Final Clinical Study Report
Protocol A0221047

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Fesoterodine
Clinical Study Report Synopsis: Protocol A0221047
Protocol Title: A 24-Week Randomized, Open-Label, Study to Evaluate the Safety andEfficacy of Fesoterodine in Subjects Aged 6 to 17 Years With Symptoms of Detrusor
Overactivity Associated With a Neurological Condition (Neurogenic Detrusor Overactivity)
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 65 study sites in Belgium, Canada, Estonia, Finland, France,
Germany, Greece, Italy, Japan, Republic of Korea, Lithuania, Malaysia, Philippines, Poland,
Russian Federation, Slovakia, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey,
United Kingdom, and United States randomized subjects in this study. Refer toAppendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study: None
Study Initiation Date: 02 July 2012 (First Subject First Visit)
Study Completion Date: 13 February 2020 (Last Subject Last Visit)
Report Date: 01 July 2020
Previous Report Date(s): Not applicable
Phase of Development: Phase 3

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CLINICAL STUDY REPORT SYNOPSIS
Primary and Secondary Study Objectives and Endpoints:
Table S1. Study Objectives
Type
Primary
Safety, Efficacy

Objective
To determine the safety and efficacy of fesoterodine 4 mg and 8 mg following once
daily treatment for 12 weeks in pediatric neurogenic detrusor overactivity (NDO)
subjects with weight >25 kg.
To determine the safety and efficacy of fesoterodine 2 mg and 4 mg following once
daily treatment for 12 weeks in pediatric NDO subjects with weight ≤25 kg.

Secondary
Safety, Efficacy

Evaluate the safety and efficacy of fesoterodine versus oxybutynin in pediatric NDO
subjects with weight >25 kg.
SafetyEvaluate the safety of fesoterodine 4 mg and 8 mg once daily treatment for up to
24 weeks in pediatric NDO subjects with weight >25 kg.
Evaluate the safety of fesoterodine 2 mg and 4 mg once daily treatment for up to
24 weeks in pediatric NDO subjects with weight ≤25 kg.
PK
Determine the steady-state population pharmacokinetics (PK) of
5-hydroxymethyltolterodine (5-HMT) following fesoterodine 4 mg and 8 mg once
daily treatment in pediatric NDO subjects with weight >25 kg.
Determine the steady-state population PK of 5-HMT following treatment with 2 dosesof fesoterodine 2 mg and 4 mg once daily in pediatric NDO subjects.
Cohort 1 (weight >25 kg) treatment: fesoterodine prolonged release (PR) 4 or 8 mg tablet or oxybutynin
extended release (XL) tablet
Cohort 2 (weight ≤25 kg) treatment: fesoterodine 2 or 4 mg beads-in-capsule (BIC)

Table S2. Study Endpoints
Type
Primary
Efficacy
Secondary
Efficacy

Endpoint
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 contraction (IDC)
Bladder volume at first IDC
Bladder compliance
Mean number of micturitions per 24 hours
Mean number of catheterizations per 24 hours
Mean number of micturitions and catheterizations combined per 24 hours
Mean number of incontinence episodes per 24 hours
Mean urgency episodes per 24 hours if applicable (only for sensate subjects)
Mean volume voided per micturition
Mean volume per catheterization
Mean volume voided per micturition or catheterization

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Endpoints
Type
SafetyPK

Endpoint
Adverse events, including monitoring of targeted events including, but not limited to: Anticholinergic effects such as dry mouth, dry eyes and constipation
 Central nervous system 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 Childhood Behavior Checklist and Grooved Pegboard Test
 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 particularreference to liver function tests and renal chemistry Post-void residual volume in subjects not performing clean intermittent
catheterization, or with >1 UTI during the study
 Physical examination and weight
Model-based PK parameter estimates for absorption rate constant (Ka), apparent oral
clearance (CL/F), and volume of distribution (Vd) to predict the area under the curve(AUC), maximum concentration (Cmax), time to reach maximum concentration (Tmax), andhalf-life of 5-HMT

METHODS
Study Design:
For Cohort 1 (weight >25 kg), this was a randomized, open-label, active comparator, parallelgroup study with 3 treatment arms. The study consisted of 2 parts: a 12-week, 3-arm phasewith an active comparator (oxybutynin extended release [XL]), followed by a 12-week,
2-arm extension phase without the active comparator.
There was a variable screening period (minimum 3 days) prior to the baseline visit, theduration of which was principally determined by the prior medication subjects may haveneeded to washout. At baseline, subjects were randomized in a 1:1:1 ratio to one of 3 arms:
4 or 8 mg per day of fesoterodine or oxybutynin XL. Subjects were stratified at
randomization into 2 groups dependent on their body weight. The lower weight group within
Cohort 1 included all those with a weight of 50 kg or less, and the higher weight groupwithin Cohort 1 included all those above 50 kg.
A sufficient number of subjects were to be randomized into Cohort 1 to ensure a total of
approximately 99 subjects (approximately 33 evaluable subjects per arm) were evaluable forthe primary efficacy and safety analyses at Week 12.
For Cohort 2 (weight ≤25 kg), the study consisted of 2 parts: a 12-week, 2-arm Efficacy
Phase, followed by a 12-week, 2-arm Safety Extension Phase.

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CLINICAL STUDY REPORT SYNOPSIS
There was a variable screening period (minimum 3 days) prior to the baseline visit, theduration of which was principally determined by the prior medication subjects may haveneeded to washout. At baseline, subjects were randomized in a 1:1 ratio to one of
2 fesoterodine beads-in-capsule (BIC) treatment arms: 2 or 4 mg per day.
It was planned that a sufficient number of subjects were to be randomized into Cohort 2 toensure a total of approximately 50 subjects (approximately 25 evaluable subjects per arm)
were evaluable for the primary efficacy and safety analyses at Week 12.
Diagnosis and Main Criteria for Inclusion: The study population consisted of subjects
aged 6 to 17 years, with stable neurological disease and clinically or urodynamicallydemonstrated neurogenic detrusor overactivity (NDO), no history of indwelling catheter
within 4 weeks of participation in the study, no history of autonomic dysreflexia, and noclinically significant urinary tract infection (UTI) at screening. Subjects not requiring
intermittent catheterization who had a post-void residual (PVR) volume greater than 20 mL
as determined by transabdominal ultrasound immediately after urination were excluded.
Study Treatment:
Fesoterodine
Subjects randomized to fesoterodine in Cohort 1 (weight >25 kg) received either 4 or 8 mg
fesoterodine prolonged release (PR) tablets once daily throughout the initial 12 weeks of the
Active Comparator Phase and continued at the same dose during the 12-week Safety
Extension Phase. All those assigned to the fesoterodine 8 mg arm started at 4 mg daily for
1 week, and then escalated to 8 mg daily.
Subjects in Cohort 2 (weight ≤25 kg) were randomized to either 2 or 4 mg fesoterodine BIC
capsules once daily throughout the initial 12 weeks of the Efficacy Phase and continued at
the same dose during the 12-week Safety Extension Phase. All those assigned to the
fesoterodine 4 mg arm started at 2 mg daily for 1 week and then escalated to 4 mg daily.
If subjects could not tolerate the doses they were randomized to, they were to be withdrawn
from the study, as a dose reduction was not permitted on this study.

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CLINICAL STUDY REPORT SYNOPSIS
Oxybutynin
Subjects in Cohort 1 (weight >25 kg) randomized to oxybutynin received oxybutynin XL
tablets at a starting dose in accordance with approved pediatric labeling and accepted practice(eg, oxybutynin XL 5 mg once a day). Dose optimization was achieved by either up or down
titration in 5-mg increments on an approximately weekly basis to achieve a balance ofefficacy and tolerability. All subjects should have achieved a minimum total daily dose ofoxybutynin XL 10 mg by the end of the dose adjustment period at Week 4. The maximum
dose used in this study did not exceed the recommended dose consistent with approved
pediatric labeling and accepted practice. Subjects who were on oxybutynin prior to study
entry and who were randomized to the oxybutynin XL treatment group may have, at thediscretion of the investigator, restarted at the equivalent pre-study total daily dose.
After Week 4, subjects taking oxybutynin XL remained on the same dose for the subsequent
8 weeks of the study, and no further dose adjustments were permitted. Subjects who wereunable to tolerate a minimum total dose of oxybutynin XL 10 mg once daily were to bewithdrawn. Subjects who withdrew from the oxybutynin treatment arm for reasons oftoleration, and who fulfilled all continuation criteria, may have been directly allocated by theinvestigator to fesoterodine treatment at either 4 or 8 mg per day for the remaining 12-week
Safety Extension Phase. All those assigned to the fesoterodine 8 mg arm started at 4 mg dailyfor 1 week, and then escalated to 8 mg daily.
At Visit 5 (or earlier if appropriate), subjects in the oxybutynin arm of the study wereallocated by the investigator to fesoterodine at either 4 or 8 mg per day. Subjects underwent aminimum 2-day washout period from oxybutynin prior to starting treatment withfesoterodine. All those assigned to the fesoterodine 8 mg arm started at 4 mg daily for 1 week
and then escalated to 8 mg daily. Once allocated, the dose remained fixed for the period of
the extension; if treatment was inadequate or the subject could not tolerate the dose,
consideration was to be given to withdrawal.

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CLINICAL STUDY REPORT SYNOPSIS
Table S3. Investigational Product Description
Investigational Product
Description
Fesoterodine Fumarate PR

Pfizer Lot
Number11-006370
12-003817
13-111228
15-005055

Strength/
Potency
4 mg

Dosage Form
CapsuleFilm-coated
Tablet11-006371
12-004327
13-111229
15-005056

8 mg

Film-coated
TabletFesoterodine Fumarate

Vendor Lot
Number8394601
86552001
89162001
15-003448/
E10453930U
8414101
86824001
89098001
15-003487/
E10432130U
SW-SDM

15-007270

2 mg

Fesoterodine Fumarate

SW-SDM

15-007271

4 mg

Oxybutynin Chloride Extended
Release1060901
1084901
125185P1
83889P2
1064501
1106801
125299P2
83890P1
BHLS000
BHLS001
CDLS000
CHLS201DBZSA00
DKBS000
EABS003
EFZS000
CALS601
CFLS103
CHZS100DBZSB00DKZSA00
DLBS001
EGZSE02
BHLS200
BHLS200

11-006670
12-000006
14-001712
13-107177
11-006671
12-000007
14-002192
13-107547
12-000223
12-001581
12-005876
13-107832
13-109719
14-001862
14-003633
14-006148
12-003396
12-005870
13-107831
13-109741
14-001749
14-003631
14-006149
12-001582
12-000225

5 mg

Controlled
Release Capsule
Controlled
Release Capsule
Tablet

10 mg

Tablet

5 mg

Tablet

10 mg

TabletFesoterodine Fumarate PR

Oxybutynin Chloride Extended
Release
Oxybutynin HCl Prolonged
Release

Oxybutynin HCl Prolonged
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CLINICAL STUDY REPORT SYNOPSIS
Efficacy Evaluations:
Urodynamic assessment was performed at Visit 2 (baseline) and Visit 5 (Week 12). The
following were 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.

Maximum detrusor pressure.

Presence of involuntary detrusor contractions (IDC).



Bladder volume at first IDC, if present.



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



Presence of subtraction test (eg, cough) on urodynamic trace.

For all subjects, eligibility for study entry or continuation on the basis of urodynamic criteria
were verified by a central reader.
At Visit 5 (or end of Active Comparator/Efficacy Phase), subjects who demonstrated aclinically relevant increased detrusor pressure, or other urodynamic findings suggestive ofworsening condition compared to baseline, were not allowed to continue into the Safety
Extension Phase. In this case, consideration was to be given to imaging of upper urinary tract(for example, videourodynamics or ultrasound) according to accepted local standard of carein subjects with vesicoureteral reflux, or other conditions that predispose to upper urinary
tract dysfunction or damage.
A bladder diary was completed for 3 consecutive days (with a minimum of 2 days) during theweek prior to Visit 2 (baseline) and Visit 5 (Week 12), using an electronic capture device.
Completion of the bladder diary prior to Visit 2 (baseline) was to begin only after previous
treatment with prohibited concomitant medications had undergone a minimum washout
appropriate to the drug so any clinical effect was at a minimum (eg, 3-day minimum washoutfor oxybutynin, 7-day minimum washout for darifenacin and solifenacin). Daily micturitionor catheterization frequency, volume of urine from each micturition or catheterization (forone of the days), incontinence episodes and urgency episodes (if appropriate) were recorded.

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CLINICAL STUDY REPORT SYNOPSIS
Pharmacokinetic Evaluations: At Visit 3 (Week 4), blood samples were collected fromeach subject assigned to receive fesoterodine for the analysis of 5-hydroxymethyltolterodine(5-HMT). Samples were analyzed for 5-HMT using a validated liquid
chromatography/tandem mass spectrometry method in compliance with Pfizer standard
operating procedures.
Safety Evaluations: Safety evaluations included adverse events (AEs), vital signs, physicalexaminations, clinical laboratory tests, weight measurements, visual acuity andaccommodation, electrocardiogram, PVR urine volume, Childhood Behavior Checklist(CBCL), Grooved Pegboard Test (GPT), and pregnancy testing.
Statistical Methods:
Efficacy
The following hypotheses are applicable only to the analyses of the heavier (>25 kg)
Cohort 1, as there was no formal hypothesis testing planned for the lighter (≤25 kg) Cohort 2.
Null Hypothesis: The difference between baseline and Week 12 in maximum cystometricbladder capacity is equal to zero.
Alternative Hypothesis: The difference between baseline and Week 12 in maximum
cystometric bladder capacity is not equal to zero.
Changes from baseline in Cohort 1 were tested at the =0.05 level, and 95% confidence
intervals (CIs) were estimated for Cohort 2.
Cohort 1 Primary Efficacy Analysis
Change from baseline to Week 12 in the primary endpoint was analyzed using an analysis ofcovariance (ANCOVA) including terms for treatment group, baseline (for the endpoint being
analyzed) and baseline weight. The least squares (LS) mean change from baseline for eachtreatment group, standard error (SE), 95% CIs and p-values associated with the LS meanchanges from baseline were presented.
The following primary comparisons of interest were assessed:Change from baseline to Week 12 for fesoterodine 4 mg PR.

Change from baseline to Week 12 for fesoterodine 8 mg PR.

The LS means and 95% CIs for the difference between each fesoterodine dose group andoxybutynin were also calculated.

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The following secondary comparisons were assessed using 95% CIs for the difference
between treatment means (for the change from baseline to Week 12):Fesoterodine 4 mg PR versus oxybutynin.

Fesoterodine 8 mg PR versus oxybutynin.

As these secondary comparisons were based on an estimation approach, no formal statistical
hypothesis testing was performed. Conclusions were based on point estimates and CIs.
The primary analysis was based on the Cohort 1 Full Analysis Set (FAS).
Cohort 2 Primary Efficacy Analysis
Change from baseline to Week 12 in the primary endpoint was analyzed using an ANCOVA
including terms for treatment group and baseline (for the endpoint being analyzed). The LSmean change from baseline for each treatment group, standard error and 95% CIs associatedwith the LS mean changes from baseline were presented.
The following primary comparisons of interest were assessed:Change from baseline to Week 12 for fesoterodine 2 mg BIC.



Change from baseline to Week 12 for fesoterodine 4 mg BIC.

As these comparisons were based on an estimation approach, no formal statistical hypothesis
testing was performed. Conclusions were based on point estimates and CIs.
The primary analysis was based on the Cohort 2 FAS.
For the FAS analysis, a baseline observation carried forward (BOCF) and a last observation
carried forward (LOCF) algorithm were used for missing data.
Secondary Efficacy Analyses
All secondary endpoints were analyzed as for the primary analyses as defined for each
respective cohort using the appropriate FAS.
The presence of IDC was presented using cell counts and proportions for each response
category. For summaries of change from baseline, the tables were presented as a crosstabulation with baseline visit along the side and Week 12 results along the top.
SafetyTables of safety and demographic data, including AEs and medical history were reported inaccordance with current Pfizer standards and were presented separately for each cohort.
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For treatment-emergent AEs (TEAEs) which occurred during the Active Comparator or
Efficacy Phases of the study for each cohort, 3-tier AE reporting was used:

Tier 1 AEs: AEs identified as targeted medical events in the safety review planTier 2 AEs: AEs that occurred in 4 or more subjects in any treatment groupTier 3 AEs: AEs that were not tier 1 or tier 2 (Tier 3 AEs were not summarized
separately)

For Cohort 1, the treatment comparisons were fesoterodine 4 mg versus oxybutynin andfesoterodine 8 mg versus oxybutynin. The risk difference was calculated as fesoterodine(4 mg PR or 8 mg PR) minus oxybutynin. There were no treatment comparisons presented
for Cohort 2, as there was no active comparator for this cohort.
The frequency and percentage of subjects for all AEs were presented by treatment group,
separately for the Active Comparator, Efficacy, and Safety Extension Phases and over theentire study.
For vital signs, change from baseline was summarized together with the number of subjects
whose blood pressure and heart rate fell outside specified ranges. Furthermore, the number ofsubjects whose decreases and increases in blood pressure fell outside specified ranges was
summarized.
Visual acuity (LogMAR units) and accommodation (the distance for each eye at which vision
becomes blurred – the mean of triplicate measurements), CBCL (Domain T Scores and Total
Scores as captured in the case report form [CRF]), GPT (time to completion, number of pegs
dropped, and number of pegs correctly placed – by dominant/non-dominant hand andwhether the 10-peg or 25-peg test was used, separately), physical examination, and weight
were summarized by visit and changes from baseline at each visit using descriptive statistics.
For visual acuity, LogMAR units were derived from the Snellen ratios recorded on the CRF.
Pharmacokinetics
Plasma concentrations of 5-HMT were listed and summarized for subjects in thepharmacokinetic (PK) analysis set (for each cohort separately).

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CLINICAL STUDY REPORT SYNOPSIS
A population PK modeling approach was used to analyze the plasma concentration-time data
following fesoterodine administration for the estimation of population PK parameters(apparent oral clearance [CL/F], absorption rate constant [Ka], and volume of distribution[Vd]) of 5-HMT in pediatric subjects in this study. Different structural models such as 1- or
2-compartment PK models with first-order absorption were considered as dictated by thedata. In all models, estimation of CL/F and apparent volume of distribution (Vd/F) were ofprimary interest. A base model was constructed with a priori allometric weight scaling factor
on CL/F and Vd/F, with clearance and volume parameters being scaled with body weightraised to power coefficients. In addition, the effect of drug formulation on some parameters
related to absorption (eg, absolute oral bioavailability [F], Ka) was also investigated. In fullmodel development, predefined covariate-parameter relationships (ie, the effects of genderand CYP2D6 metabolizer status, as predictors of CL/F and Vd/F) were identified based on
exploratory graphics. These covariates are selected from those which were found in the prioradult population analysis. However, age was not included in this full model, because age wasconsidered to be a potential confounding factor in the relationship between body weight andPK parameters.
RESULTS
Subject Disposition and Demography:
Cohort 1
Overall, a higher proportion of subjects randomized to fesoterodine 4 mg discontinued fromthe study (12 subjects [28.6%]) than those randomized to fesoterodine 8 mg (6 subjects[14.3%]) or oxybutynin (5 of 40 subjects [12.5%], 1 of these discontinued from the study
while receiving fesoterodine 4 mg in the Safety Extension Phase), with the most common
reasons being AE and withdrawal by parent/guardian (Figure S1).
In the Active Comparator Phase, a higher proportion of subjects discontinued from the study
in the fesoterodine 4 mg arm (9 subjects [21.4%]) than the fesoterodine 8 mg arm (2 subjects[4.8%]) or the oxybutynin arm (4 subjects [10.0%]).
In the fesoterodine 4 mg arm, the majority of discontinuations from the study occurred
during the Active Comparator Phase (9 subjects), with 3 subjects discontinuing from thestudy after completing the Active Comparator Phase.
In Cohort 1, 6 subjects (15.0%) permanently discontinued treatment with oxybutynin during
the Active Comparator Phase. Two of these subjects continued into the Safety Extension
Phase; therefore, they did not discontinue from the study during the Active Comparator
Phase, as allowed per the protocol for subjects randomized to oxybutynin. In the Safety
Extension Phase, these 2 subjects received fesoterodine and completed the study. The other4 subjects discontinued from the study during the Active Comparator Phase.

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Figure S1. Disposition Flow Chart - Cohort 1

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For Cohort 1, demographic and baseline characteristics (age, ethnicity, and weight) weregenerally well balanced between treatment arms, but there were more male subjects (n=26)
than female subjects (n=16) in the fesoterodine 4 mg arm and more male subjects (n=23)
than female subjects (n=17) in the oxybutynin arm. Additionally, the proportion of whitesubjects was lower in the oxybutynin arm than in the fesoterodine arms, and the proportion of
Asian subjects was higher in the oxybutynin arm than in the fesoterodine arms. The mean
weight was 43.26, 42.02, and 43.20 kg and the mean age was 10.74, 11.02, and 11.15 years
for the fesoterodine 4 mg, fesoterodine 8 mg, and oxybutynin arms, respectively.
Cohort 2
Overall, a higher proportion of subjects discontinued from the study in the fesoterodine 2 mg
BIC arm (8 subjects [28.6%]) than in the fesoterodine 4 mg BIC arm (1 subject [3.4%]), withthe most common reasons being AE and withdrawal by parent/guardian (Figure S2).
In the Efficacy Phase, a higher proportion of subjects discontinued the study in the
fesoterodine 2 mg BIC arm (7 subjects [25.0%]) than in the fesoterodine 4 mg BIC arm(1 subject [3.4%]).
In the fesoterodine 2 mg BIC arm, the majority of discontinuations occurred during the
Efficacy Phase, with only 1 subject discontinuing from the study after completing the
Efficacy Phase. In the fesoterodine 4 mg BIC arm, 1 subject discontinued from the study
during the Efficacy Phase, and no subjects discontinued from the study after completing the
Efficacy Phase.

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Figure S2. Disposition Flow Chart - Cohort 2

For Cohort 2, demographic and baseline characteristics (age, ethnicity, and weight) weregenerally well balanced between treatment arms, but there were more male subjects (n=16)
than female subjects (n=12) in the fesoterodine 2 mg BIC arm and more female subjects(n=19) than male subjects (n=10) in the fesoterodine 4 mg BIC arm. The mean weight was
21.1 and 21.3 kg and the mean age was 7.5 and 7.9 years for the fesoterodine 2 and 4 mg BIC
arms, respectively, as expected given the weight constraint of Cohort 2.
There were more Asian subjects than white subjects in both fesoterodine BIC treatment arms,
which is consistent with the higher enrollment at sites in Asian countries than in all othercountries.
Efficacy Results:
For Cohort 1, changes from baseline were tested at the =0.05 significance level. Therefore,
results with p≤0.05 are described as significant changes from baseline (improvements,
increases, or decreases), and results with p>0.05 are described as numerical changes frombaseline (improvements, increases, or decreases).

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For Cohort 2, 95% CIs were estimated for the mean changes from baseline. Therefore, results
for which the 95% CI excluded zero are described as improvements, increases or decreases
from baseline, whereas, results for which the 95% CI included zero are described as
numerical changes from baseline (improvements, increases, or decreases).
Primary Efficacy Analysis
For Cohort 1 (subjects >25 kg), treatment with fesoterodine 4 and 8 mg and oxybutynin
resulted in significant increases from baseline to Week 12 in maximum cystometricbladder capacity (p=0.0001, p<0.0001, and p<0.0001, respectively; Table S4). The 95% CIs
for the mean difference for fesoterodine 4 and 8 mg versus oxybutynin included zero.

Table S4. Statistical Analysis of Change from Baseline in Maximum Cystometric
Bladder Capacity (ml) at Week 12 - Full Analysis Set - Cohort 1
Feso 4mg(N=41)WEEK 12N

Feso 8mg(N=41)

Oxybutynin(N=38)

41

41

38

LS Mean (SE)58.12 ( 14.78)

83.36 ( 14.71)

87.17 ( 15.33)

95% CI for mean

(28.84,87.39)(54.22,112.49)(56.82,117.53)

0.0001<.0001<.0001LS Mean (SE)-29.06 ( 21.39)-3.82 ( 21.23)

95% CI for mean(-71.42,13.31)(-45.87,38.23)

P-value
Versus Oxybutynin

Baseline is defined as the last available measurement prior to the start of treatment.
Based on an ANCOVA model with terms for treatment group, baseline (for the endpoint being analyzed) and baseline
weight.
LOCF/BOCF was used for imputing missing values.
PFIZER CONFIDENTIAL SDTM Creation: 09MAR2020 (08:02) Source Data: ADUR Output File:./CDISC/A0221047/desc_infr_chg_ur_mbc_1 Date of Generation: 07APR2020 (13:46)
Table 14.2.2.1a is for Pfizer internal use.

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For Cohort 2 (subjects ≤25 kg), treatment with fesoterodine 2 and 4 mg BIC resulted inincreases from baseline to Week 12 in maximum cystometric bladder capacity, with 95%
CIs for the mean change from baseline excluding zero (Table S5).

Table S5. Statistical Analysis of Change from Baseline in Maximum Cystometric
Bladder Capacity (ml) at Week 12 - Full Analysis Set - Cohort 2

WEEK 12N

Fesoterodine 2mg BIC(N=25)

Fesoterodine 4mg BIC(N=28)

25

28

LS Mean (SE)23.49 ( 10.18)

40.17 ( 9.62)

95% CI for mean

(3.03,43.95)(20.84,59.50)

Baseline is defined as the last available measurement prior to the start of treatment. Based on an ANCOVA model withterms for treatment group,
baseline (for the endpoint being analyzed) and baseline weight.
LOCF/BOCF was used for imputing missing values.
BIC= Beads-in-Capsule.
PFIZER CONFIDENTIAL SDTM Creation: 03MAR2020 (05:17) Source Data: ADUR Output File:./CDISC/A0221047_CH2/desc_infr_chg_ur_mbc_1_c2 Date of Generation: 07APR2020 (09:49)
Table 14.2.2.1b is for Pfizer internal use.

Secondary Efficacy Analyses


Detrusor Pressure at Maximum Bladder Capacity:
For Cohort 1 (subjects >25 kg), treatment with fesoterodine 4 and 8 mg and oxybutynin
resulted in numerical decreases from baseline to Week 12 in detrusor pressure at
maximum bladder capacity (LS mean [SE]: -2.86 cm H2O [2.39], p=0.2334; LS mean[SE]: -1.57 cm H2O [2.37], p=0.5087; and LS mean [SE]: -2.39 cm H2O [2.46],
p=0.3333, respectively). The 95% CIs for the mean difference for fesoterodine 4 and
8 mg versus oxybutynin included zero.
For Cohort 2 (subjects ≤25 kg), treatment with fesoterodine 4 mg BIC resulted in adecrease from baseline to Week 12 in detrusor pressure at maximum bladder capacity(LS mean [SE]: -9.73 cm H2O [3.71]), with the 95% CI for the mean change frombaseline excluding zero. Treatment with fesoterodine 2 mg BIC resulted in a numericaldecrease from baseline to Week 12 in detrusor pressure at maximum bladder capacity(LS mean [SE]: -2.74 cm H2O [3.92]), with the 95% CI for the mean change frombaseline including zero.

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Presence of Involuntary Detrusor Contractions:
For Cohort 1, a numerically higher proportion of subjects showed improvement frombaseline to Week 12 for the presence of IDC in the fesoterodine 8 mg arm (18 subjects[43.9%]) than the fesoterodine 4 mg arm (9 subjects [22.0%]). Fewer than 5% of subjects
in any treatment arm worsened from baseline to Week 12.
For Cohort 2, a numerically higher proportion of subjects showed improvement frombaseline to Week 12 for the presence of IDC in the fesoterodine 4 mg BIC arm(11 subjects [39.3%]) than the fesoterodine 2 mg BIC arm (6 subjects [24.0%]). No
subjects in either treatment arm worsened from baseline to Week 12.

Bladder Volume at First Involuntary Detrusor Contraction:
For Cohort 1, treatment with fesoterodine 4 and 8 mg and oxybutynin resulted in asignificant increases from baseline to Week 12 in bladder volume at first IDC (LS mean[SE]: 30.53 mL [14.15], p=0.0336; LS mean [SE]: 26.06 mL [12.01], p=0.0327; and LS
mean [SE]: 41.31 mL [12.78], p=0.0017, respectively). The 95% CIs for the meandifference for fesoterodine 4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 4 mg BIC resulted in an increase from baseline
to Week 12 in bladder volume at first IDC (LS mean [SE]: 31.26 mL [12.14]), with the
95% CI for the mean change from baseline excluding zero. Treatment with fesoterodine
2 mg BIC resulted in a numerical increase from baseline to Week 12 in bladder volume atfirst IDC (LS mean [SE]: 23.80 mL [12.63]), with the 95% CI for the mean change frombaseline including zero.

Bladder Compliance:
For Cohort 1, treatment with fesoterodine 4 and 8 mg resulted in numerical increases
from baseline to Week 12 in bladder compliance (LS mean [SE]: 6.40 mL/cm
H2O [3.47], p=0.0679 and LS mean [SE]: 5.41 mL/cm H2O [3.48], p=0.1233,
respectively). Treatment with oxybutynin resulted in a significant increase from baseline
to Week 12 in bladder compliance (LS mean [SE]: 11.36 mL/cm H2O [3.56], p=0.0019).
The 95% CIs for the mean difference for fesoterodine 4 and 8 mg versus oxybutynin
included zero.
For Cohort 2, treatment with fesoterodine 4 mg BIC resulted in an increase from baseline
to Week 12 in bladder compliance (LS mean [SE]: 16.44 mL/cm H2O [6.15]), with the
95% CI for the mean change from baseline excluding zero. Treatment with fesoterodine
2 mg BIC resulted in a numerical increase from baseline to Week 12 in bladdercompliance (LS mean [SE]: 12.44 mL/cm H2O [6.51]), with the 95% CI for the meanchange from baseline including zero.

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Mean Number of Micturitions per 24 Hours:
For Cohort 1, treatment with fesoterodine 4 mg and oxybutynin resulted in significant
decreases from baseline to Week 12 in the mean number of micturitions per 24 hours (LSmean [SE]: -1.07 [0.41], p=0.0116 and LS mean [SE]: -0.97 [0.34], p=0.0061,
respectively). Treatment with fesoterodine 8 mg resulted in a numerical decrease frombaseline to Week 12 in the mean number of micturitions per 24 hours (LS mean[SE]: -0.68 [0.38], p=0.0765). The 95% CIs for the mean difference for fesoterodine
4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 4 mg BIC resulted in a decrease from baseline
to Week 12 in the mean number of micturitions per 24 hours (LS mean[SE]: -0.70 [0.32]), with the 95% CI for the mean change from baseline excluding zero.
Treatment with fesoterodine 2 mg BIC resulted in a numerical decrease from baseline to
Week 12 in the mean number of micturitions per 24 hours (LS mean [SE]: -0.37 [0.35]),
with the 95% CI for the mean change from baseline including zero.

Mean Number of Catheterizations per 24 Hours:
For Cohort 1, treatment with fesoterodine 4 and 8 mg and oxybutynin resulted innumerical decreases from baseline to Week 12 in the mean number of catheterizations
per 24 hours (LS mean [SE]: -0.30 [0.17], p=0.0787; LS mean [SE]: -0.32 [0.18],
p=0.0727; and LS mean [SE]: -0.34 [0.18], p=0.0666; respectively). The 95% CIs for themean difference for fesoterodine 4 and 8 mg versus oxybutynin included zero.
Treatment with fesoterodine 2 and 4 mg BIC resulted in numerical decreases frombaseline to Week 12 in the mean number of catheterizations per 24 hours (LS mean[SE]: -0.10 [0.20] and -0.22 [0.19], respectively), with the 95% CIs for the mean change
from baseline including zero.

Mean Number of Micturitions or Catheterizations Combined per 24 Hours:
For Cohort 1, treatment with fesoterodine 4 and 8 mg and oxybutynin resulted insignificant decreases from baseline to Week 12 in the mean number of micturitions andcatheterizations combined per 24 hours (LS mean [SE]: -0.61 [0.24], p=0.0111; LS mean[SE]: -0.60 [0.25], p=0.0171; and LS mean [SE]: -0.75 [0.24], p=0.0028; respectively).
The 95% CIs for the mean difference for fesoterodine 4 and 8 mg versus oxybutynin
included zero.
Treatment with fesoterodine 2 and 4 mg BIC resulted in numerical decreases frombaseline to Week 12 in the mean number of micturitions and catheterizations combined
per 24 hours (LS mean [SE]: -0.24 [0.21] and -0.28 [0.20], respectively), with the
95% CIs for the mean change from baseline including zero.

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Mean Number of Incontinence Episodes per 24 Hours:
For Cohort 1, treatment with fesoterodine 4 and 8 mg and oxybutynin resulted insignificant decreases from baseline to Week 12 in the mean number of incontinence
episodes per 24 hours (LS mean [SE]: -0.46 [0.23], p=0.0496; LS mean[SE]: -0.89 [0.23], p=0.0002; and LS mean [SE]: -1.01 [0.23], p<0.0001; respectively).
The 95% CIs for the mean difference for fesoterodine 4 and 8 mg versus oxybutynin
included zero.
For Cohort 2 (subjects ≤25 kg), treatment with fesoterodine 4 mg BIC resulted in adecrease from baseline to Week 12 in the mean number of incontinence episodes per
24 hours (LS mean [SE]: -0.69 [0.30]), with the 95% CI for the mean change frombaseline excluding zero. Treatment with fesoterodine 2 mg BIC resulted in a numericaldecrease from baseline to Week 12 in the mean number of incontinence episodes per
24 hours (LS mean [SE]: -0.38 [0.29]), with the 95% CI for the mean change frombaseline including zero.

Mean Number of Urgency Episodes per 24 Hours:
For Cohort 1, treatment with fesoterodine 4 mg resulted in a significant decrease frombaseline to Week 12 in the mean number of urgency episodes per 24 hours (LS mean[SE]: -0.62 [0.28], p=0.0298). Treatment with fesoterodine 8 mg and oxybutynin resulted
in numerical decreases from baseline to Week 12 in the mean number of urgency
episodes per 24 hours (LS mean [SE]: -0.50 [0.33], p=0.1417 and LS mean[SE]: -0.14 [0.28], p=0.6219, respectively). The 95% CIs for the mean difference forfesoterodine 4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 2 and 4 mg BIC resulted in numericaldecreases from baseline to Week 12 in the mean number of urgency episodes per
24 hours (LS mean [SE]: -0.23 [0.29] and -0.62 [0.35], respectively), with the 95% CIs
for the mean change from baseline including zero.

Mean Volume Voided per Micturition:
For Cohort 1, treatment with fesoterodine 4 and 8 mg and oxybutynin resulted innumerical increases from baseline to Week 12 in the mean volume voided per micturition(LS mean [SE]: 4.10 mL [15.96], p=0.7986; LS mean [SE]: 19.21 mL [15.83], p=0.2313;
and LS mean [SE]: 4.15 mL [13.32], p=0.7571; respectively). The 95% CIs for the meandifference for fesoterodine 4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 2 and 4 mg BIC resulted in numericaldecreases from baseline to Week 12 in the mean volume voided per micturition (LS mean[SE]: -12.72 mL [10.37] and -8.41 mL [9.26], respectively), with the 95% CIs for themean change from baseline including zero.

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Mean Volume per Catheterization:
For Cohort 1, treatment with fesoterodine 8 mg and oxybutynin resulted in significant
increases from baseline to Week 12 in the mean volume per catheterization (LS mean[SE]: 47.18 mL [16.33], p=0.0048 and LS mean [SE]: 45.90 mL [17.45], p=0.0100,
respectively). Treatment with fesoterodine 4 mg resulted in a numerical increase frombaseline to Week 12 in the mean volume per catheterization (LS mean [SE]:29.47 mL [15.53], p=0.0610). The 95% CIs for the mean difference for fesoterodine
4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 2 and 4 mg BIC resulted in numerical increases
from baseline to Week 12 in the mean volume per catheterization (LS mean [SE]:11.50 mL [10.60] and 1.74 mL [10.17], respectively), with the 95% CIs for the meanchange from baseline including zero.

Mean Volume Voided per Micturition or Catheterization:
For Cohort 1, treatment with fesoterodine 8 mg and oxybutynin resulted in significant
increases from baseline to Week 12 in the mean volume voided per micturition orcatheterization (LS mean [SE]: 55.55 mL [15.01], p=0.0003 and LS mean [SE]:36.69 mL [15.01], p=0.0161, respectively). Treatment with fesoterodine 4 mg resulted ina numerical increase from baseline to Week 12 in the mean volume voided per
micturition or catheterization (LS mean [SE]: 18.45 mL [15.11], p=0.2246). The 95% CIs
for the mean difference for fesoterodine 4 and 8 mg versus oxybutynin included zero.
For Cohort 2, treatment with fesoterodine 2 mg BIC resulted in a numerical increase frombaseline to Week 12 in the mean volume voided per micturition or catheterization (LSmean [SE]: 7.12 mL [9.44]), with the 95% CI for the mean change from baseline
including zero. Treatment with fesoterodine 4 mg BIC resulted in a numerical decrease
from baseline to Week 12 in the mean volume voided per micturition or catheterization(LS mean [SE]: -2.65 mL [8.74]), with the 95% CI for the mean change from baseline
including zero.

Pharmacokinetic Results:
One hundred twenty-one patients from this study were included in the PK analysis. A total of
163 and 112 PK observations were collected from fesoterodine treated patients in Cohort 1
and Cohort 2, respectively.
The 5-HMT plasma concentration data were adequately described by a one-compartment
model with first-order absorption and elimination, including a fixed allometric relationship of
CL/F and Vd/F, as well as the effect of drug formulation on the extent of absorption (BIC
versus tablet).

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The mean (percent relative standard error [%RSE]) for fesoterodine CL/F, fesoterodine Vd/F,and Ka were 71.6 (6.7) L/hour, 68.1 (29.7) L, and 0.0897 (5.99)/hour, respectively. CL/F for
subjects with CYP2D6 poor metabolizer (PM) status was estimated to be 0.546 times lower
than subjects who are CYP2D6 extensive metabolizers (EMs). Absorption was describedwith a lag time estimated at 0.285 hours, and the estimated relative bioavailability for BIC
compared with tablet was 64.8%.
For Cohort 1, the observed plasma concentrations of 5-HMT in fesoterodine-treated subjects
increased proportionally with fesoterodine 4 and 8 mg doses given as the tablet formulation.
The observed mean plasma concentrations of 5-HMT appear to increment in a similar way tothe increment between different doses.
For Cohort 2, similar to Cohort 1, the plasma concentrations of 5-HMT infesoterodine-treated subjects increased proportionally with dose, 2 and 4 mg doses given as
the BIC formulation. For Cohort 2, mean plasma concentrations of 5-HMT increased inrelation to the dose. The plasma 5-HMT concentrations in Cohort 2 following fesoterodine
2 mg BIC once daily were considerably lower and those following fesoterodine 4 mg BIC
once daily were generally similar to the concentrations following fesoterodine 4 mg tablet
once daily in Cohort 1.
Safety Results:
For Cohort 1 during the Active Comparator Phase, TEAEs were reported for 61.9% ofsubjects in the fesoterodine 4 mg arm, 47.6% of subjects in the fesoterodine 8 mg arm, and75.0% of subjects in the oxybutynin arm (Table S6). Serious AEs (SAEs), severe TEAEs,
and TEAEs leading to discontinuation from the study or from study drug were reported for
fewer than 10% of subjects in any treatment arm.
During the Active Comparator Phase, treatment-related TEAEs were reported for 28.6% ofsubjects in the fesoterodine 4 mg arm, 23.8% of subjects in the fesoterodine 8 mg arm, and37.5% of subjects in the oxybutynin arm. There were no treatment-related SAEs, andtreatment-related severe TEAEs were reported for 1 subject (2.4%) in the fesoterodine 4 mg
arm, no subjects in the fesoterodine 8 mg arm, and 2 subjects (5.0%) in the oxybutynin arm.

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Table S6. Treatment-Emergent AEs (All Causalities) - Safety Analysis Set (Active
Comparator Phase) - Cohort 1
Feso 4mg Feso 8mg

Oxybutynin

Number (%) of Subjects

n (%)

n (%)

n (%)

Subjects evaluable for adverse events

42

42

40

Number of adverse events

80

46

83

Subjects with adverse events

26 (61.9)

20 (47.6)

30 (75.0)

Subjects with serious adverse events

3 (7.1)2 (4.8)1 (2.5)

Subjects with severe adverse events

4 (9.5)

1 (2.4)3 (7.5)

Subjects discontinued from study due to adverse events (a)3 (7.1)

0

0

0

0

1 (2.5)2 (4.8)02 (5.0)Subjects discontinued study drug due to AE and continue Study (b)Subjects with dose reduced or temporary discontinuation due to adverse
eventsIncludes data up to 7 days after last dose of study drug for subjects who discontinued in the Active Comparator phase,otherwise for subjects continuing into the Safety
Phase, it includes data up to the last dose of study drug in the Active Comparator Phase.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but AE
did not Cause the Subject to be discontinued from Study
MedDRA v22.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 05MAR2020 (02:33) Source Data: ADAE Output File:./CDISC/A0221047/adae_s020_1 Date of Generation: 07APR2020 (15:00)
Table 14.3.1.2.1.1a is for Pfizer internal use.

Among subjects who received at least 1 dose of fesoterodine in both the Active Comparator
and Safety Extension Phases of Cohort 1, TEAEs were reported for 76.7% of subjects in the
fesoterodine 4 mg arm and 62.2% of subjects in the fesoterodine 8 mg arm (Table S7). The
incidence of SAEs in the fesoterodine 8 mg arm (10.8%) was numerically higher than in the
fesoterodine 4 mg arm (3.3%). The incidence of severe AEs was comparable acrossfesoterodine treatment arms, and 1 subject in the fesoterodine 8 mg arm discontinued fromthe study due to an AE.

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Among subjects who received at least 1 dose of fesoterodine in both the Active Comparator
and Safety Extension Phases of Cohort 1, treatment-related TEAEs were reported for 33.3%
of subjects in the fesoterodine 4 mg arm and 29.7% of subjects in the fesoterodine 8 mg arm.
There were no treatment-related SAEs or treatment-related TEAEs leading to discontinuationfrom the study or from study drug, and treatment-related severe TEAEs were infrequently
reported.

Table S7. Treatment-Emergent AEs (All Causalities) - Safety Analysis Set (Overall
Fesoterodine 24 Weeks) - Cohort 1
Feso 4mg

Feso 8mg

Number (%) of Subjects

n (%)

n (%)

Subjects evaluable for adverse events

30

37

Number of adverse events

78

62

Subjects with adverse events

23 (76.7)

23 (62.2)

Subjects with serious adverse events

1 (3.3)4 (10.8)

Subjects with severe adverse events

2 (6.7)2 (5.4)

Subjects discontinued from study due to adverse events (a)0

1 (2.7)

Subjects discontinued study drug due to AE and continue Study (b)00

1 (3.3)0Subjects with dose reduced or temporary discontinuation due to adverse events

Includes data up to 7 days after last dose of study drug.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but AE
did not Cause the Subject to be discontinued from Study
MedDRA v22.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 05MAR2020 (02:33) Source Data: ADAE Output File:./CDISC/A0221047/adae_s020_3 Date of Generation: 07APR2020 (15:03)
Table 14.3.1.2.1.3a is for Pfizer internal use.

For Cohort 2 during the Efficacy Phase, TEAEs were reported for 67.9% of subjects in the
fesoterodine 2 mg BIC arm and 62.1% of subjects in the fesoterodine 4 mg BIC arm(Table S8). The incidence of SAEs was comparable across both fesoterodine BIC treatment
arms, and severe TEAEs occurred infrequently. Three subjects discontinued from the study
due to TEAEs in the fesoterodine 2 mg BIC arm, whereas there were no discontinuations
from the study due to TEAEs in the fesoterodine 4 mg BIC arm.
During the Efficacy Phase, treatment-related TEAEs were reported for 32.1% of subjects inthe fesoterodine 2 mg BIC arm and 10.3% of subjects in the fesoterodine 4 mg BIC arm.
There were no treatment-related SAEs or treatment-related severe TEAEs. Treatment-related
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TEAEs leading to discontinuation from the study were reported for 2 subjects (7.1%) in the
fesoterodine 2 mg BIC arm.

Table S8. Treatment-Emergent AEs (All Causalities) - Safety Analysis Set (Efficacy
Phase) - Cohort 2
Fesoterodine 2mg BIC

Fesoterodine 4mg BIC

Number (%) of Subjects

n (%)

n (%)

Subjects evaluable for adverse events

28

29

Number of adverse events

40

39

Subjects with adverse events

19 (67.9)

18 (62.1)

Subjects with serious adverse events

2 (7.1)2 (6.9)Subjects with severe adverse events0

1 (3.4)3 (10.7)

0Subjects discontinued study drug due to AE and continue Study
(b)

0

0

Subjects with dose reduced or temporary discontinuation due toadverse events

1 (3.6)

1 (3.4)

Subjects discontinued from study due to adverse events (a)Includes data up to 7 days after last dose of study drug for subjects who discontinued in the efficacy phase, otherwise forsubjects continuing into the Safety Phase,
it includes data up to the last dose of study drug in the Efficacy Phase.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but AE
did not Cause the Subject to be discontinued from Study
MedDRA v22.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 03MAR2020 (05:43) Source Data: ADAE Output File:./CDISC/A0221047_CH2/adae_s020_1_c2 Date of Generation: 07APR2020 (10:45)
Table 14.3.1.2.1.1b is for Pfizer internal use.

For Cohort 2 during the overall study, TEAEs were reported for 75.0% of subjects in the
fesoterodine 2 mg BIC arm and 79.3% of subjects in the fesoterodine 4 mg BIC arm(Table S9). The incidence of severe TEAEs was low, and the incidence of SAEs wascomparable between the 2 treatment arms. Three subjects (10.7%) discontinued the study due
to TEAEs in the fesoterodine 2 mg BIC arm. The incidence of dose reduction or temporary
discontinuations (interruption) of study drug due to TEAEs was low in the 2 arms in
Cohort 2.
During the overall study, treatment-related TEAEs were reported for 32.1% of subjects in the
fesoterodine 2 mg BIC arm and 10.3% of subjects in the fesoterodine 4 mg BIC arm.

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Table S9. Treatment-Emergent AEs (All Causalities) - Safety Analysis Set (Overall)- Cohort 2
Fesoterodine 2mg BIC

Fesoterodine 4mg BIC

Number (%) of Subjects

n (%)

n (%)

Subjects evaluable for adverse events

28

29

Number of adverse events

58

58

Subjects with adverse events

21 (75.0)

23 (79.3)

Subjects with serious adverse events

2 (7.1)3 (10.3)

Subjects with severe adverse events0

1 (3.4)3 (10.7)

0Subjects discontinued study drug due to AE and continue Study
(b)

0

0

Subjects with dose reduced or temporary discontinuation due toadverse events

1 (3.6)

1 (3.4)

Subjects discontinued from study due to adverse events (a)Includes data up to 7 days after last dose of study drug.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study(b) Subjects who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but AE
did not Cause the Subject to be discontinued from Study
MedDRA v22.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 03MAR2020 (05:43) Source Data: ADAE Output File:./CDISC/A0221047_CH2/adae_s020_3_c2 Date of Generation: 07APR2020 (10:47)
Table 14.3.1.2.1.3b is for Pfizer internal use.



Tier 1 Treatment-Emergent Adverse Events:
For subjects in Cohort 1 during the Active Comparator Phase, the incidence of Dry
mouth was significantly higher in the oxybutynin arm (11 subjects [27.5%]) than in the
fesoterodine 4 mg (3 subjects [7.1%]) and fesoterodine 8 mg arms (4 subjects [9.5%])(p=0.0155 and p=0.0406, respectively). There was no significant difference in theincidence of any other reported Tier-1 TEAE between the oxybutynin arm and thefesoterodine arms.
For subjects in Cohort 2, the incidence of any reported Tier-1 TEAE was similar (95%
CIs for the risk difference included zero) between the fesoterodine 2 and 4 mg BIC arms
during the Efficacy Phase.

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Tier 2 Treatment-Emergent Adverse Events:
For subjects in Cohort 1 during the Active Comparator Phase, the incidence of Dry
mouth was numerically higher in the oxybutynin arm (11 subjects [27.5%]) than in the
fesoterodine 4 mg (3 subjects [7.1%]) and fesoterodine 8 mg arms (4 subjects [9.5%])(upper limit of the 95% CI for the risk difference was <0). The incidence of Urinary
incontinence was numerically higher in the oxybutynin arm (4 subjects [10.0%]) than in
the fesoterodine 8 mg arm (0 subjects) (upper limit of the 95% CI for the risk difference
was <0). In addition, the incidence of Viral upper respiratory tract infection was
numerically higher in the fesoterodine 4 mg arm (4 subjects [9.5%]) than in the
oxybutynin arm (0 subjects) (lower bound of the 95% CI for the risk difference was >0).
No TEAEs of Viral upper respiratory tract infection were reported in the fesoterodine
8 mg or oxybutynin arms during the Active Comparator Phase.
For subjects in Cohort 2, the incidence of any reported Tier-2 TEAE was similar (95%
CIs for the risk difference included zero) between the fesoterodine 2 and 4 mg BIC arms
during the Efficacy Phase.

Deaths: There were no deaths among subjects who participated in this study.

Serious Adverse Events:
For subjects in Cohort 1 during the Active Comparator Phase, UTI was the most common
SAE (all causality), reported for 1 subject each in the fesoterodine 4 mg and oxybutynin
treatment arms. All other preferred terms (PTs) were each reported for only 1 subject.
Among subjects who received at least 1 dose of fesoterodine in both the Active
Comparator and Safety Extension Phases of Cohort 1, the incidence of SAEs (allcausality) was low. All PTs were each reported for only 1 subject.
For Cohort 2 during the Efficacy Phase, UTI was the most common SAE (all causality),
reported for 1 subject in each treatment arm. All other PTs were each reported for only
1 subject.
For Cohort 2 during the overall study, UTI was the most common SAE (all causality),
reported for 1 subject in each treatment arm. All other PTs were each reported for only
1 subject.
No treatment-related SAEs were reported during the study.

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Clinical Laboratory Evaluations
While there were individual cases that exceeded the normal range for individuallaboratory parameters, there were no trends in occurrences of markedly abnormal
laboratory findings during the Active Comparator or Safety Extension Phases of
Cohort 1.
While there were individual cases that exceeded the normal range for individuallaboratory parameters, there were no trends in occurrences of markedly abnormal
laboratory findings during the Efficacy or Safety Extension Phases of Cohort 2.



Vital Signs
For Cohort 1, no clinically relevant changes from baseline were observed for vital sign
parameters in any of the treatments arms at the time points assessed. Increases frombaseline in mean pulse rate were observed in the fesoterodine treatment arms, with thehighest mean increase being 10.41 bpm at Week 4 of the Active Comparator Phase in the
fesoterodine 8 mg treatment arm, but by Week 24 this had trended downwards to a mean
increase of 6.54 bpm with a mean increase in the fesoterodine 4 mg arm of only
1.80 bpm. A mild TEAE of Heart rate increased was reported for 1 subject in the
fesoterodine 8 mg arm. The TEAE was considered related to study treatment by theinvestigator, and the subject completed the study.
For Cohort 2, no clinically relevant changes from baseline were observed for vital sign
parameters in the fesoterodine 2 or 4 mg BIC arms at the time points assessed. Increases
from baseline in mean pulse rate were observed in both fesoterodine treatment arms at
Week 4 in the Efficacy Phase with the highest mean increase being 5.36 bpm in the
fesoterodine 4 mg BIC arm, but by Week 24 there was no increase in mean pulse rate in
the fesoterodine 2 mg BIC arm and only a mean increase of 4.86 bpm in the fesoterodine
4 mg BIC arm. A mild TEAE of Heart rate increased was reported for 1 subject in the
fesoterodine 4 mg BIC arm. The TEAE was considered not related to study treatment by
the investigator, and the subject completed the study. A mild TEAE of Tachycardia thatwas considered related to study treatment by the investigator was reported for 1 subject in
the fesoterodine 2 mg BIC arm. The subject discontinued study drug and discontinued
from the study due to the TEAE.



Physical Examination
For Cohort 1, there was no clinically relevant difference in the incidence of changes frombaseline to Week 12 or Week 24 in physical examination findings between the treatment
arms.
For Cohort 2, there was no clinically relevant difference in the incidence of changes frombaseline to Week 12 or Week 24 in physical examination findings between the
fesoterodine 2 and 4 mg BIC arms.
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Visual Acuity and Accommodation
For Cohort 1, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in visual accommodation or visual acuity in either eye, for any of the treatment
arms.
For Cohort 2, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in visual accommodation or visual acuity in either eye, for either treatment arm.

Cognitive Function
For Cohort 1, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in the T score or 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 any of the treatment arms. There were no clinically relevant changes frombaseline to Week 12 or Week 24 in GPT results in either the dominant or non-dominant
hand for any of the treatment arms.
For Cohort 2, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in the T score or total score of any CBCL assessments for either treatment arm.
There were no clinically relevant changes from baseline to Week 12 or Week 24 in GPTresults in either the dominant or non-dominant hand for either treatment arm.



Post-Void Residual Volume
For Cohort 1, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in PVR volume for any of the treatment arms.
For Cohort 2, there were no clinically relevant changes from baseline to Week 12 or
Week 24 in PVR volume for either treatment arm.
PVR volume was only assessed for subjects not performing clean intermittent
catheterization, resulting in small sample sizes. Therefore, it is not possible to draw any
meaningful conclusions about the changes from baseline in PVR volume in this study.

Conclusions:
Efficacy
Cohort 1Treatment with fesoterodine 4 and 8 mg tablets resulted in significant improvements frombaseline to Week 12 in the primary efficacy endpoint, maximum cystometric bladdercapacity, for pediatric subjects with NDO aged 6 to 17 years weighing >25 kg, withPFIZER CONFIDENTIAL
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numerically higher changes from baseline for fesoterodine 8 mg than for fesoterodine
4 mg.



The improvement from baseline in the primary efficacy endpoint observed forfesoterodine 8 mg was of comparable magnitude to that of oxybutynin.

Of the 11 secondary efficacy endpoints that were formally analyzed, 5 endpoints
demonstrated significant improvements from baseline following treatment withfesoterodine 4 and 8 mg, whereas 7 demonstrated significant improvements from baseline
following treatment with oxybutynin.

Cohort 2Treatment with fesoterodine 2 and 4 mg BIC resulted in improvements from baseline to
Week 12 in the primary efficacy endpoint, maximum cystometric bladder capacity, forpediatric subjects with NDO aged 6 to 17 years weighing ≤25 kg, with numericallyhigher changes from baseline for fesoterodine 4 mg BIC than for fesoterodine 2 mg BIC.

Of the 11 secondary efficacy endpoints that were formally analyzed, 5 endpoints
demonstrated improvements from baseline following treatment with fesoterodine 4 mg
BIC.



Improvements from baseline were not demonstrated for any of the secondary efficacy
endpoints following treatment with fesoterodine 2 mg BIC.

SafetyCohort 1Treatment with fesoterodine 4 and 8 mg once daily for 12 weeks and for up to 24 weeks
was well tolerated in pediatric subjects with NDO aged 6 to 17 years weighing >25 kg.

There were no treatment-related SAEs and no deaths. Treatment-related TEAEs were
mostly of mild to moderate severity.



During the overall study for Cohort 1, the Infections and infestations system organ class(SOC) was the body system with the highest incidence of TEAEs. The most frequently
observed infections were upper respiratory tract infections of a nature commonly seen inchildren or UTIs to which children with NDO are susceptible. The majority of reported
infections were considered not to be related to study treatment by the investigators.



During the Active Comparator Phase and the overall study, the most common
treatment-related TEAEs were gastrointestinal disorders of Dry mouth, Constipation,
Diarrhea, and Abdominal pain, which are consistent with the known safety profile ofantimuscarinic agents when administered to adults.
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During the Active Comparator Phase, the incidence of Dry mouth was significantly
higher in the oxybutynin arm than in the fesoterodine 4 and 8 mg arms. There was no
significant difference in the incidence of any other reported Tier-1 TEAE between the
oxybutynin arm and the fesoterodine arms. Overall, there was a numerically higher
incidence of antimuscarinic effects in the oxybutynin arm compared with the fesoterodine
arms.



During the overall study, there were no TEAEs of seizures or somnolence and noclinically relevant changes were observed in cognitive function or behavior measured by
CBCL and GPT.

No clinically relevant changes were observed for visual acuity and accommodation, PVR
volume, vital signs, physical examinations, weight, or clinical laboratory tests for
Cohort 1 during the overall study.

Cohort 2Treatment with fesoterodine 2 and 4 mg BIC once daily for 12 weeks and for up to
24 weeks was well tolerated in pediatric subjects with NDO aged 6 to 17 years weighing≤25 kg.



There were no treatment-related SAEs and no deaths. Treatment-related TEAEs were of
mild to moderate severity.



During the Efficacy Phase and the overall study for Cohort 2, the Infections andinfestations SOC was the body system with the highest incidence of TEAEs. The mostfrequently observed infections were upper respiratory tract infections of a naturecommonly seen in children or UTIs to which children with NDO are susceptible. All
reported infections were considered not to be related to study treatment by theinvestigators.

In the study overall, the highest incidence of treatment-related TEAEs by body systemoccurred in the Gastrointestinal disorders SOC, which is consistent with the known safety
profile of antimuscarinic agents when administered to adults.



The only central nervous system TEAEs reported were headache and dizziness, which areboth consistent with the known safety profile in adults. There were no TEAEs of seizures
or somnolence, and no clinically relevant changes were observed in cognitive function or
behavior measured by CBCL or GPT.

No clinically relevant changes were observed for visual acuity and accommodation, PVR
volume, vital signs, physical examinations, weight, or clinical laboratory tests for
Cohort 2 during the overall study.

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Pharmacokinetics
The mean (%RSE) values of 5-HMT CL/F, Vd/F and Ka in pediatric subjects with NDO
aged 6 to 17 years are estimated to be 71.6 (6.7) L/hour, 68.1 (29.7) L, and
0.0897 (5.99)/hour, respectively.

Within each cohort of pediatric subjects with NDO aged 6 to 17 years, the individual andmean plasma 5-HMT concentrations following administration of fesoterodine 4 and 8 mg
tablets once daily (Cohort 1) and those following fesoterodine 2 and 4 mg BIC
formulation once daily (Cohort 2) increased in a proportion similar to the increment in
doses.

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