Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Fesoterodine
Clinical Study Report Synopsis: Protocol A0221109
Protocol Title: Long-Term Extension Study to Evaluate the Safety of Fesoterodine inJapanese Pediatric Subjects With Symptoms of Detrusor Overactivity Associated With a
Neurological Condition (Neurogenic Detrusor Overactivity) Who Have Completed 24 Weeks
Treatment in Study A0221047
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Centers: This study was conducted at 7 centers in Japan. Refer to Appendix 16.1.4.1
for a list of sites involved in this study.

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Publications Based on the Study: None
Study Initiation Date: 05 June 2015
Study Completion Date: 01 April 2020
Report Date: 13 August 2020
Previous Report Date(s): Not applicable
Phase of Development: Phase 3
Primary and Secondary Study Objectives and Endpoints:
The study objectives and endpoints are summarized in Table S1.

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Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives and Endpoints

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)Type
SafetyObjective
To investigate the safety
and tolerability offesoterodine following
once daily long-term
treatment in Japanesepediatric NDO subjects.

Endpoint• Adverse events, including monitoring of targeted events
including, but not limited to:• Serious adverse event.
• Anticholinergic effects such as dry mouth, dry eyes andconstipation.
• Central nervous system effects such as behavioral
changes (eg, aggression), decreased cognitive function,
headache, seizures and somnolence.
• Visual effects such as accommodation disorder, blurredvision, and amblyopia.
• Visual acuity and accommodation tests.
• Cognitive function by the CBCL and GPT.
• Vital signs, including heart rate in the context ofage-appropriate norms.
• UTI, as evidenced by urinalysis, urine microscopy, culture
and sensitivity.
• Clinical laboratory evaluations in the context ofage-appropriate norms, with particular reference to liverfunction tests and renal chemistry.
• PVR in subjects not performing CIC, or with >1 UTI during
the study.
Efficacy
To investigate the• Maximum cystometric bladder capacity defined as maximal
efficacy of fesoterodine
tolerable cystometric capacity or until voiding/leaking begins
following once daily
or at 40 cm H2O.
long-term treatment in• Detrusor pressure at maximum bladder capacity.
Japanese pediatric NDO • Presence of IDC.
subjects.
• 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 forsensate subjects).
• Mean volume voided per micturition and/or mean volume
per catheterization.
Abbreviations: CBCL=child behavior checklist; CIC=clean intermittent catheterization; GPT=grooved
pegboard test; H2O=water; IDC=involuntary detrusor contractions; NDO=neurogenic detrusor overactivity;
PVR=post-void residual volume; UTI=urinary tract infection.

METHODS
Study Design: This was a Phase 3, multicenter, open-label long-term treatment study inJapanese neurogenic detrusor overactivity (NDO) subjects aged 6 to 17 years old who
participated in and completed the precedent Study A0221047 (A 24-week randomized,
open-label, study to evaluate the safety and efficacy of fesoterodine in subjects aged

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Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
6 to 17 years with symptoms of detrusor overactivity associated with a neurologicalcondition [neurogenic detrusor overactivity] [NCT01557244]).

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)This study consisted of a 28-week open-label treatment period followed by a
4-week follow-up for subjects who were treated with 4 mg or 8 mg tablet of fesoterodine in
the precedent Study A0221047. However, subjects who were treated with oxybutynin andswitched to 4 mg or 8 mg tablet of fesoterodine in the precedent Study A0221047 were tocontinue treatment with 4 mg or 8 mg fesoterodine tablet until Week 40 in this study, in orderto obtain fesoterodine 1 year treatment data. A target number of subjects was not determinedbecause this was the safety extension study but approximately 9 subjects were expected to
become eligible for the study.
Diagnosis and Main Criteria for Inclusion: Subjects who completed 24 week treatment
and all visit procedures up to Visit 7 (Week 24) in the precedent Study A0221047 with nofindings suggestive of worsening condition of NDO compared to baseline of the precedent
Study A0221047. Subjects who did not tolerate the higher dose of fesoterodine (8 mg/day
for subjects >25 kg or 4 mg/day beads-in-capsule (BIC) for subjects ≤25 kg) well but were
not withdrawn could be included; for this study the dose could be reduced to low dose of thesame formulation (4 mg/day tablet for subjects >25 kg or 2 mg/day BIC for subjects ≤25 kg)
were included in the study.
Subjects who had major protocol violation (as determined by the sponsor) in
Study A0221047, subjects with intermittent or unstable use of diuretics or α blockers,
tricyclic antidepressants or any other treatment that could have confound the results of thestudy during the course of the study, and subjects not requiring intermittent catheterization
who had a post-void residual volume (PVR) >20 mL as determined by transabdominal
ultrasound (eg, bladder scan) immediately after urination were excluded.
Study Treatment:This was an open-label study. All subjects continued to receive the dose randomized inStudy A0221047.
For subjects who were assigned to Cohort 1 (subjects >25 kg) in the precedent
Study A0221047, fesoterodine prolonged release (PR) 4 mg and 8 mg were provided by thesponsor as PR tablets for oral administration. Subjects swallowed 1 tablet each day withoutchewing.
For subjects who were assigned to Cohort 2 (subjects ≤25 kg) in the precedent
Study A0221047, fesoterodine 2 mg and 4 mg once daily were provided by the sponsor as a
BIC formulation for oral administration. Subjects took 1 capsule per day without chewing.
For subjects who could not swallow whole capsules, the capsule could have been opened andthe beads sprinkled on a suitable medium (eg, apple sauce).

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Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
Subjects were provided with the study medication at each clinic visit except for the Final
Visit.
Subjects >25 kg who could not swallow tablets were not permitted to take the BIC
formulation, and were excluded from the study.
All subjects were also asked to complete a daily dosing log. If information from the dosing
log indicated that the subject had not taken study drug in accordance with dosing
instructions, the subject and their legal representatives were re-instructed on how to take theinvestigational product, and followed-up as appropriate by the investigator or approved
representative to ensure understanding and compliance.
The description of the investigational product is provided in Table S2.
Table S2. Investigational Product Description

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Investigational Product Description
Fesoterodine fumarate PR 4 mg light blue oval
film coated tablet
Fesoterodine fumarate PR 4 mg light blue oval
film coated tablet

Vendor Lot
Number15-003448

Pfizer Lot
Number15-004990

Strength/
Potency
4 mg

Dosage Form

89162001

13-111228

4 mg

Tablet8 mg

Tablet8 mg

Tablet2 mg

Capsule4 mg

CapsuleFesoterodine fumarate PR 8 mg blue oval film
15-003488
15-004983
coated tablet
Fesoterodine fumarate PR 8 mg blue oval film
89098001
13-111229
coated tablet
PF-00695838-42 fesoterodine fumarate 2 mg
SW-SDM
15-007270
CR capsules SR4
PF-00695838-42 fesoterodine fumarate 4 mg
SW-SDM
15-007271
CR capsules SR4
Abbreviations: CR=controlled release; PR=prolonged release; SR=sustained release.

TabletEfficacy Evaluations:
Urodynamic Assessments: Urodynamic assessment was performed at Final Visit. The
urodynamic assessments included evaluation of following parameters:•

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.

•

Maximum detrusor pressure.

•Presence of involuntary detrusor contractions (IDC).

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CLINICAL STUDY REPORT SYNOPSIS•

Bladder volume at first IDC, if present.

•

Bladder wall compliance (mL/cm H2O), defined as Δvolume/Δpressure during thatchange in bladder volume.

Where possible, urodynamic assessments for a subject were to be performed by the same
person in this study who performed in precedent Study A0221047. Only the central reader’sassessment of the urodynamic evaluation was recorded.
Bladder Diary: A bladder diary was completed for 3 consecutive days (with a minimum of
2 days) during the week prior to Final Visit, using paper diary. Daily micturition orcatheterization frequency, volume of urine from each micturition or catheterization (for oneof the days), incontinence episodes and urgency episodes (if appropriate) were recorded.

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Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:
There were no pharmacokinetic (PK), pharmacodynamics (PD), pharmacogenomic, and/or
other evaluations done in this study.
Safety Evaluations: Safety assessments consisted of the collection of adverse events (AEs),serious adverse events (SAEs), vital signs, physical examination, weight measurements,
visual acuity and accommodation, PVR, clinical laboratory evaluations, Child Behavior
Checklist (CBCL), Grooved Pegboard Test (GPT) pregnancy testing and dosing log.
Statistical Methods:
The following analysis sets were used in this study:
Full Analysis Set (FAS): The FAS included all subjects who had been enrolled and received
at least 1 dose of investigational product and had at least 1 observation in efficacy endpoint
data after baseline visit in Study A0221109.
Safety Analysis Set: The safety analysis set included all subjects who had been enrolled andreceived at least 1 dose of investigational product in Study A0221109.
Efficacy endpoints and treatment-emergent adverse event (TEAEs) were summarized using
merged data of precedent Study A0221047 and Study A0221109. When the longitudinalchanges were analyzed for the merged data, baseline was Visit 1 (Screening) or Visit 2(Day 1) of Study A0221047. Demographics and baseline characteristics including medical
history, prior drug/non-drug treatments used baseline information at Visit 1 (Screening) orVisit 2 (Day 1) of Study A0221047. Other safety endpoints were summarized for the data of
Study A0221109 alone, and baseline was Week 0 of Study A0221109.
There were no statistical hypotheses in this study. No imputation for missing data wasplanned for efficacy and safety analyses.

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Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
All efficacy endpoints of continuous data and their change from baseline were summarized
descriptively by each visit. The presence of IDC was summarized by each visit.
TEAEs were summarized for the total of treatment groups, each cohort and each treatmentgroup of Study A0221047, using the merged data of Study A0221047 and this study. TEAEs
were also summarized by the period of the onset time from the start of the fesoterodine
treatment (0 to 12 weeks, 13 to 24 weeks, 25 to 36 weeks, or after 37 weeks).
The incidence of laboratory abnormalities observed at any time during the study wastabulated following Pfizer Data Standard and summary statistics for changes from baseline
was provided by each visit.
Blood pressure (BP) and pulse rate and their changes from baseline were summarized
descriptively for each treatment group by each visit. PVR, visual acuity and accommodation,
CBCL, and GPT and their changes from baseline were summarized descriptively for eachlabel, by each visit.

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)RESULTS
Subject Disposition and Demography: Of the 12 subjects screened for entry into the study;
2 subjects were assigned to treatment in Cohort 1, and 10 subjects were assigned to treatment
in Cohort 2.
In Cohort 1, 2 subjects were assigned to treatment in fesoterodine 8 mg arm. In Cohort 2,
10 subjects were assigned to treatment: 7 subjects to fesoterodine 2 mg BIC arm and3 subjects to fesoterodine 4 mg BIC arm. There were no subjects who had been initiallyrandomized to oxybutynin arm in Study A0221047 and participated in this study.
Eleven subjects (91.7%) completed the study. One subject in Cohort 2 in the
fesoterodine 2 mg BIC arm discontinued the study due to withdrawal by parent/guardian (thesubject and parent/guardian decided to withdraw from this study at their own will due tosurgery for ventriculo-peritoneal shunt reconstruction). All subjects were analyzed for
efficacy and safety.
The subject evaluation by treatment groups at baseline is presented in Table S3.

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CLINICAL STUDY REPORT SYNOPSIS

2 (100.0)0Completed

Discontinued

CCI

Safety Analysis Set

Analysis for Safety:

Full Analysis Set

2 (100.0)

2 (100.0)

2 (100.0)

TreatedAnalysis for Efficacy:

2 (100.0)

10 (100.0)

10 (100.0)

1 (10.0)9 (90.0)

10 (100.0)

10 (100.0)

n (%)

n (%)

Assigned to Treatment

Screened: 12

Cohort 2(N=10)

Cohort 1
(N=2)

0

0

0

0

0

0

2 (100.0)

2 (100.0)02 (100.0)

2 (100.0)

2 (100.0)

n (%)

Fesoterodine
8 mg Tab(A0221109)(N=2)

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Page 7n (%)

Fesoterodine
4 mg Tab(A0221109)(N=0)

7 (100.0)

7 (100.0)

1 (14.3)

6 (85.7)

7 (100.0)

7 (100.0)

n (%)

Fesoterodine
2 mg BIC(A0221109)(N=7)

Table S3. Subject Evaluation Groups by Treatment Groups at Baseline in A0221109

Final Clinical Study Report
Protocol A0221109

3 (100.0)

3 (100.0)03 (100.0)

3 (100.0)

3 (100.0)

n (%)

Fesoterodine
4 mg BIC(A0221109)(N=3)

12 (100.0)

12 (100.0)

1 (8.3)11 (91.7)

12 (100.0)

12 (100.0)

n (%)

Total
(N=12)

Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSISIn Cohort 1, fesoterodine 8 mg arm, both the subjects were female. Additionally, both thesubjects were Asian with a mean weight of 51.7 kg, and the mean age was 13.5 years.
In Cohort 2, 9 subjects were male and 1 subject was female. In the fesoterodine 2 mg BIC
arm all the subjects were male (n=7) while in the fesoterodine 4 mg BIC arm, 2 subjects weremale and 1 subject was female. Additionally, all the subjects were Asian with a mean weightof the subjects was 18.99 kg and 20.77 kg in the fesoterodine 2 mg and 4 mg BIC arms,
respectively. The mean age of the subjects was 7.9 years and 7.3 years in the
fesoterodine 2 mg and 4 mg BIC arms, respectively.
Efficacy Results:

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Maximum Cystometric Bladder Capacity:
The maximum cystometric bladder capacity (MCBC) was increased in subjects treated withfesoterodine at Week 12; a numerical increase was consistent with the results seen acrossboth cohorts for Study A0221047. The numerical increase was also observed at Week 52(Week 28 in the current study) in subjects treated with fesoterodine. The mean (standard
deviation [SD]) change from baseline in MCBC in total fesoterodine treated subjects was
61.3 mL (53.98) and 53.1 mL (59.74) at Week 12 and Week 52, respectively.
Detrusor Pressure at Maximum Bladder Capacity:
Detrusor pressure at maximum bladder capacity was decreased in subjects treated withfesoterodine at Week 12; a numerical decrease was consistent with the results seen acrossboth cohorts for Study A0221047. The numerical decrease was also observed at Week 52(Week 28 in the current study). The mean (SD) change from baseline in detrusor pressure at
maximum bladder capacity in total fesoterodine treated subjects was -12.3 cm H2O (22.74)
and -4.8 cm H2O (21.43) at Week 12 and Week 52, respectively.
Presence of Involuntary Detrusor Contractions:
Out of 12 subjects treated with fesoterodine, 11 subjects (91.7%) had IDC at baseline. Of
these 11 subjects with IDC, 2 subjects (18.2%) showed improvement at Week 52. Other
subjects had no change in IDC from baseline at Week 52.
Bladder Volume at First Involuntary Detrusor Contractions:
The bladder volume at first IDC was increased in subjects treated with fesoterodine at
Week 12; a numerical increase was consistent with the results seen across both cohorts forStudy A0221047. The numerical increase was also observed at Week 52 (Week 28 in thecurrent study) in subjects treated with fesoterodine. The mean (SD) change from baseline inbladder volume at first IDC in total fesoterodine treated subjects was 95.0 mL (53.88) and
50.4 mL (36.38) at Week 12 and Week 52, respectively.

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CLINICAL STUDY REPORT SYNOPSIS
Bladder Compliance:
The bladder compliance was increased in subjects treated with fesoterodine at Week 12; anumerical increase was consistent with the results seen across both cohorts forStudy A0221047. The numerical increase was also observed at Week 52 (Week 28 in thecurrent study) in subjects treated with fesoterodine. The mean (SD) summary of change
from baseline in bladder compliance in total fesoterodine treated subjects
was 18.22 mL/cm H2O (42.021) and 12.39 mL/cm H2O (15.194) at Week 12 and Week 52(Week 28 in the current study), respectively.
Mean Number of Micturitions or Catheterizations per 24 Hours:

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)The mean (SD) change from baseline in mean number of micturitions or catheterizations per
24 hours was -0.46 (1.055) at Week 12 and -0.41 (0.758) at Week 52 (Week 28 in the current
study) in subjects treated with fesoterodine.
Mean Number of Micturitions per 24 Hours: The mean (SD) change from baseline in mean
number of micturitions per 24 hours was -1.50 (1.036) at Week 12 and -1.08 (0.631) at
Week 52 (Week 28 in the current study) in subjects treated with fesoterodine.
Mean Number of Catheterizations per 24 Hours: The mean (SD) change from baseline inmean number of catheterizations per 24 hours was 0.04 (0.353) at Week 12 and -0.02 (0.302)
at Week 52 (Week 28 in the current study) in subjects treated with fesoterodine.
Mean Number of Incontinence Episodes per 24 Hours:
The mean (SD) change from baseline in mean number of incontinence episodes per 24 hours
was -0.07 (1.586) at Week 12 and 0.08 (1.615) at Week 52 (Week 28 in the current study) insubjects treated with fesoterodine.
Mean Urgency Episodes per 24 Hours (Only for Sensate Subjects):
The mean (SD) change from baseline in mean number of urgency episodes per 24 hours
was -0.61 (0.347) at Week 12 and Week 52 (Week 28 in the current study) in subjects treatedwith fesoterodine.
Mean Volume Voided per Micturition and/or Mean Volume per Catheterization:
The mean (SD) change from baseline in mean volume voided per micturition orcatheterization was 14.75 mL (18.638) at Week 12 and 4.75 mL (29.583) at Week 52(Week 28 in the current study) in subjects treated with fesoterodine.
The mean (SD) change from baseline in mean volume voided per micturition was
15.77 mL (6.924) at Week 12 and 4.75 mL (14.496) at Week 52 (Week 28 in the current
study) in subjects treated with fesoterodine.
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CLINICAL STUDY REPORT SYNOPSIS
The mean (SD) change from baseline in mean volume per catheterization was 17.06 mL(21.739) at Week 12 and 4.12 mL (29.591) at Week 52 (Week 28 in the current study) insubjects treated with fesoterodine.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Results:
There were no PK, PD, pharmacogenomic, and/or other evaluations done in this study.
Safety Results:
Summary of Adverse Events:

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For all the subjects treated with fesoterodine, 1 SAE was reported in fesoterodine 2 mg BIC
arm. This SAE was not treatment-related. There were no severe TEAEs, and no TEAEs
leading to discontinuation from the study or from study drug in this study. There was
1 subject (14.3%) with dose reduction or temporary discontinuation due to TEAEs in the
fesoterodine 2 mg BIC arm.
For Cohort 1, the TEAEs were reported for 2 subjects (100.0%) in the fesoterodine 8 mg
arm. There were no treatment-related TEAEs in Cohort 1.
For Cohort 2, the TEAEs were reported for 9 subjects (90.0%); 6 subjects (85.7%) in the
fesoterodine 2 mg BIC arm and 3 subjects (100.0%) in the fesoterodine 4 mg BIC arm. One
subject (14.3%) in fesoterodine 2 mg BIC arm and 1 subject (33.3%) in the
fesoterodine 4 mg BIC arm reported treatment-related TEAEs.
All-Causality Adverse Events:
The TEAEs by system organ classes (SOCs) and preferred terms (PTs) by cohorts andrandomized treatment groups (all-causalities) for safety analysis set are presented inTable S4.
For all the subjects treated with fesoterodine, the TEAEs (all-causalities) by PTs in≥2 subjects were nasopharyngitis (7 subjects [58.3%]), asymptomatic bacteriuria(4 subjects [33.3%]), pyrexia (3 subjects [25.0%]), influenza, pharyngitis, diarrhea, myopia,
upper respiratory tract inflammation and sinusitis (2 subjects [16.7%] each). All the TEAEs
reported in each treatment arm were mild to moderate in severity.
For Cohort 1, the incidence of reported TEAEs by SOC are described below:
In Cohort 1, all the TEAEs reported were mild in severity.
For eye disorders SOC, there was a TEAE of visual acuity reduced reported in
1 subject (50.0%).

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CLINICAL STUDY REPORT SYNOPSIS
For gastrointestinal disorders SOC, the TEAEs of anal fissure and diarrhea were eachreported in 1 subject (50.0%).
For infections and infestations SOC, the TEAEs of bronchitis and nasopharyngitis were eachreported in 1 subject (50.0%).
For Cohort 2, the incidence of reported TEAEs by SOC are described below:
In Cohort 2, the majority of the TEAEs reported in the fesoterodine 2 mg and 4 mg BIC arm
were mild in severity except abscess limb in 1 subject (10.0%) and urinary tract infection in
1 subject (10.0%), which were moderate in severity.

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)For eye disorders SOC, the TEAEs of astigmatism, conjunctivitis allergic, and strabismus
were each reported in 1 subject (14.3%) in the fesoterodine 2 mg BIC arm. The TEAE of
myopia was reported in 2 subjects (66.7%) in the fesoterodine 4 mg BIC arm.
For infections and infestations SOC, the TEAEs of asymptomatic bacteriuria was reported in
3 subjects (42.9%) and 1 subject (33.3%), and nasopharyngitis was reported in
4 subjects (57.1%) and 2 subjects (66.7%) respectively in the fesoterodine 2 mg and 4 mg
BIC arms.
For skin and subcutaneous tissue disorders SOC, the TEAEs of decubitus ulcer, eczema andseborrheic dermatitis were each reported in 1 subject (14.3%) in the fesoterodine 2 mg BIC
arm. The TEAE of dermal cyst was reported in 1 subject (33.3%) in the fesoterodine 4 mg
BIC arm.

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CLINICAL STUDY REPORT SYNOPSIS

0
0
0
0

Astigmatism

Conjunctivitis allergic

MyopiaStrabismus

INFECTIONS AND INFESTATIONS

Seasonal allergy

IMMUNE SYSTEM DISORDERS

Pyrexia

Fatigue

GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONS

Faeces soft

Diarrhoea

Aphthous ulcer

Anal fissure

GASTROINTESTINAL DISORDERS

2 (100)001 (50.0)

1 (50.0)

1 (50.0)0

1 (50.0)0

1 (50.0)

2 (100)1 (50.0)

0

0

0

0

1 (50.0)

2 (100.0)

n (%)

Fesoterodine
8 mg Tab(N=2)

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Page 129 (90.0)

1 (10.0)02 (100)1 (10.0)

2 (20.0)

1 (50.0)00

1 (50.0)

2 (20.0)

1 (10.0)0
1 (50.0)

1 (10.0)

1 (10.0)02 (20.0)0

1 (10.0)

2 (20.0)

1 (10.0)

1 (10.0)

4 (40.0)9 (90.0)n (%)

Cohort 2(N=10)

1 (50.0)0

1 (50.0)

2 (100)1 (50.0)

1 (50.0)

EYE DISORDERS

Visual acuity reduced

2 (100.0)n (%)

Cohort 1(N=2)

With Any adverse event

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

Number of Subjects Evaluable for AEs

6 (85.7)

1 (14.3)

1 (14.3)

1 (14.3)

0

1 (14.3)

1 (14.3)

1 (14.3)

1 (14.3)02 (28.6)

0

1 (14.3)

0

1 (14.3)

1 (14.3)

2 (28.6)

6 (85.7)n (%)

Fesoterodine
2 mg BIC(N=7)

3 (100)001 (33.3)

0

1 (33.3)

0

0

0

0

0

0

0

2 (66.7)

00

2 (66.7)

3 (100.0)

n (%)

Fesoterodine
4 mg BIC(N=3)

11 (91.7)

1 (8.3)1 (8.3)3 (25.0)

1 (8.3)3 (25.0)

1 (8.3)2 (16.7)

1 (8.3)1 (8.3)4 (33.3)

1 (8.3)1 (8.3)2 (16.7)

1 (8.3)1 (8.3)5 (41.7)

11 (91.7)

n (%)

Total
(N=12)

Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by Cohorts and Randomized
Treatment Groups (All Causalities) - Safety Analysis Set (Merged Data)

Final Clinical Study Report
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CLINICAL STUDY REPORT SYNOPSIS

00

Influenza00Sinusitis

Urinary tract infection

HeadacheNERVOUS SYSTEM DISORDERS

Spinal deformity

MUSCULOSKELETAL AND CONNECTIVE TISSUEDISORDERS

1 (50.0)

1 (50.0)

1 (50.0)

0

0

0

0

1 (50.0)

1 (50.0)

0

0

0

0

1 (50.0)0001 (50.0)

0

0

n (%)

Fesoterodine
8 mg Tab(N=2)

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1 (10.0)0
1 (50.0)

1 (10.0)

1 (10.0)

1 (10.0)00

1 (10.0)

2 (20.0)

2 (20.0)

1 (10.0)

6 (60.0)

2 (20.0)

1 (10.0)

1 (10.0)04 (40.0)

1 (10.0)n (%)

Cohort 2(N=10)000

INVESTIGATIONSUrodynamics measurement abnormal

1 (50.0)

Chillblains

1 (50.0)0

INJURY, POISONING AND PROCEDURALCOMPLICATIONS

0

Oral herpes

Pharyngitis

1 (50.0)0Nasopharyngitis

0

Conjunctivitis bacterial

Impetigo

1 (50.0)

Asymptomatic bacteriuria

Bronchitis

0

n (%)

Cohort 1(N=2)

Abscess limb

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

Number of Subjects Evaluable for AEs00

1 (14.3)

1 (14.3)

0

0

0

0

1 (14.3)

1 (14.3)

1 (14.3)

04 (57.1)

2 (28.6)

1 (14.3)003 (42.9)

1 (14.3)n (%)

Fesoterodine
2 mg BIC
(N=7)

0

0

0

0

1 (33.3)

1 (33.3)0001 (33.3)

1 (33.3)

1 (33.3)

2 (66.7)

00

1 (33.3)

0

1 (33.3)

0n (%)

Fesoterodine
4 mg BIC(N=3)

1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)1 (8.3)2 (16.7)

2 (16.7)

1 (8.3)7 (58.3)

2 (16.7)

1 (8.3)1 (8.3)1 (8.3)4 (33.3)

1 (8.3)

n (%)

Total
(N=12)

Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by Cohorts and Randomized
Treatment Groups (All Causalities) - Safety Analysis Set (Merged Data)

Final Clinical Study Report
Protocol A0221109

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CLINICAL STUDY REPORT SYNOPSIS

0
0
0
0

Decubitus ulcer

Dermal cyst

EczemaSeborrhoeic dermatitis

00SKIN AND SUBCUTANEOUS TISSUE DISORDERS

0

Upper respiratory tract inflammation00

1 (50.0)

0

0

0

0

0

0

0

0

0

1 (50.0)

1 (50.0)

0

0

n (%)

Fesoterodine
8 mg Tab(N=2)

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1 (10.0)

1 (10.0)

1 (10.0)

1 (10.0)

4 (40.0)

2 (20.0)

1 (10.0)

3 (30.0)

1 (10.0)0

1 (10.0)

1 (10.0)0
1 (50.0)

1 (10.0)n (%)

Cohort 2(N=10)

0n (%)

Cohort 1(N=2)

AsthmaRESPIRATORY, THORACIC AND MEDIASTINALDISORDERS

Urinary incontinence

Renal failure

RENAL AND URINARY DISORDERS

Device malfunction

PRODUCT ISSUES

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

Number of Subjects Evaluable for AEs

1 (14.3)

1 (14.3)

0

1 (14.3)

3 (42.9)

1 (14.3)

1 (14.3)

2 (28.6)

0001 (14.3)

1 (14.3)n (%)

Fesoterodine
2 mg BIC
(N=7)

0

0

1 (33.3)

0

1 (33.3)

1 (33.3)

0

1 (33.3)

1 (33.3)

0

1 (33.3)

0

0

n (%)

Fesoterodine
4 mg BIC(N=3)

1 (8.3)1 (8.3)1 (8.3)1 (8.3)4 (33.3)

2 (16.7)

1 (8.3)3 (25.0)

1 (8.3)1 (8.3)2 (16.7)

1 (8.3)1 (8.3)

n (%)

Total
(N=12)

Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by Cohorts and Randomized
Treatment Groups (All Causalities) - Safety Analysis Set (Merged Data)

Final Clinical Study Report
Protocol A0221109

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)

CLINICAL STUDY REPORT SYNOPSISn (%)

Cohort 1
(N=2)
n (%)

Cohort 2(N=10)n (%)

Fesoterodine
8 mg Tab
(N=2)
n (%)

Fesoterodine
2 mg BIC
(N=7)
n (%)

Fesoterodine
4 mg BIC
(N=3)

n (%)

Total
(N=12)CCI

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Randomized Treatment Groups is based on the randomization information at baseline in A0221047.
Subjects are only counted once per treatment per event.
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may report two or more different adverse events within thehigher level category.
Includes all data collected since the first dose of study drug.
MedDRA v22.1 coding dictionary applied.

Number (%) of Subjects:
by SYSTEM ORGAN CLASS
and Preferred Term

Number of Subjects Evaluable for AEs

Table S4. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term by Cohorts and Randomized
Treatment Groups (All Causalities) - Safety Analysis Set (Merged Data)

Final Clinical Study Report
Protocol A0221109

Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
Treatment-Related Adverse Events:
Three treatment-related TEAEs were observed in 2 subjects treated with fesoterodine. The
observed treatment-related TEAEs were diarrhea and faeces soft, each reported in
1 subject (14.3%) in fesoterodine 2 mg BIC arm, and urinary incontinence reported in
1 subject (33.3%) in fesoterodine 4 mg BIC arm.
All the treatment-related TEAEs were mild in severity.
Deaths: There were no deaths reported among subjects who participated in this study.
Serious Adverse Events:
In Cohort 1, no SAEs were reported. In Cohort 2, there was an SAE of urinary tract infection
reported for 1 subject (14.3%) in the fesoterodine 2 mg BIC arm. This was an SAE occurred
during the precedent Study A0221047.

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Discontinuations and Dose Reductions due to Adverse Events:
No subject discontinued from the study due to AEs.
Among the subjects treated with fesoterodine, the TEAEs leading to dose reduction or
temporary discontinuation (interruption) of study drug were reported for 1 subject infesoterodine 2 mg BIC arm. These TEAEs were urinary tract infection (moderate in severity
and considered as an SAE), pyrexia and nasopharyngitis (mild in severity). There were nodose reductions or temporary discontinuations due to TEAEs in the fesoterodine 4 mg BIC
and fesoterodine 8 mg arms.
There were TEAEs of special interest of visual acuity reduced and headache reported in
1 subject (50.0%) in Cohort 1, fesoterodine 8 mg arm. In Cohort 2, an SAE of special
interest of urinary tract infection was reported in 1 subject (14.3%) in the fesoterodine 2 mg
BIC arm. There were no TEAEs of special interest in the fesoterodine 4 mg BIC arm.
Clinical Laboratory Evaluations:
In Cohort 1, the laboratory test abnormalities (without regard to baseline abnormality) werereported for 2 subjects (100.0%) in the fesoterodine 8 mg arm. The laboratory test
abnormalities were reported as follows:•

Leukocyte esterase ≥1 (1 of 2 subjects [50.0%] in the fesoterodine 8 mg arm);•

Urine leukocytes ≥20/high power field (HPF) (1 of 2 subjects [50.0%] in the fesoterodine
8 mg arm);•

Epithelial cells ≥6/low power field (LPF) (2 of 2 subjects [100.0%] in the fesoterodine
8 mg arm).
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Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)In Cohort 2, the laboratory test abnormalities (without regard to baseline abnormality) werereported for 8 subjects (80.0%) in the fesoterodine 2 mg and 4 mg BIC arm. The mostfrequently reported laboratory test abnormalities (reported by ≥20% of subjects in either arm)
were as follows:•

Eosinophils (103/mm3) >1.2 × upper limit of normal (3 of 7 subjects [42.9%] in the
fesoterodine 2 mg BIC arm and 1 of 3 subjects [33.3%] in the fesoterodine 4 mg BIC
arm);

•

Specific gravity (scalar) >1.030 (2 of 7 subjects [28.6%] in the fesoterodine 2 mg BIC
arm and 1 of 3 subjects [33.3%] in the fesoterodine 4 mg BIC arm);•

Nitrite ≥1 (2 of 7 subjects [28.6%] in the fesoterodine 2 mg BIC arm and 1 of 3 subjects[33.3%] in the fesoterodine 4 mg BIC arm);•

Leukocyte esterase ≥1 (2 of 7 subjects [28.6%] in the fesoterodine 2 mg BIC arm and
1 of 3 subjects [33.3%] in the fesoterodine 4 mg BIC arm);•

Urine leukocytes ≥20/HPF (1 of 4 subjects [25.0%] in the fesoterodine 2 mg BIC arm);•

Epithelial cells ≥6/LPF (4 subjects [100.0%] in the fesoterodine 2 mg BIC arm and2 subjects [100.0%] in the fesoterodine 4 mg BIC arm);•

Hyaline casts >1/LPF (1 subject [100.0%] in the fesoterodine 2 mg BIC arm);•

Bacteria >20/HPF (1 of 2 subjects [50.0%] in the fesoterodine 4 mg BIC arm).

There were no apparent trends in median changes from baseline to the last observation in any
hematology and clinical chemistry parameters in Cohort 1 and Cohort 2, except for theplatelets (103/mm3). The total median value at baseline for both the cohorts for platelet(103/mm3) was 326, while the total median change from baseline for both the cohorts was 22.
Vital Signs:
For Cohort 1, there were no subjects who met criteria for sitting systolic BP (value of<90 mm Hg), sitting diastolic BP (value of <50 mm Hg) and sitting pulse rate (value of<40 bpm, value of >120 bpm). There were no subjects who met categorical increase or
decrease criteria from baseline in sitting systolic/diastolic BP values in Cohort 1.
In Cohort 2, 1 subject (14.3%) had a post-baseline sitting systolic BP value of <90 mm Hg
and 2 subjects (28.6%) had sitting diastolic BP value of <50 mm Hg in the fesoterodine 2 mg
BIC arm. There were no subjects who met the above categorical criteria for BP in the
fesoterodine 4 mg BIC arm. Also, there were no subjects who met the criteria for sitting
pulse rate (value of <40 bpm, value of >120 bpm) in Cohort 2.

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Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS
One subject (14.3%) met the increase in sitting diastolic BP criterion (change of ≥20 mm Hg
increase) in the fesoterodine 2 mg BIC arm. There were no subjects who met this criterion in
the fesoterodine 4 mg BIC arm and no subjects meeting the increase in sitting systolic BP
criterion (change of ≥30 mm Hg) in either treatment arm. There were no subjects who met
categorical decrease from baseline in sitting BP values in Cohort 2.
For Cohort 1 and Cohort 2, no clinically relevant changes from baseline were observed forvital sign parameters.
Physical Findings: There were no clinically significant changes from baseline reported as
AEs.
Visual Acuity and Accommodation: For Cohort 1 and Cohort 2, there were no clinically
relevant changes from baseline to Week 36 or Week 52 (Week 12 or Week 28 in the current
study, respectively) in visual accommodation or visual acuity in either eye.

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)

Cognitive Function:
For Cohort 1 and Cohort 2, there were no clinically relevant changes from baseline to
Week 36 or Week 52 (Week 12 or Week 28 in the current study, respectively) in the T scoreor total score of any CBCL assessments (aggressive behavior, anxious/depressed, attention
problems, rule-breaking behavior, social problems, somatic complaints, thought problems,
withdrawn, externalizing, internalizing and total problems).
For Cohort 1 and Cohort 2, there were no clinically relevant changes from baseline to
Week 36 or Week 52 (Week 12 or Week 28 in the current study, respectively) in GPT resultsin either the dominant or non-dominant hand.
For the GPT, subjects were assigned to either a 10- or 25-peg assessment based on their age,resulting in small sample sizes for the 25-peg assessment in Cohort 1 and Cohort 2.
Post-Void Residual Volume: In this study, all subjects were performing intermittent
catheterization. Therefore, no subjects had a post-void residual urine volume assessment.
Conclusions:
Safety•Treatment with fesoterodine once daily for 52 weeks was well tolerated in Japanesepediatric NDO subjects with no discontinuations for safety reasons and notreatment-related SAEs.

•

No clinically relevant changes were observed for visual acuity and accommodation,
cognitive function or behaviour, vital signs values and clinical laboratory tests.

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Final Clinical Study Report
Protocol A0221109

CLINICAL STUDY REPORT SYNOPSIS•

No increase in frequency, severity or nature of treatment-related AEs with longer-term
exposure was observed in this study, although with limited sample size.

Efficacy

090177e194d8047c\Approved\Approved On: 07-Sep-2020 08:45 (GMT)•The sample size of this study was very limited, however, in subjects treated withfesoterodine there was a numerical increase (improvement) in the efficacy endpoint,
MCBC, at Week 12, consistent with the A0221047 overall result, and this was also
observed at Week 52 (Week 28 in the current study). Numerical improvements frombaseline were also observed in other urodynamic endpoints, but this was not consistently
observed in the diary-based efficacy endpoints at Week 52.

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