Conditions: Urinary Bladder, Neurogenic
Keywords: neurogenic detrusor overactivity fesoterodine Japan
Allocation: NON_RANDOMIZED | Intervention model: 
Enrollment: 12
Healthy volunteers: no

Brief summary:
The purpose of this study is to investigate the safety and tolerability of fesoterodine following once daily long-term treatment in Japanese pediatric neurogenic detrusor overactivity (NDO) subjects.

Detailed description:
This is a Phase 3, multi-center, open-label long-term extension study in Japanese NDO subjects who participated and completed in the precedent Study A0221047 which is a 24 weeks, randomized, open label study, to investigate the safety and tolerability of fesoterodine.

This study consists of a 28-week open-label treatment period followed by a 4-week follow-up. In addition, subjects in the oxybutynin arm of the precedent Study A0221047 will continue the fesoterodine treatment until Week 40 visit in this study, in order to obtain fesoterodine 1 year treatment data.

Arms:
arm 1: Fesoterodine PR 4 mg for 28 or 40 weeks in open-label treatment period arm 2: Fesoterodine PR 8 mg for 28 or 40 weeks in open-label treatment period arm 3: Fesoterodine BIC 2 mg for 28 weeks in open-label treatment period arm 4: Fesoterodine BIC 4 mg for 28 weeks in open-label treatment period

Interventions: intervention 1: Fesoterodine PR 4 mg intervention 2: Fesoterodine PR 8 mg intervention 3: Fesoterodine BIC 2 mg intervention 4: Fesoterodine BIC 4 mg
Intervention descriptions: intervention 1: Fesoterodine 4 mg tablet once daily for 28 or 40 weeks intervention 2: Fesoterodine PR 8 mg tablet once daily for 28 or 40 weeks intervention 3: Fesoterodine BIC 2 mg tablet once daily for 28 weeks intervention 4: Fesoterodine BIC 4 mg tablet once daily for 28 weeks

Protocol document:
Prot_000.pdf: 
Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 1
CLINICAL PROTOCOL
LONG-TERM EXTENSION STUDY TO EVALUATE THE SAFETY OF 
FESOTERODINE IN JAPANESE PEDIATRIC SUBJECTS WITH SYMPTOMS 
OF DETRUSOR OVERACTIVITY ASSOCIATED WITH A NEUROLOGICAL 
CONDITION (NEUROGENIC DETRUSOR OVERACTIVITY) WHO HAVE 
COMPLETED 24 WEEKS TREATMENT IN STUDY A0221047
Compound:
PF-00695838
Compound Name:
Fesoterodine
United States (US) Investigational New 
Drug (IND) Number:
Not applicable
European Clinical Trial Database 
(EudraCT) Number:
Not applicable
Protocol Number:
A0221109
Phase:
3


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 2
Document History
Document
Version Date
Summary of Changes and 
Rationale
Original protocol
28-Jan-2015
Not applicable (N/A)


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 3
ABBREVIATIONS
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
5-HMT
5-hydroxymethyltolterodine
Abs
Absolute
AE
adverse event
ALT
alanine transaminase
AST
aspartate transaminase
BIC
beads-in-capsule
BUN
blood urea nitrogen
CBCL
Child Behavior Checklist
CDS
core data sheet
CIC
clean intermittent catheterization
CNS
central nervous system
CPK
creatine phosphokinase
CRF
case report form
CRO
contract research organization
CSA
clinical study agreement
DMC
data monitoring committee
EC
ethics committee
EBC
expected bladder capacity
ECG
electrocardiogram
EDMC
external data monitoring committee 
EDP
exposure during pregnancy
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration (United 
States)
FDAAA
Food and Drug Administration Amendments 
Act (United States)
GCP
Good Clinical Practice
GPT
Grooved Pegboard Test
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IDC
involuntary detrusor contractions
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
LDH
lactate dehydrogenase
LFT
liver function test
LSLV
last subject last visit 
N/A
not applicable
NDO
neurogenic detrusor overactivity
OAB
overactive bladder
PCD
primary completion date


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 4
PK
pharmacokinetics
PR
prolonged release
PT
prothrombin time
PVR
post-void residual volume
SAE
serious adverse event
SRSD
single reference safety document
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
UUT
upper urinary tract
VUR
vesicoureteral reflux
XL
extended release


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 5
PROTOCOL SUMMARY
Mechanism of Action/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.
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).1  Of these, 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 upper urinary tract (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.
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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 6
Study Objectives

Primary Objective:

To investigate the safety and tolerability of fesoterodine following once daily long-
term treatment in Japanese pediatric NDO subjects.

Secondary Objective:

To investigate the efficacy of fesoterodine following once daily long-term 
treatment in Japanese pediatric NDO subjects.
Study Endpoints

Efficacy Endpoints

Maximum cystometric bladder capacity defined as maximal tolerable cystometric 
capacity or until voiding/leaking begins or at 40 cm H2O.

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 hours.

Mean number of incontinence episodes/24 hours.

Mean urgency episodes/24 hours if applicable (only for sensate subjects).

Mean volume voided per micturition or mean volume per catheterization.

Safety Endpoints

Adverse events, including monitoring of targeted events including, but not limited 
to:

Serious adverse event.

Anticholinergic effects such as dry mouth, dry eyes and constipation.

Central nervous system (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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 7

Cognitive function by the Child Behavior Checklist (CBCL) and Grooved 
Pegboard Test (GPT).

Vital Signs, including heart rate in the context of age-appropriate norms.

Urinary tract infection (UTI), 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 clean intermittent 
catheterization (CIC), or with >1 UTI during the study.
Study Design
This is a Phase 3, multi-center, open-label long-term extension study in Japanese NDO 
subjects who participated and completed in the precedent Study A0221047 which is a 
24 weeks, randomized, open label study, to investigate the safety and tolerability of 
fesoterodine.
This study consists of a 28-week open-label treatment period followed by a 4-week 
follow-up. In addition, subjects in the oxybutynin arm of the precedent Study A0221047 
will continue the fesoterodine treatment until Week 40 visit in this study, in order to 
obtain fesoterodine 1 year treatment data.
Target number of subjects is not determined because this is the safety extension study but 
approximately 9 subjects are expected to become eligible for the study.
Subjects who were randomized to Fesoterodine arms in Study A0221047
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 8
Subjects who were randomized to Oxybutynin arm in Study A0221047
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.
As a rule, all subjects should continue to receive the allocated dose in Study A0221047 
until the end of the trial, unless a safety/toleration problem occurs. But, only if the 
investigator judges that the continued treatment with low dose (4 mg/day for subjects 
>25 kg or 2 mg/day for subjects 25 kg) is useful to the subject although the high dose 
(8 mg/day for subjects >25 kg or 4 mg/day for subjects 25 kg) is likely to cause some 
problems with tolerability, and the subject wants the treatment with the low dose, the 
dosage may be reduced to the low dose at each clinic visits. Dose should not be increased
to the high dose.
Subjects >25 kg who cannot swallow tablets are not permitted to take the beads-in-
capsule (BIC) formulation and are excluded from the study.
Even if the body weight of subjects with 25 kg at baseline of the precedent Study 
A0221047 increase >25 kg during Study A0221047 or this study, they should maintain 
the same dose and formulation.
Sample Size Determination
No target number of subjects is determined.
This is an extension study for the subjects who completed Study A0221047 in Japan, and 
the primary objective is to investigate the safety and tolerability of fesoterodine for these 
subjects. No statistical testing will be planned but descriptive statistics will be used along 
with subject narratives. Therefore, the number of subjects to be enrolled in this study is 
not based on any formal sample size calculation.
In Study A0221047, a few Japanese subjects in cohort 1 (body weight >25 kg) and 9 
Japanese subjects in cohort 2 (body weight 25 kg) are planned to be enrolled as potential
candidate subjects for this study. Assuming a 12.5% drop-out rate in Study A0221047, 
out of Japanese subjects who are enrolled to Study A0221047, approximately 9 subjects 
are expected to be enrolled in this study. 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 9
SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and 
procedures.  Refer to the Study Procedures and Assessments sections of the protocol for 
detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the 
schedule of activities, in order to conduct evaluations or assessments required to protect 
the well-being of the subject.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 10
Table 1.
Subjects who were randomized to Fesoterodine arms in Study A0221047
Visit
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Final 
Visit b
Follow-Up 
Visit l
Week (Weeks from baseline 
of the precedent Study A0221047)
Week 0
(24)
Week 6
(30)
Week 12
(36)
Week 18
(42)
Week 24
(48)
Week 28
(52)
Week 32
(56)
Allowance (weeks)
-
2
2
2
2
2
+2
Clinic visit/Phone call
Clinic 
visit
Phone 
call c
Clinic 
visit
Phone 
call c
Phone 
call c
Clinic 
visit
Phone 
call c
Informed Consent & Assent
X
Demography
X
Review Concomitant Medications
X a
X
X
X
X
X
X
Adverse Event Monitoring
X a
X
X
X
X
X
X
Child Behavior Checklist 
X a
X
X
Grooved Pegboard Test
X a
X
X
Vital Signs d
X a
X
X
Weight
X a
X
X
Physical Examination d
X a
X
X
Visual acuity and accommodation
X a
X
X
Post-void residual volume (PVR) e
X a
X
X
Laboratory f
Hematology
X a
X
X
Blood Chemistry
X a
X
X
Urinalysis g
X a
X
X
Urine Pregnancy Test h
X a
X
X
Urodynamic Studies
X
Bladder diary i
X
Dosing log j
X a
X
X
X
X
X k
Study Medication Dispensed
X
X
Study Medication return/count
X a
X
X
Assess Study Medication 
compliance
X a
X
X
a.
The Week 0 visit of Study A0221109 is the same visit as Week 24 visit of Study A0221047. All procedures done at 
Week 24 visit of Study A0221047 will be used as the Week 0 data for Study A0221109. These procedures (Study 
A0221047 procedures) will not be repeated at Week 0 of Study A0221109. 
b.
Or in the event of the subject withdrawing early from the study.  Urodynamic assessment should only be performed 
in subjects who have not missed any doses in the 3 days prior to the visit.
c.
Telephone calls may be substituted by a clinic visit at the discretion of the investigator.
d.
If vital signs or physical examinations show a clinically relevant change from baseline of the precedent Study 
A0221047, 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.
Only for female subjects of child-bearing potential.  Pregnancy tests may also be repeated as per request of 
Institutional Review Board (IRB)/Ethics Committee (EC) or if required by local regulations.
i.
The bladder diary will be completed for 3 days prior to Final Visit.
j.
The dosing log will be completed on a daily basis.
k.
At Final Visit, the time of last dose should be recorded.
l.
Follow up visit will be done at 4 weeks after Final Visit.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 11
Table 2.
Subjects who were randomized to Oxybutynin arm in Study A0221047
Visit
Visit
1
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Final 
Visit b Follow-Up 
Visit l
Week (Weeks from baseline 
of the precedent Study A0221047)
Week
0 (24)
Week
6 (30)
Week
12 (36)
Week
18 (42)
Week
24 (48)
Week
28 (52)
Week
34 (58)
Week
40 (64)
Week
44 (68)
Allowance (weeks)
-
2
2
2
2
2
2
2
+2
Clinic visit/Phone call
Clinic 
visit
Phone 
call c
Clinic 
visit
Phone 
call c
Phone 
call c
Clinic 
visit
Phone 
call c
Clinic 
visit
Phone 
call c
Informed Consent & Assent
X
Demography
X
Review Concomitant Medications
X a
X
X
X
X
X
X
X
X
Adverse Event Monitoring
X a
X
X
X
X
X
X
X
X
Child Behavior Checklist 
X a
X
X
X
Grooved Pegboard Test
X a
X
X
X
Vital Signs d
X a
X
X
X
Weight
X a
X
X
X
Physical Examination d
X a
X
X
X
Visual acuity and accommodation
X a
X
X
X
Post-void residual volume (PVR) e
X a
X
X
X
Laboratory f
Hematology
X a
X
X
X
Blood Chemistry
X a
X
X
X
Urinalysis g
X a
X
X
X
Urine Pregnancy Test h
X a
X
X
X
Urodynamic Studies
X
Bladder diary i
X
Dosing log j
X a
X
X
X
X
X
X
X k
Study Medication Dispensed
X
X
X
Study Medication return/count
X a
X
X
X
Assess Study Medication 
compliance
X a
X
X
X
a.
The Week 0 visit of Study A0221109 is the same visit as Week 24 visit of Study A0221047. All procedures done at 
Week 24 visit of Study A0221047 will be used as the Week 0 data for Study A0221109. These procedures (Study 
A0221047 procedures) will not be repeated at Week 0 of Study A0221109.
b.
Or in the event of the subject withdrawing early from the study.  Urodynamic assessment should only be performed 
in subjects who have not missed any doses in the 3 days prior to the visit.
c.
Telephone calls may be substituted by a clinic visit at the discretion of the investigator.
d.
If vital signs or physical examinations show a clinically relevant change from baseline of the precedent Study 
A0221047, 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.
Only for female subjects of child-bearing potential.  Pregnancy tests may also be repeated as per request of 
Institutional Review Board (IRB)/Ethics Committee (EC) or if required by local regulations.
i.
The bladder diary will be completed for 3 days prior to Final Visit.
j.
The dosing log will be completed on a daily basis.
k.
At Final Visit, the time of last dose should be recorded.
l.
Follow up visit will be done at 4 weeks after Final Visit.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 12
TABLE OF CONTENTS
ABBREVIATIONS .............................................................................................................3
PROTOCOL SUMMARY...................................................................................................5
SCHEDULE OF ACTIVITIES............................................................................................9
1. INTRODUCTION .........................................................................................................16
1.1. Mechanism of Action/Indication.......................................................................16
1.2. Background and Rationale ................................................................................16
2. STUDY OBJECTIVES AND ENDPOINTS.................................................................18
2.1. Objectives..........................................................................................................18
2.1.1. Primary Objective.................................................................................18
2.1.2. Secondary Objective.............................................................................18
2.2. Endpoints...........................................................................................................19
2.2.1. Efficacy Endpoints................................................................................19
2.2.2. Safety Endpoints...................................................................................19
3. STUDY DESIGN...........................................................................................................20
3.1. Study Visits .......................................................................................................21
4. SUBJECT SELECTION................................................................................................22
4.1. Inclusion Criteria...............................................................................................23
4.2. Exclusion Criteria..............................................................................................24
4.3. Lifestyle Guidelines ..........................................................................................25
4.4. Sponsor’s Qualified Medical Personnel............................................................26
5. STUDY TREATMENTS...............................................................................................26
5.1. Allocation to Treatment ....................................................................................26
5.2. Subject Compliance...........................................................................................26
5.3. Drug Supplies....................................................................................................27
5.3.1. Dosage Form(s) and Packaging............................................................27
5.3.2. Preparation and Dispensing ..................................................................27
5.4. Administration...................................................................................................28
5.5. Drug Storage .....................................................................................................28
5.6. Drug Accountability..........................................................................................29
5.7. Concomitant Treatment(s).................................................................................30
5.7.1. Permitted Concomitant Therapies ........................................................30
5.7.2. Prohibited Concomitant Therapies .......................................................30
6. STUDY PROCEDURES ...............................................................................................31


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 13
6.1. Subjects who were randomized to Fesoterodine arms in Study A0221047......31
6.1.1. Visit 1 (Week 0)....................................................................................31
6.1.2. Visit 2 (Week 6, 14 days)...................................................................31
6.1.3. Visit 3 (Week 12, 14 days).................................................................31
6.1.4. Visit 4 and 5 (Week 18 and 24, 14 days) ...........................................32
6.1.5. Final Visit (Week 28, 14 days) or Early Withdrawal.........................32
6.1.6. Follow-up visit (Week 32 +14 days) ....................................................32
6.2. Subjects who were randomized to Oxybutynin arm in Study A0221047.........33
6.2.1. Visit 1 (Week 0)....................................................................................33
6.2.2. Visit 2 (Week 6, 14 days)...................................................................33
6.2.3. Visit 3 (Week 12, 14 days).................................................................33
6.2.4. Visit 4 and 5 (Week 18 and 24, 14 days) ...........................................34
6.2.5. Visit 6 (Week 28, 14 days).................................................................34
6.2.6. Visit 7 (Week 34, 14 days).................................................................34
6.2.7. Final Visit (Week 40, 14 days) or Early Withdrawal.........................34
6.2.8. Follow-up visit (Week 44 +14 days) ....................................................35
6.3. Additional Contacts...........................................................................................35
6.4. Subject Withdrawal...........................................................................................35
7. ASSESSMENTS............................................................................................................36
7.1. Efficacy Assessments........................................................................................36
7.1.1. Urodynamic Assessments.....................................................................36
7.1.2. Bladder Diary........................................................................................37
7.2. Safety Assessments ...........................................................................................37
7.2.1. Vital Signs ............................................................................................37
7.2.2. Physical Examination ...........................................................................38
7.2.3. Weight Measurements ..........................................................................38
7.2.4. Visual Acuity and Accommodation......................................................39
7.2.5. Post-Void Residual Volume (PVR)......................................................39
7.2.6. Clinical Laboratory Evaluation.............................................................39
7.2.7. Childhood Behavior Checklist (CBCL) (Appendix 3).........................40
7.2.8. Grooved Pegboard Test (GPT).............................................................40
7.2.9. Pregnancy Testing ................................................................................41
7.2.10. Dosing Log .........................................................................................41
8. ADVERSE EVENT REPORTING................................................................................41


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 14
8.1. Adverse Events..................................................................................................41
8.2. Reporting Period ...............................................................................................41
8.3. Definition of an Adverse Event.........................................................................42
8.4. Medication Errors..............................................................................................42
8.5. Abnormal Test Findings....................................................................................43
8.6. Serious Adverse Events.....................................................................................43
8.6.1. Protocol-Specified Serious Adverse Events.........................................44
8.6.2. Potential Cases of Drug-Induced Liver Injury......................................44
8.7. Hospitalization ..................................................................................................45
8.8. Severity Assessment..........................................................................................46
8.9. Causality Assessment........................................................................................46
8.10. Exposure During Pregnancy............................................................................47
8.11. Occupational Exposure ...................................................................................48
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal).........................................................................................................48
8.13. Eliciting Adverse Event Information ..............................................................48
8.14. Reporting Requirements..................................................................................48
8.14.1. Serious Adverse Event Reporting Requirements ...............................48
8.14.2. Nonserious Adverse Event Reporting Requirements .........................49
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities .............49
9. DATA ANALYSIS/STATISTICAL METHODS.........................................................49
9.1. Sample Size Determination...............................................................................49
9.2. Efficacy Analysis ..............................................................................................50
9.2.1. Efficacy Analysis Sets..........................................................................50
9.2.1.1. Full Analysis Set (FAS) ......................................................50
9.2.2. Analysis of Efficacy Endpoints ............................................................50
9.2.3. Analysis of Other Endpoints.................................................................50
9.3. Safety Analysis..................................................................................................50
9.4. Interim Analysis ................................................................................................51
9.5. Data Monitoring Committee .............................................................................51
10. QUALITY CONTROL AND QUALITY ASSURANCE...........................................52
11. DATA HANDLING AND RECORD KEEPING .......................................................52
11.1. Case Report Forms/Electronic Data Record ...................................................52
11.2. Record Retention.............................................................................................52


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 15
12. ETHICS........................................................................................................................53
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).............................53
12.2. Ethical Conduct of the Study ..........................................................................53
12.3. Subject Information and Consent....................................................................53
12.4. Subject Recruitment ........................................................................................54
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .....................................................................................................................55
13. DEFINITION OF END OF TRIAL.............................................................................55
14. SPONSOR DISCONTINUATION CRITERIA ..........................................................55
15. PUBLICATION OF STUDY RESULTS....................................................................55
15.1. Communication of Results by Pfizer ..............................................................55
15.2. Publications by Investigators ..........................................................................56
16. REFERENCES ............................................................................................................58
LIST OF TABLES
Table 1.
Subjects who were randomized to Fesoterodine arms in Study 
A0221047 .......................................................................................................10
Table 2.
Subjects who were randomized to Oxybutynin arm in Study A0221047 ......11
Table 3.
Safety Laboratory ...........................................................................................40
LIST OF FIGURES
Figure 1.
Study Design (Subjects who were randomized to Fesoterodine arms in 
Study A0221047)............................................................................................20
Figure 2.
Study Design (Subjects who were randomized to Oxybutynin arm in 
Study A0221047)............................................................................................21
APPENDICES
Appendix 1. Examples of CYP3A4 Inducers and Potent CYP3A4 Inhibitors.................59
Appendix 2. Total Volume of Trial-Related Blood Loss..................................................60
Appendix 3. Child Behavior Checklist (CBCL)...............................................................61


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 16
1. INTRODUCTION
1.1. Mechanism of Action/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).3  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).4
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).5
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);2 (Aslan & 
Kogan, 2002).4 In children with myelodysplasia, the risk of UUT deterioration and renal 
damage approaches 80% when no intervention is instituted (Bauer et al, 2002). 3
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);2 (Aslan &  Kogan, 2002).4
Treatment of NDO in children depends on presentation, underlying cause, and the risk of 
deterioration in function of both upper and lower urinary tract.  CIC is first line therapy 
for bladder emptying in children with areflexic bladders and high PVR, and may be 
combined with antimuscarinic therapy in specific populations, eg, patients with high 
pressure bladders as below (Aslan & Kogan, 2002);4 (Kennelly & DeVoe, 2008).1
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).1 Of these, 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 17
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)2 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 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 OAB in adults; it is not approved for use in the pediatric population.
Fesoterodine functions as a prodrug of 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 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 18
An 8-week open-label, uncontrolled pharmacokinetics and safety study was conducted in 
21 pediatric OAB and NDO 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 mg and 8 mg once-daily doses to pediatric patients of ages 8-17 years 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 (SAE) 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 objective of this study is to investigate the safety and tolerability of 
fesoterodine PR tablet 4 mg and 8 mg once daily for 1 year in pediatric NDO subjects 
aged between 6-17 years with a body weight >25 kg, and fesoterodine BIC 2 mg and 4 
mg in subjects ≤25 kg.  
Dose Selection Rationale
Study A0221109 is an extension to the 24 weeks randomized, open-label, Phase 3 study 
(Study A0221047) to provide subjects long-term open-label therapy, thus the doses 
included in this study are supported by the dose selection rationale for Study A0221047.
Single Reference Safety Document
Complete information for fesoterodine may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB). 
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

To investigate the safety and tolerability of fesoterodine following once daily long-
term treatment in Japanese pediatric NDO subjects.
2.1.2. Secondary Objective

To investigate the efficacy of fesoterodine following once daily long-term treatment 
in Japanese pediatric NDO subjects.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 19
2.2. Endpoints
2.2.1. Efficacy Endpoints

Maximum cystometric bladder capacity defined as maximal tolerable cystometric 
capacity or until voiding/leaking begins or at 40 cm H2O.

Detrusor pressure at maximum bladder capacity.

Presence of IDC.

Bladder volume at first IDC.

Bladder compliance.

Mean number of micturitions and/or catheterizations/24 hours.

Mean number of incontinence episodes/24 hours.

Mean urgency episodes/24 hours if applicable (only for sensate subjects).

Mean volume voided per micturition and/or mean volume per catheterization.
2.2.2. Safety Endpoints

Adverse events, including monitoring of targeted events including, but not limited to:

Serious adverse event.

Anticholinergic effects such as dry mouth, dry eyes and constipation.

CNS effects such as behavioral changes (eg, aggression), decreased cognitive 
function, headache, seizures and somnolence.

Visual effects such as accommodation disorder, blurred vision, and amblyopia.

Visual acuity and accommodation tests.

Cognitive function by the CBCL and GPT.

Vital Signs, including heart rate in the context of age-appropriate norms.

UTI, 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.

PVR in subjects not performing CIC, or with >1 UTI during the study.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 20
3. STUDY DESIGN
This is a Phase 3, multi-center, open-label long-term extension study in Japanese NDO 
subjects who participated and completed in the precedent Study A0221047 which is a 
24 weeks, randomized, open label study, to investigate the safety and tolerability of 
fesoterodine.
This study consists of a 28-week open-label treatment period followed by a 4-week 
follow-up. In addition, subject in the oxybutynin arm of the precedent Study A0221047 
will continue the fesoterodine treatment until Week 40 visit in this study, in order to 
obtain fesoterodine 1 year treatment data (Figure 1 and Figure 2).
Target number of subjects is not determined because this is the safety extension study but 
approximately 9 subjects are expected to become eligible for the study.
Figure 1.
Study Design (Subjects who were randomized to Fesoterodine arms in 
Study A0221047)
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 21
Figure 2.
Study Design (Subjects who were randomized to Oxybutynin arm in 
Study A0221047)
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.
As a rule, all subjects should continue to receive the allocated dose in Study A0221047 
until the end of the trial, unless a safety/toleration problem occurs. But, only if the 
investigator judges that the continued treatment with low dose (4 mg/day for subjects 
>25 kg or 2 mg/day for subjects 25 kg) is useful to the subject although the high dose 
(8 mg/day for subjects >25 kg or 4 mg/day for subjects 25 kg) is likely to cause some 
problems with tolerability, and the subject wants the treatment with the low dose, the 
dosage may be reduced to the low dose at each clinic visits. Dose should not be increased
to the high dose.
Subjects >25 kg who cannot swallow tablets are not permitted to take the BIC 
formulation and are excluded from the study.
Even if the body weight of subjects with 25 kg at baseline of the precedent Study 
A0221047 increase >25 kg during Study A0221047 or this study, they should maintain 
the same dose and formulation.
3.1. Study Visits
There will be the following clinic visits: 
Subjects who were randomized to Fesoterodine arms in active comparator/efficacy phase
in Study A0221047

Visit 1 (Week 0 [Week 24 in Study A0221047])

Visit 3 (Week 12)

Final Visit (Week 28)
Subjects who were randomized to Oxybutynin arms in active comparator phase in Study 
A0221047

Visit 1 (Week 0 [Week 24 in Study A0221047])


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 22

Visit 3 (Week 12)

Visit 6 (Week 28)

Final Visit (Week 40)
The Week 0 visit of Study A0221109 is the same visit as Week 24 visit of the precedent 
Study A0221047. All procedures done at Week 24 visit of Study A0221047 will be used 
as the Week 0 data for Study A0221109. 
There will also be a minimum of 3 or 4 telephone calls (or clinic visits) to subjects to 
identify any new adverse events, review concomitant medication usage and the dosing log
at the following telephone calls (or clinic visits).
Subjects who were randomized to Fesoterodine arms in active comparator/efficacy phase
in Study A0221047

Visit 2 (Week 6)

Visit 4 (Week 18)

Visit 5 (Week 24)
Subjects who were randomized to Oxybutynin arms in active comparator phase in Study 
A0221047

Visit 2 (Week 6)

Visit 4 (Week 18)

Visit 5 (Week 24)

Visit 7 (Week 34)
And there will be a further telephone call (or clinic visit) at:

Follow-up Visit.  To review ongoing or new adverse events, review concomitant 
medications for subjects 4 weeks after Final Visit.  It will also be completed for all 
subjects who withdraw early from the study and take at least 1 dose of study 
medication in the A0221109 study.
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 daily dosing log, if needed.
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 nonmedical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 23
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate 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. Subjects who completed 24 week treatment and all visit procedures in the precedent 
Study A0221047, and who met the following criteria; 
a.
No findings suggestive of worsening condition of NDO compared to baseline of 
the precedent Study A0221047.
b. Tolerated the dose of fesoterodine.
Subjects who did not tolerate the higher dose of fesoterodine (8 mg/day for 
subjects >25 kg or 4 mg/day for subjects 25 kg) well but were not withdrawn can 
be included; for the A0221109 study the dose can be  reduced to low dose of the 
same formulation (4 mg/day tablet for subjects >25 kg or 2 mg/day BIC for 
subjects 25 kg) (See Section 3).
2. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative/parent(s)/legal guardian) 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.
3. 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 confirmed negative pregnancy tests
during Study A0221047. 
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 4.3.
4. 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 24
b. Subjects ≤25 kg can either swallow the capsules whole or sprinkle on food.
5. 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:
1. Subjects who had major protocol violation (as determined by the Sponsor) in Study
A0221047.
2. Unwilling or unable to comply with the Lifestyle guidelines described in this 
protocol.
3. Subjects required to take or expected to initiate concomitant medications during this 
study that can interact with the PK and/or pharmacodynamics of fesoterodine, such 
as:

Potent CYP3A4 inhibitors.

Medications capable of inducing CYP3A4 enzyme metabolism.

Drugs for the treatment of overactive bladder (eg, darifenacin, oxybutynin 
[including intravesical], propiverine, tolterodine, fesoterodine, solifenacin, 
mirabegron and trospium).

Treatment with botulinum-toxin A.

Drugs with antispasmodic, parasympathetic, or cholinergic effects.  Stable use of 
desmopressin for enuresis is allowed if established for at least 3 months prior to 
the precedent Study A0221047 and during Study A0221047.
4. Intermittent or unstable use of diuretics or alpha blockers, tricyclic antidepressants or 
any other treatment that may confound the results of the study during the course of the 
study.  Stable usage/dosage is allowed if established for at least 3 months prior to the 
precedent Study A0221047 and during Study A0221047.
5. Electrostimulation therapy or bladder retraining if started during the precedent Study 
A0221047 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.
6. Subjects not requiring intermittent catheterization who have a PVR greater than 
20 mL as determined by transabdominal ultrasound (eg, bladder scan) immediately 
after urination. Subjects found to have an elevated PVR >20 mL at Visit 1 (Week 0 
[Week 24 in Study A0221047]) will be excluded from the study.
7. Participation in other studies involving investigational drug(s) (Phases 1-4) during 
study participation.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 25
8. 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.
9. Subjects who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.
10. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male and female subjects of childbearing potential who are 
unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the study and for at least 28 days after the last dose of 
investigational product.
4.3. 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 26
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.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for 
the study is documented in the study contact list.  
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, at a minimum, protocol and investigational compound identifiers, subject study 
numbers, 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 subject’s 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 the 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, he or she will be directed back to the 
investigational site.
5. STUDY TREATMENTS
5.1. Allocation to Treatment
This is an open label study.  As a rule, all subjects should continue to receive the 
allocated dose in Study A0221047 until the end of the trial, unless a safety/toleration 
problem occurs. But, only if the investigator judges that the continued treatment with low 
dose (4 mg/day for subjects >25 kg or 2 mg/day for subjects 25 kg) is useful to the 
subject although the high dose (8 mg/day for subjects >25 kg or 4 mg/day for subjects 
25 kg) is likely to cause some problems with tolerability, and the subject wants the 
treatment with the low dose, the dosage may be reduced to the low dose at each clinic 
visits. Dose should not be increased to the high dose. 
5.2. Subject 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 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 since the last clinic visit
x 100
Total number of tablets/capsules supposed to be taken since the last clinic visit


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 27
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 
each clinic visit (Week 12, Week 28, Week 40 [only for subjects who were randomized to 
Oxybutynin arm in Study A0221047], 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 one day prior to urodynamic 
evaluation at Final Visit.
5.3. Drug Supplies
5.3.1. Dosage Form(s) and Packaging
For subjects who was assigned to Cohort 1 (subjects >25 kg) in the precedent Study 
A0221047, fesoterodine PR 4 mg and 8 mg will be provided by Pfizer as tablets.  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. 
For subjects who was assigned to Cohort 2 (subjects ≤25 kg) in the precedent Study 
A0221047, fesoterodine 2 mg and 4 mg once daily will be provided by Pfizer as a BIC 
formulation.   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 each clinic visit except for Final Visit, subjects will be provided study medication.
Subjects >25 kg who cannot swallow tablets are not permitted to take the BIC 
formulation and are excluded from the study.
5.3.2. Preparation and Dispensing
Pfizer will provide sufficient amounts of the fesoterodine 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 28
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 contract research organization (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. Administration
Study drug will be prepared in an open-label fashion.
Subjects who were assigned to Cohort 1 (subjects >25 kg) in the precedent Study 
A0221047
Subjects will be instructed to take study medication according to this protocol.  
For fesoterodine 4 mg and 8 mg, subjects will swallow one tablet each day without 
chewing.  
Subjects who were assigned to Cohort 2 (subjects ≤25 kg) in the precedent Study 
A0221047
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). 
All Subjects
Subjects will also be asked to complete a daily dosing log (Section 7.2.10).  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.
5.5. Drug Storage 
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products is stored in a secured area with controlled access under 
recommended storage conditions and in accordance with applicable regulatory 
requirements.
Investigational product should be stored in its original container and in accordance with 
the drug label.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 29
The BIC product (2 mg and 4 mg) should be stored at 2-8°C.  Fesoterodine PR tablets 
should be stored at room temperature (1-30°C).
Storage conditions stated in the SRSD, which for this study is the IB, will be superseded 
by the storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should 
be captured from the time of investigational product receipt throughout study.  Even for 
continuous monitoring systems, a log or site procedure which ensures active daily 
evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon 
discovery. The site should actively pursue options for returning the product to labeled 
storage conditions, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not 
used until the sponsor provides documentation of permission to use the investigational 
product.  Specific details regarding information the site should report for each excursion 
will be provided to the site. 
Site staff will instruct subjects on the storage requirements for take home medications 
including how to report temperature excursions. 
5.6. Drug Accountability 
The investigator’s site must maintain adequate records documenting the receipt, use, loss, 
or other disposition of the drug supplies.
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 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 each clinic visit, subjects must return all unused study medication and packaging (eg, 
bottles) to the investigator or an approved representative (eg, pharmacist).  
The sponsor or designee will provide guidance on the destruction of unused 
investigational product (eg, at the site).
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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 30
5.7. Concomitant Treatment(s)
Concomitant medication information will be collected for all subjects during the study.  
Information collected must include medication, total daily dose, start date, stop date (if 
applicable), and primary reason for use.
5.7.1. 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 before and during the precedent Study 
A0221047.

Stable use of desmopressin for enuresis is allowed if established for at least 3 months
before and during the precedent Study A0221047.

Subjects who are on an established regimen of electrostimulation therapy or bladder 
retraining (for at least 30 days prior to screening in the precedent Study A0221047) 
may remain on this for the duration of the study.
5.7.2. Prohibited Concomitant Therapies
The following concomitant therapies are not permitted:

Potent CYP3A4 inhibitors (Appendix 1).

Medications capable of inducing CYP3A4 enzyme metabolism (Appendix 1).

Drugs for treatment of overactive bladder, (eg, darifenacin, oxybutynin [including 
intravesical], propiverine, tolterodine, fesoterodine, solifenacin, mirabegron and 
trospium).

Treatment with botulinum-toxin A.

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 during the course of the 
study.

Electrostimulation therapy or bladder retraining if started during the precedent Study 
A0221047 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.
Subjects should avoid the consumption of grapefruit juice as it interferes with the 
metabolism of fesoterodine.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 31
The agreement of the subject and their legally-acceptable representative(s) should be 
gained before withdrawal of any therapies.
6. STUDY PROCEDURES 
6.1. Subjects who were randomized to Fesoterodine arms in Study A0221047
6.1.1. Visit 1 (Week 0)
Visit 1 (Week 0) is the same visit as Week 24 visit of Study A0221047. All procedures 
done at Week 24 visit of Study A0221047 will be used as the Visit 1 (Week 0) data for 
Study A0221109. The Study A0221047 procedures will not be repeated at Week 0 of 
Study A0221109.  The following assessments will be performed:

Informed consent and subject assent prior to the following assessments at Visit 1 
(Week 0).

Subject demographic details.

Evaluation of subject’s eligibility based on inclusion and exclusion criteria.

Dispense study medication.
6.1.2. Visit 2 (Week 6, 14 days) 
The following assessments will be performed at Visit 2 (Week 6) by telephone or clinic 
visit:

Concomitant medication review.

Review of adverse events.

Review dosing log.
6.1.3. Visit 3 (Week 12, 14 days)
The following assessments will be performed at Visit 3 (Week 12):

Concomitant medication review.

Review of adverse events.

CBCL (see Appendix 3).

GPT.

Vital signs measurement (blood pressure, heart rate, temperature) after the subject has 
been in a sitting/resting position for at least 5 minutes.

Physical examination and weight measurement.

Visual acuity and accommodation assessment.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 32

In subjects who are not performing intermittent catheterization, perform PVR 
assessment using trans-abdominal ultrasound (eg, bladder scan) immediately after 
urination. Assessment of PVR in subjects performing CIC should also be carried out 
in the event that they experience >1 UTI during the study A0221047 and this study.
PVR assessment is not required in subjects who empty their bladder using intermittent 
catheterization unless otherwise indicated (Section 7.2.5).

Clinical laboratory testing (approximately 5.5 mL of blood; see Appendix 2) 
including:

Hematology.

Blood chemistry.

Urinalysis and urine microscopy, culture and sensitivity if indicated.

Urine pregnancy test for all female subjects of childbearing potential.

Review dosing log.

Dispense study medication.

Study medication return/count; assess compliance with study medication regimen.
6.1.4. Visit 4 and 5 (Week 18 and 24, 14 days) 
The same assessments as on Visit 2 (Week 6) will be performed at Visit 4 and 5 (Week 
18 and 24) by telephone or clinic visit.
6.1.5. Final Visit (Week 28, 14 days) or Early Withdrawal
Final Visit (Week 28) may be performed over 2 separate days if required. The same 
assessments as on Visit 3 (Week 12) will be performed at Final Visit (Week 28), except 
for study medication dispensing. 
In addition, the following assessments will be performed:

Review bladder diary for completeness and check subject understanding of 
completion.

Perform urodynamic assessment including imaging of UUT if appropriate.  Attempts 
should be made to perform an urodynamic assessment in subjects who withdraw prior 
to Final Visit and who have not missed any doses in the three days prior to the visit.

Review dosing log, and record details of time of the last dose of fesoterodine.
6.1.6. Follow-up visit (Week 32 +14 days)
The following assessments will be performed at Follow-up visit (Week 32) by telephone 
or clinic visit:


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 33

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 4 weeks after stopping study 
medication.
6.2. Subjects who were randomized to Oxybutynin arm in Study A0221047
6.2.1. Visit 1 (Week 0)
Visit 1 (Week 0) is the same visit as Week 24 visit of Study A0221047. All procedures 
done at Week 24 visit of Study A0221047 will be used as the Visit 1 (Week 0) data for 
Study A0221109. The Study A0221047 procedures will not be repeated at Week 0 of 
Study A0221109. The following assessments will be performed:

Informed consent and subject assent prior to the following assessments at Visit 1 
(Week 0).

Subject demographic details.

Evaluation of subject’s eligibility based on inclusion and exclusion criteria.

Dispense study medication.
6.2.2. Visit 2 (Week 6, 14 days) 
The following assessments will be performed at Visit 2 (Week 6) by telephone or clinic 
visit:

Concomitant medication review.

Review of adverse events.

Review dosing log.
6.2.3. Visit 3 (Week 12, 14 days)
The following assessments will be performed at Visit 3 (Week 12):

Concomitant medication review.

Review of adverse events.

CBCL (see Appendix 3).

GPT.

Vital signs measurement (blood pressure, heart rate, temperature) after the subject has 
been in a sitting/resting position for at least 5 minutes.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 34

Physical examination and weight measurement.

Visual acuity and accommodation assessment.

In subjects who are not performing intermittent catheterization, perform PVR 
assessment using trans-abdominal ultrasound (eg, bladder scan) immediately after 
urination. Assessment of PVR in subjects performing CIC should also be carried out 
in the event that they experience >1 UTI during the study A0221047 and this study.
PVR assessment is not required in subjects who empty their bladder using intermittent 
catheterization unless otherwise indicated (Section 7.2.5).

Clinical laboratory testing (approximately 5.5 mL of blood; see Appendix 2) 
including:

Hematology.

Blood chemistry.

Urinalysis and urine microscopy, culture and sensitivity if indicated.

Urine pregnancy test for all female subjects of childbearing potential.

Review dosing log.

Dispense study medication.

Study medication return/count; assess compliance with study medication regimen.
6.2.4. Visit 4 and 5 (Week 18 and 24, 14 days) 
The same assessments as on Visit 2 (Week 6) will be performed at Visit 4 and 5 (Week 
18 and 24) by telephone or clinic visit.
6.2.5. Visit 6 (Week 28, 14 days)
The same assessments as on Visit 3 (Week 12) will be performed at Visit 6 (Week 28).
6.2.6. Visit 7 (Week 34, 14 days) 
The same assessments as on Visit 2 (Week 6) will be performed at Visit 7 (Week 34) by 
telephone or clinic visit.
6.2.7. Final Visit (Week 40, 14 days) or Early Withdrawal
Final Visit (Week 40) may be performed over 2 separate days if required.  The same 
assessments as on Visit 3 (Week 12) will be performed at Final Visit (Week 40), except 
for study medication dispensing. 
In addition, the following assessments will be performed:

Review bladder diary for completeness and check subject understanding of 
completion.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 35

Perform urodynamic assessment including imaging of UUT if appropriate.  Attempts 
should be made to perform an urodynamic assessment in subjects who withdraw prior 
to Final Visit and who have not missed any doses in the three days prior to the visit.

Review dosing log, and record details of time of the last dose of fesoterodine.
6.2.8. Follow-up visit (Week 44 +14 days)
The following assessments will be performed at Follow-up visit (Week 44) 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 4 weeks after stopping study 
medication.
6.3. Additional Contacts
Other contacts may also be made, as appropriate, 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:

Approximately 1 week prior to Final visit, to remind the subject to complete the 
bladder diary and to review instructions on proper completion if needed.  
6.4. Subject Withdrawal
If treatment is inadequate or the subject cannot tolerate the dose of fesoterodine, 
consideration should be given to withdrawal.
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. All attempts to contact the subject and information received during contact 
attempts must be documented in the subject’s medical record. 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), request the subject to return for a final visit, if applicable, and 
follow-up with the subject regarding any unresolved AEs.
If a subject withdraws from the study prior to Final visit (Week 28 in subjects who were 
randomized to Fesoterodine arms in Study A0221047, or Week 40 in subjects who were 
randomized to Oxybutinin arm in Study A0221047), the same assessments as at Final 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 36
visit should be performed if possible.  Urodynamic assessment should only be performed 
in subjects who have not missed any doses in the 3 days prior to the visit.
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 4 weeks after stopping 
study medication, and have the same assessments performed as at Follow-up visit.
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.
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 it unfeasible to 
perform the test. 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 that he or she has 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 Final Visit (Neveus, et al, 2006).5  It should 
be performed with the subject awake, or if necessary under sedation, but general 
anesthesia is not permitted under this protocol.  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 (EBC) 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 case report form (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 H2O.

Detrusor pressure at maximum bladder capacity.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 37

Maximum detrusor pressure.

Presence of 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, urodynamic assessments for a subject should be performed by the same 
person in both this study and Study A0221047.  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 an urodynamic assessment in subjects who withdraw 
prior to Final Visit and who have not missed any doses in the 3 days prior to the visit.
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 Final Visit, using paper diary.  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). 5
A proxy (eg, parent or teacher) may assist with completion of the diary if necessary.  
Contact should be made approximately 1 week prior to Final Visit, to remind the subject 
to complete the bladder diary and to review instructions on proper completion.  
7.2. Safety Assessments
7.2.1. Vital Signs
Blood pressure, temperature and pulse rate should be measured at each clinic visit.  This 
schedule of measurements should provide adequate indication of any clinically relevant 
changes.  However, if vital signs show a clinically relevant change from baseline of Study 
A0221047, 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 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 38
used.  The same method as Study A0221047 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) as Study A0221047 will be used throughout the study.
The same size blood pressure cuff as Study A0221047, which has been properly sized and 
calibrated, will be used to measure blood pressure each time.  The use of automated 
devices for measuring blood pressure 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 each clinic visit, 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;

Gastrointestinal;

Musculoskeletal;

Neurological.
If physical examinations show a clinically relevant change from baseline of the precedent 
Study A0221047, 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 each clinic visit.  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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 39
Even if the body weight of subjects with 25 kg at baseline of the precedent Study 
A0221047 increase >25 kg during Study A0221047 or this study, they should maintain 
the same dose and formulation.
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 each clinic visit.
Amplitude of accommodation will be assessed by the push up test to assess minimum 
focusing distance at each clinic visit.  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. Post-Void Residual Volume (PVR) 
PVR urine volume in subjects not performing CIC will be assessed using trans-abdominal 
ultrasound (eg, bladder scan) immediately after urination.  If at Visit 1 (Week 0 [Week 24 
in Study A0221047]), the measured volume is higher than 20 mL (see exclusion criterion 
6), 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 A0221047 and this study.
7.2.6. Clinical Laboratory Evaluation
Safety laboratory tests will be performed at each clinic visit, or as needed to follow-up on 
significant findings.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 40
Table 3.
Safety Laboratory
Hematology
Chemistry
Urinalysis
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
Creatinine a
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 sensitivity
b
Pregnancy Test c
(urine)
a.
When 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.
b.
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).
c.
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 Institutional Review Board (IRB)/Ethics Committee (EC) or 
if required by local regulations.
7.2.7. Childhood Behavior Checklist (CBCL) (Appendix 3)
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 each clinic visit.
7.2.8. Grooved Pegboard Test (GPT)
The GPT 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 each clinic visit.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 41
7.2.9. Pregnancy Testing
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed before investigational product administration at Visit 
1 (Week 0 [Week 24 in Study A0221047]) and at the end of treatment visit.  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
each study visit to confirm the subject has not become pregnant during the study.  
Pregnancy tests may also be repeated as per request of IRB/EC or if required by local 
regulations.
7.2.10. 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 paper dosing diary. The dosing log should be completed every day.  A 
proxy (eg, parent) may assist with completion of the dosing log if necessary.
The time of the last dose prior to Final Visit 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. 
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 nonserious AE 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 study.  
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins 
from the time that the subject provides 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.  SAEs occurring to a subject after the 
active reporting period has ended should be reported to the sponsor if the investigator 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 42
becomes aware of them; at a minimum, all SAEs that the investigator believes have at 
least a reasonable possibility of being related to study drug are to be reported to the 
sponsor.
AEs (serious and nonserious) should be recorded on the CRF from the time the subject 
has taken at least 1 dose of study treatment through the last subject visit.  
8.3. Definition of an Adverse Event
An AE 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 AEs 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;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
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.  


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 43
Such medication errors occurring to a study participant are to be captured on the 
medication error CRF which is a specific version of the AE page, 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 should be captured on the medication error version of 
the AE page and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE 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 AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE.  Any abnormal test result that is determined to be an error does not 
require reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 44
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 
AE 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.
8.6.1. 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).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate transaminase (AST) and/or alanine transaminase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level 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 (baseline of the precedent Study A0221047) 
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 values 3 times the upper limit 
of normal (X ULN) concurrent with a total bilirubin value 2 X ULN with no 
evidence of hemolysis and an alkaline phosphatase value 2 X ULN or not 
available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 X ULN
or if the value reaches ≥3 X ULN (whichever is smaller).


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 45
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 measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (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 
person, 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 liver function test 
(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 
SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital 
or equivalent healthcare facility or any prolongation to an existing admission.  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, or neurological 
floor to a tuberculosis unit).  An emergency room visit does not necessarily constitute a 
hospitalization; however, the event leading to the emergency room visit should be 
assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, 
for workup of persistent pre-treatment laboratory abnormality);


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 46

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the 
study protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the 
baseline documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should 
not be reported as AEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an AE.  For example, an acute 
appendicitis that begins during the AE reporting period should be reported as the AE, and 
the resulting appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  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.
Note the distinction between the severity and the seriousness of an AE.  A severe event is 
not necessarily an SAE.  For example, a headache may be severe (interferes significantly 
with the subject’s usual function) but would not be classified as serious unless it met one 
of the criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the SAE 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 (see section on 
Reporting Requirements).  If the investigator’s causality assessment is "unknown but not 
related to investigational product," this should be clearly documented on study records.  


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 47
In addition, if the investigator determines that an SAE 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 SAE
reporting requirements, if applicable.
8.10. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy 
occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having 
been exposed (eg, because of treatment or environmental exposure) to the 
investigational product; or the female becomes, or is found to be pregnant after 
discontinuing and/or being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).
2. A male subject has been exposed (eg, because of 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 a 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 (SAE) Report
Form and Exposure During Pregnancy (EDP) 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 EDP supplemental form.  This must be done irrespective of whether an AE 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).
Follow-up is conducted to obtain general information on the pregnancy and its outcome 
for all EDP 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 EDP supplemental 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 preprocedure 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 48
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs.  In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to 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 Pregnant 
Partner Release of Information Form to deliver to his partner. The investigator must 
document in the source documents that the subject was given the Pregnant Partner 
Release of Information Form to provide to his partner.
8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to safety within 24 hours of Investigator’s 
awareness, using the SAE Report form, regardless of whether there is an associated 
AE/SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not reported on a CRF, however a copy of the completed SAE Report form 
is maintained in the study master file.
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance 
with the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported 
by the study subject/parent/legally acceptable representative.  In addition, each study 
subject/parent/legally acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE
occurs, expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 49
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of exposure during pregnancy, exposure 
via breastfeeding and occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE
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 or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames 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 SAEs is more 
detailed than that captured on the AE CRF.  In general, this will include a description of 
the AE 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, vaccines, and/or 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. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form 
for collection of SAE information is not the same as the AE CRF.  Where the same data 
are collected, the forms must be completed in a consistent manner.  For example, the 
same AE term should be used on both forms.  AEs should be reported using concise 
medical terminology on the CRFs as well as on the form for collection of SAE
information.
8.14.3. Sponsor Reporting Requirements to Regulatory Authorities
AE 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.
9.1. Sample Size Determination
No target number of subjects is determined.
This is an extension study for the subjects who completed Study A0221047 in Japan and 
the primary objective is to investigate the safety and tolerability of fesoterodine for these 
subjects. No statistical testing will be planned but descriptive statistics will be used along 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 50
with subject narratives. Therefore, the number of subjects to be enrolled in this study is 
not based on any formal sample size calculation.
In Study A0221047, a few Japanese subjects in cohort 1 (body weight >25 kg) and 9 
Japanese subjects in cohort 2 (body weight 25 kg) are planned to be enrolled as potential
candidate subjects for this study. Assuming a 12.5% drop-out rate in Study A0221047, 
out of Japanese subjects who are enrolled to Study A0221047, approximately 9 subjects 
are expected to be enrolled in this study. 
9.2. Efficacy Analysis
9.2.1. Efficacy Analysis Sets
All efficacy analysis will be used the following full analysis set.
9.2.1.1. Full Analysis Set (FAS)
The Full Analysis Set will include all subjects who have been enrolled and received at 
least one dose of study medication and have at least 1 observation in efficacy endpoint 
data after baseline visit in this study.
9.2.2. Analysis of Efficacy Endpoints
All Efficacy endpoints will be summarized descriptively for FAS by timepoint from 
baseline visit of A0221047 to final visit of this study, using: N, mean, standard deviation, 
median, minimum and maximum. Subgroup analyses will be conducted that exclude 
oxybutynin treatment group in cohort 1 of A0221047 from FAS for all efficacy endpoints 
if any subjects who were randomized to oxybutynin group in A0221047 are included in 
FAS. In addition, summary statistics for each cohort and that for each randomized
treatment group by cohorts in study A0221047 will be provided as same manner as the 
above. 
Listing tables will be provided at each timepoint from baseline visit of A0221047 to final
visit of this study for all efficacy endpoints with subjects information (i.e., subject ID, 
gender, age, body weight at baseline of A0221047, cohort of A0221047, randomized 
treatment group in A0221047 and treatment history from the A0221047 start to the end of 
this study). Also, a summary narrative of efficacy and safety data in each subject will be 
provided.
9.2.3. Analysis of Other Endpoints
No other endpoint in this study.
9.3. Safety Analysis
The Safety Analysis Set will be defined as all randomized subjects who have received at 
least one dose of study medication in this study.
Results from the safety assessments and any AEs will be presented in tabular and/or 
graphical format adhering to current Pfizer Data Standards.  These presentations will be 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 51
split by treatment group at baseline in this study. In addition, AE tables during the period 
from A0221047 study start to end of this study will be produced by cohort and 
randomized treatment group in A0221047 (including overall summary of safety analysis 
set in this study). Safety endpoints such as vital signs, laboratory evaluations, weight, 
PVR, vision testing and CBCL/GPT results will be presented descriptively by treatment 
group at baseline in this study.  Adverse event incidence rates will be provided 
descriptively.
9.4. Interim Analysis
No interim analysis will be planned in this study.
9.5. Data Monitoring Committee 
This study will use an external data monitoring committee (EDMC). 
The EDMC will be responsible for ongoing monitoring of the safety of subjects in the 
study according to the charter.  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 that 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 AEs, vision testing, CBCL/GPT assessments, vital signs including heart 
rate, incidence of UTI (as evidenced by urinalysis, urine microscopy and culture), clinical 
laboratory evaluations in the context of age-appropriate norms, with particular reference 
to LFTs and renal chemistry, and PVR in subjects not performing CIC, or with >1 UTI 
during the study.
Assessment of AEs 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 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 52
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors 
may review source documents to confirm that the data recorded on CRFs are accurate.  
The investigator and institution will allow Pfizer monitors/auditors 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)/ethics 
committee (EC), 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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term 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 are true. Any corrections to entries made in 
the CRFs or 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 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 53
information to link records, eg, CRFs and hospital records), all original signed informed 
consent/assent documents, 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, and telephone call reports).  The records 
should be retained by the investigator according to International Conference on 
Harmonisation (ICH), according to 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 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.
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)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study 
protocol, protocol amendments, informed consent/assent documents, and other relevant 
documents, eg, recruitment advertisements, if applicable, from the IRB/EC.  All 
correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval 
is where the change is necessary to eliminate apparent immediate hazards to the subjects.  
In that event, the investigator must notify the IRB/EC 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 GCP (ICH 1996), and the Declaration of 
Helsinki (World Medical Association). 
In addition, the study will be conducted in accordance with the protocol, the ICH
guideline on GCP, 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 or other identifiable data in any reports, publications, or other disclosures, except 
where required by law.
When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 54
consisting of a numbering system provided by Pfizer in order to de-identify study 
subjects. The study site will maintain a confidential list of subjects who participated in 
the study linking their numerical code to the subject’s actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subject 
personal data consistent with applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must 
be reviewed by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study and possible risks associated with participation.  
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s)
or legal guardian, the subject’s assent (affirmative agreement) must subsequently be 
obtained when the subject has the capacity to provide assent, as determined by the 
IRB/EC.  If the investigator determines that a subject’s decisional capacity is so limited 
he/she cannot reasonably be consulted, as permitted by the IRB/EC and consistent with 
local regulatory and legal requirements, then the subject’s assent may be waived with 
source documentation of the reason assent was not obtained.  If the study subject does not 
provide his/her own consent, the source documents must record why the subject did not 
provide consent (eg, minor, decisionally impaired adult), how the investigator determined 
that the person signing the consent was the subject’s legally acceptable representative, the 
consent signer’s relationship to the study subject (eg, parent, spouse) and that the 
subject’s assent was obtained, or waived.  If assent is obtained verbally it must be 
documented in the source documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must be re-consented as adults to remain in the study.  If 
the enrollment of ‘emancipated minors’ is permitted by the study age criteria, the 
IRB/EC, and local law, they must provide documentation of legal status to give consent 
without the permission of a parent or legal guardian.   
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject’s legally acceptable representative, parent(s) or 
legal guardian and the subject’s assent, when applicable, before any study-specific 
activity is performed, unless a waiver of informed consent has been granted by an 
IRB/EC. The investigator will retain the original of each subject’s signed consent/assent
document.
12.4. Subject Recruitment
Advertisements approved by ECs 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 ECs.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 55
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 that 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.
13. DEFINITION OF END OF TRIAL
End of trial in all participating countries is defined as last subject last visit (LSLV). 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, 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 studies on www.clinicaltrials.gov (ClinicalTrials.gov), www.pfizer.com, and/or 
the European Clinical Trials Database (EudraCT), and other public registries in 
accordance with applicable local laws/regulations. 
www.clinicaltrials.gov
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of 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, Food and Drug 
Administration (FDA)-approved products, Pfizer posts results within 1 year of the 
primary completion date (PCD). For studies involving products approved in any 
country, but not FDA approved, Pfizer posts results 1 year from LSLV;

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 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 56
approval, or 1 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 1 year of discontinuation of the program 
(if there are no plans for outlicensing, or within 2 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 study concluded according to the prespecified protocol or 
was terminated.
www.pfizer.com
Pfizer posts clinical trial results on www.pfizer.com for all Pfizer-sponsored 
interventional studies in patients that assess the safety and/or efficacy of an FDA-
approved Pfizer product with a LSLV on or after 27-Sep-2007 for which Basic Results 
were posted on www.clinicaltrials.gov.
EudraCT
Pfizer posts clinical trial results on EudraCT in accordance with Commission Guideline 
2012/C 302/03 Guidance on posting and publication of result-related information on 
clinical trials in relation to the implementation of Article 57(2) of Regulation (EC) No 
726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 for studies with centers in 
the European Economic Area and with LSLV on or after 01-May-2004, regardless of the 
marketing status of the compound.
15.2. Publications by Investigators
Pfizer has no objection to publication by an investigator of any information collected or 
generated by the investigator, whether or not the results are favorable to the 
investigational drug. However, to ensure against inadvertent disclosure of confidential 
information or unprotected inventions, the investigator will provide Pfizer an opportunity 
to review any proposed publication or other type of disclosure before it is submitted or 
otherwise disclosed.
The 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, the investigator agrees 
to delay the disclosure for a period not to exceed an additional 60 days.
The 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 multicenter study, the 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 


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 57
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the 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 CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall 
have the meanings given to them in the CSA.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 58
16. 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.
3. 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; 2002:2231-61.
4. Aslan AR, Kogan BA. Conservative management in neurogenic bladder dysfunction. 
Curr Opin Urol 2002;12:473-77.
5. 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.


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 59
Appendix 1. Examples of CYP3A4 Inducers and Potent CYP3A4 Inhibitors
Potent CYP3A4 inhibitors, 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


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 60
Appendix 2. Total Volume of Trial-Related Blood Loss
Volume of whole blood
Study Arm in Study A0221047
Fesoterodine arm
Oxybutynin arm
Test panel
Test
Visit 3
Week 12
Final Visit
Week 28
Visit 3
Week 12
Visit 6
Week 28
Final 
Visit
Week 40
Hematology
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count with 
differential of total 
neutrophils, eosinophils, 
monocytes,  basophils, 
lymphocytes
2 mL
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)
3.5 mL
3.5 mL
3.5 mL
3.5 mL
3.5 mL
Total blood 
volume
Total volume per visit
5.5 mL
5.5 mL
5.5 mL
5.5 mL
5.5 mL
Total volume over study
11.0 mL
16.5 mL
Additional blood samples may be taken as needed to follow-up on significant findings, or as clinically indicated. 
Guidelinesa
A0221109 blood loss volume 
Maximum total volume at a single time
20 mLb
5.5 mL
Maximum total volume in a 4 week period
60 mLc
5.5 mL
Maximum possible total volume in a 4 week period 
(assuming subject withdraws prior to Final Visit, 
and within 4 weeks of Visit 7 of Study A0221047, 
or Visit 3 or 6 of Study A0221109)
60 mL
11.0 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


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 61
Appendix 3. 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


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 62
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


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 63
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


Fesoterodine
A0221109
Final Protocol, 28-Jan-2015
Page 64
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

SAP_001.pdf: 
Protocol A0221109
Statistical Analysis Plan
Page 1
Protocol A0221109
LONG-TERM EXTENSION STUDY TO EVALUATE THE SAFETY OF 
FESOTERODINE IN JAPANESE PEDIATRIC SUBJECTS WITH SYMPTOMS OF 
DETRUSOR OVERACTIVITY ASSOCIATED WITH A NEUROLOGICAL 
CONDITION (NEUROGENIC DETRUSOR OVERACTIVITY) WHO HAVE 
COMPLETED 24 WEEKS TREATMENT IN STUDY A0221047
Statistical Analysis Plan 
(SAP)
Version:
2.1
Author: 
 (Statistical Research & Data Science Group) 
Date:
9-April-2020
PPD


Protocol A0221109
Statistical Analysis Plan
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................4
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................8
4. HYPOTHESES AND DECISION RULES...........................................................................8
4.1. Statistical Hypotheses ...............................................................................................8
4.2. Statistical Decision Rules..........................................................................................8
5. ANALYSIS SETS .................................................................................................................8
5.1. Full Analysis Set .......................................................................................................8
5.2. ‘Per Protocol’ Analysis Set .......................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................8
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................9
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .....................................................................................................11
6.2.1. Adverse Events...........................................................................................11
6.2.2. Vital Signs ..................................................................................................11
6.2.3. Physical Examination .................................................................................12
6.2.4. Weight Measurements ................................................................................13
6.2.5. Visual Acuity and Accommodation............................................................13
6.2.6. Post-Void Residual Volume (PVR)............................................................13
6.2.7. Clinical Laboratory Evaluation...................................................................13
6.2.8. Childhood Behavior Checklist (CBCL)......................................................14
6.2.9. Grooved Pegboard Test (GPT)...................................................................14
6.3. Other Endpoints.......................................................................................................15
6.4. Covariates................................................................................................................15


Protocol A0221109
Statistical Analysis Plan
Page 3
7. HANDLING OF MISSING VALUES ................................................................................15
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................15
8.1. Statistical Methods ..................................................................................................15
8.1.1. Analyses for Continuous Data....................................................................16
8.1.2. Analyses for Categorical and Binary Data .................................................16
8.2. Statistical Analyses .................................................................................................16
8.2.1. Analysis of Efficacy Data...........................................................................16
8.2.2. Analysis of Safety Data ..............................................................................17
8.2.3. Summary of Efficacy Analyses ..................................................................20
9. REFERENCES ....................................................................................................................22
10. APPENDICES ...................................................................................................................22
LIST OF TABLES
Table 1.
Summary of Changes..............................................................................................4
Table 2.
Safety Laboratory .................................................................................................14
Table 3.
Summary of Efficacy Endpoint Analyses.............................................................20
Table 4.
Visit Windows for Efficacy Endpoints.................................................................22
Table 5.
Visit Windows for Safety Endpoints ....................................................................23
LIST OF FIGURES
Figure 1.
Study Design (Subjects who were randomized to Fesoterodine arms in 
Study A0221047)....................................................................................................6
Figure 2.
Study Design (Subjects who were randomized to Oxybutynin arm in Study 
A0221047)..............................................................................................................7
APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................22
Appendix 1.1. Definition and Use of Visit Windows in Reporting.........................................22


Protocol A0221109
Statistical Analysis Plan
Page 4
1. AMENDMENTS FROM PREVIOUS VERSION(S)
Summary of changes is described in Table 1. No changes spoiling the integrity of this clinical 
study are included.
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1.0
05 Jun 2015
Original 
28 Jan 2015
N/A
N/A
2.0
6 April 2020
None
Minor changes
to clarify the 
detailed analysis 
plan

The objective of “to investigate the 
efficacy of fesoterodine following once 
daily long-term treatment in Japanese 
pediatric NDO subjects” was set as 
secondary objective in accordance with 
the protocol version 1.

Description of treatment misallocations 
were minor changed to clarify the 
treatment group used in the analyses.

Efficacy endpoints of “Mean number of 
micturitions/24hours”, “Mean number of 
catheterizations/24hours” and “Mean 
number of micturitions and
catheterizations combined/24hours” 
were changed to analyze for the subjects 
with >0 episodes at baseline of Study 
A0221047, in accordance with 
A0221047 SAP version 2.0.

Remove an endpoint of “Presence of 
subtraction test (eg, cough) on 
urodynamic trace” in accordance with
A0221047 SAP version 2.0.

The definition of treatment emergent was 
changed for AE occur in 
oxybutinine-treatment period and 
become more severe; evaluation period 
of AE was changed from the period in 
A0221109 to the fesoterodine treatment 
period from A0221047 in Section 6.2.1.

To clarify that Demographics and 
baseline characteristics data would be
summarized based on baseline 
information of the A0221047.

To clarify that observed values and 
change from baseline in efficacy 


Protocol A0221109
Statistical Analysis Plan
Page 5
endpoints would be provided in listings.

To clarify the analysis of onset time of 
AEs.

Analysis of GPT was changed in 
accordance with A0221047 SAP version 
2.0.

Change visit window definition 
appropriately.
2.1
9 April 2020
None
Minor error was 
revised

The date of SAP was changed from 6 
Apr 2019 to 9 Apr 2020.
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicised.
This document describes the statistical analysis plan for the safety and efficacy.
Drug Development Rationale
Antimuscarinic drugs are the cornerstone of pharmacotherapy in the pediatric NDO 
(neurogenic detrusor overactivity) 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).1
Of these, 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 (upper urinary tract) 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 objective of this study is to investigate the safety and tolerability of fesoterodine 
PR (prolonged release) tablet 4 mg and 8 mg once daily for 1 year in pediatric NDO subjects 


Protocol A0221109
Statistical Analysis Plan
Page 6
aged between 6-17 years with a body weight >25 kg, and fesoterodine BIC 
(beads-in-capsule) 2 mg and 4 mg in subjects ≤25 kg.  
2.1. Study Design
This is a Phase 3, multi-center, open-label long-term extension study in Japanese NDO 
subjects who participated and completed in the precedent Study A0221047 which is a 
24 weeks, randomized, open label study, to investigate the safety and tolerability of 
fesoterodine.
This study consists of a 28-week open-label treatment period followed by a 4-week follow-up.
In addition, subject in the oxybutynin arm of the precedent Study A0221047 will continue the 
fesoterodine treatment until Week 40 visit in this study, in order to obtain fesoterodine 1 year 
treatment data (Figure 1 and Figure 2).
Target number of subjects is not determined because this is the safety extension study but 
approximately 9 subjects are expected to become eligible for the study.
Figure 1.
Study Design (Subjects who were randomized to Fesoterodine arms in Study 
A0221047)
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.


Protocol A0221109
Statistical Analysis Plan
Page 7
Figure 2.
Study Design (Subjects who were randomized to Oxybutynin arm in Study 
A0221047)
( ) weeks from baseline of Study A0221047 
* Week 0 visit is the same visit as Week 24 visit of Study A0221047.
As a rule, all subjects should continue to receive the allocated dose in Study A0221047 until 
the end of the trial, unless a safety/toleration problem occurs. But, only if the investigator
judges that the continued treatment with low dose (4 mg/day for subjects >25 kg or 2 mg/day 
for subjects 25 kg) is useful to the subject although the high dose (8 mg/day for subjects 
>25 kg or 4 mg/day for subjects 25 kg) is likely to cause some problems with tolerability,
and the subject wants the treatment with the low dose, the dosage may be reduced to the low 
dose at each clinic visits.  Dose should not be increased to the high dose. 
Subjects >25 kg who cannot swallow tablets are not permitted to take the BIC formulation 
and are excluded from the study.  Even if the body weight of subjects with 25 kg at 
baseline of the precedent Study A0221047 increase >25 kg during Study A0221047 or this 
study, they should maintain the same dose and formulation.
2.2. Study Objectives
Primary Objective

To investigate the safety and tolerability of fesoterodine following once daily long-term 
treatment in Japanese pediatric NDO subjects.
Secondary Objective

To investigate the efficacy of fesoterodine following once daily long-term treatment in 
Japanese pediatric NDO subjects.


Protocol A0221109
Statistical Analysis Plan
Page 8
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis will be planned in this study.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses.
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Full Analysis Set
The Full Analysis Set will include all subjects who have been enrolled and received at least 
one dose of study medication and have at least 1 observation in efficacy endpoint data after 
baseline visit in Study A0221109.
The Full Analysis Set (FAS) will be used for all efficacy analyses.
For all efficacy analyses, the data from Study A0221047 and Study A0221109 will be 
merged (see the details in Section 8.1).
5.2. ‘Per Protocol’ Analysis Set 
Not applicable.
5.3. Safety Analysis Set
The Safety Analysis Set will include all subjects who have been enrolled and received at 
least one dose of study medication in Study A0221109.
For analyses of adverse events, the data from Study A0221047 and Study A0221109 will be 
merged (see the details in Section 8.1).
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations
Subjects who are enrolled but never treated in Study A0221109 will not be included in either 
safety or efficacy analyses. For an enrolled subject who took the incorrect treatment (i.e., a 
subject who does not start dosing with the randomized dose in Study A0221047), he/she will 
be reported under the randomized treatment group in Study A0221047 for all efficacy 
analyses, but will be reported under the treatment they actually received for all safety 
analyses.


Protocol A0221109
Statistical Analysis Plan
Page 9
If misallocations already occurred in Study A0221047, the definition determined in Study 
A0221047 is followed. Hence, 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
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure and a decision taken regarding evaluation for each 
analysis population.
At enrollment, the investigator will assess patients against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints

Maximum cystometric capacity defined as maximal tolerable cystometric capacity or 
until voiding/leaking begins or at 40 cm H2O.

Detrusor pressure at maximum bladder capacity.

Presence of IDC (involuntary detrusor contractions)

Bladder volume at first IDC, if present.

Bladder wall compliance (mL/cm H2O), defined as volume/pressure during that 
change in bladder volume.

Mean number of micturitions/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 of Study 
A0221047.

Mean number of catheterizations/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 of Study 
A0221047.

Mean number of micturitions and catheterizations combined/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 


Protocol A0221109
Statistical Analysis Plan
Page 10
the total number of diary days collected at that assessment. This endpoint will only be 
calculated for subjects with >0 episodes at baseline of Study A0221047.
*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 incontinence episodes/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 incontinence 
episodes at baseline of Study A0221047.

Mean urgency episodes/24 hours if applicable (only for sensate subjects).
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 urgency episodes at baseline of 
Study A0221047.

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 or 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


Protocol A0221109
Statistical Analysis Plan
Page 11
6.2. Safety Endpoints

Adverse events, including monitoring of targeted events including, but not limited to:

Serious adverse event.

Anticholinergic effects such as dry mouth, dry eyes and constipation.

Central nervous system (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 (CBCL) and Grooved Pegboard Test
(GPT).

Vital Signs, including heart rate in the context of age-appropriate norms.

Urinary Tract Infection (UTI), 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 clean intermittent 
catheterization (CIC), or with >1 UTI during the study.
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.
Any events occurring following the start of study drug of fesoterodine or increasing in 
severity will be counted as treatment emergent. Events that occur in the 
oxybutynin-treatment period in Cohort 1 of Study A0221047 will NOT be attributed to 
fesoterodine, unless they started in the oxybutynin-treatment period in Cohort 1 of Study 
A0221047 and became more severe in the fesoterodine-treatment period.
6.2.2. Vital Signs
Blood pressure, temperature and pulse rate should be measured at each clinic visit.  This 
schedule of measurements should provide adequate indication of any clinically relevant 
changes.  However, if vital signs show a clinically relevant change from baseline of Study 
A0221047, then safety monitoring will occur at a minimum of monthly intervals, or more 


Protocol A0221109
Statistical Analysis Plan
Page 12
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 as Study A0221047 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) as Study A0221047 will be used throughout the study.
The same size blood pressure cuff as Study A0221047, which has been properly sized and 
calibrated, will be used to measure blood pressure each time.  The use of automated devices 
for measuring blood pressure 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 Examination
A physical examination will be performed at each clinic visit, and will include the following 
systems:

General appearance (including weight);

Skin;

Head, eyes, ears, nose, and throat; including visual acuity and accommodation (see 
Section 6.2.5);

Respiratory;

Cardiovascular;

Gastrointestinal;

Musculoskeletal;

Neurological.
If physical examinations show a clinically relevant change from baseline of the precedent 
Study A0221047, 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.


Protocol A0221109
Statistical Analysis Plan
Page 13
6.2.4. Weight Measurements
Weight will be recorded at each clinic visit.  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.
Even if the body weight of subjects with 25 kg at baseline of the precedent Study A0221047 
increase >25 kg during Study A0221047 or this study, they should maintain the same dose 
and formulation.
6.2.5. 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 each clinic visit.
Amplitude of accommodation will be assessed by the push up test to assess minimum focusing 
distance at each clinic visit.  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.
6.2.6. Post-Void Residual Volume (PVR) 
PVR urine volume in subjects not performing CIC will be assessed using trans-abdominal 
ultrasound (eg, bladder scan) immediately after urination.  If at Visit 1 (Week 0 [Week 24 in 
Study A0221047]), the measured volume is higher than 20 mL (see exclusion criterion 6), 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 A0221047 and this study.
6.2.7. Clinical Laboratory Evaluation
Safety laboratory tests will be performed at each clinic visit, or as needed to follow-up on 
significant findings.


Protocol A0221109
Statistical Analysis Plan
Page 14
Table 2.
Safety Laboratory
Hematology
Chemistry
Urinalysis
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
Creatinine a
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 sensitivity
b
Pregnancy Test c
(urine)
a.
When 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.
b.
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).
c.
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 Institutional Review Board (IRB)/Ethics Committee (EC) or 
if required by local regulations.
6.2.8. Childhood Behavior Checklist (CBCL)
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 each clinic visit.
6.2.9. Grooved Pegboard Test (GPT)
The GPT 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 


Protocol A0221109
Statistical Analysis Plan
Page 15
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 each clinic visit.
6.3. Other Endpoints
None.
6.4. Covariates 
None.
7. HANDLING OF MISSING VALUES
No imputation for missing data will be planned in efficacy and safety analysis.
In the case that the data of patient’s background in Study A0221047 is used for the analysis 
of this study, handling of missing data in Study A0221047 will be employed in this study.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods 
Efficacy endpoints and treatment-emergent adverse events will be summarized using merged 
data of Study A0221047 and Study A0221109.  When the longitudinal changes are analyzed 
for the merged data, baseline will be Visit 1 (Screening) or Visit 2 (Day 1) of Study 
A0221047. Demographics and baseline characteristics including medical history, prior
drug/Non-drug treatments will use baseline information at Visit 1 (Screening) or Visit 2 (Day 
1) of Study A0221047. Other safety endpoints will be summarized for the data of Study 
A0221109 alone, and baseline will be Week 0 of Study A0221109.
Treatments will be labeled as follows:
Cohorts of Study A0221047 (for analysis using the merged data of Study A0221047 and 
A0221109)
Cohort 1
Cohort 2
Treatment groups of Study A0221047 (for analysis using the merged data of Study 
A0221047 and A0221109, demographics and baseline characteristics)
Fesoterodine 4 mg Tab
Fesoterodine 8 mg Tab
Oxybutynin->Fesoterodine 4 mg Tab
Oxybutynin->Fesoterodine 8 mg Tab


Protocol A0221109
Statistical Analysis Plan
Page 16
Fesoterodine 2 mg BIC
Fesoterodine 4 mg BIC
Treatment group at baseline in Study A0221109 (for analysis using the data of Study 
A0221109 alone)
Fesoterodine 4 mg Tab (A0221109)
Fesoterodine 8 mg Tab (A0221109)
Fesoterodine 2 mg BIC (A0221109)
Fesoterodine 4 mg BIC (A0221109)
The cohorts and the treatment groups of Study A0221047 will be used for data summaries of 
efficacy endpoints and treatment-emergent adverse events.  The treatment groups at 
baseline in Study A0221109 will be used for data summaries of the safety endpoints
excluding adverse events, although the dosage can be reduced to the lower dose at each clinic 
visit for subjects on the higher dose.
8.1.1. Analyses for Continuous Data
Continuous data will be summarized using descriptive statistics.
The following will be 
presented: number of subjects, arithmetic mean, standard deviation, median, minimum, and 
maximum.
8.1.2. Analyses for Categorical and Binary Data
Categorical and binary data will be presented using cell counts and percentages for each 
category.  For summaries of change from baseline, the tables will be presented as a cross 
tabulation with baseline visit along the side and results of each visit along the top.
8.2. Statistical Analyses 
8.2.1. Analysis of Efficacy Data
For the following efficacy analyses, data will be summarized for the total of treatment 
groups, each cohort and each treatment group of Study A0221047, using the merged data of 
Study A0221047 and Study A0221109.  Subgroup analyses will be conducted that exclude 
oxybutynin treatment group in cohort 1 of A0221047 from the total for all efficacy endpoints 
if any subjects who were randomized to oxybutynin group in A0221047 are in FAS.
All efficacy endpoints of continuous data and their change from baseline will be summarized 
descriptively by each visit according to 8.1.1.
The presence of IDC will be summarized by each visit according to 8.1.2.
Listing tables will be provided at each timepoint from baseline visit of A0221047 to final visit 
of this study for all efficacy endpoints of observed values and changes from baseline with 


Protocol A0221109
Statistical Analysis Plan
Page 17
subjects information (ie., subject ID, gender, age, body weight at baseline of A0221047, 
cohort of A0221047, randomized treatment group in A0221047 and treatment history from 
the A0221047 start to the end of this study).
8.2.2. Analysis of Safety Data
Tables and listings of safety and demographic data, including adverse events and medical 
history will be reported in accordance with current Pfizer standards using baseline 
information at start of A0221047.
Treatment emergent adverse events will be summarized for the total of treatment groups, 
each cohort and each treatment group of Study A0221047, using the merged data of Study 
A0221047 and Study A0221109.  Treatment emergent adverse events (PT; preferred term) 
will be also summarized by the period of the onset time from the start of the fesoterodine 
treatment (0 – 12 weeks (1-84 days), 13 – 24 weeks (85-168 days), 25 – 36 weeks (169-252 
days), in or after 37 weeks (>= 253 days)).
For the following safety analyses, data will be summarized for each treatment group at 
baseline of Study A0221109, using the data of Study A0221109 alone.
Vital Signs
Blood pressure and pulse rate and their change from baseline will be summarized 
descriptively for each treatment group, by each visit according to 8.1.1.
Listings of all vital signs will also be created.
Visual Acuity and Accommodation
Visual acuity (LogMAR units) and accommodation (the distance for each eye at which vision 
becomes blurred – the mean of triplicate measurements) and their change from baseline will 
be summarized descriptively for each label, by each visit according to 8.1.1.
Listings of visual acuity and accommodation will also be created.
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.


Protocol A0221109
Statistical Analysis Plan
Page 18
PVR
PVR and their change from baseline will be summarized descriptively for each label, by each 
visit according to 8.1.1.
Listings of PVR will also be created.
Clinical Laboratory Evaluation
The incidence of laboratory abnormalities observed at any time during the study will be 
tabulated following PDS and summary statistics for changes from baseline will be provided 
by each visit.
Listings of clinical laboratory evaluation will also be created.
CBCL
CBCL(Domain T Scores and Total Scores as captured in the CRF) and their change from 
baseline will be summarized descriptively for each label, by each visit according to 8.1.1.
Listings of CBCL will also be created.


Protocol A0221109
Statistical Analysis Plan
Page 19
GPT
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)
and their change from baseline will be summarized descriptively for each label, by each visit 
according to 8.1.1.
Listings of GPT will also be created.


Protocol A0221109
Statistical Analysis Plan
Page 20
8.2.3. Summary of Efficacy Endpoint Analyses
Table 3.
Summary of Efficacy Endpoint Analyses
Endpoint
Analysis 
Set
Assessment
Planned
Statistical 
Method
Missing Data
Objective
Change in maximum 
cystometric capacity at 
each visit relative to 
baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous
summaries
No imputation
Efficacy following 
long-term treatment
Change in detrusor 
pressure at maximum 
bladder capacity at each 
visit relative to baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment
Presence of IDC
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Categorical
summaries
No imputation
Efficacy following 
long-term treatment
Change in bladder
volume at first IDC at 
each visit
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment
Change in bladder 
compliance at each visit 
relative to baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment


Protocol A0221109
Statistical Analysis Plan
Page 21
Table 3.
Summary of Efficacy Endpoint Analyses
Endpoint
Analysis 
Set
Assessment
Planned
Statistical 
Method
Missing Data
Objective
Change in mean number 
of micturitions and 
catheterizations/24 hours 
at each visit relative to 
baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment
Change in mean number 
of incontinence 
episodes/24 hours at 
each visit relative to the 
baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment
Change in mean number 
of urgency 
episodes/24 hours at 
each visit relative to the 
baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment
Change in mean voided 
volume per micturition 
or catheterization at each 
visit relative to baseline
FAS
Week 12
Week 52 (for Fesoterodine arm in Study 
A0221047)
Week 64 (for Oxybutynin arm in Study 
A0221047)
Final Visit
Continuous 
summaries
No imputation
Efficacy following 
long-term treatment


Protocol A0221109
Statistical Analysis Plan
Page 22
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.
10. APPENDICES 
Appendix 1. DATA DERIVATION DETAILS
Appendix 1.1. Definition and Use of Visit Windows in Reporting
There were no visit windows defined for Study A0221047.  The target observation of 
“Week 12 from Day 1 of Study A0221047” will also be that taken at a time closest to when 
the scheduled visit should have occurred.
Visit windows for after Study A0221109 are defined.
Table 4.
Visit Windows for Efficacy Endpoints
Visit Label
Endpoint
Definition [Day window]
A0221047:Day1
Urodynamic Assessments
Bladder Diary
Same definitions of A0221047 
will be used.
A0221047:Week12
Urodynamic Assessments
Bladder Diary
Same definitions of A0221047 
will be used.
A0221047:Week52/
A0221109:Week28
(for Fesoterodine arms in 
Study A0221047)
Urodynamic Assessments
Bladder Diary
= An assessment where
‘Date of assessment’ – ‘Date Day 
1 of Study A0221047’ + 1 = 
[310, 407]
A0221047:Week 64/
A0221109:Week40
(for Oxybutynin arm in Study 
A0221047)
Urodynamic Assessments
Bladder Diary
= An assessment where
‘Date of assessment’ – ‘Date Day 
1 of Study A0221047’ + 1 = 
[408, 491]
Final Visit
Urodynamic Assessments
Bladder Diary
= The last assessment where 
‘Date of assessment’ – ‘Date Day 
1 of Study A0221047’ + 1 > 169


Protocol A0221109
Statistical Analysis Plan
Page 23
Table 5.
Visit Windows for Safety Endpoints
Visit Label
Endpoint
Definition [Day window]
A0221047:Week24/
A0221109:Day1
Vital Signs
Visual Acuity and 
Accommodation
PVR
Clinical Laboratory Evaluation
CBCL
GPT
= An assessment where 
‘Date of assessment’ – ‘Date 
Week 0 of Study A0221109’ + 1 
is in [-20, 42]
A0221047:Week36/
A0221109:Week12
Vital Signs
Visual Acuity and 
Accommodation
PVR
Clinical Laboratory Evaluation
CBCL
GPT
= An assessment where 
‘Date of assessment’ – ‘Date 
Week 0 of Study A0221109’ + 1 
is in [43, 140]
A0221047:Week52/
A0221109:Week28
Vital Signs
Visual Acuity and 
Accommodation
PVR
Clinical Laboratory Evaluation
CBCL
GPT
= An assessment where 
‘Date of assessment’ – ‘Date 
Week 0 of Study A0221109’ + 1 
is in [141, 238]
A0221047:Week64/
A0221109:Week40
(for Oxybutynin arm in Study 
A0221047)
Vital Signs
Visual Acuity and 
Accommodation
PVR
Clinical Laboratory Evaluation
CBCL
GPT
= An assessment where 
‘Date of assessment’ – ‘Date 
Week 0 of Study A0221109’ + 1 
is in [239, 322]
Final Visit
Vital Signs
Visual Acuity and 
Accommodation
PVR
Clinical Laboratory Evaluation
CBCL
GPT
= The last assessment after
‘Date of assessment’ – ‘Date 
Week 0 of Study A0221109’ + 1 
>= 43