2. Secondary Endpoints ................................................................................. 16
6.2. Safety Endpoints..................................................................................................... 17
6.2.1. Adverse Events .......................................................................................... 18
6.2.2. Vital Signs ................................................................................................. 18
6.2.3. Physical Exam ........................................................................................... 19
6.2.4. Weight Measurements ............................................................................... 19
6.2.5. Electrocardiogram...................................................................................... 20
6.2.6. Clinical Laboratory Evaluation.................................................................. 20
6.2.7. Childhood Behavior Checklist (CBCL)..................................................... 20
6.2.8. Grooved Pegboard Test (GPT) .................................................................. 21


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6.3. Pharmacokinetic Evaluations ................................................................................. 21
6.4. Covariates............................................................................................................... 21
7. HANDLING OF MISSING VALUES ............................................................................... 22
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ......................... 23
8.1. Statistical METHODS............................................................................................ 23
8.1.1. Analysis of Continuous Data..................................................................... 24
8.1.2. Analysis of Binary Data............................................................................. 24
8.2. Statistical Analyses................................................................................................. 24
8.2.1. Cohort 1: Primary Analysis ....................................................................... 24
8.2.2. Cohort 2: Primary Analysis ....................................................................... 25
8.2.3. Secondary Analyses................................................................................... 26
8.2.4. Other Endpoints......................................................................................... 26
8.2.5. Safety Analyses ......................................................................................... 27
8.2.6. Summary of Efficacy Endpoint Analyses.................................................. 32
9. REFERENCES ................................................................................................................... 35
10. APPENDIX....................................................................................................................... 36
10.1. APPENDIX A: SCHEDULE OF EVENTS......................................................... 36
10.2. Appendix B: DEFINITION OF ASSESSMENT WINDOWS ............................ 38
LIST OF TABLES
Table 1.
Summary of Changes................................................................................. 4


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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
The table below outlines the changes that have been made to this SAP.
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
(PA)
Rationale
Specific Changes
Use whole 
numbers 
starting with 
1 for original 
SAP.
Ensure the 
date matches 
the final 
approval 
date.
Specify if and 
what 
amendment is 
associated: 
Terms should 
be: N/A, 
Original, or 
Amendment 
number;
Include date
of protocol.
Specify the 
primary reason 
for the changes –
Specific reasons 
to use can be:

Regulatory 
input.

DMC request.

External 
environment 
(competitor 
information).

Blinded data 
review.

Clarification 
or completion 
of prior 
version (eg, 
when a section 
was initially 
TBD).
Summarize the changes; use bullets if 
needed. Be specific about which sections 
major changes impact.  Minor 
clarifications can be grouped together.
1
25 Jan 2012
Original 
03 Aug 2010
N/A
N/A
1.1
12 Feb 2013
PA 4
02 Oct 2012
Updates prior to 
first EDMC 
meeting to clarify 
some of the safety 
analyses
following further 
discussions with 
programming

Included information on how missing 
days and months for Dates of Birth 
will be imputed.

The AE tables for the safety extension 
phase will have two additional 
treatment groups: Feso 4mg>Feso 
4mg and Feso 8mg>Feso 8mg.

The treatment groups to be used for 
each of the safety analysis sets have 
been specified.

Additional detail added about which 
PVR results to use and the conversion 
to LogMAR values for visual acuity.

Additional pulse rate cut-offs added.


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
Additional minor clarifications to 
align with the updated DMB02-
GSOP-RF02 Statistical Analysis Plan 
Template (SAP), effective 31-Jan-
2013
1.2
14 Apr 2014
PA 5
3 Mar 2014
Protocol amended 
to include lighter 
weight cohort 
(Cohort 2 -
subjects ≤25kg), 
originally planned 
to be studied 
under a separate 
protocol 
(A0221074).

The SAP has been amended to 
describe the analyses for Cohort 2. 
The intention is to analyse and 
summarize each cohort separately, 
therefore additional sections have 
been added into the SAP specifically 
to describe the Cohort 2 analyses and 
summaries.
2.0
25 Feb 2020
N/A
Prior to DB 
Release

Removal of figures and listings that 
have been removed from the List of 
Tables (LOT) as part of the TLF
reduction exercise. The data presented 
in the figures that have been removed 
are presented in tables.

Exploratory analyses and subgroup 
figures removed as these won’t be 
included in the CSR. Some have been 
replaced by descriptive subgroup 
summary tables instead.

As some subjects will only record 
micturitions in their bladder diary (if 
they are not catheterizing) and some 
will only record catheterizations (if 
they only catheterize), these two 
endpoints will only be calculated for 
subjects with >0 episodes at baseline.

Section 8.2.5 (Other Adverse Event 
Reporting) has been updated to clarify 
that the lag period is only applied if a 
subject discontinues study medication
in the Active Comparator/ Efficacy 
Phase (otherwise, for subjects who 
continue into the Safety Extension
AEs could be counted twice).

Other minor updates to ensure SAP is 
aligned with how results are being 
presented in tables, figures and 
listings.


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The study is ongoing, and unblinded data from the study have been reviewed by an 
External Data Monitoring Committee; however that review has not influenced any of
the changes documented in this amendment.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised. 

Drug Development rationale
Antimuscarinic drugs are the cornerstone of pharmacotherapy in the pediatric 
neurogenic bladder population, and have been shown to improve intravesicular 
pressure, and decrease symptoms.  Four antimuscarinic drugs (oxybutynin, trospium 
chloride, tolterodine and darifenacin) have documented results in the pediatric 
neurogenic bladder population - Kennelly & DeVoe, 2008 [1].  Of these, only 
oxybutynin is widely approved for use in children, and is available as a once a day 
extended release tablet, as well as an immediate release tablet. Although effective,
oxybutynin use has been limited by a side effect profile which may have particular 
relevance in the pediatric population where development (eg, physical, cognitive, 
psychosocial) is still ongoing.
A particular medication’s effectiveness is highly dependent on patient compliance 
which is itself dependent on tolerability.  Given individual differences in toleration 
and the limited choice available there is an unmet need for alternative treatments.
Children with neurogenic bladder therefore represent a disease population with a 
need for an alternative effective, safe and well-tolerated therapy to help manage the 
overactive detrusor, reducing or preventing incontinence, as well as the high pressure 
bladder contractions that can result in UUT deterioration and renal damage.
Other treatments such as alpha blockers, anxiolytics, tricyclic antidepressants, 
intravesical oxybutynin, botulinum-A toxin, electrical stimulation and biofeedback, 
may also be used - Coward & Saleem, 2001 [2], although safety and efficacy have not 
been reliably demonstrated.

Study rationale
The primary purpose of this study is to evaluate the safety and efficacy of fesoterodine 
4 mg and 8 mg PR (prolonged release) once daily (body weight >25 Kg) and 
fesoterodine 2 mg and 4 mg BIC (beads-in-capsule) once daily (body weight ≤25 Kg)
in pediatric NDO subjects aged between 6-17 years. Additionally, the safety and 
efficacy of oxybutynin extended release (XL) will be evaluated in subjects >25 kg 
only.   
Sparse PK samples will also be obtained to determine the steady-state population 
pharmacokinetics of 5- hydroxymethyltolterodine (5-HMT) following fesoterodine 
treatment in pediatric NDO subjects.


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The study will enroll two weight cohorts as follows:

Cohort 1
For subjects >25 kg, following 12 weeks of treatment with either fesoterodine 4 
mg, 8 mg PR (adult tablet formulation) or oxybutynin XL in an active comparator 
phase, subjects will then enter a safety extension phase and continue to receive 4 
mg or 8 mg of fesoterodine PR for an additional 12 weeks.  Subjects that received 
oxybutynin in the active comparator phase will receive 4 mg or 8 mg fesoterodine 
PR for the 12 weeks safety extension phase. This cohort will include subjects 25.1 
kg and above.

Cohort 2
For subjects ≤25 kg, following 12 weeks of treatment with either fesoterodine 2 
mg or 4 mg BIC (beads-in-capsule formulation) in an efficacy phase, subjects will 
then enter a safety extension phase receiving the same dose of fesoterodine for an 
additional 12 weeks. NB. This cohort will include subjects 25.0 kg and below.
2.1. Study Design
The study was designed to be in line with clinical practice and to minimize disruption, 
discomfort and inconvenience for subjects whilst maintaining scientific integrity.
Cohort 1 (Subjects >25 kg)
For this cohort this is a randomized, open label, active comparator parallel group 
study with three treatment arms.


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Note: The first week of the fesoterodine 8 mg PR group will be at a dose of 4 mg PR 
each day, for both the active comparator phase and for those subjects changing from 
oxybutynin to the safety extension phase.
The study design for this cohort consists of two parts: a 12 week three arm phase with 
an active comparator (oxybutynin XL), followed by a 12 week two arm extension 
phase without the active comparator.
There is a variable screening period (minimum 3 days) prior to the baseline visit, the 
duration of which is principally determined by the prior medication subjects may need 
to washout.  At baseline, subjects will be randomized to one of three arms: 4 mg or 8 
mg/day of fesoterodine PR or oxybutynin XL.  Subjects will be randomized to each 
arm in a 1:1:1 ratio.
After 12 weeks (or earlier if appropriate), subjects in the oxybutynin arm of the study 
will be allocated by the investigator to fesoterodine PR at either 4 mg or 8 mg/day.
Subjects in the fesoterodine arms will remain on the same dose they were randomized 
to during the 12 week safety extension phase.
A sufficient number of subjects will be randomized into Cohort 1 to ensure a total of 
approximately 99 subjects (approximately 33 evaluable subjects per arm) are 
evaluable for the primary efficacy and safety analyses at Week 12.


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Cohort 2 (Subjects ≤25 kg)
Note: The first week of the fesoterodine 4 mg group will be at a dose of 2 mg each day, for the efficacy 
phase.
For this cohort the study design consists of two parts: a 12 week two arm efficacy 
phase, followed by a 12 week two arm safety extension phase.
There is a variable screening period (minimum 3 days) prior to the baseline visit, the 
duration of which is principally determined by the prior medication subjects may need 
to washout.
At baseline, subjects will be randomized to one of two fesoterodine treatment arms: (2 
mg and 4 mg/day – both Beads in Capsule (BIC) formulations). Subjects will be 
randomized to each arm in a 1:1 ratio.    Once allocated, subjects will remain on that 
dose for the 12 week efficacy phase, and will continue at the same dose during the 12 
week safety extension phase.
It is planned that a sufficient number of subjects will be randomized into this cohort to 
ensure a total of approximately 50 subjects (approximately 25 evaluable subjects per 
arm) are evaluable for the primary efficacy and safety analyses at Week 12.
For both cohorts, the dose assigned at randomization (Day 1) will not be changed 
irrespective of any change in weight.


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2.2. Study Objectives 
The primary objectives of this study are:

To determine the safety and efficacy of fesoterodine 4 mg and 8 mg PR 
following once daily treatment for 12 weeks in pediatric NDO subjects with 
weight >25 kg.

To determine the safety and efficacy of fesoterodine 2 mg and 4 mg following 
once daily treatment for 12 weeks in pediatric NDO subjects with weight 25 
kg.
The secondary objectives of this study are to:

evaluate the safety and efficacy of fesoterodine PR versus oxybutynin in 
pediatric NDO subjects with weight >25 kg.

evaluate the safety of fesoterodine 4 mg and 8 mg PR once daily treatment for 
up to 24 weeks in pediatric NDO subjects with weight >25 kg.

evaluate the safety of fesoterodine 2 mg and 4 mg BIC once daily treatment 
for up to 24 weeks in pediatric NDO subjects with weight ≤25 kg.

determine the steady-state population pharmacokinetics of 5-HMT following 
fesoterodine 4 mg and 8 mg PR once daily treatment in pediatric NDO 
subjects with weight >25 kg.

determine the steady-state population pharmacokinetics of 5-HMT following 
treatment with two doses of fesoterodine 2 mg and 4 mg BIC treatment once 
daily in pediatric NDO subjects with weight ≤25 kg.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING 
A blinded interim analysis may be performed after approximately 50% of randomized 
subjects in Cohort 1 have completed the active comparator phase of the study and 
provided data for the primary endpoint (including the corresponding baseline value) 
as a tool to reassess the sample size.  The sample size will be recalculated based on 
the variability of the primary endpoint obtained from this analysis.  Even though this 
is an open label study, data utilized in this interim analysis will remain blinded to 
treatment allocation to minimize bias.  Based on this, the study statistician and 
clinician will assess whether an adjustment to the sample size is required.
These results will not be used to modify the design of the study, other than a potential 
adjustment to the sample size.  No adjustment will be made to the nominal p-values to 
account for this analysis.  The results of this analysis will not be made available to the 
investigator and site staff, other than to inform them of any adjustment to the sample 
size that is recommended.  A similar blinded interim analysis may be performed after 
approximately 50% of randomized subjects in Cohort 2 have completed the efficacy 
phase of the study.


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This study will use an External Data Monitoring Committee (EDMC) for the purpose 
of protecting the safety of patients by regular independent assessment of risk/benefit 
during the conduct of the study (for each cohort separately as well as combined).
The EDMC will meet at specified intervals during the study to assess its progress 
including the safety data and/or critical efficacy endpoints.  Safety data will include 
assessment of adverse events, vision testing, CBCL/GPT assessments, vital signs 
including heart rate, incidence of urinary tract infection (as evidenced by urinalysis, 
urine microscopy and culture), clinical laboratory evaluations in the context of age-
appropriate norms, with particular reference to liver function tests and renal 
chemistry, and post-void residual volume (PVR) in subjects not performing CIC, or 
with >1 urinary tract infection (UTI) during the study.
Assessment of adverse events of particular interest will include, but not be limited to, 
anticholinergic effects such as dry mouth, dry eyes and constipation, CNS effects such 
as behavioral changes (eg, aggression), decreased cognitive function, headache, 
seizures, somnolence and visual effects such as accommodation disorder, blurred 
vision, and amblyopia,
The remit of the EDMC will be to, and to recommend whether to continue or, modify, 
or stop the study.  In the event that a negative benefit-risk is determined, the EDMC 
may recommend that the study (or recruitment to a particular cohort) be terminated. 
The EDMC will be advisory to the sponsor, Pfizer Inc. The sponsor will promptly 
review the EDMC recommendations, and will make decisions regarding accepting, 
modifying or rejecting those recommendations. The final decisions regarding trial 
continuation, modification or termination will be made by the sponsor.
Full technical details for the EDMC, including its primary responsibilities, 
relationship with other trial components, membership, timing of meetings, and rules 
will be provided in the EDMC Charter, which will be drawn up by the sponsor study 
team and agreed to by the EDMC.  All members included in an EDMC must have 
acceptable conflict of interest status and a contract should be in place before the work 
commences.
The final analysis will be performed following official database release, once all 
subjects have completed the whole study.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
The following hypotheses are applicable only to the analyses of the heavier (>25 Kg) 
Cohort 1, as there is no formal hypothesis testing planned for the lighter (≤25 Kg)
Cohort 2
Null Hypothesis: The difference between baseline and week 12 in maximum 
cystometric bladder capacity is equal to zero.


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Alternative Hypothesis: The difference between baseline and week 12 in maximum 
cystometric bladder capacity is not equal to zero.
Sample Size Determination
Cohort 1 (>25 kg)
A sample size of 33 evaluable subjects per group is sufficient to give a power of at 
least 90% to detect a change from baseline of 70 mL in the primary endpoint, 
maximum cystometric capacity (MCC), when the standard deviation of the change 
from baseline is 120 mL.  This calculation assumes the testing will be performed at a 
two-sided 5% significance level and is based on results observed from the two highest 
dose periods (each 4 weeks) in previous tolterodine neurogenic bladder studies 583E-
URO-0581-001, 583E-URO-0581-002 and 583-URO-0581-003, as well as published 
data from studies of oral oxybutynin in neurogenic bladder subjects.  An oxybutynin 
active comparator arm will enable comparisons between fesoterodine and oxybutynin 
to be made; therefore a sufficient number of subjects will be randomized into Cohort 
1 to ensure a total of approximately 99 subjects (33 evaluable subjects per arm) are 
evaluable at Week 12.
This sample size will also provide a 2-sided 95% confidence interval for the change 
from baseline in MCC of approximately ±70 mL around the point estimate for the
difference between each fesoterodine arm and oxybutynin, with 90% coverage 
probability.  Using this estimation approach, these confidence intervals will be used 
to assess the comparability of each fesoterodine dose and oxybutynin.
Cohort 2 (≤25 kg)
A sample size of approximately 25 evaluable subjects per arm will provide a 2-sided 
95% confidence interval for the change from baseline in maximum cystometric 
capacity (MCC) of approximately ± 55 mL around the point estimate for the mean, 
with 80% coverage probability.  This assumes a standard deviation of 120 mL.  This 
is based on results observed from the two highest dose periods (each 4 weeks) in 
previous tolterodine neurogenic bladder studies 583E-URO-0581-001, 583E-URO-
0581-002 and 583-URO-0581-003, as well as published data from studies of oral 
oxybutynin in neurogenic OAB patients.  It is planned that a sufficient number of 
subjects will be randomized into this cohort to ensure a total of approximately 50 
subjects (25 evaluable subjects per arm) are evaluable at Week 12.
4.2. Statistical Decision Rules
Changes from baseline in Cohort 1 will be tested at the α=0.05 level, and 95% 
Confidence Intervals will be estimated for Cohort 2.
5. ANALYSIS SETS
The following efficacy analysis sets will be determined separately for each cohort.


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5.1. Full Analysis Set
The Full Analysis Set will include all subjects who have been randomized and 
received at least one dose of study medication and have provided baseline primary 
endpoint data.
This is to utilize as much data as possible from any subjects with urodynamic data
available for analysis and will not exclude subjects with only baseline data available.
5.2. Per Protocol Analysis Set
The Per Protocol Analysis Set will include all subjects who have completed the active
comparator/efficacy phase of the study, and who have not violated any of the 
inclusion/exclusion criteria or deviated from the protocol in a way that could affect 
the efficacy outcome of the study.
The PPAS for each cohort will be defined prior to unblinding.
5.2.1. Deviations assessed prior to randomization
Violation of a major inclusion/exclusion criterion prior to randomisation would be 
considered a protocol violation. The criteria and determination of protocol 
violation/deviation will be determined by Pfizer prior to database lock.
5.2.2. Deviations assessed post-randomization
Violation of a major inclusion/exclusion criterion post randomisation would be 
considered a protocol violation, for example:

Initiation of a prohibited concomitant medication.

Study drug compliance <80% or >120%.

Incomplete primary endpoint data at week 12.
The criteria and determination of protocol violation/deviation will be determined by 
Pfizer prior to database lock.
5.3. Safety Analysis Set
There will be three safety analysis sets for Cohort 1 (to be utilized for AEs and 
duration of treatment summaries):

Active Comparator Phase safety set: all subjects who received at least one 
dose of study medication during the active comparator phase. The following 
treatment assignments will be used for this analysis set:

Fesoterodine 4mg PR;

Fesoterodine 8mg PR;

Oxybutynin.


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
Safety Extension Phase safety set: all subjects who received at least one dose 
of study medication during the safety extension phase. The following 
treatment assignments will be used for this analysis set:

Oxybutynin -> Fesoterodine 4mg PR;

Oxybutynin -> Fesoterodine 8mg PR;

Fesoterodine 4mg PR -> Fesoterodine 4mg PR;

Fesoterodine 8mg PR -> Fesoterodine 8mg PR.

Overall study safety set: subjects who were randomized to fesoterodine during 
the active comparator phase and received at least one dose of study medication 
during both phases of the study:

Fesoterodine 4mg PR (24 weeks);

Fesoterodine 8mg PR (24 weeks).

For all other Safety tables, the Safety Analysis Set will just consist of all 
subjects who received at least one dose of study medication at any time during 
the study (ie, in either phase). The following treatment assignments should be 
used for this:

Oxybutynin -> Fesoterodine 4mg PR;

Oxybutynin -> Fesoterodine 8mg PR;

Oxybutynin;

Fesoterodine 4mg PR -> Fesoterodine 4mg PR;

Fesoterodine 8mg PR -> Fesoterodine 8mg PR.
NB: All randomized subjects will be used for summarizing discontinuations in the
Active Comparator Phase and overall, and for data collected at baseline.
There will be three safety analysis sets for Cohort 2 (to be utilized for AEs and 
duration of treatment summaries):

Efficacy Phase safety set: all subjects who received at least one dose of study 
medication during the efficacy phase. The following treatment assignments 
will be used for this analysis set:

Fesoterodine 2mg BIC;

Fesoterodine 4mg BIC.

Safety Extension Phase safety set: all subjects who received at least one dose 
of study medication during the safety extension phase. The following 
treatment assignments will be used for this analysis set:

Fesoterodine 2mg BIC -> Fesoterodine 2mg BIC;

Fesoterodine 4mg BIC -> Fesoterodine 4mg BIC.


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
For all other Safety tables, the Safety Analysis Set will just consist of all 
subjects who received at least one dose of study medication at any time during 
the study (ie, in either phase). The following treatment assignments should be 
used for this:

Fesoterodine 2mg BIC -> Fesoterodine 2mg BIC;

Fesoterodine 4mg BIC -> Fesoterodine 4mg BIC.
NB: All randomized subjects will be used for summarizing discontinuations in the 
Efficacy Phase and overall, and for data collected at baseline.
5.4. Pharmacokinetic (PK) Analysis Set
The following PK Analysis Sets will be determined for each cohort separately.
Concentration Analysis Set
The PK concentration population is defined as all subjects randomized and treated 
who have at least 1 concentration during the study.
Parameter Analysis Set
The PK parameter analysis population is defined as all subjects randomized and 
treated who have at least 1 of the PK parameters of primary interest during the study.
5.5. Treatment Misallocations 
Subjects who are randomized but never treated will not be included in either safety or 
efficacy analyses.  For a randomized subject who took the incorrect treatment, he/she 
will be reported under the randomized treatment group for all efficacy analyses, but 
will be reported under the treatment they actually received for all safety analyses.
5.6. Protocol Deviations
5.6.1. Deviations assessed prior to randomization
See Section 5.2.1
5.6.2. Deviations assessed post-randomization
See Section 5.2.2
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
6.1.1. Primary Endpoint

Maximum cystometric bladder capacity defined as maximal tolerable 
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6.1.2. Secondary Endpoints

Detrusor pressure at maximum bladder capacity;

Presence of involuntary detrusor contractions (IDC);

Bladder volume at first IDC;

Bladder compliance.
Defined as volume/pressure during that change in bladder volume.

Mean number of micturitions per 24 hours.
The mean number of micturitions per 24 hours will be calculated as the total number 
of micturitions divided by the total number of diary days collected at that assessment. 
This endpoint will only be calculated for subjects with >0 episodes at baseline.

Mean number of catheterizations per 24 hours.
The mean number of catheterizations per 24 hours will be calculated as the total 
number of catheterizations divided by the total number of diary days collected at that 
assessment.* This endpoint will only be calculated for subjects with >0 episodes at 
baseline.
*Note: The number of diary days collected at that assessment is the number of 
calendar days that the diary has been completed on (even if this may not be a full 24 
hour period). For example, if a diary has been completed for 3 complete days and the 
morning of the fourth day, this would count as 4 days. This derivation is the same for 
all the diary endpoints listed ‘per 24 hours’.

Mean number of micturitions and catheterizations combined per 24 hours.
The mean number of micturitions and catheterizations combined per 24 hours will be 
calculated as the total number of micturitions and catheterizations combined divided 
by the total number of diary days collected at that assessment. 

Mean number of incontinence episodes per 24 hours.
The mean number of incontinence episodes per 24 hours will be calculated as the total 
number of incontinence episodes divided by the total number of diary days collected 
at that assessment. This endpoint will only be calculated for subjects with >0 episodes 
at baseline.

Mean urgency episodes per 24 hours if applicable (only for sensate subjects, 
ie, able to physically experience the sensation of urgency - as indicated in 
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The mean number of urgency episodes per 24 hours will be calculated as the total 
number of urgency episodes divided by the total number of diary days collected at 
that assessment. Urgency episodes are defined as Urgency marked as ‘yes’ in the 
diary. This endpoint will only be calculated for subjects with >0 episodes at baseline.

Mean volume voided per micturition.
The mean voided volume per micturition will be calculated as sum of voided volume 
divided by the total number of micturition episodes with a recorded voided volume 
greater than 0, regardless of the number of available diary days at that assessment.  
Note: missing or zero voided volume will not be included in this calculation

Mean volume per catheterization.
The mean volume per catheterization will be calculated as sum of voided volume 
divided by the total number of catheterization volume greater than 0, regardless of the 
number of available diary days at that assessment.  Note: missing or zero voided 
volume will not be included in this calculation

Mean volume voided per micturition or catheterization.
The mean voided volume per micturition or catheterization will be calculated as sum 
of voided volume divided by the total number of micturition episodes with a recorded 
voided volume greater than 0, regardless of the number of available diary days at that 
assessment.  Note: missing or zero voided volume will not be included in this 
calculation
6.2. Safety Endpoints

Adverse events, including monitoring of targeted events including, but not 
limited to:

Anticholinergic effects such as dry mouth, dry eyes and constipation.

CNS effects such as behavioral changes (eg, aggression), decreased 
cognitive function, headache, seizures, somnolence.

Visual effects such as accommodation disorder, blurred vision, and 
amblyopia.

Visual acuity and accommodation tests.

Cognitive function by the Child Behavior Checklist and Grooved Pegboard 
Test.

Vital Signs, including heart rate in the context of age-appropriate norms.


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
Urinary Tract Infection, as evidenced by urinalysis, urine microscopy, culture 
and sensitivity.

Clinical Laboratory Evaluations in the context of age-appropriate norms, with 
particular reference to liver function tests and renal chemistry.

Post-void residual volume (PVR) in subjects not performing CIC, or with >1 
urinary tract infection (UTI) during the study.

Physical Examination and weight.
6.2.1. Adverse Events
Adverse event information will be collected for all subjects.  Information that will be 
collected includes: nature of event, whether event was serious; date of onset; date of 
cessation or event continuing; severity of event; relationship of event to study drug; 
action taken regarding study drug due to the event; clinical outcome of event.
A 3-tier approach will be used to summarize AEs. Under this approach, AEs are 
classified into 1 of 3 tiers. Different analyses will be performed for different tiers (See 
Section 8.2.5). 
Tier-1 events: These are pre-specified events of clinical importance and are 
maintained in a list in the product’s Safety Review Plan.
Tier-2 events: These are events that are not tier-1 but are “common”. A MedDRA PT 
is defined as a tier-2 event if there are at least 4 subjects in any treatment group.
Tier-3 events: These are events that are neither tier-1 nor tier-2 events
Visual acuity and accommodation tests
Visual acuity will be assessed using the Snellen method, using an optotype that is 
appropriate to the child’s intellectual development at Visit 2, Visit 5, and Visit 7.
Amplitude of accommodation will be assessed by the push up test to assess minimum 
focusing distance at Visit 2, Visit 5, and Visit 7. The subject will focus on a single 
letter of the 20/40 line of an eye chart (appropriate optotype) and this will be moved 
slowly toward the subject until it blurs. At this point the distance from eye to letter
will be measured for each eye.
For both visual acuity and accommodation assessments the same optotype will be 
used for a specific subject throughout the study to ensure standardization and validity.
6.2.2. Vital Signs
Blood pressure, temperature and pulse rate should be measured at Visit 1, Visit 2, 
Visit 3, Visit 5 and Visit 7.  This schedule of measurements should provide adequate 
indication of any clinically relevant changes.  However, if vital signs show a clinically 
relevant change from baseline, then safety monitoring will occur at a minimum of 
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resolves.  The measured results will be assessed in the context of age appropriate 
norms.
Temperature may be taken via oral, tympanic or axillary routes as per local accepted 
practice. Digital devices are permitted; however, mercury thermometers should not 
be used.  The same method should be used for the subject throughout the study.
Blood pressure should be measured using a pediatric or appropriately sized 
sphygmomanometer in the sitting/resting position with the subject’s arm supported at 
the level of the heart, and recorded to the nearest mmHg.  The same arm (preferably 
the dominant arm) will be used throughout the study.
The same size blood pressure cuff, which has been properly sized and calibrated, will 
be used to measure blood pressure each time.  The use of automated devices for 
measuring BP and pulse rate are acceptable, although, when done manually, pulse 
rate will be measured in the brachial/radial artery for at least 30 seconds.
6.2.3. Physical Exam
A physical examination will be performed at V1/Screening, and will include the 
following systems:

General appearance (including weight).

Skin.

HEENT (head, eyes, ears, nose, throat, visual acuity and accommodation).

Respiratory.

Cardiovascular.

Gastrointestinal.

Musculoskeletal.

Neurourological.
Additional physical assessments will be performed as necessary to evaluate the 
subject.  Any clinically significant negative changes from the entry examination will
be recorded as adverse events.
6.2.4. Weight Measurements
Weight will be recorded at Screening and used to assess eligibility and for 
stratification purposes. Subsequently weight will be recorded at Visit 3, Visit 5, and 
Visit 7. All weight measurements should be standardized using the same equipment 
and measuring technique for an individual subject. Any clinically significant change 
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6.2.5. Electrocardiogram
Scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position.  A single 12-lead ECG will be obtained on all 
subjects at screening.
6.2.6. Clinical Laboratory Evaluation
The following safety laboratory tests will be performed at Visit 1 (Screening) and 
additional visits as below, or as needed to follow-up on significant findings.
Safety Laboratory
Hematology – V1, V5, 
V7
Chemistry - V1, V5, V7
Urinalysis – V1, V3, 
V5, V7
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count with
differential as below:
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
GOT (AST)
GPT (ALT)
Total bilirubin
Alkaline phosphatase
LDH
CPK
BUN
Creatininec
Uric acid
Total protein 
Sodium
Potassium
Corrected calcium
Glucose
Urine will be tested
for the following 
using a urine 
dipstick:
pH
Specific gravity
Leukocyte esterase
Nitrites
Glucose
Protein
Blood
Ketones
Urine microscopy, 
culture and 
sensitivitya
Pregnancy Testb 
(serum V1, urine at 
subsequent visits, 2, 3, 
5, and 7)
Unanonymized 
pharmacogenomic 
sample (V3 only) d
PK sample (V3 only) d
a Urine microscopy, culture and sensitivity to be performed in the event of the presence of symptoms (eg, fever, 
flank pain), positive leucocytes and/or nitrites on urinalysis, or if the subject has a documented history of 
vesicoureteral reflux (VUR).
Subjects who are found to have an active UTI during screening as defined in exclusion criterion 12 may 
continue screening activities on resolution of symptoms or treatment of the UTI to the satisfaction of the
treating physician.
b Females of childbearing potential only (9 years old or have experienced menarche, whichever is earlier).
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
cWhen indicated, the investigator may request calculation of an estimated GFR using the Schwartz equation 
GFR = (k x H)/Cr where k = constant, H = Height (length) and Cr = Creatinine. In this case, the laboratory will 
need to be provided with the subject's height in cm.
d PG and PK samples are for fesoterodine group subjects only.
6.2.7. Childhood Behavior Checklist (CBCL)
The CBCL is a questionnaire by which a child's problem behaviors and competencies 
can be assessed. This instrument can either be self-administered or administered 
through an interview. The CBCL can also be used to measure a child's change in 
behavior over time or following a treatment. The first section of this questionnaire 
consists of 20 competence items and the second section consists of 120 items on 
behavior or emotional problems. For the purpose of this trial, subjects will be asked 
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The CBCL will be completed at Visit 2, Visit 5 and Visit 7.
6.2.8. Grooved Pegboard Test (GPT)
The Grooved Pegboard Test is a manipulative dexterity test that assesses 
psychomotor speed, fine motor control, and rapid-visual motor coordination. It 
consists of a small board of 25 holes with randomly positioned slots. Pegs with a key 
along one side must be rotated to match the hole before they can be inserted. Time to 
completion is scored, and higher scores represent lower levels of performance.
The GPT will be assessed at Visit 2, Visit 5 and Visit 7.
6.3. Pharmacokinetic Evaluations
Variation in the CYP2D6 gene plays a role in metabolism of active metabolite (5-
HMT) of fesoterodine.  The alleles which will be genotyped are *3, *4, *5, *6, *7, *8, 
*10, *14, *17, *18, *21, *36, *41 and duplication.  Homozygous or heterozygous 
combinations of *3, *4, *5, *6, *7, *8, *14, *17, *18, and *21 will be classified as 
poor metabolizer (PM) of CYP2D6.  Other genotypes will be classified as extensive 
metabolizer (EM). CYP2D6 genotype and metabolizer status of subjects randomized 
to fesoterodine treatment will be reported as an individual-subject listing. 
For those subjects who are randomized to fesoterodine and who do not have sufficient
laboratory documentation, a 2-ml whole blood sample will be collected for CYP2D6
genotype analysis. All samples will be discarded following analysis. Subjects who 
have prior laboratory documentation of their CYP2D6 genotype will not be required 
to submit a blood sample for pharmacogenomics. Subjects randomized to treatment 
with oxybutynin will also not be required to provide a sample for pharmacogenomic 
assessment.
Population pharmacokinetic analyses will be conducted via nonlinear mixed-effects 
modeling with the NONMEM® software, Version VI (ICON Development Solutions, 
Ellicott City, MD). Model-based parameter estimates for absorption rate constant 
(Ka), apparent oral clearance (CL/F) and volumes of distribution (Vd) will be 
determined to predict the area under the curve (AUC), maximum concentration
(Cmax), time to reach Cmax (Tmax) and half-life of 5-HMT in patients randomized to 
fesoterodine treatment. Possible influences of patient covariates (eg, age, body 
weight, gender, CYP2D6 metabolizer status etc.) on 5-HMT exposure will be 
assessed.
6.4. Covariates
The baseline observation for the endpoint being analyzed will be used as a continuous 
covariate in any ANCOVA analyses.


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Baseline weight will be used as a continuous endpoint in any ANCOVA analyses.
The following subgroups will be assessed for the primary endpoint:
Age: Ages ≥6-9, ≥10-12, ≥13-17
Weight: Cohort 1: ≤50 kg, >50 kg, Cohort 2: ≤20 kg, >20 kg
Gender: Male, Female
Region: Cohort 1: North America, Europe, Asia, Cohort 2: North America and 
Europe, Asia
Type of Underlying Disease: Congenital, Acquired, Unknown
Race: White, Asian, Black, Other (where Other includes: American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander)
Ethnicity: Hispanic/Latino, Not Hispanic/Latino
Underlying disease will be categorised as 'congenital' or 'acquired' and will be 
determined through manual review of medical history listings (by the clinician) for 
Cohort 1. If this is unable to be determined, this will be categorized as ‘Unknown’. 
For Cohort 2 the answer to the question “Underlying Cause of Primary Diagnosis” on 
the Primary Diagnosis eCRF page will be utilized, for which the responses are 
‘Congenital’ or ‘Acquired’.
7. HANDLING OF MISSING VALUES
Missing visits
For the PPAS analysis no imputation techniques for missing data will be employed.  
For the FAS analysis a combination of Baseline Observation Carried Forward
(BOCF) and a Last Observation Carried Forward (LOCF) algorithm will be used for 
missing data. For example, where a subject has no post-baseline observation then the 
baseline observation will be carried forward and used for Week 12 analyses; if a 
subject withdraws early then their termination visit will be carried forward (note this 
will be labelled as ‘Week 12’ in the dataset).
Diary Data
For the analysis involving diaries, time-points will be defined as non-overlapping 
periods.  See Appendix B for definition of time intervals.  Missing daily micturition 
data will be estimated as the following: 
1. If one out of three days is missing, the mean of the remaining days will be 
used to impute the micturition data for the missing day/days. 
2. The LOCF/BOCF imputations will be carried out for time-intervals with 
missing diary data.  For intervals where less than two days of diary data are 
available, the previous available 3-day post-baseline interval values will then 
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Micturition volume is collected on one day only therefore if it is missing at a visit the 
previous visit’s data will be carried forward.
Note: In subjects who withdraw after a minimum of 2 weeks of treatment, attempts 
should be made to perform a urodynamic assessment, provided that they have not 
missed any doses in the three days previous to the visit.
Plasma concentrations
Concentrations below the limit of quantification
In listings BLQ values will be reported as “<LLQ”, where LLQ will be replaced with 
the value for the lower limit of quantification.
Missing concentrations values
In summary tables, statistics will be calculated having set concentrations to missing if 
the following case is true:

A concentration has been collected as ND (ie not done) or NS (ie no sample).
Note that summary statistics will not be presented at a particular time point if more 
than 50% of the data are missing.
Date of Birth
In the case where the whole Date of Birth is not entered, the last day of the month will 
be used to impute the missing day, and 31st December will be used if both the day 
and month are missing. 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical METHODS 
Treatments will be labeled as follows in all the data summaries:
Cohort 1:
Fesoterodine 4 mg PR
Fesoterodine 8 mg PR
Oxybutynin
Cohort 2:
Fesoterodine 2 mg BIC
Fesoterodine 4 mg BIC


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8.1.1. Analysis of Continuous Data 
Where data is to be summarized using descriptive statistics the following will be 
presented: n, mean, standard deviation, median, minimum, and maximum.
8.1.2. Analysis of Binary Data
Binary endpoints will be presented using cell counts and proportions for each 
response category. For summaries of change from baseline the tables will be
presented as a cross tabulation with baseline visit along the side and week 12 results
along the top.
8.2. Statistical Analyses 
8.2.1. Cohort 1: Primary Analysis
Change from baseline to Week 12 in the primary endpoint will be analysed using an 
ANCOVA including terms for treatment group, baseline (for the endpoint being 
analyzed) and baseline weight.  The Least Squares mean change from baseline for
each treatment group, standard error, 95% confidence intervals and p-values 
associated with the Least Squares mean changes from baseline will be presented.
All endpoints will also be summarized descriptively for each treatment group, by 
timepoint as for a continuous endpoint.  Should any of the assumptions of the analysis 
methods not be adequately met, alternative procedures will be used and fully 
documented.
The following primary comparisons of interest will be assessed:

Change from Baseline to Week 12 for fesoterodine 4 mg PR.

Change from Baseline to Week 12 for fesoterodine 8 mg PR.
The Least Squares means and 95% confidence intervals for the difference between 
each fesoterodine dose group and oxybutynin will also be calculated.
The following secondary comparisons will be assessed using 95% confidence 
intervals for the difference between treatment means (for the change from baseline to 
Week 12):

Fesoterodine 4 mg PR vs Oxybutynin.

Fesoterodine 8 mg PR vs Oxybutynin.
As these secondary comparisons are based on an estimation approach, no formal 
statistical hypothesis testing will be performed.  Conclusions will be based on point 
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Forest plots presenting the mean and 95% confidence intervals for the change from 
baseline for Fesoterodine 4mg PR, Fesoterodine 8mg PR and Oxybutynin will be 
produced. In addition the mean difference and its associated 95% confidence interval 
between change from baseline for Fesoterodine 4 mg PR vs. Oxybutynin and 
Fesoterodine 8 mg PR vs. Oxybutynin will be also presented in a separate plot.
The primary analysis will be based on the Full Analysis Set (FAS).  The secondary 
analysis set will be the Per Protocol Analysis Set (PPAS).
Data from the active comparator phase of the study may be summarized, analyzed and 
reported after all subjects have either completed or withdrawn prior to the Week 12 
visit or from both phases after all subjects in Cohort 1 have either completed or 
withdrawn prior to the end of the study (ie, prior to formal completion of the whole 
study for both cohorts).  If performed, the results of these analyses will be assessed by 
the EDMC and will be available to limited members of the study team as a 
management tool in order to aid decision making, and may also be shared with 
regulators in order to facilitate timely discussion of the overall program; they will not 
be used to stop or modify the design of the study.
Descriptive subgroup analyses of the change from baseline to Week 12 in the primary
endpoint will be produced by age group, weight group, race, ethnicity, gender, region 
and underlying type of disease.
8.2.2. Cohort 2: Primary Analysis
Change from baseline to Week 12 in the primary endpoint will be analyzed using an 
ANCOVA including terms for treatment group and baseline (for the endpoint being 
analyzed).  The Least Squares mean change from baseline for each treatment group, 
standard error and 95% confidence intervals associated with the Least Squares mean 
changes from baseline will be presented.
All endpoints will also be summarized descriptively for each treatment group, by 
timepoint, using: N, mean, standard deviation, median, minimum and maximum.  
Should any of the assumptions of the analysis methods not be adequately met, 
alternative procedures will be used and fully documented.
The following primary comparisons of interest will be assessed:

Change from Baseline to Week 12 for fesoterodine 2 mg BIC.

Change from Baseline to Week 12 for fesoterodine 4 mg BIC.
As these comparisons are based on an estimation approach, no formal statistical 
hypothesis testing will be performed.  Conclusions will be based on point estimates 
and confidence intervals.


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The primary analysis will be based on the Cohort 2 Full Analysis Set (FAS2).  The 
secondary analysis set will be the Cohort 2 Per Protocol Analysis Set (PPAS2).
For the PPAS analysis no imputation techniques for missing data will be employed.  
For the FAS analysis a Baseline Observation Carried Forward (BOCF) and a Last 
Observation Carried Forward (LOCF) algorithm will be used for missing data.
Data from the efficacy phase for this cohort may be summarized, analyzed and 
reported after all patients in this cohort have either completed or withdrawn prior to 
the Week 12 visit (ie, prior to formal completion of the study). The results of these 
analyses will be available to limited members of the study team as a management tool 
in order to aid decision making, and may also be shared with regulators in order to 
facilitate timely discussion of the overall program; they will not be used to stop or
modify the design of the study.
Descriptive subgroup analyses of the change from baseline to Week 12 in the primary 
endpoint will be produced by age group, weight group, race, ethnicity, gender, region 
and underlying type of disease.
8.2.3. Secondary Analyses
All secondary endpoints will be analysed as for the primary analyses as defined for 
each respective cohort using the appropriate full analysis set. A further analysis of the 
key secondary endpoints of Bladder compliance and IDC will use the per protocol 
analysis set. 
The presence of IDC will be analyzed as for discrete endpoints.
8.2.4. Other Endpoints
The following analyses will be carried out for subjects randomised to Fesoterodine 
only (for each cohort separately).
Pharmacokinetic Concentrations
Plasma concentrations of 5-HMT will be listed and summarized for subjects in the PK 
analysis set, where missing and BLQ values will be handled as detailed in Section 7.
Presentations will include:

a listing of all concentrations sorted by visit, dose, subject ID and nominal 
time postdose.  The listing of concentrations will include the actual times. 

if data permit, a summary of concentrations by visit, dose and nominal time 
postdose, where the set of statistics will include n, mean, median, standard 
deviation, minimum, maximum, coefficient of variation (cv) and the number 
of concentrations above the lower limit of quantification.


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Pharmacokinetic Parameters
Model based PK parameters (from POP PK analysis) will be described in a separate 
plan.
8.2.5. Safety Analyses
Tables of safety and demographic data, including adverse events and medical history 
in this report will be reported in accordance with current Pfizer standards, and will be 
presented separately for each cohort.  Safety summaries of both cohorts combined 
may also be produced. Adverse events will be summarized by treatment group as 
specified for the Three Tier Adverse Event Reporting and for Other Adverse Event 
Reporting.
All other safety summaries will be summarised by the following treatment groups (as 
safety data will be captured throughout the Active Comparator/Efficacy and Safety 
Extension phases):
Cohort 1:
Oxybutynin -> Fesoterodine 4mg PR
Oxybutynin -> Fesoterodine 8mg PR
Oxybutynin (only)
Fesoterodine 4mg PR -> Fesoterodine 4mg PR
Fesoterodine 8mg PR -> Fesoterodine 8mg PR
Cohort 2:
Fesoterodine 2mg BIC -> Fesoterodine 2mg BIC
Fesoterodine 4mg BIC -> Fesoterodine 4mg BIC
Three Tier Adverse Event Reporting
The presentations described in this section will only concern treatment emergent 
adverse events which occurred during the active comparator/efficacy phases of this 
study for each cohort, and will be presented separately for each cohort. The active 
comparator/efficacy phase is defined as first dose to week 12 plus a lag time of 7 
days.
Where presented, for Cohort 1, the treatment comparisons will be Fesoterodine 4mg 
vs. Oxybutynin and Fesoterodine 8mg vs. Oxybutynin. The risk difference will be 
calculated as Fesoterodine (4mg PR or 8mg PR) minus Oxybutynin. There will be no 
treatment comparisons presented for Cohort 2, as there is no active comparator for 
this cohort.
Adverse events will be presented in order of system organ class.
Tier 1 Adverse Event Reporting
Tier 1 summaries will only report those adverse events which have been identified as 
targeted medical events (TMEs) in the safety review plan.


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The percentage of subjects experiencing a particular adverse event in each treatment 
group will be presented both in a table and graphically. The table will present the 
point estimate for the percentage of affected subjects, along with risk differences, 
their 95% confidence intervals and p-values, for Cohort 1 (fesoterodine 4mg PR or 
8mg PR minus Oxybutynin). However for Cohort 2, only point estimates will be 
presented, as there is no active comparator for this cohort.
Graphical presentations will include the point estimate for the percentage of affected 
subjects, along with the risk differences and their 95% confidence intervals for Cohort 
1, and point estimates only for Cohort 2.
Tier 2 Adverse Event Reporting
Tier 2 summaries will only report those adverse events which occurred to 4 or more 
subjects in any treatment group.
The percentage of subjects experiencing a particular adverse event in each treatment 
group will be presented both in a table and graphically. The table will present the 
point estimate for the percentage of affected subjects, along with the risk differences
and their 95% confidence intervals, for Cohort 1. However for Cohort 2, only point 
estimates will be presented, as there is no active comparator for this cohort.
Graphical presentations will include the point estimate for the percentage of affected 
subjects, along with the risk differences and their 95% confidence intervals for Cohort 
1, and point estimates only for Cohort 2.
Tier 3 Adverse Event Reporting
Tier 3 adverse events are events that are neither tier-1 nor tier-2 events, however these 
will not be summarized separately. All adverse events (Tier 1, 2 and 3 adverse events) 
will be presented together in table form only. The frequency and percentage of 
subjects will be presented by treatment group.
It should be recognized that most studies are not designed to reliably demonstrate a 
causal relationship between the use of a pharmaceutical product and an adverse event 
or a group of adverse events. Except for select events in unique situations, studies do 
not employ formal adjudication procedures for the purpose of event classification. As 
such, safety analysis is generally considered as an exploratory analysis and its purpose 
is to generate hypotheses for further investigation. The 3-tier approach facilitates this 
exploratory analysis.
Other Adverse Event Reporting
Adverse events will be reported separately for the active comparator phase, the safety 
extension phase and over the entire study. Summaries will be presented as follows:


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For the Active Comparator/Efficacy Phase:
The active comparator/efficacy phase is defined as the first dose up to week 12 if the 
subject continues into the Safety Extension Phase.  If a subject has discontinued early
during the active comparator/efficacy phase, the reporting period for this phase will 
be up to their last dose of study medication plus the drug specific lag time. For 
Fesoterodine this will be 7 days, however for Oxybutynin (Cohort 1 only) this will be 
either 2 days or the time until first treatment of Fesoterodine in the safety extension 
phase, whichever is longer. The following treatment groups will be summarized.
Cohort 1:
Fesoterodine 4mg PR
Fesoterodine 8mg PR
Oxybutynin
Cohort 2:
Fesoterodine 2mg BIC
Fesoterodine 4mg BIC
For the Safety Extension Phase:
The safety extension phase is started after the first dose of fesoterodine in the safety 
extension phase is administered. Only adverse events that started or worsened in the 
Safety Extension phase would be counted as treatment emergent in this phase. Note 
that treatment emergent AEs will be defined as described in the Pfizer Data Standards 
for cross over studies. The following treatment groups will be summarized.
Cohort 1:
Oxybutynin -> Fesoterodine 4mg PR
Oxybutynin -> Fesoterodine 8mg PR
Fesoterodine 4mg PR -> Fesoterodine 4mg PR
Fesoterodine 8mg PR -> Fesoterodine 8mg PR
Cohort 2:
Fesoterodine 2mg BIC -> Fesoterodine 2mg BIC
Fesoterodine 4mg BIC -> Fesoterodine 4mg BIC
For the whole study (overall):
These presentations will only include subjects who were randomised to fesoterodine.
Cohort 1:
Fesoterodine 4mg PR (24 weeks)
Fesoterodine 8mg PR (24 weeks)
Cohort 2:
Fesoterodine 2mg BIC (24 weeks)
Fesoterodine 4mg BIC (24 weeks)


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Plots displaying the point estimate for the percentage of subjects in each treatment
group who experience adverse events of particular interest will be presented for the 
Safety Extension phase and for the study as a whole. 
Vital Sign Reporting
For vital signs change from baseline will be summarized together with the number of 
subjects whose blood pressure and heart rate fall outside specified ranges. 
Furthermore, the number of subjects who decreases and increases in responses fall 
outside specified ranges will be summarized (for blood pressure only). 
Endpoint
Cutoff
Systolic Blood Pressure
SBP Increase from Baseline
SBP Decrease from Baseline
<90
≥30
≥30
Diastolic Blood Pressure
DBP Increase from Baseline
DBP Decrease from Baseline
<50
≥20
≥20
Pulse
<40 or >120
At all visits, for replicates, the second PVR value should be reported. This should also 
be the smallest if done per protocol. This should be footnoted as follows: “Only the 
second PVR urine volume is reported in the summary tables in cases where a repeat 
PVR assessment is made”. 
Visual Acuity (LogMAR units) and Accommodation (the distance for each eye at 
which vision becomes blurred – the mean of triplicate measurements), CBCL 
(Domain T Scores and Total Scores as captured in the CRF), GPT (Time to 
completion, Number of pegs dropped and Number of pegs correctly placed – by 
dominant/non-dominant hand and whether the 10-peg or 25-peg test was used, 
separately), Physical Exam and Weight will be summarized by visit and changes from 
baseline at each visit using descriptive statistics.
For Visual Acuity, LogMAR units will be derived from the Snellen ratios recorded on 
the CRF, as shown in the table below. The decimal is the Snellen ratio (whether it is 
recorded in metres or feet) expressed as a decimal and LogMAR=Log10(1/decimal) 
(recorded to 1 d.p.). Due to the limited space available in the CRF, the Snellen ratio
‘20/12.5’ will be recorded as ‘20/13’, however this should still be converted to a 
decimal value of 1.60 and a LogMAR value of -0.2 as shown in the table below. If the 
Snellen Visual Acuity has been recorded in any other format than those shown below, 
the appropriate conversion to decimal will be determined prior to database lock.


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8.2.6. Summary of Efficacy Endpoint Analyses 
Endpoint
Analysis Set
Assessment
PLANNED Statistical Method 
Missing Data
Interpretation
Change in maximum 
cystometric bladder capacity
at week 12 relative to 
baseline
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics
and subgroup summaries. 
BOCF/LOCF (for 
ANCOVA only)
Primary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics
and subgroup summaries. 
BOCF/LOCF (for 
ANCOVA only)
Primary analysis 
(for Cohort 2)
PPAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
No imputation
Supportive to the 
primary analysis 
(for Cohort 1)
PPAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
No imputation
Supportive to the 
primary analysis 
(for Cohort 2)
Change in maximum 
detrusor pressure at 
maximum bladder capacity 
at week 12 relative to 
baseline
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis
(for Cohort 2)
Presence of IDC
FAS (Cohort 1)
Week 12
Categorical summaries
BOCF/LOCF
Secondary analysis
(for Cohort 1)
FAS (Cohort 2)
Week 12
Categorical summaries
BOCF/LOCF
Secondary analysis 
(for Cohort 2)
PPAS (Cohort 1)
Week 12
Categorical summaries
No imputation
Secondary analysis 
(for Cohort 1)


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Endpoint
Analysis Set
Assessment
PLANNED Statistical Method 
Missing Data
Interpretation
PPAS (Cohort 2)
Week 12
Categorical summaries
No imputation
Secondary analysis 
(for Cohort 2)
Change in bladder 
compliance at week 12 
relative to baseline
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)
PPAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
No imputation
Secondary analysis 
(for Cohort 1)
PPAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
No imputation
Secondary analysis 
(for Cohort 2)
Change in Bladder volume at
first IDC at week 12 relative 
to baseline
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)
Change in mean number of 
micturitions per 24 hours at 
Week 12 relative to baseline.  
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)
Change in mean number of 
incontinence episodes per 24 
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)


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Endpoint
Analysis Set
Assessment
PLANNED Statistical Method 
Missing Data
Interpretation
hours at Week 12 relative to 
the baseline 
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)
Change in mean number of
urgency episodes per 24 
hours at Week 12 relative to 
the baseline 
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)
Change in mean voided 
volume per micturition at 
Week 12 relative to baseline.  
FAS (Cohort 1)
Week 12
ANCOVA – hypothesis testing 
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 1)
FAS (Cohort 2)
Week 12
ANCOVA – estimation
approach; Descriptive statistics. 
BOCF/LOCF (for 
ANCOVA only)
Secondary analysis 
(for Cohort 2)


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9. REFERENCES
1.
Kennelly MJ, DeVoe WB. Overactive bladder: pharmacologic treatments in the 
neurogenic population. Rev Urol 2008; 10(3):182-91.
2.
Coward RJM, Saleem MA. The neuropathic bladder of childhood. Current 
Paediatrics 2001;11:135-42.


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10. APPENDIX
10.1. APPENDIX A: SCHEDULE OF EVENTS
Protocol Activity
Visit
1
Visit
2
Phone 
Call 
all
groups
q
Oxybutynin 
dose 
optimization
perioda,q
Visit 
3
Visit 
4q
Visit
5b
Visit
6q
Visit
7c
Visit
8
Screening Rand
Phone Calls
Oxybutynin 
subjects
Feso 
PK & 
Fix 
Oxy
dose
Phone 
call
Start of 
Extension
Phone 
Call
End of 
Treat-
ment
Follow-up 
call
Day -30
to
Day -3
Day 1
Week
1
Week 
2
Week 
3
Week 
4
Week 
8
Week
12
Week
18
Week 24
Week
26
Informed Consent & 
Assent
X
Demography
X
Medical History
X
Review Concomitant
Medications
X
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
Child Behavior Check 
List (CBCL)
X
X
X
Grooved Pegboard test
X
X
X
Vital Signsd
X
X
X
X
X
Weight
X
X
X
X
Physical Examinationd
X
X
X
Visual acuity and
accommodation
X
X
X
Post-void residual (PVR) 
urine volumee
X
X
X
X
X
Laboratoryf
Hematology
X
X
X
Blood Chemistry
X
X
X
Urinalysisg
X
X
X
X
Urine/Serum Pregnancy 
Testh
X
X
X
X
X
Pharmacokinetics (PK) 
blood samplingi
X
Pharmacogenomics (PG) 
blood samplingj
X
X
Urodynamic Studiesk
X
X
Dispense electronic data 
capture devicel
X
Collect/review electronic 
data capture devicem
X
X
X
X
Bladder diary 
Completion instructions
X
Completion reminder 1 
week before
X
X
Review bladder diaryn
X
X
Dosing log
Completion instructions
X
Review dosing logn,o
X
X
X
Xp
X
Xp
X
X
Study Medication 
Dispensed
X
X
X


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Protocol Activity
Visit
1
Visit
2
Phone 
Call 
all
groups
q
Oxybutynin 
dose 
optimization
perioda,q
Visit 
3
Visit 
4q
Visit
5b
Visit
6q
Visit
7c
Visit
8
Screening Rand
Phone Calls
Oxybutynin 
subjects
Feso 
PK & 
Fix 
Oxy
dose
Phone 
call
Start of 
Extension
Phone 
Call
End of 
Treat-
ment
Follow-up 
call
Day -30
to
Day -3
Day 1
Week
1
Week 
2
Week 
3
Week 
4
Week 
8
Week
12
Week
18
Week 24
Week
26
Study Medication 
return/count
X
X
X
Assess Study Medication
compliance
X
X
Oxybutynin dose 
adjustmenta
X
X
X
Dispense appointment & 
dosing record card
X
Review and collect 
appointment & dosing 
record card
X
a.
Subjects who are receiving oxybutynin (>25 kg subjects) will have additional contacts, by telephone or clinic visits, 
as deemed appropriate, at approximately weekly intervals for dose adjustment to optimize efficacy and tolerability.
b.
Or in the event of the subject withdrawing early from the active comparator treatment/efficacy phase. Urodynamic 
assessment should only be performed in subjects who have been on a stable dose of study medication for at least 2 
weeks, and who have not missed any doses in the 3 days prior to the visit.
c.
Or in the event of the subject withdrawing early from the safety extension phase.
d.
If vital signs or physical examinations show a clinically relevant change from baseline, then safety monitoring will 
occur at a minimum of monthly intervals, or more frequently as clinically appropriate, until the abnormality resolves.
e.
PVR only in subjects who are not performing intermittent catheterization or in any subjects who have >1 urinary tract
infection (UTI) during the study.
f.
Laboratory assessments may be repeated as needed to follow-up on significant findings.
g.
Urinalysis: Urine microscopy, culture, and sensitivity to be performed in the event of the presence of symptoms (eg, 
fever, flank pain), positive leucocytes and/or nitrites on urinalysis, or if the subject has a documented history of 
vesicoureteral reflux (VUR).
h.
Serum pregnancy test at Visit 1, urine pregnancy test at all other visits.  Only for female subjects of child-bearing
potential. Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
i.
PK blood sampling only in subjects randomized to treatment with fesoterodine during the active comparator/efficacy
phase.  A maximum of three PK samples will be collected from each subject. Subjects randomized to treatment with 
oxybutynin will not be required to provide PK samples. In the event of subject withdrawing early from the active 
comparator phase prior to Visit 3, PK samples should be obtained at the early termination visit.
j.
At Visit 3 PG samples only in subjects randomized to treatment with fesoterodine during the active comparator phase, 
and who do not have prior laboratory documentation of their CYP2D6 genotype. At Visit 5 (or early withdrawal 
from the active comparator/efficacy phase), only subjects who were on oxybutynin who will continue into the safety 
extension phase and who do not have prior laboratory documentation of their CYP2D6 genotype.
k.
Urodynamic studies: subjects who demonstrate a clinically relevant increased detrusor pressure or other urodynamic 
findings suggestive of worsening condition compared to baseline should not be allowed to continue into the safety 
extension phase.  Consideration should be given to imaging of upper urinary tract (for example, videourodynamics, or 
ultrasound) according to accepted local standard of care in subjects with VUR, or other conditions that predispose to 
upper urinary tract dysfunction or damage.
l.
Bladder diary and dosing log data will be recorded on the same electronic data capture device. The bladder diary will 
be completed for 3 days prior to Visits 2 and 5; the dosing log will be completed on a daily basis. Subjects and/or 
their caregivers should be re-educated and re-trained if review of data suggests that the bladder diary or dosing log are 
not being completed correctly.
m.
Electronic data capture device should be collected at Visit 2 for subjects who are not randomized, or at other visits if 
the subject discontinues.
n.
Assessment of the bladder diary or dosing log may be performed via remote electronic review.
o.
Review of dosing log should occur as indicated and also within 2 - 3 days following initiation in treatment or change 
in dose, tablet strength or treatment (oxybutynin) or as otherwise appropriate.
p.
At Visit 3, the time of last 3 doses should be recorded for fesoterodine, and at Visit 5 the time of last dose of 
fesoterodine or oxybutynin.
q.
Telephone calls may be substituted by a clinic visit at the discretion of the investigator and when indicated by local 
circumstances and/or regulatory requirements (eg for Japan, clinic visits should be the default option).


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10.2. Appendix B: DEFINITION OF ASSESSMENT WINDOWS
There will be no visit windows defined for this study. The target observation will be 
that taken at a time closest to when the scheduled visit should have occurred.
The LOCF1 rule will be used to impute data at missing visits (ie, the last non-missing 
reading prior to the window will be used; the observation does not have to have fallen 
inside a window).
Diary data should be completed within +/- 14 days of a visit whether this is a formal 
visit or a withdrawal visit.