Clinical trial NCT03175029
Conditions: Detrusor Underactivity Overactive Bladder
Keywords: Lower Urinary Tract Symptoms
Sponsor: Taiho Pharmaceutical Co., Ltd.
Start date: 2017-09-09; Completion date: 2020-03-27
Enrollment: 195 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of TAC-302 in detrusor underactivity patients with overactive bladder.

Detailed description:
The main purpose of this study is to assess the efficacy of TAC-302 for 12 weeks in detrusor underactivity patients with overactive bladder by measuring the following parameters of pressure-flow study.

* Male; bladder contractility index (BCI)
* Female; projected isovolumetric pressure (PIP) 1

Arms: arm 1: None arm 2: None
Interventions: intervention 1: TAC-302 intervention 2: Placebo
Intervention descriptions: intervention 1: TAC-302 200 mg administered orally twice per day after meals, for 12 weeks. intervention 2: Placebo administered orally twice per day after meals, for 12 weeks.

Protocol documents:
Prot_000.pdf: 
1
A Phase 2a Study of TAC-302 in Detrusor Underactivity Patients with 
Overactive Bladder
TAC-302 [test product]
Protocol Number:
Issue Date:
Amendment Date:
10054040 Ver.P02
April 14, 2017
September 19, 2018
Sponsor:
Taiho Pharmaceutical Co., Ltd.
1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan
This clinical study will be conducted in accordance with the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Good 
Clinical Practice (GCP) Guidelines and applicable regulatory requirements in Japan.
CONFIDENTIAL
The information contained in this protocol is the confidential information owned by Taiho 
Pharmaceutical Co., Ltd. None of the information may be published or disclosed without 
the written approval of Taiho Pharmaceutical Co., Ltd., except when requested by 
competent authorities or when it is necessary to obtain informed consent from persons 
who are considering participation in this study.


2
TABLE OF CONTENTS
TABLE OF CONTENTS ................................................................................................2
SYNOPSIS......................................................................................................................10
1.
BACKGROUND INFORMATION......................................................................25
1.1
Introduction ....................................................................................................25
1.2
TAC-302 [test product] ..................................................................................28
1.2.1
Mechanism of Action...........................................................................28
1.3
Placebo [Comparator].....................................................................................28
1.4
Benefit-Risk Overview...................................................................................28
1.4.1
TAC-302...............................................................................................28
1.4.1.1
Potential Benefits .......................................................................28
1.4.1.2
Potential Safety Risks.................................................................29
1.4.2
Benefits and Risks Expected in This Study .........................................30
1.5
Main Study Results ........................................................................................30
1.5.1
Nonclinical Studies ..............................................................................30
1.5.2
Clinical Studies ....................................................................................30
1.5.2.1
Phase 1 Single-dose Study (Study 10054010) ...........................30
1.5.2.2
Phase 1 Repeated-dose Study (Study 10054020).......................31
1.6
Justification of Study Population and Study Design......................................33
1.6.1
Study Population ..................................................................................33
1.6.2
Study Design ........................................................................................33
1.6.3
TAC-302 Dose .....................................................................................34
1.6.4
Selection of Placebo.............................................................................34
2.
STUDY OBJECTIVES..........................................................................................35
2.1
Primary Objective ..........................................................................................35
2.2
Secondary Objectives.....................................................................................35
2.3
Endpoints........................................................................................................35
2.3.1
Primary Endpoint .................................................................................35
2.3.2
Secondary Endpoints............................................................................35
2.3.2.1
Efficacy ......................................................................................35
2.3.2.2
Safety..........................................................................................36
3.
STUDY DESIGN....................................................................................................37
3.1
Study Period ...................................................................................................37
3.1.1
Definition of Each Period for Each Patient..........................................37
3.2
Patient Assignment and Blinding...................................................................38
3.2.1
Method of Assignment.........................................................................38
3.2.2
Blinding................................................................................................39
4.
SELECTION AND WITHDRAWAL OF PATIENTS.......................................40
4.1
Inclusion Criteria............................................................................................40
4.1.1
Registration in the Observation Period ................................................40


3
4.1.2
Registration in the Treatment Period ...................................................40
4.2
Exclusion Criteria...........................................................................................41
4.2.1
Registration in the Observation Period ................................................41
4.2.2
Registration in the Treatment Period ...................................................43
4.3
Discontinuation Criteria for Individual Patients ............................................44
5.
STUDY ASSESSMENTS.......................................................................................45
5.1
Study Procedures............................................................................................50
5.1.1
Obtaining informed consent.................................................................50
5.1.2
Assigning of Patient Identification Codes............................................50
5.1.3
Patient backgrounds .............................................................................50
5.1.4
Physical examination............................................................................50
5.1.5
Blood Pressure (Systolic and Diastolic), Pulse Rate, Body Temperature
..............................................................................................................50
5.1.6
Compliance with administration of the investigational drug ...............50
5.1.7
Concomitant medication and concomitant therapy..............................50
5.1.8
12-lead electrocardiography.................................................................51
5.1.9
Laboratory Values................................................................................51
5.1.10
Pregnancy Test .....................................................................................51
5.1.11
Symptom Score Evaluation (IPSS, OABSS) .......................................51
5.1.12
King’s Health Questionnaire (KHQ)....................................................51
5.1.13
Bladder diary records ...........................................................................51
5.1.14
Pressure Flow Study (PFS) ..................................................................51
5.1.15
Uroflowmetry.......................................................................................51
5.1.16
Post void residual measured by ultrasound..........................................52
5.1.17
Prostate gland volume measurement....................................................52
5.1.18
Evaluation of adverse events................................................................52
5.2
Evaluations and Examination Items at Each Visit .........................................52
6.
INVESTIGATIONAL PRODUCTS.....................................................................53
6.1
Name, etc. of Investigational Products...........................................................53
6.2
Packaging and Labeling of Investigational Products .....................................53
6.3
Control of Investigational Products................................................................54
6.4
Instructions on the Handling of Investigational Product for Patients ............54
6.5
Implementation of Assignment Confirmation Test........................................54
7.
ADMINISTRATION METHOD ..........................................................................55
7.1
Administration Procedure ..............................................................................55
7.1.1
Method of Administration....................................................................55
7.1.1.1
Observation period .....................................................................55
7.1.1.2
Treatment period ........................................................................55
7.2
Restrictions.....................................................................................................56
7.2.1
Contraception .......................................................................................56


4
7.3
Concomitant medication and concomitant therapy........................................56
7.3.1
Prohibited Concomitant Drugs.............................................................56
7.3.2
Prohibited Concomitant Therapy .........................................................57
8.
PHARMACOKINETICS/PHARMACODYNAMICS .......................................58
9.
PHARMACOGENOMICS....................................................................................58
10. DISCONTINUATION/TERMINATION OF STUDY .......................................59
10.1
Criteria for Discontinuation of the Study at Study Sites................................59
10.2
Criteria for Discontinuation of the Entire Study ............................................59
11. EFFICACY EVALUATIONS...............................................................................60
11.1
Pressure Flow Study (PFS) ............................................................................60
11.2
Uroflowmetry.................................................................................................60
11.3
Symptom score evaluation .............................................................................60
11.3.1
IPSS and QOL Scores ..........................................................................60
11.3.2
Overactive Bladder Symptom Score (OABSS) ...................................61
11.4
King’s health questionnaire (KHQ) ...............................................................61
11.5
Bladder diary records .....................................................................................62
12. SAFETY EVALUATIONS....................................................................................63
12.1
Adverse Events...............................................................................................63
12.1.1
Definitions of Adverse Events .............................................................63
12.1.2
Severity of Adverse Events..................................................................63
12.1.3
Causal Relationship with Investigational Product ...............................64
12.1.4
Outcome of Adverse Events.................................................................64
12.1.5
Reporting of Adverse Events ...............................................................65
12.1.6
Follow-up of Adverse Events...............................................................65
12.2
Serious Adverse Events..................................................................................65
12.2.1
Definitions of Serious Adverse Events ................................................65
12.2.2
Reporting of Serious Adverse Events ..................................................66
12.2.3
Follow-up of Serious Adverse Events..................................................67
12.2.4
Expectedness to Investigational Product..............................................67
12.3
Adverse Events of Special Interest.................................................................67
12.3.1
Definition of Adverse Events of Special Interest.................................67
12.4
Adverse Reactions..........................................................................................67
12.4.1
Definition of Adverse Reactions..........................................................67
12.5
Other Information...........................................................................................68
12.5.1
Pregnancy.............................................................................................68
12.5.2
Medication Errors.................................................................................68
13. STATISTICAL CONSIDERATIONS..................................................................69
13.1
Analysis Plan..................................................................................................69
13.1.1
Timing of Statistical Analysis..............................................................69
13.1.2
Analysis Sets and Criteria for Handling Patient Data..........................69


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13.1.2.1
Analysis set ................................................................................69
13.1.2.2
Criteria for Handling Patient Data .............................................70
13.1.3
Methods of Statistical Analysis............................................................70
13.1.3.1
Patient Disposition and Patient Backgrounds ............................70
13.1.3.2
Analysis of the Primary Endpoint ..............................................71
13.1.3.3
Analysis of Secondary Endpoints ..............................................71
13.1.4
Target Sample Size and Rationale for the Sample Size.......................74
14. RATIONALES .......................................................................................................75
14.1
Rationale for the Endpoints............................................................................75
14.2
Rationale for the Method of Administration..................................................75
14.3
Rationale for the Inclusion/Exclusion Criteria...............................................75
14.3.1
Rationale for the Inclusion Criteria......................................................75
14.3.1.1
Registration in the Observation Period ......................................75
14.3.1.2
Registration in the Treatment Period .........................................76
14.3.2
Rationale for the Exclusion Criteria.....................................................76
14.3.2.1
Registration in the Observation Period ......................................76
14.3.2.2
Registration in the Treatment Period .........................................76
14.4
Rationale for Prohibited Concomitant Medications.......................................76
14.5
Rationale for Prohibited Concomitant Therapies...........................................77
14.6
Rationale for the Contraception Period..........................................................77
15. CASE REPORT FORMS ......................................................................................78
15.1
eCRF Documentation.....................................................................................78
15.2
eCRF Completion Instructions.......................................................................78
16. PROTOCOL COMPLIANCE, DEVIATIONS, AND AMENDMENTS..........80
16.1
Protocol Compliance......................................................................................80
16.2
Protocol Deviations........................................................................................80
16.3
Protocol Amendments....................................................................................80
17. Access to Source Data/Documents........................................................................81
17.1
Source Data/Documents.................................................................................81
17.2
Direct Access..................................................................................................81
18. QUALITY CONTROL AND QUALITY ASSURANCE IN THE STUDY......82
18.1
Quality Control in the Study ..........................................................................82
18.2
Sponsor’s Auditing and Regulatory Inspection .............................................82
19. DATA HANDLING AND RECORD KEEPING ................................................83
19.1
Handling of Data ............................................................................................83
19.2
Retention of Records......................................................................................83
19.2.1
Principal Investigator and Study Site...................................................83
19.2.2
Sponsor.................................................................................................83
20. COMPENSATION FOR HEALTH INJURY .....................................................84
21. PUBLICATION AND SECONDARY USE OF DATA......................................85


6
21.1
Publication......................................................................................................85
21.2
Secondary Use of Data...................................................................................85
22. ETHICS...................................................................................................................86
22.1
Ethical Conduct of the Study .........................................................................86
22.2
Approval by the Institutional Review Board..................................................86
22.3
Procedure for Obtaining Informed Consent...................................................86
23. STUDY ADMINISTRATIVE STRUCTURE......................................................87
24. REFERENCES.......................................................................................................88
25. APPENDICES ........................................................................................................90
Appendix 1
International Prostate Symptom Score (IPSS) and QOL scores ..........90
Appendix 2
Overactive Bladder Symptom Score (OABSS) ...................................91
Appendix 3
King’s Health Questionnaire: KHQ .....................................................92


7
List of Figures
Figure 3-1  Study Design......................................................................................................42
List of Tables
Table 5-1  Evaluations and Examination Items....................................................................51
Table 5-2  Observation and Testing Schedule......................................................................53
Table 6.1-1  Overview of TAC-302 [Test Product] .............................................................58
Table 6.1-2  Overview of Placebo [Comparator] .................................................................58
Table 7.1.1.1-1  Number of Investigational Drug Capsules Per Dose .................................60
Table 7.1.1.2-1  Number of Investigational Drug Capsules Per Dose .................................60
Table 11.3.1-1  IPSS Definition ...........................................................................................66
Table 13.1.2.1-1  Definition of Analysis Sets ......................................................................74


8
LIST OF ABBREVIATIONS
Term
Definition
ACTH
adrenocorticotrophic hormone
A/G
albumin/globulin ratio
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC0-t
area under the plasma concentration-time curve from time zero to t 
(where t = the final time of detection)
BCI
bladder contractility index
BMI
body mass index
BOO
bladder outlet obstruction
BUN
blood urea nitrogen
BVE
bladder voiding efficiency
Cmax
maximum plasma concentration
CRP
C-reactive protein
DU
detrusor underactivity
eCRF
electronic case report form
EDC
electronic data capture
FAS
full analysis set
free T3
free triiodothyronine
free T4
free thyroxine
GCP
Good Clinical Practice
γ-GTP
γ-glutamyltranspeptidase
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IPSS
International Prostate Symptom Score
IRB
institutional review board
IWRS
Interactive Web Response System
KHQ
King's Health Questionnaire
LDH
lactate dehydrogenase
LUTD
lower urinary tract dysfunction
LUTS
lower urinary tract symptoms
NAG
N-acetyl-β-D-glucosaminidase
OAB
overactive bladder
OABSS
overactive bladder symptom score
PFS
pressure flow study
PIP
projected isovolumetric pressure
PPS
per protocol set
free Qave
Average flow rate in uroflowmetry


9
Term
Definition
free Qmax
Maximum flow rate in uroflowmetry
QOL
quality of life
QTcF
QT corrected for heart rate by Fridericia’s formula
SOP
standard operating procedure
TAC-302
 
 
T-Bil
total bilirubin
ULN
upper limit of normal
TSH
thyroid stimulating hormone
UAB
underactive bladder


10
SYNOPSIS
Sponsor:
Taiho Pharmaceutical Co., Ltd.
Test product:
TAC-302
Generic name
-
Title of Study: A Phase 2a Study of TAC-302 in Detrusor Underactivity Patients with 
Overactive Bladder
Protocol Number:
10054040
Phase of Development:
Phase 2a
Indication:
Lower urinary tract symptoms (storage, voiding, and post-
micturition symptoms) in detrusor underactivity and overactive 
bladder
Background/Rationale:
The lower urinary tract, which consists of the bladder and 
urethra, has a urine storage function, involving the storage of 
urine in the bladder, and a voiding function, involving the 
excretion of the stored urine. The general term for a condition 
where the urine storage function and urination function are 
impaired (storage disorder and urination disorder) is lower 
urinary tract dysfunction (LUTD). Symptoms caused by LUTD 
are called lower urinary tract symptoms (LUTS), which are 
classified into “storage symptoms,” “voiding symptoms,” and 
“post-micturition symptoms.” Each of these symptoms is a 
problem that greatly affects the patients’ activities of daily life 
and markedly impairs their quality of life (QOL). Recent 
clinical and basic research data have suggested that partial 
denervation of lower urinary tract organ tissues induced by 
various factors is importantly involved in the progression of 
impaired urinary function and serves as a key to the treatment 
of LUTS.
 
 
 
 
 
 
 
 
 
 
 


11
 
 
 
 
 
 
 
Based on the background/rationale above, a phase 2a study in 
detrusor underactivity patients with overactive bladder has 
been planned to evaluate the efficacy of TAC-302 in these 
patients.
Study 
Objectives/Endpoints:
Primary Objective:
To investigate the efficacy of TAC-302 in detrusor 
underactivity (DU) patients with overactive bladder (OAB), 
using evaluation of the bladder contractility index (BCI) 
(males) or projected isovolumetric pressure (PIP) 1 (females) at 
each time point as an indicator.
Secondary Objectives:
•
To investigate the efficacy of TAC-302 in DU patients 
with OAB, using the changes in values including pressure 
flow study (PFS) parameters, uroflowmetry parameters, 
bladder voiding efficiency (BVE), the international 
prostate symptom score (IPSS) or the overactive bladder 
symptom score (OABSS) as indicators.
•
To investigate the efficacy of TAC-302 in DU patients 
with OAB in comparison with placebo.
•
To investigate the safety of TAC-302 in DU patients with 
OAB, using data including the incidence of adverse events 
and adverse reactions as indicators.
Primary Endpoints:
•
BCI [maximum detrusor pressure at peak urine flow 
(PdetQmax) + 5 × peak urine flow rate (Qmax)] (males)
•
PIP1 (PdetQmax + Qmax) (females)
[Evaluation time points: week 0, week 12]
Secondary Endpoints:
•
PFS parameters (filling phase)
•
PFS parameters (voiding phase)
•
Uroflowmetry parameters
•
Post void residual measured by ultrasonography


12
•
BVE [voided volume / (voided volume + post void 
residual)]
•
IPSS
•
OABSS
•
Bladder diary record data
•
King’s health questionnaire (KHQ)
•
Occurrence of adverse events and adverse reactions
Study Design:
This study is a central-registration, multi-center, double-blind, 
placebo-controlled, randomized parallel-group comparative 
study to investigate the efficacy and safety of TAC-302 in DU 
patients with OAB. The design of this study is shown in the 
figure below. This study is composed of a single-blind 
observation period, a double-blind treatment period, and a 
follow-up period. In the observation period, the investigational 
drug (placebo) will be administered orally twice daily after 
breakfast and dinner for 2 to 4 weeks. The investigational drug 
in the treatment period will be randomly assigned, with patients 
allocated to the TAC-302 and placebo group in a 2:1 ratio. In 
the treatment period, the investigational drug (TAC-302 
200 mg or placebo) will be administered orally twice daily after 
breakfast and dinner for 12 weeks. After the start of the 
treatment period (registration in the treatment period), patients 
will make visits in weeks 2, 4, 8, and 12, and the designated 
observations and tests will be performed. A follow-up 
examination will be performed 1 week after the visit in week 
12 of the treatment period.
Figure  Study Design
Implementation Status:
Study completion date (planned): December 2019
Country: Japan
Planned Number of 
Patients:
In this study, 75 patients (48 men and 27 women) will be 
registered in the treatment period by central registration.
Patient Eligibility:
Inclusion criteria at registration in the observation period:
(1) Provided written informed consent in person
(Visit)
(Registration)
(Timing)
(Drug)
(Pressure flow 
study)
Registration in 
the observation 
period
Registration in
the treatment period
Randomization
Observation period (single-blind)
Placebo BID (p.o.)
Follow-up 
examination
Follow-up period
Placebo BID (p.o.)
Treatment period (double-blind)


13
(2) Aged ≥ 20 years at the time of obtaining informed consent 
and able to receive treatment as an outpatient (irrespective 
of sex)
(3) Being able to use the toilet himself/herself and make 
accurate bladder diary records, in the opinion of the 
principal investigator or subinvestigator
(4) Having had lower urinary tract symptoms (storage 
symptoms, voiding symptoms, and post-micturition 
symptoms) for at least 12 weeks before registration in the 
observation period
(5) Scoring ≥ 2 points on any of the following questions for 
the IPSS voiding symptoms score at registration in the 
observation period
•
Over the past month, how often have you found you 
stopped and started again several times when you 
urinated?
•
Over the past month, how often have you had a weak 
urinary stream?
•
Over the past month, how often have you had a push 
or strain to begin urination?
(6) Scoring ≥ 2 points for the urinary urgency score (Question 
3), and having an OABSS total score of ≥ 3 points in 
OABSS evaluation at registration in the observation period
•
Question 3: How often do you have a sudden desire to 
urinate, which is difficult to defer?
(7) Post void residual ≤ 300 mL measured at registration in the 
observation period
Inclusion criteria at registration in the treatment period:
(1) Scoring ≥ 2 points on any of the following questions for 
the IPSS voiding symptoms score at registration in the 
observation period
•
Over the past month, how often have you found you 
stopped and started again several times when you 
urinated?
•
Over the past month, how often have you had a weak 
urinary stream?
•
Over the past month, how often have you had a push 
or strain to begin urination?


14
(2) Meeting all of the following conditions based on 
information from bladder diary records in the 3 days 
directly before registration in the treatment period
1)
Being able to use the toilet himself/herself and make 
accurate bladder diary records, in the opinion of the 
principal investigator or subinvestigator
2)
An average of ≥ 8 urinations per 24 hours and meeting 
either of the following conditions
•
An average of ≥ 1 urinary urgency episodes per 24 
hours
•
An average of ≥ 1 urgency urinary incontinence 
episode per 24 hours
(3) Post void residual ≤ 300 mL measured at registration in the 
treatment period
(4) Meeting the following criteria based on a urodynamic 
study (UDS) performed at registration in the treatment 
period
[a, b: Calculated from PFS parameters, c: Calculated from 
uroflowmetry parameters and the measurement of the post 
void residual according to ultrasound]
1)
Criteria for males
a)
BCI (PdetQmax+5Qmax) < 100
b)
Bladder outlet obstruction index 
(BOOI=PdetQmax−2Qmax) < 40
c)
BVE [voided volume / (voided volume + post 
void residual)] < 90%
2)
Criteria for females
a)
PdetQmax < 20
b)
Qmax < 15
c)
BVE [voided volume / (voided volume + post 
void residual)] < 90%
Exclusion criteria at registration in the observation period:
(1) Having the following concurrent or historical conditions, 
and having been diagnosed with neurogenic bladder 
accompanied by obvious neurological abnormality 
associated with the following diseases
1)
Cerebrovascular disorder (cerebral hemorrhage, 
cerebral infarction, etc.)
2)
Parkinson’s disease


15
3)
Alzheimer’s disease
4)
Multiple sclerosis
5)
Spina bifida
6)
Spinal cord disorder (spinal cord injury, etc.)
(2) Concurrent urinary tract infection (prostatitis, cystitis, etc.) 
or historical recurrent urinary tract infection [occurring ≥ 3 
times within a period of 168 days (24 weeks) before 
registration in the observation period]. Concurrent urinary 
disease impairing determination of the effect of the 
investigational drug, such as cystitis interstitial, urinary 
tract stenosis, urinary tract obstruction, calculus urinary 
(calculus ureteric, calculus urethral, calculus bladder, etc.), 
benign tumor of the urethra (urethral polyp, cyst, 
papilloma, etc.) and urethral diverticulum.
(3) Concurrent bladder cancer or prostate cancer, or suspected 
bladder cancer or prostate cancer, or a history of these
(4) Cystocele classified as stage III or higher according to the 
pelvic organ prolapse quantification (POP-Q) stage 
classification (females)
(5) Prostate gland volume ≥ 30 mL (males)
(6) Overflow urinary incontinence
(7) Clinically significant concurrent conditions (including 
symptoms and findings) such as severe liver disease 
(hepatitis viral, drug-induced liver injury, etc.), severe 
renal disease (acute renal failure, glomerulonephritis, 
nephritis interstitial, etc.), severe cardiovascular disease 
(cardiac failure congestive, symptomatic unstable angina 
pectoris, poorly controlled arrhythmia, myocardial 
infarction, etc.), severe blood dyscrasia (pancytopenia, 
leukopenia, etc.), severe respiratory disease (bronchial 
asthma, bronchitis chronic, etc.), severe digestive disease 
(peptic ulcer, reflux esophagitis, Crohn’s disease, colitis 
ulcerative, etc.), severe neuropsychiatric disease 
(schizophrenia, dementia, etc.), severe immune disease 
(collagen disorder, etc.), severe metabolic or endocrine 
disease or malignant tumor
(8) Having received urethral catheter placement, or performing 
intermittent self-catheterization due to the inability to 
urinate spontaneously


16
(9) Meeting the following conditions at laboratory tests 
performed in the period of 14 days before registration in 
the observation period
1)
Aspartate aminotransferase (AST) > 3 × upper limit of 
normal (ULN)
2)
Alanine aminotransferase (ALT) > 3 × ULN
3)
Total bilirubin (T-Bil) > 1.5 × ULN
4)
Serum creatinine > 1.5 × ULN
(10)The following have been performed in the period of 154 
days (22 weeks) before registration in the observation 
period.
1)
Surgery of the pelvic organs (radical hysterectomy, 
radical surgery for rectal cancer, radical pelvic lymph 
node dissection, etc.) injuring the pelvic nerve or 
hypogastric nerve
2)
Prostatectomy
3)
Radiotherapy that may affect voiding function
(11)Having received another investigational drug in the period 
of 90 days before registration in the observation period
(12)Being pregnant, breastfeeding, or a female patient of 
childbearing potential with a positive (urine or serum) 
pregnancy test result in the period of 7 days before 
registration in the observation period
Note) Women without childbearing potential are women 
who have undergone hysterectomy and 
postmenopausal women who have not experienced 
menstruation for at least 1 year with no associated 
medical reason such as administration of 
contraceptives
(13)In the case of women with reproductive potential, not 
consenting to use contraception during the study period 
and for a period of 30 days after the end of administration 
of the investigational drug*
(14)In the case of male patients, not consenting to use 
contraception during the study period and for a period of 
90 days after the end of administration of the 
investigational drug*
(15)Being determined to be ineligible for this study in the 
opinion of the principal investigator or subinvestigator
*
The principal investigator or subinvestigator will instruct patients to always 
perform contraception using a method such as the double-barrier method (a 


17
condom and pessary), an intrauterine device or oral contraceptives during 
the period of administration of the investigational drug and the period of 
contraception after the end of administration of the investigational drug.
Exclusion criteria at registration in the treatment period:
(1) A rate of compliance with administration of the 
investigational drug of < 80% in the observation period
(2) Having the following concurrent conditions, and having 
been diagnosed with neurogenic bladder accompanied by 
obvious neurological abnormality associated with the 
following diseases
1)
Cerebrovascular disorder (cerebral hemorrhage, 
cerebral infarction, etc.)
2)
Parkinson’s disease
3)
Alzheimer’s disease
4)
Multiple sclerosis
5)
Spina bifida
6)
Spinal cord disorder (spinal cord injury, etc.)
(3) Concurrent urinary disease impairing determination of the 
effect of the investigational drug, such as urinary tract 
infection (prostatitis, cystitis, etc.), cystitis interstitial, 
stenosis, urinary tract obstruction, calculus urinary 
(calculus ureteric, calculus urethral, calculus bladder, etc.), 
benign tumor of the urethra (urethral polyp, cyst, 
papilloma, etc.) and urethral diverticulum.
(4) Concurrent bladder cancer or prostate cancer, or suspected 
bladder cancer or prostate cancer
(5) Cystocele classified as stage III or higher according to the 
POP-Q stage classification (females)
(6) Overflow urinary incontinence
(7) Clinically significant concurrent conditions (including 
symptoms and findings) such as severe liver disease 
(hepatitis viral, drug-induced liver injury, etc.), severe 
renal disease (acute renal failure, glomerulonephritis, 
nephritis interstitial, etc.), severe cardiovascular disease 
(cardiac failure congestive, symptomatic unstable angina 
pectoris, poorly controlled arrhythmia, myocardial 
infarction, etc.), severe blood dyscrasia (pancytopenia, 
leukopenia, etc.), severe respiratory disease (bronchial 
asthma, bronchitis chronic, etc.), severe digestive disease 
(peptic ulcer, reflux esophagitis, Crohn’s disease, colitis 
ulcerative, etc.), severe neuropsychiatric disease 


18
(schizophrenia, dementia, etc.), severe immune disease 
(collagen disorder, etc.), severe metabolic or endocrine 
disease or malignant tumor
(8) Having received urethral catheter placement, or performing 
intermittent self-catheterization due to the inability to 
urinate spontaneously
(9) Being determined to be ineligible for this study in the 
opinion of the principal investigator or subinvestigator
Method of 
Administration:
Observation period:
Placebo will be administered orally twice daily after breakfast 
and dinner for 2 to 4 weeks.
Treatment period:
TAC-302 200 mg or placebo will be administered orally twice 
daily after breakfast and dinner for 12 weeks.
Study Period:
Study Period:
From the time of obtaining informed consent to the end of the 
follow-up examination
Observation period:
From the time of registration in the observation period to the 
registration in the treatment period (registration in the treatment 
period will be performed between 2 to 4 weeks after 
registration in the observation period)
Treatment period:
From the time of registration in the treatment period to the end 
of week 12 of the treatment period
Follow-up period:
From the end of week 12 of the treatment period to the end of 
the follow-up examination (performed 1 week after the end of 
week 12 of the treatment period)
Analytical Methods:
Analysis sets:
The definitions of the analysis sets in this study are as follows.
Analysis set
Definition
Screening patients
The set of all patients who 
provided informed consent
All enrolled patients in 
the observation period
The set of all patients who were 
enrolled in the observation period
All enrolled patients in 
the treatment period
The set of all patients who were 
enrolled in the treatment period


19
All treated patients in 
the observation period
The set of patients enrolled in the 
observation period who took the 
investigational drug at least once
All treated patients in 
the treatment period
The set of patients enrolled in the 
treatment period who took the 
investigational drug at least once
Full analysis set
(FAS)
The set of patients enrolled in the 
treatment period who took the 
investigational drug for the 
treatment period at least once and 
who had at least 1 efficacy 
endpoint measurement before the 
start of the treatment period and 
in the treatment period
Per protocol set
(PPS)
The set of patients in the full 
analysis set (FAS), excluding 
patients who met any of the 
following criteria:
(1) Being discovered to have a 
violation of the inclusion 
criteria
(2) Being discovered to meet any 
of the exclusion criteria 
(criteria affecting efficacy 
evaluation)
(3) A compliance rate for the 
treatment period of < 80%
(4) Being administered 
prohibited concomitant drugs 
or prohibited concomitant 
therapy considered likely to 
influence efficacy evaluation
(5) No evaluation of the primary 
endpoint at week 12 of the 
treatment period
Primary Endpoints:
The primary endpoint, BCI (males) or PIP1 (females), will be 
analyzed as follows.
(1)
Primary analysis


20
-
Summary statistics and 95% confidence intervals 
at each evaluation time point will be calculated by 
group in the per protocol set (PPS).
(2)
Sensitivity analysis of the primary analysis
-
(1) will be evaluated in the FAS.
(3)
Secondary analysis of the primary endpoint
The following analysis will be performed in the FAS 
and PPS.
-
Time course plots at each evaluation time point 
will be prepared by group.
-
Paired t-tests for the values at baseline (week 0) 
and week 12 of the treatment period will be 
performed by group.
-
Summary statistics and 95% confidence intervals 
for the change and percentage change at week 12 
of the treatment period relative to baseline (week 
0) will be calculated by group.
-
The treatment effect in the TAC-302 group 
relative to the placebo group will be estimated 
using model analysis of the change and percentage 
change at week 12 of the treatment period relative 
to baseline (week 0).
Justification for the 
Sample Size:
 
 
 


21
Table 1  Evaluations and Examination Items
Obtaining informed consent
Date of obtaining informed consent
Patient backgrounds
Sex
Date of birth
Age*1
Race
Height
Weight
BMI*2
History of participation in clinical 
studies (within the past 90 days)
Medical history (within the past 
180 days)*3
Onset time of lower urinary tract symptoms (LUTS) (storage symptoms, voiding symptoms, and post-micturition 
symptoms)
Concurrent conditions
History of prior treatment
Patient registration
Patient identification code
Drug number
Symptoms and findings
Blood pressure (systolic and 
diastolic)
Pulse rate
Body temperature
Compliance with administration of the investigational drug
Concomitant medication and concomitant therapy
12-lead electrocardiography
Heart rate
QT interval
RR interval
QTcF interval*4
Hematology tests
Red blood cell count
Hemoglobin
Hematocrit
Platelet count
White blood cell count
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Biochemistry tests
Total protein
Albumin
A/G
T-Bil
Direct bilirubin
AST(GOT)
ALT(GPT)
ALP
LDH
γ-GTP
BUN
Creatinine
Creatine kinase
Blood glucose
Amylase
Triglycerides
Total cholesterol
CRP
Na
K
Cl
Ca*5
Endocrinological tests
Thyroid stimulating hormone 
(TSH)
free T3
free T4
Cortisol
Adrenocorticotropic hormone (ACTH)
Urinalysis
Protein
Glucose
Urobilinogen
Urine NAG
Urine β2-microglobulin
Urine sediment*6
Pregnancy test*7
Serum or urine human chorionic gonadotropin
Prostate gland volume measurement
PFS (filling phase)
Volume at first desire to void
Maximum bladder volume
Bladder compliance
Appearance of bladder 
involuntary contraction
Bladder volume up to appearance of bladder involuntary 
contraction
PFS (voiding phase)
BCI (PdetQmax + 5Qmax): males
PIP1 (PdetQmax + Qmax): females
Detrusor pressure at maximum flow (PdetQmax)
Detrusor pressure at start of voiding (Pdet open)
Maximum detrusor pressure (Pdet max)
Maximum flow rate (Qmax)
Average flow rate (Qave)
Duration of bladder contraction
Voided volume
Post void residual
Uroflowmetry
Maximum flow rate (free 
Qmax)
Average flow rate (free Qave)
Voided volume
Voiding time
Post void residual measured by ultrasound
BVE [voided volume/(voided volume + post void residual)]
Post void residual measured by ultrasound and voided volume measured by uroflowmetry
Symptom score evaluation
IPSS
OABSS
QOL score evaluation
KHQ
Bladder diary records
Dates and times of voiding 
and urinary incontinence
Urinary urgency
Voided volume
Evaluation of adverse events
*1: Automatically calculated from the date of birth.  *2: Automatically calculated from height and weight.
*3: This is a medical history determined by the principal investigator or subinvestigator to be important in the conduct of this study (such as 
diseases related to urinary organs).
*4: Automatically calculated from the QT interval and RR interval.
*5: In the evaluation of adverse events, if albumin is < 4.0 g/dL, determinations will be made using values corrected by the following 
formula.
[Corrected calcium (mg/dL)] = [calcium (mg/dL)] – 0.8 × {[albumin (g/dL)] – 4}


22
*6: Urine sediment will only be examined at registration in the observation period and registration in the treatment period.
*7: Required for female patients with childbearing potential. However, a pregnancy test will not be required for patients more than 1 year 
after menopause or patients in whom the possibility of pregnancy is medically ruled out.




24
1)
Obtaining informed consent: Obtained within the period of 28 days before registration in the observation period.
2)
Assigning of patient identification codes: Assigned to patients providing informed consent.
3)
Laboratory tests: Hematology tests, biochemistry tests, endocrinological tests and urinalysis will be performed. However, the urinalysis test urine sediment will only be performed at registration in 
the observation period and at registration in the treatment period.
4)
Pregnancy tests: Required for female patients with childbearing potential. However, a pregnancy test will not be required for patients more than 1 year after menopause or patients in whom the 
possibility of pregnancy is medically ruled out. At tests before registration in the observation period, pregnancy tests (serum or urine) must be negative. The time window for performing the test is 
the period of 7 days before registration in the observation period.
5)
Time window for registration in the treatment period: All observation and examination items at registration in the treatment period will be performed by registration in the treatment period, 2 to 4 
weeks after registration in the observation period.
6)
Time window for visits in the treatment period: Visits at weeks 2, 4, and 8 of the treatment periods will be allowed to be within the range of the standard date ±3 days. The visit at week 12 will be 
allowed to be within the range of the standard date −3 days to the standard date +7 days.
7)
Time window for the follow-up examination: This will be performed 1 to 2 weeks after the end of week 12 of the treatment period. If the patient discontinued during the treatment period, it will be 
performed 1 to 2 weeks after the final dose of the investigational drug.
8)
At discontinuation: The designated observations and examination items will be performed as far as possible. For patients providing informed consent but not enrolled in the treatment period, the 
observations and tests relating to safety evaluation will be performed as far as possible.
9)
If the designated observations or tests are performed in the period of 14 days before registration in the observation period, even if this is before informed consent is obtained, these can be used as 
data at registration in the observation period.
10)
PFS will be performed on the same date as uroflowmetry and measurement of the post void residual by ultrasound as far as possible.
11)
For evaluating BVE, measurement of the post void residual by ultrasound will be performed after uroflowmetry.
12)
Concomitant drugs/concomitant therapy and evaluation of adverse events: These will be investigated from informed consent to the end of follow-up.


25
1.
BACKGROUND INFORMATION
1.1
Introduction
The lower urinary tract, which consists of the bladder and urethra, has a urine storage 
function, involving the storage of urine in the bladder, and a voiding function, involving the 
excretion of the stored urine. The general term for a condition where the urine storage 
function and urination function are impaired (storage disorder and urination disorder) is lower 
urinary tract dysfunction (LUTD). Symptoms caused by LUTD are called lower urinary tract 
symptoms (LUTS), which are classified into “storage symptoms,” “voiding symptoms,” and 
“post-micturition symptoms.”1) Storage symptoms include increased daytime frequency, 
nocturia, urinary urgency, urinary incontinence, and bladder sensation. Voiding symptoms 
include slow stream, intermittent stream, hesitancy, straining, and terminal dribble. Post-
micturition symptoms include feeling of residual urine and post-micturition dribble. Each of 
these symptoms is a problem that greatly affects the patients’ activities of daily life and 
markedly impairs their quality of life (QOL).
In Japan, an epidemiological study on LUTS was conducted by the Japanese Continence 
Society in 10096 men and women aged 40 years or older (4570 included in the analysis) 
between November 2002 and March 2003.2) The incidence of any LUTS increased with age in 
both men and women, and some LUTS was present in approximately 78% of the elderly aged 
60 years or older. The most frequent symptoms were nocturia and increased daytime 
frequency, followed by slow stream, feeling of residual urine, urinary urgency, and urgency 
urinary incontinence in this order. When the number of patients with symptoms was estimated 
based on their age and sex, the number of men and women with increased daytime frequency 
was 15.95 million and 17.22 million, respectively, the number of men and women with slow 
stream was 10.88 million and 6.57 million, respectively, the number of men and women with 
feeling of residual urine was 7.92 million and 3.75 million, respectively, and the number of 
men and women with urinary urgency was 4.49 million and 4.6 million, respectively. A recent 
epidemiological study has reported a relationship between metabolic syndrome and LUTS, 
indicating that the onset of LUTS including OAB is significantly more frequent in patients 
with 2 or more risk factors for arteriosclerosis, which causes blood flow disturbance.3)
One cause of impaired urination is DU, and this is considered to manifest as underactive 
bladder (UAB). UAB is a condition where bladder contraction is impaired during voiding, 
manifesting as voiding symptoms. The most important peripheral nerve controlling the 
bladder is the pelvic nerve (parasympathetic nerve), and the occurrence of UAB is due to 
disorder of the pelvic nerve. LUTD due to bladder outlet obstruction (BOO) such as prostatic 
hyperplasia is impaired urination resulting from urethral obstruction, and it is reported that 
voiding symptoms that recur after transurethral prostatectomy are often caused not by 
obstruction due to recurrence of prostatic adenoma but by failure of detrusor contraction.4) It 
has been reported that failure of detrusor contraction is found frequently (48%) in patients 
with LUTS aged 70 years or older, and that it is more common among those who have a 
history of urinary retention.5) In typical UAB where the patient has little desire to void despite 


26
a large volume of urine in the bladder, and detrusor contraction is extremely weak or absent, 
the patient develops dysuria, and because voiding is also inefficient, there is a large amount of 
residual urine. Voiding symptoms of UAB include hesitancy, slow stream, and straining. 
UAB is treated firstly with intermittent urinary catheterization. The main drugs used to treat 
UAB are cholinergics, but drug therapy is positioned as adjuvant therapy in addition to 
intermittent urinary catheterization and is recommended to be administered after evaluation of 
the therapeutic effect of intermittent urinary catheterization for 4 weeks. Drugs include 
bethanechol chloride and distigmine bromide. Bethanechol chloride constricts the bladder by 
directly stimulating muscarinic receptors, and distigmine bromide constricts the bladder by 
increasing the amount of free bethanechol chloride via its inhibitory effect on cholinesterase. 
However, since these drugs may cause a serious adverse reaction that may be fatal, attention 
should be paid to the onset of cholinergic crisis (acute exacerbation of the condition of 
excessive acetylcholine that accompanies dyspnea and requires mechanical ventilation). 
Among the main pathological conditions due to urine storage dysfunction is OAB. OAB 
involves urinary urgency as a necessary condition, and it is usually accompanied by 
pollakiuria and nocturia. LUTD due to BOO is urine storage dysfunction related to impaired 
bladder function occurring secondary to urethral obstruction, other than directly impaired 
urination due to urethral obstruction. In a bladder with BOO, it has been shown from animal 
experiments that in many cases, the volume of blood flow decreases, and in addition partial 
denervation occurs,6) and partial denervation has also been observed in bladder biopsy 
specimens from OAB patients.7,8) BOO causes the pressure inside the bladder to increase 
during voiding, increasing the tension in the bladder wall and leading to impaired blood flow 
in the bladder. As a result, the nerves inside the bladder wall (postganglionic fibers of the 
pelvic nerve) are susceptible to degeneration, and partial denervation develops. It is thought 
that this is accompanied by excessive reaction of the smooth muscle of the bladder to 
acetylcholine (denervation supersensitivity), leading to detrusor overactivity. OAB symptoms 
are storage symptoms such as urinary urgency, pollakiuria (daytime frequency and nocturia) 
and urgency urinary incontinence, and the filling phase is often accompanied by involuntary 
contraction of the bladder (detrusor overactivity).
It is known that elderly people may develop both voiding and storage symptoms. It has been 
reported that among elderly men with LUTS and without BOO such as prostatic hyperplasia, 
40% had detrusor overactivity only, 31% had failure of detrusor contraction only, and 11% 
had both.9) An epidemiological study has revealed that LUTS includes various symptoms and 
that both storage and voiding symptoms coexist.10) Urinary urgency, nocturia, and urgency 
urinary incontinence are often present in patients with BOO such as prostatic hyperplasia and 
bladder neck sclerosis. Detrusor hyperactivity with impaired contractile function (DHIC) has 
been reported to be commonly present in elderly people, and inadvertent administration of 
anticholinergics to these patients may increase residual urine and cause urinary retention or 
overflow urinary incontinence.
As stated above, UAB symptoms are due to peripheral neuropathy, and since there are few 
therapeutics with satisfactory actions improving symptoms such as increased post void 


27
residual, hesitancy and slow stream, efficacious therapeutics for impaired urination are to be 
hoped for. In addition, in some cases of OAB, impaired urine storage and impaired urination 
coexist and are interrelated, and it is thought to be necessary to consider the balance between 
both of these when administering treatment.11) In this case, also, no efficacious therapeutic is 
available.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


28
 
 
 
 
 
 
 
 
 
 
 
Based on these findings, we have planned to conduct an early phase 2 study to evaluate the 
efficacy of TAC-302 in DU patients with OAB.
1.2
TAC-302 [test product]
1.2.1
Mechanism of Action
 
 
 
 
 
 
 
 
1.3
Placebo [Comparator]
Placebo, the comparator, contains no active ingredient of the test product and is a capsule 
indistinguishable from the test product in appearance.
1.4
Benefit-Risk Overview
1.4.1
TAC-302
1.4.1.1
Potential Benefits
There are few drugs to treat UAB/DU, and the development of effective drugs for impaired 
urination is expected.12) In addition, in some cases of OAB, impaired urine storage and 
impaired urination coexist and are interrelated, and it is thought to be necessary to consider 
the balance between both of these when administering treatment.11) In this case, also, no 
efficacious therapeutic is available.


29
 
 
 
 
 
 
Since the clinical studies conducted to date enrolled healthy adults, no benefits to patients 
have been evaluated.
1.4.1.2
Potential Safety Risks
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




31
 
 
 
 
 
 
 
1.5.2.1.2
Safety
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.2.2
Phase 1 Repeated-dose Study (Study 10054020)
 
 
 
1.5.2.2.1
Pharmacokinetics
 
 


32
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.5.2.2.2
Safety
 
 
 
 
 
 
 
 
 
 
 
 


33
 
 
 
 
 
 
 
 
 
 
 
 
1.6
Justification of Study Population and Study Design
1.6.1
Study Population
This study will target patients with OAB and voiding symptoms who have been confirmed to 
have DU based on the results of PFS and uroflowmetry. Patients with a strong placebo 
response under single-blind conditions in the observation period who do not meet the 
definition of OAB and voiding symptoms14) at registration in the treatment period, and 
patients who do not meet the criteria for DU based on PFS and uroflowmetry selected with 
reference to past reports15,16) will be deemed ineligible for registration in the treatment period, 
in order to select a study population which allows appropriate evaluation of the drug efficacy.
1.6.2
Study Design
 
 
 
 
 
 
 
 
 
 
 
 
 
 


34
 
 
 
 
 
 
 
1.6.3
TAC-302 Dose
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.6.4
Selection of Placebo
To objectively evaluate the efficacy and safety of TAC-302, a placebo group was established 
in the treatment period. PFS is currently essential for the diagnosis and evaluation of DU.21) 
Although PFS is considered to have a smaller placebo effect than symptoms and QOL 
evaluations,17) there is no evidence of variation associated with the natural course of DU or 
the PFS procedure in the study population of this study. Given this, as described in the 
objectives of the control group in the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) E10,22) it was considered necessary 
to establish a placebo group because it is necessary to distinguish the results occurring in 


35
patients after the test treatment (outcomes) from the results caused by factors such as natural 
progression of the disease and expectations of observers/patients.
The therapeutic effect on OAB is determined by evaluation of data including the number of 
urinations and questionnaires, but there is a large placebo effect involved in the evaluation of 
these. Accordingly, for studies verifying the clinical effect of OAB therapeutics, a placebo-
controlled double-blind study is recommended.17,18,19) Evaluation of OAB symptoms in this 
study is a secondary endpoint, but it was considered to be necessary to establish a placebo 
group to evaluate OAB symptoms.
2.
STUDY OBJECTIVES
2.1
Primary Objective
To investigate the efficacy of TAC-302 in DU patients with OAB, using evaluation of the 
BCI (males) or PIP 1 (females) at each time point as an indicator.
2.2
Secondary Objectives
(1) To investigate the efficacy of TAC-302 in DU patients with OAB, using the changes in 
values including PFS parameters, uroflowmetry parameters, BVE, the IPSS or the 
OABSS as indicators.
(2) To investigate the efficacy of TAC-302 in DU patients with OAB in comparison with 
placebo.
(3) To investigate the safety of TAC-302 in DU patients with OAB using data including the 
incidence of adverse events and adverse reactions as indicators.
2.3
Endpoints
2.3.1
Primary Endpoint
•
BCI [maximum detrusor pressure at peak urine flow (PdetQmax) + 5 × peak urine flow 
rate (Qmax)] (males)
•
PIP1 (PdetQmax + Qmax) (females)
[Evaluation time points: week 0, week 12]
2.3.2
Secondary Endpoints
2.3.2.1
Efficacy
(1) PFS parameters (filling phase) [Evaluation time points: week 0, week 12]
•
Volume at first desire to void
•
Maximum bladder volume
•
Bladder compliance
•
Appearance of bladder involuntary contraction
•
Bladder volume up to appearance of bladder involuntary contraction
(2) PFS parameters (voiding phase) [Evaluation time points: week 0, week 12]
•
Detrusor pressure at start of voiding (Pdet open)
•
Maximum detrusor pressure (Pdet max)
•
Maximum flow rate (Qmax)


36
•
Average flow rate (Qave)
•
Detrusor pressure at maximum flow (PdetQmax)
•
Duration of bladder contraction
•
Voided volume
•
Post void residual
(3) Uroflowmetry parameters [Evaluation time points: weeks 0, 4, 8, 12]
•
Maximum flow rate (free Qmax)
•
Average flow rate (free Qave)
•
Voided volume
•
Voiding time
(4) Post void residual measured by ultrasonography [Evaluation time points: at registration in 
observation period, weeks 0, 4, 8, 12]
(5) BVE [Voided volume / (voided volume + post void residual)] [Evaluation time points: 
weeks 0, 4, 8, 12]
Calculated from the voided volume measured by uroflowmetry and the post void residual 
measured by ultrasonography
(6) Change in IPSS score at weeks 4, 8, and 12 of the treatment periods relative to baseline 
(week 0)
•
IPSS total score
•
IPSS storage symptoms score
•
IPSS voiding symptoms score
•
IPSS QOL score
(7) Change in IPSS score at weeks 4, 8, and 12 of the treatment periods relative to baseline 
(week 0)
(8) Change in KHQ score (by domain) at week 12 of the treatment period relative to baseline 
(week 0)
(9) Change in bladder diary record data at weeks 4, 8, and 12 of the treatment periods relative 
to baseline (week 0)
•
Average number of micturition per 24 hours
•
Average number of urgency urinary incontinence episodes per 24 hours
•
Average number of urinary urgency episodes per 24 hours
•
Average voided volume per urination
•
Average number of nocturnal urinations
2.3.2.2
Safety
(1) Occurrence of adverse events and adverse reactions
(2) Blood pressure, pulse rate, body temperature, 12-lead electrocardiogram, and laboratory 
tests


37
3.
STUDY DESIGN
This study is a central-registration, multi-center, double-blind, placebo-controlled, 
randomized parallel-group comparative study to investigate the efficacy and safety of TAC-
302 in DU patients with OAB. The design of this study is shown in Figure 3-1. This study is 
composed of a single-blind observation period, a double-blind treatment period, and a follow-
up period.
Patients considered eligible for the enrollment in the observation period after providing 
written informed consent will proceed to the observation period. The investigational drug for 
the observation period will be administered under single-blind conditions. In the observation 
period, the investigational drug (placebo) will be administered orally twice daily after 
breakfast and dinner for 2 to 4 weeks. Patients considered eligible for the enrollment in the 
treatment period after the end of the observation period will proceed to the treatment period. 
The investigational drug for the treatment period will be administered under double-blind 
conditions. The investigational drug in the treatment period will be randomly assigned, with 
patients allocated to the TAC-302 and placebo group in a 2:1 ratio. To maintain a balance 
between groups, dynamic assignment using assignment factors [sex (male and female), age at 
informed consent (< 65 years and ≥ 65 years)] will be performed. In the treatment period, the 
investigational drug (TAC-302 200 mg or placebo) will be administered orally twice daily 
after breakfast and dinner for 12 weeks. After the start of the treatment period (registration in 
the treatment period), patients will make visits in weeks 2, 4, 8, and 12, and the designated 
observations and tests will be performed. A follow-up examination will be performed 1 week 
after the end of week 12 of the treatment period. If any adverse event is considered to be an 
adverse reaction after the follow-up examination, the follow-up investigation should be 
performed until it is confirmed that the symptom (including abnormal laboratory values) has 
recovered to the state of before the onset as much as possible or is resolving.
Figure 3-1  Study Design
3.1
Study Period
Study initiation date (planned): August 2017
Study completion date (planned): December 2019
[Region/Country]: Japan
3.1.1
Definition of Each Period for Each Patient
Each period described in this protocol is defined as follows.
(Visit)
(Registration)
(Timing)
(Drug)
(Pressure flow study)
Registration in 
the observation 
period
Registration in
the treatment period
Randomization
Observation period (single-blind)
Placebo BID (p o )
Follow-up 
examination
Treatment period (double-blind)
Follow-up period
Placebo BID (p o )


38
Study period:
From the time of obtaining informed consent to the end of the 
follow-up examination
Observation period: The period from registration in the observation period up to 
registration in the treatment period (registration in the treatment 
period will be performed between 2 to 4 weeks after registration 
in the observation period)
Treatment period:
From the time of registration in the treatment period to the end of 
week 12 of the treatment period
Follow-up period:
From the end of week 12 of the treatment period to the end of the 
follow-up examination (performed 1 week after the end of week 
12 of the treatment period)
3.2
Patient Assignment and Blinding
3.2.1
Method of Assignment
This study is a randomized study conducted by central registration using an Interactive Web 
Response System (IWRS). Data will be entered according to the IWRS procedure.
The principal investigator or subinvestigator will provide each target patient with an 
explanation and then obtain written informed consent. A patient identification code will 
consist of a TAC302-site number (2 digits) - the order of consent obtainment at each site (3 
digits). After it is confirmed that the patient meets the inclusion criteria and does not meet any 
exclusion criteria for registration in the observation period and has no problems with his/her 
eligibility, the patient will be enrolled in the observation period via the IWRS. After it is 
confirmed that the patient meets the inclusion criteria and does not meet any exclusion criteria 
for registration in the treatment period and has no problems with his/her eligibility, the patient 
will be enrolled in the treatment period via the IWRS.
When the registration in the treatment period is complete, patients will be randomly assigned 
to the TAC-302 group and the placebo group in a ratio of 2:1 via the IWRS based on a 
dynamic allocation method (minimization method) including the stochastic process.
Patients will be stratified according to the following assignment adjustment factors:
•
Sex (male or female)
•
Age at informed consent (< 65 years or ≥ 65 years)
The IWRS will assign an investigational drug to each patient, notify the study site of the drug 
number assigned to the patient, and give instructions for prescription of the investigational 
drug. Detailed information will be provided in the IWRS procedure.
If an investigational drug different from the drug number assigned by the IWRS should be 
dispensed in error to a patient, the site must notify the sponsor immediately. The site must 
also document the cause of investigational drug prescribing or dispensing errors. If a patient 
starts to receive an investigational drug in a group different from the group to which he/she 
has actually been assigned, administration of the investigational drug will be continued.


39
3.2.2
Blinding
This study is a double-blind study. During the conduct of the study, neither any of the 
patients, nor the principal investigator, subinvestigator, study coordinator, or sponsor will be 
informed about the treatment groups. Key codes will be prepared and unblinded according to 
the procedures for investigational drug assignment. The investigational drug assignment 
manager will store and manage the key codes until unblinding.
The following details will be shown in documents such as the procedures for investigational 
drug assignment, the emergency key code unblinding procedure or the key unblinding 
procedure.
•
The method for assuring indistinguishability (the timing, person performing the 
procedures, the items carried out, etc.)
•
Methods for storing, managing and handling key codes and emergency key codes and 
identification of the person storing the key codes
•
Emergency key code unblinding procedure
•
Timing and procedure for unblinding after data lock


40
4.
SELECTION AND WITHDRAWAL OF PATIENTS
4.1
Inclusion Criteria
At each registration, patients meeting all of the following inclusion criteria will be eligible.
The rationale is shown in Section 14.3.
4.1.1
Registration in the Observation Period
(1) Provided written informed consent in person
(2) Aged ≥ 20 years at the time of obtaining informed consent and able to receive 
treatment as an outpatient (irrespective of sex)
(3) Being able to use the toilet himself/herself and make accurate bladder diary records, in 
the opinion of the principal investigator or subinvestigator
(4) Having had lower urinary tract symptoms (storage symptoms, voiding symptoms, and 
post-micturition symptoms) for at least 12 weeks before registration in the observation 
period
(5) Scoring ≥ 2 points on any of the following questions for the IPSS voiding symptoms 
score at registration in the observation period
•
Over the past month, how often have you found you stopped and started again 
several times when you urinated?
•
Over the past month, how often have you had a weak urinary stream?
•
Over the past month, how often have you had a push or strain to begin urination?
(6) Scoring ≥ 2 points for the urinary urgency score (Question 3), and having an OABSS 
total score of ≥ 3 points in OABSS evaluation at registration in the observation period
•
Question 3: How often do you have a sudden desire to urinate, which is difficult 
to defer?
(7) Post void residual ≤ 300 mL measured at registration in the observation period
4.1.2
Registration in the Treatment Period
(1) Scoring ≥ 2 points on any of the following questions for the IPSS voiding symptoms 
score at registration in the observation period
•
Over the past month, how often have you found you stopped and started again 
several times when you urinated?
•
Over the past month, how often have you had a weak urinary stream?
•
Over the past month, how often have you had a push or strain to begin urination?
(2) Meeting all of the following conditions based on information from bladder diary 
records in the 3 days directly before registration in the treatment period
1)
Being able to use the toilet himself/herself and make accurate bladder diary 
records, in the opinion of the principal investigator or subinvestigator
2)
An average of ≥ 8 urinations per 24 hours and meeting either of the following 
conditions
•
An average of ≥ 1 urinary urgency episodes per 24 hours
•
An average of ≥ 1 urgency urinary incontinence episode per 24 hours


41
(3) Post void residual ≤ 300 mL measured at registration in the treatment period
(4) Meeting the following criteria based on a urodynamic study (UDS) performed at 
registration in the treatment period
[a, b: Calculated from PFS parameters, c: Calculated from uroflowmetry parameters and 
the measurement of the post void residual according to ultrasound]
1)
Criteria for males
a) BCI (PdetQmax+5Qmax) < 100
b) Bladder outlet obstruction index (BOOI=PdetQmax-2Qmax) < 40
c) BVE [voided volume / (voided volume + post void residual)] < 90%
2)
Criteria for females
a) PdetQmax < 20
b) Qmax < 15
c) BVE [voided volume / (voided volume + post void residual)] < 90%
4.2
Exclusion Criteria
At each registration, patients meeting any of the following criteria will be ineligible.
The rationale is shown in Section 14.3.
4.2.1
Registration in the Observation Period
(1) Having the following concurrent or historical conditions, and having been diagnosed 
with neurogenic bladder accompanied by obvious neurological abnormality associated 
with the following diseases
1)
Cerebrovascular disorder (cerebral hemorrhage, cerebral infarction, etc.)
2)
Parkinson’s disease
3)
Alzheimer’s disease
4)
Multiple sclerosis
5)
Spina bifida
6)
Spinal cord disorder (spinal cord injury, etc.)
(2) Concurrent urinary tract infection (prostatitis, cystitis, etc.) or historical recurrent 
urinary tract infection [occurring ≥ 3 times within a period of 168 days (24 weeks) 
before registration in the observation period]. Concurrent urinary disease impairing 
determination of the effect of the investigational drug, such as cystitis interstitial, 
urinary tract stenosis, urinary tract obstruction, calculus urinary (calculus ureteric, 
calculus urethral, calculus bladder, etc.), benign tumor of the urethra (urethral polyp, 
cyst, papilloma, etc.) and urethral diverticulum.
(3) Concurrent bladder cancer or prostate cancer, or suspected bladder cancer or prostate 
cancer, or a history of these
(4) Cystocele classified as stage III or higher according to the POP-Q stage classification 
(females)
(5) Prostate gland volume ≥ 30 mL (males)
(6) Overflow urinary incontinence


42
(7) Clinically significant concurrent conditions (including symptoms and findings) such 
as severe liver disease (hepatitis viral, drug-induced liver injury, etc.), severe renal 
disease (acute renal failure, glomerulonephritis, nephritis interstitial, etc.), severe 
cardiovascular disease (cardiac failure congestive, symptomatic unstable angina 
pectoris, poorly controlled arrhythmia, myocardial infarction, etc.), severe blood 
dyscrasia (pancytopenia, leukopenia, etc.), severe respiratory disease (bronchial 
asthma, bronchitis chronic, etc.), severe digestive disease (peptic ulcer, reflux 
esophagitis, Crohn’s disease, colitis ulcerative, etc.), severe neuropsychiatric disease 
(schizophrenia, dementia, etc.), severe immune disease (collagen disorder, etc.), 
severe metabolic or endocrine disease or malignant tumor
(8) Having received urethral catheter placement, or performing intermittent self-
catheterization due to the inability to urinate spontaneously
(9) Meeting the following conditions at laboratory tests performed in the period of 14 
days before registration in the observation period
1)
Aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN)
2)
ALT > 3 × ULN
3)
T-Bil > 1.5 × ULN
4)
Serum creatinine > 1.5 × ULN
(10) The following have been performed in the period of 154 days (22 weeks) before 
registration in the observation period.
1)
Surgery of the pelvic organs (radical hysterectomy, radical surgery for rectal 
cancer, radical pelvic lymph node dissection, etc.) injuring the pelvic nerve or 
hypogastric nerve
2)
Prostatectomy
3)
Radiotherapy that may affect voiding function
(11) Having received another investigational drug in the period of 90 days before 
registration in the observation period
(12) Being pregnant, breastfeeding, or a female patient of childbearing potential with a 
positive (urine or serum) pregnancy test result in the period of 7 days before 
registration in the observation period
Note) Women without childbearing potential are women who have undergone 
hysterectomy and postmenopausal women who have not experienced 
menstruation for at least 1 year with no associated medical reason such as 
administration of contraceptives
(13) In the case of women with reproductive potential, not consenting to use contraception 
during the study period and for a period of 30 days after the end of administration of 
the investigational drug*
(14) In the case of male patients, not consenting to use contraception during the study 
period and for a period of 90 days after the end of administration of the investigational 
drug*


43
(15) Being determined to be ineligible for this study in the opinion of the principal 
investigator or subinvestigator
*
The principal investigator or subinvestigator will instruct patients to always perform contraception using a method 
such as the double-barrier method (a condom and pessary), an intrauterine device or oral contraceptives during the 
period of administration of the investigational drug and the period of contraception after the end of administration of 
the investigational drug.
4.2.2
Registration in the Treatment Period
(1) A rate of compliance with administration of the investigational drug of <80% in the 
observation period
(2) Having the following concurrent conditions, and having been diagnosed with 
neurogenic bladder accompanied by obvious neurological abnormality associated with 
the following diseases
1) Cerebrovascular disorder (cerebral hemorrhage, cerebral infarction, etc.)
2) Parkinson’s disease
3) Alzheimer’s disease
4) Multiple sclerosis
5) Spina bifida
6) Spinal cord disorder (spinal cord injury, etc.)
(3) Concurrent urinary disease impairing determination of the effect of the investigational 
drug, such as urinary tract infection (prostatitis, cystitis, etc.), cystitis interstitial, 
urinary tract stenosis, urinary tract obstruction, calculus urinary (calculus ureteric, 
calculus urethral, calculus bladder, etc.), benign tumor of the urethra (urethral polyp, 
cyst, papilloma, etc.) and urethral diverticulum.
(4) Concurrent bladder cancer or prostate cancer, or suspected bladder cancer or prostate 
cancer
(5) Cystocele classified as stage III or higher according to the POP-Q stage classification 
(females)
(6) Overflow urinary incontinence
(7) Clinically significant concurrent conditions (including symptoms and findings) such 
as severe liver disease (hepatitis viral, drug-induced liver injury, etc.), severe renal 
disease (acute renal failure, glomerulonephritis, nephritis interstitial, etc.), severe 
cardiovascular disease (cardiac failure congestive, symptomatic unstable angina 
pectoris, poorly controlled arrhythmia, myocardial infarction, etc.), severe blood 
dyscrasia (pancytopenia, leukopenia, etc.), severe respiratory disease (bronchial 
asthma, bronchitis chronic, etc.), severe digestive disease (peptic ulcer, reflux 
esophagitis, Crohn’s disease, colitis ulcerative, etc.), severe neuropsychiatric disease 
(schizophrenia, dementia, etc.), severe immune disease (collagen disorder, etc.), 
severe metabolic or endocrine disease or malignant tumor


44
(8) Having received urethral catheter placement, or performing intermittent self-
catheterization due to the inability to urinate spontaneously
(9) Being determined to be ineligible for this study in the opinion of the principal 
investigator or subinvestigator
4.3
Discontinuation Criteria for Individual Patients
Administration of the investigational drug will be discontinued in a patient meeting any of the 
following criteria. Discontinuation criteria for individual patients are shown below:
(1) It becomes unfeasible to continue administration due to the occurrence of an adverse 
event
(2) The patient requests withdrawal of his/her consent
(3) Major noncompliance with the study procedures is observed.
(4) The patient becomes unable to continue the study due to circumstances such as 
moving house, being transferred to another medical institution or being too busy
(5) It is discovered that the patient is not in the target population for this study (the patient 
does not meet the inclusion criteria, or meets any of the exclusion criteria).
(6) The patient becomes pregnant.
(7) Because the effect of the investigational drug is incomplete or symptoms have 
worsened, the principal investigator or subinvestigator determines that administration 
should be discontinued.
(8) It becomes necessary to discontinue the patient from the study for any other reason in 
the opinion of the principal investigator or subinvestigator.


45
5.
STUDY ASSESSMENTS
The evaluations and examination items to be performed in this study are shown in Table 5-1 
and the detailed schedule is shown in Table 5-2.
All information stipulated in the protocol should be recorded. If the designated observations 
or tests are performed in the period of 14 days before registration in the observation period, 
even if this is before informed consent is obtained, these can be used as data at registration in 
the observation period.


46
Table 5-1  Evaluations and Examination Items
Obtaining informed consent
Date of obtaining informed consent
Patient backgrounds
Sex
Date of birth
Age*1
Race
Height
Weight
BMI*2
History of participation in clinical 
studies (within the past 90 days)
Medical history (within the past 
180 days)*3
Onset time of lower urinary tract symptoms (LUTS) (storage symptoms, voiding symptoms, and post-micturition 
symptoms)
Concurrent conditions
History of prior treatment
Patient registration
Patient identification code
Drug number
Symptoms and findings
Blood pressure (systolic and 
diastolic)
Pulse rate
Body temperature
Compliance with administration of 
the investigational drug
Concomitant medication and concomitant therapy
12-lead electrocardiography
Heart rate
QT interval
RR interval
QTcF interval*4
Hematology tests
Red blood cell count
Hemoglobin
Hematocrit
Platelet count
White blood cell count
Neutrophils
Eosinophils
Basophils
Lymphocytes
Monocytes
Biochemistry tests
Total protein
Albumin
A/G
T-Bil
Direct bilirubin
AST(GOT)
ALT(GPT)
ALP
LDH
γ-GTP
BUN
Creatinine
Creatine kinase
Blood glucose
Amylase
Triglycerides
Total cholesterol
CRP
Na
K
Cl
Ca*5
Endocrinological tests
Thyroid stimulating hormone 
(TSH)
free T3
free T4
Cortisol
Adrenocorticotropic hormone (ACTH)
Urinalysis
Protein
Glucose
Urobilinogen
Urine NAG
Urine β2-microglobulin
Urine sediment*6
Pregnancy test*7
Serum or urine human chorionic gonadotropin
Prostate gland volume measurement
Pressure flow study (PFS) (filling 
phase)
Volume at first desire to void
Maximum bladder volume
Bladder compliance
Appearance of bladder 
involuntary contraction
Bladder volume up to appearance of bladder involuntary 
contraction
Pressure flow study (PFS) (voiding 
phase)
BCI (PdetQmax + 5Qmax): males
PIP1 (PdetQmax + Qmax): females
Detrusor pressure at maximum flow (PdetQmax)
Detrusor pressure at start of voiding (Pdet open)
Maximum detrusor pressure (Pdet max)
Maximum flow rate (Qmax)
Average flow rate (Qave)
Duration of bladder contraction
Voided volume
Post void residual
Uroflowmetry
Maximum flow rate (free 
Qmax)
Average flow rate (free Qave)
Voided volume
Voiding time
Post void residual measured by ultrasound
be [voided volume/(voided volume + post void residual)]
Post void residual measured by ultrasound and voided volume measured by uroflowmetry
Symptom score evaluation
IPSS
OABSS
QOL score evaluation
KHQ
Bladder diary records
Dates and times of voiding 
and urinary incontinence
Urinary urgency
Voided volume
Evaluation of adverse events
*1: Automatically calculated from the date of birth.  *2: Automatically calculated from height and weight.
*3: This is a medical history determined by the principal investigator or subinvestigator to be important in the conduct of this study (such as 
diseases related to urinary organs).
*4: Automatically calculated from the QT interval and RR interval.


47
*5: In the evaluation of adverse events, if albumin is < 4.0 g/dL, determinations will be made using values corrected by the following 
formula.
[Corrected calcium (mg/dL)] = [Calcium (mg/dL)] – 0.8 × {[Albumin (g/dL)] – 4}
*6: Urine sediment will only be examined at registration in the observation period and registration in the treatment period.
*7: Required for female patients with childbearing potential. However, a pregnancy test will not be required for patients more than 1 year 
after menopause or patients in whom the possibility of pregnancy is medically ruled out.




49
1)
Obtaining informed consent: Obtained within the period of 28 days before registration in the observation period.
2)
Assigning of patient identification codes: Assigned to patients providing informed consent.
3)
Laboratory tests: Hematology tests, biochemistry tests, endocrinological tests and urinalysis will be performed. However, the urinalysis test urine sediment will only be performed at registration in 
the observation period and at registration in the treatment period.
4)
Pregnancy tests: Required for female patients with childbearing potential. However, a pregnancy test will not be required for patients more than 1 year after menopause or patients in whom the 
possibility of pregnancy is medically ruled out. At tests before registration in the observation period, pregnancy tests (serum or urine) must be negative. The time window for performing the test is 
the period of 7 days before registration in the observation period.
5)
Time window for registration in the treatment period: All observation and examination items at registration in the treatment period will be performed by registration in the treatment period, 2 to 4 
weeks after registration in the observation period.
6)
Time window for visits in the treatment period: Visits at weeks 2, 4, and 8 of the treatment periods will be allowed to be within the range of the standard date ±3 days. The visit at week 12 will be 
allowed to be within the range of the standard date −3 days to the standard date +7 days.
7)
Time window for the follow-up examination: This will be performed 1 to 2 weeks after the end of week 12 of the treatment period. If the patient discontinued during the treatment period, it will be 
performed 1 to 2 weeks after the final dose of the investigational drug.
8)
At discontinuation: The designated observations and examination items will be performed as far as possible. For patients providing informed consent but not enrolled in the treatment period, the 
observations and tests relating to safety evaluation will be performed as far as possible.
9)
If the designated observations or tests are performed in the period of 14 days before registration in the observation period, even if this is before informed consent is obtained, these can be used as 
data at registration in the observation period.
10)
PFS will be performed on the same date as uroflowmetry and measurement of the post void residual by ultrasound as far as possible.
11)
For evaluating BVE, measurement of the post void residual by ultrasound will be performed after uroflowmetry.
12)
Concomitant drugs/concomitant therapy and evaluation of adverse events: These will be investigated from informed consent to the end of follow-up.


50
5.1
Study Procedures
The following evaluations and examinations must be recorded in the patient’s source 
documents.
5.1.1
Obtaining informed consent
Informed consent will be obtained within 28 days before enrollment in the observation period, 
and eligibility will be confirmed subsequently.
5.1.2
Assigning of Patient Identification Codes
Each patient will be assigned a unique patient identification code (Section 3.2) for screening 
at the study site.
5.1.3
Patient backgrounds
Patient background information shown in Table 5-1 will be collected.
5.1.4
Physical examination
Physical examination findings will be evaluated at the time points shown in Table 5-2. 
Adverse events will be evaluated as shown in Section 12.
5.1.5
Blood Pressure (Systolic and Diastolic), Pulse Rate, Body Temperature
Blood pressure (systolic and diastolic), pulse rate, and body temperature will be measured at 
the time points shown in Table 5-2. Measurement should be performed at the same site and by 
the same method for each patient at all measurement time points while the patient is at rest.
The principal investigator or subinvestigator will be responsible for the assessment of changes 
in blood pressure (systolic and diastolic), pulse rate, and body temperature. Adverse events 
will be evaluated as shown in Section 12.
5.1.6
Compliance with administration of the investigational drug
From the start of administration of the investigational drug to the end of administration, at 
each visit, compliance with treatment with the investigational drug was checked, including 
checks using drug diaries, empty sheets of used investigational drug, and interview.
5.1.7
Concomitant medication and concomitant therapy
Information on all concomitant medications (prescription drugs and over-the-counter drugs) 
and therapies will be collected by interviews, etc. at least at each visit from the time of 
informed consent to the end of the study period, and the status of their use will be recorded in 
the source documents. Concomitant medications include drugs used to treat adverse events or 
serious adverse events. Concomitant medications and therapies used to treat adverse events or 
serious adverse events requiring follow-up at the follow-up examination will be collected 
until the end of the follow-up, and the status of their use will be recorded in the source 
documents. However, it is not necessary to enter test drugs, diagnostic drugs, and fluid 
replacement at the time of administration of injectable drugs in the electronic case report form 
(eCRF).


51
5.1.8
12-lead electrocardiography
12-lead ECG will be performed at the time points shown in Table 5-2. Measurement should 
be performed at rest using the same method for each patient.
The principal investigator or subinvestigator will be responsible for the assessment of the 
results of ECG. Adverse events will be evaluated as shown in Section 12.
5.1.9
Laboratory Values
Laboratory tests (hematology, biochemistry, endocrinology, and urinalysis) will be performed 
for the parameters listed in Table 5-1. Blood and urine samples for laboratory tests will be 
collected at the time points shown in Table 5-2.
The principal investigator or subinvestigator will assess whether all laboratory values are 
clinically significant changes or not. Any clinically significant change must be followed as 
specified in the protocol and recorded as an adverse event. Adverse events will be evaluated 
as shown in Section 12.
5.1.10
Pregnancy Test
For patients of childbearing potential, serum or urine human chorionic gonadotrophin will be 
tested at the time point shown in Table 5-2 to confirm that they are not pregnant. It is not 
necessary to perform the test in patients without childbearing potential.
Note) Women without childbearing potential are women who have undergone 
hysterectomy and postmenopausal women who have not experienced menstruation 
for at least 1 year with no associated medical reason such as administration of 
contraceptives
5.1.11
Symptom Score Evaluation (IPSS, OABSS)
As the evaluation of symptom scores, IPSS and OABSS will be evaluated by patients at the 
time points shown in Table 5-2.
5.1.12
King’s Health Questionnaire (KHQ)
Patients will be asked to evaluate KHQ at the time points shown in Table 5-2.
5.1.13
Bladder diary records
The bladder diary will be supplied and collected from patients at the time points shown in 
Table 5-2 to check the contents of the diary.
5.1.14
Pressure Flow Study (PFS)
Pressure flow study will be performed at the time points shown in Table 5-2. For details, the 
procedure for pressure flow study will be followed.
5.1.15
Uroflowmetry
Pressure flow study will be performed at the time points shown in Table 5-2. For details, the 
procedure for uroflowmetry will be followed.


52
5.1.16
Post void residual measured by ultrasound
Post void residual will be measured by ultrasound at the time points shown in Table 5-2. For 
measurement after the registration in the treatment period, residual urine after uroflowmetry 
will be measured to evaluate the secondary endpoint of BVE.
5.1.17
Prostate gland volume measurement
For males only, prostate gland volume measurement will be performed at the time point 
shown in Table 5-2.
5.1.18
Evaluation of adverse events
Any untoward medical event (adverse event) will be checked at each visit from the time of 
informed consent to the end of the study period, as shown in Table 5-2. Adverse events will 
be evaluated as shown in Section 12.
5.2
Evaluations and Examination Items at Each Visit
The evaluations and examinations shown in Table 5-1 will be performed according to the 
schedule shown in Table 5-2.


53
6.
INVESTIGATIONAL PRODUCTS
The sponsor will provide TAC-302 and placebo until the end of the study period.
6.1
Name, etc. of Investigational Products
The physical and chemical properties of the test product and the comparator are presented in 
Table 6.1-1 and Table 6.1-2.
Table 6.1-1  Overview of TAC-302 [Test Product]
Investigational 
drug code name
TAC-302
Generic name
Undetermined
 
 
 
Dosage form
Capsule
 
 
Expiry date
Shown in the investigational drug control and handling procedure
Table 6.1-2  Overview of Placebo [Comparator]
Composition
Capsule containing no active ingredient of the test product and 
indistinguishable from the test product in appearance.
Expiry date
Shown in the investigational drug control and handling procedure
6.2
Packaging and Labeling of Investigational Products
The following information is indicated on the outer box and aluminum bag of the 
investigational products. Details are shown in the investigational product control and handling 
procedure.
(1)
Name of the sponsor
(2)
Address
(3)
Storage
(4)
Quantity
(5)
Manufacturing number


54
(6)
Date of manufacture
6.3
Control of Investigational Products
The principal investigator and the investigational product manager will manage the 
investigational products in accordance with the provided investigational product control and 
handling procedure. The prescription history of the investigational products will be recorded 
in the investigational product accountability record.
The investigational products must not be used outside of this study.
6.4
Instructions on the Handling of Investigational Product for Patients
The principal investigator or subinvestigator will instruct patients to take the investigational 
product as specified during the study period. Detailed instructions are provided in the 
investigational product control and handling procedure and the medication diary. If a patient 
does not follow the specified method, the principal investigator or the sponsor may 
discontinue the study for the patient. Treatment compliance will be confirmed by checking the 
records in the investigational product accountability record and the consistency with the 
medication diary and source documents.
6.5
Implementation of Assignment Confirmation Test
This is a double-blind, controlled study, and the assignment confirmation test will be 
conducted to confirm that each treatment group (TAC-302 group and placebo group) has been 
allocated appropriately after assignment.


55
7.
ADMINISTRATION METHOD
All administration status will be recorded in the source documents. Patients will be instructed 
on the administration method in accordance with the investigational drug control and handling 
procedure and the medication diary.
7.1
Administration Procedure
7.1.1
Method of Administration
7.1.1.1
Observation period
In the observation period, placebo will be administered orally twice daily after breakfast and 
dinner for 2 to 4 weeks under single-blind conditions. The number of investigational drug 
capsules per dose is shown in Table 7.1.1.1-1.
Table 7.1.1.1-1  Number of Investigational Drug Capsules Per Dose 
(Observation Period)
Group
Number of capsules per dose
Placebo
Placebo × 2 capsules
7.1.1.2
Treatment period
In the treatment period, under double-blind conditions, the investigational drug (TAC-302 or 
placebo) will be administered orally twice daily after breakfast and dinner for 12 weeks. The 
number of investigational drug capsules per dose is shown in Table 7.1.1.2-1.
Table 7.1.1.2-1  Number of Investigational Drug Capsules Per Dose 
(Treatment Period)
Group
Number of capsules per dose
TAC-302
TAC-302 100 mg × 2 capsules
Placebo
Placebo × 2 capsules


56
7.2
Restrictions
7.2.1
Contraception
The principal investigator or subinvestigator will instruct patients to ensure measures are 
taken to prevent pregnancy by using a double-barrier method (condom and diaphragm) or an 
intrauterine contraceptive device, etc. during the study period and the contraception period 
(for female patients with reproductive potential, 30 days after the completion of 
investigational product administration; for male patients, 90 days after the completion of 
investigational product administration).
7.3
Concomitant medication and concomitant therapy
7.3.1
Prohibited Concomitant Drugs
The following drugs will be prohibited from registration in the observation period to the visit 
at week 12 of the treatment period or the end of administration of the investigational drug. 
The rationale is shown in Section 14.4.
(1) Following drugs for OAB or impaired urination:
•
Anticholinergics (oxybutynin hydrochloride, propiverine hydrochloride, 
tolterodine tartrate, solifenacin succinate, imidafenacin, fesoterodine fumarate, 
propantheline bromide, etc.)
•
β3 receptor agonists (mirabegron, etc)
•
Flavoxate hydrochloride
•
Tricyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, 
clomipramine hydrochloride, etc)
•
Chinese herbal medicines (hachimijiogan, goshajinkigan, etc)
•
Estrogen (estriol)
•
Botulinum toxin
•
Resiniferatoxin, capsaicin
•
Anti-diuretic hormones (desmopressin, etc)
•
Cholinergics (bethanechol chloride, etc)
•
Cholinesterase inhibitors (distigmine bromide, etc)
•
α1 adrenaline receptor blockers (tamsulosin hydrochloride, naftopidil, silodosin, 
terazosin hydrochloride hydrate, urapidil, prazosin hydrochloride, alfuzosin 
hydrochloride, etc)
•
5α reductase inhibitors (dutasteride, finasteride)
•
Phosphodiesterase (PDE) 5 inhibitors (tadalafil, sildenafil citrate, etc)
•
Antiandrogens (chlormadinone acetate, allylestrenol)
•
Other oral drugs (Paraprost, Eviprostat, Cernilton)
(2) Other drugs predicted to influence voiding function
(3) Other investigational drugs


57
7.3.2
Prohibited Concomitant Therapy
The following concomitant therapies will be prohibited from registration in the observation 
period to the visit at week 12 of the treatment period or the end of administration of the 
investigational drug. The rationale is shown in Section 14.5.
•
Surgery of the pelvic organs (radical hysterectomy, radical surgery for rectal 
cancer, radical pelvic lymph node dissection, etc.) injuring the pelvic nerve or 
hypogastric nerve
•
Prostatectomy
•
Radiotherapy that may affect voiding function
•
Physiotherapy (pelvic floor muscle training, feedback training, biofeedback 
training, bladder training, electric stimulation therapy, magnetic stimulation 
therapy, etc)


58
8.
PHARMACOKINETICS/PHARMACODYNAMICS
Pharmacokinetics and pharmacodynamics will not be evaluated in this study.
9.
PHARMACOGENOMICS
Pharmacogenomic research will not be conducted in this study.


59
10. DISCONTINUATION/TERMINATION OF STUDY
10.1
Criteria for Discontinuation of the Study at Study Sites
The sponsor or principal investigator may terminate the study at a study site where major or 
continuous non-compliance with GCP or the study protocol by the principal investigator or 
subinvestigator has interfered or may have interfered with the proper conduct of the study. In 
such a case, the institutional review board (IRB) should be notified immediately according to 
the applicable standard operating procedure (SOP) of the study site.
10.2
Criteria for Discontinuation of the Entire Study
The sponsor also reserves the right to discontinue this study for administrative reasons at any 
time. If becoming aware of circumstances that warrant termination of the study during the 
course of the study, the sponsor will terminate the study or part of the study appropriately. In 
such a case, the head of the study site should be notified immediately of the fact and the 
reason for discontinuation in writing. The head of the study site will promptly inform the IRB 
and the principal investigator in writing. The principal investigator or subinvestigator will 
promptly inform the patients and change the treatment to other therapies. The sponsor will 
promptly notify the regulatory authorities of the discontinuation of the study.


60
11. EFFICACY EVALUATIONS
11.1
Pressure Flow Study (PFS)
The principal investigator or subinvestigator will perform PFS. It has been reported to be 
advisable for PFS results to be found by central determination, for example by a central 
committee, in order to maintain objectivity and consistency in interpretation.17) To perform 
central determination in this study, test results will be provided to the sponsor as electronic 
data as far as possible. Details such as the procedures for performing PFS and method of 
providing PFS are shown in the procedures for performing pressure flow studies. Details of 
the organization and methods for central determination are shown in the procedures relating to 
central determination. To check inclusion criterion (4) for registration in the treatment period 
at registration in the treatment period, the principal investigator or subinvestigator will 
evaluate the PFS parameters, maximum flow rate (Qmax) and maximum detrusor pressure at 
peak urine flow (PdetQmax). For male patients, BCI and BOOI will be calculated.
11.2
Uroflowmetry
The principal investigator or subinvestigator will perform uroflowmetry. Uroflowmetry test 
results will be provided to the sponsor on paper form so that they can be evaluated by central 
determination together with the PFS results. Details such as the procedures for performing 
uroflowmetry and the method of providing uroflowmetry are shown in the procedures for 
performing uroflowmetry. Details of the organization and methods for central determination 
are shown in the procedures relating to central determination. The principal investigator or 
subinvestigator will evaluate the voided volume to check BVE [voided volume/(voided 
volume + post void residual)] for inclusion criterion (4) for registration in the treatment period 
at registration in the treatment period.
11.3
Symptom score evaluation
11.3.1
IPSS and QOL Scores
Voiding symptoms and storage symptoms will be evaluated using the IPSS and QOL scores. 
The definition of IPSS is shown in Table 11.3.1-1 and details of the contents are shown in 
Appendix 1.
The principal investigator or subinvestigator will instruct the patients to write down the 
applicable scores for each question. While the patients are making evaluations, care should be 
taken not to bias this evaluation, for example by standing next to the patients or talking to 
them.


61
Table 11.3.1-1  IPSS Definition
Question 1 (feeling of 
residual urine)
Over the past month, how often have you had a sensation of not emptying your bladder 
completely after you finished urinating?
Question 2 (increased 
daytime frequency)
Over the past month, how often have you had to urinate again less than two hours after you 
finished urinating?
Question 3 
(intermittent stream)
Over the past month, how often have you found you stopped and started again several times when 
you urinated?
Question 4 (urinary 
urgency)
Over the past month, how often have you found it difficult to postpone urination?
Question 5 (slow 
stream)
Over the past month, how often have you had a weak urinary stream?
Question 6 (straining)
Over the past month, how often have you had a push or stain to begin urination?
Question 7 (nocturia)
Over the past month, how many times did you most typically get up to urinate from the time you 
went to bed at night until the time you got up in the morning?
Source: Adapted from Japanese Continence Society, Clinical Practice Guideline for Overactive Bladder Writing Committee 
Eds. Clinical Practice Guideline for Overactive Bladder (2nd Edition). Tokyo: RichHill Medical Inc.; 2015. p.105.
The IPSS total score will be the total score of questions 1 to 7, and a score of 0 to 7 points 
will be classified as mild, a score of 8 to 19 points, as moderate, and a score of 20 to 35 
points, as severe.23) The total of the scores for question 1 on post-micturition symptoms and 
questions 3, 5, and 6 on voiding symptoms will be taken to be the IPSS voiding symptoms 
score, and the total of the scores for questions 2, 4, and 7 on storage symptoms will be taken 
to be the score for IPSS storage symptoms.24)
The score for the question “If you were to spend the rest of your life with your urinary 
condition as it is right now, how would you feel about that?” will be taken to be the IPSS 
QOL score, and a score of 0 to 1 points will be classified as mild, a score of 2 to 4 points, as 
moderate, and a score of 5 to 6 points, as severe.23)
11.3.2
Overactive Bladder Symptom Score (OABSS)
OAB symptoms will be evaluated using the OABSS. The contents of the OABSS are shown 
in Appendix 2.
The principal investigator or subinvestigator will instruct the patients to write down the 
applicable scores for each question. While the patients are making evaluations, care should be 
taken not to bias this evaluation, for example by standing next to the patients or talking to 
them.
The definition of the OABSS total score will be the total score for all questions, and a 
score ≤ 5 will be determined to be mild, a score of 6 to 11, to be moderate, and a score ≥ 12, 
to be severe.23)
11.4
King’s health questionnaire (KHQ)
The QOL in DU patients with OAB will be evaluated using the KHQ. The contents of KHQ 
are shown in Appendix 3.
The principal investigator or subinvestigator will instruct the patients to write down the 
applicable scores for each question. While the patients are making evaluations, care should be 
taken not to bias this evaluation, for example by standing next to the patients or talking to 
them.


62
The definition of each domain in the Japanese edition of the KHQ and the method for 
calculating the score are decided with reference to the Clinical Practice Guideline for 
Overactive Bladder.23)
11.5
Bladder diary records
The times of urination, times of urinary incontinence, whether urinary urgency is present and 
voided volume for each urination recorded by the patient will be evaluated using bladder 
diary records.
The principal investigator or subinvestigator will explain the method for writing bladder diary 
records. Details of the method for writing records are shown in the manual explaining bladder 
diary records and how to write them. Patients will be instructed to write the following in 
bladder diary records for the 3 days before the next visit: times of urination, times of urinary 
incontinence, whether urinary urgency was present and the voided volume for each urination. 
The decision on whether to select bladder diary records will not depend on whether or not 
data for voided volume are missing.
Bladder diary records will be supplied to patients at each visit, and patients were instructed to 
bring them to the next visit. In principle, bladder diary records will be collected at the next 
visit.


63
12. SAFETY EVALUATIONS
12.1
Adverse Events
12.1.1
Definitions of Adverse Events
An adverse event is any untoward medical occurrence in a patient participating in a clinical 
study which does not necessarily have to have a causal relationship with an investigational 
product.
For adverse event terms, diagnoses should be recorded as much as possible. If a diagnosis is 
not available, then signs and symptoms will be reported.
Any sign, symptom, or abnormal laboratory test or test finding due to an underlying disease 
(LUTS [urine storage, voiding and post-micturition symptoms] accompanying OAB or DU) 
or any concurrent condition that is present before the start of this study will not be regarded as 
an adverse event. However, any newly occurring symptom or worsening of a concurrent 
condition will be reported as an adverse event.
All clinically significant or medically important changes in laboratory values will be reported 
as adverse events. Any symptom reported by the principal investigator or subinvestigator as 
an adverse event derived from a diagnosis will not be regarded as an adverse event.
Cases where a laboratory test value will be regarded as an adverse event:
•
Requires treatment
•
Requires interruption or discontinuation of the investigational product
•
Any other change considered to be medically significant in the opinion of the principal 
investigator or subinvestigator
Details on how to enter data are provided in the Manual for eCRF 
Completion/Change/Modification.
Pregnancy and medication error are described in Section 12.5.
12.1.2
Severity of Adverse Events
The severity of adverse events will be rated as one of the following (; [semicolon] means 
“or”):
(1) Mild
Mild; No symptom or mild symptom; Clinical or laboratory findings only; Requires no 
treatment
(2) Moderate
Moderate; Requires minimal/local/noninvasive treatment; Limiting age-appropriate 
instrumental activities of daily living*
(3) Severe
Severe or medically significant but not immediately life-threatening; Requires inpatient 
hospitalization or prolongation of existing hospitalization; Inactivity/Inactivity; Limiting 
self-care activities of daily living** In addition, life-threatening events or events 
requiring emergency intervention, or death due to an adverse event are also regarded as 


64
severe.
*:
Instrumental activities of daily living refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc
**: Self-care activities of daily living refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.
12.1.3
Causal Relationship with Investigational Product
The causal relationship between an adverse event and the investigational product will be 
assessed using the following 2-point scale, taking into account various factors (eg, patient’s 
condition, medical history, concomitant medications, temporal relationship between the 
investigational product administration and onset of the adverse event). When the causal 
relationship with the investigational product is evaluated as “no reasonable possibility,” the 
reason will be entered in the eCRF.
(1) Reasonable possibility (Related): The event follows a reasonable temporal sequence 
from administration of the investigational product, and any of the following conditions 
are met:
-
A positive dechallenge: This means that the event improves or resolves after the 
investigational product is stopped (temporarily or permanently).
-
A positive rechallenge: This means that the event reappears after the 
investigational product is restarted.
-
The event cannot be reasonably explained by the patient’s clinical state and/or 
therapies administered other than the investigational product.
-
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, Stevens-Johnson syndrome).
(2) No reasonable possibility (Not related): There is no evidence to suggest a reasonable 
possibility between the investigational product and the adverse event.
If considered as “no reasonable possibility”:
-
The adverse event occurred prior to investigational product administration.
-
When the adverse event may have occurred due to the primary disease, 
complications, concomitant drugs, patient’s predisposition, etc.
12.1.4
Outcome of Adverse Events
The outcome of an adverse event will be classified into the following:
(1) Recovered/resolved
The symptom or finding has disappeared or returned to the previous condition.
(2) Recovering/resolving
The symptom or finding has almost disappeared or almost returned to the previous 
condition.
(3) Not recovered/not resolved
When the symptom or finding has not improved and remains unchanged


65
(4) Recovered/resolved with sequelae
The symptom has resolved, but dysfunction that interferes with daily life is considered 
to have occurred due to the adverse event.
(5) Fatal
The patient died due to the adverse event.
12.1.5
Reporting of Adverse Events
Adverse events will be reported from the time of informed consent through the end of the 
follow-up examination. All adverse events will be documented in the source documents. The 
eCRF should include adverse events occurring in relation to this study from the time of 
informed consent to the start of investigational product administration and adverse events 
occurring after the start of investigational product administration. The evaluation in the 
observation period will be performed using the observations and tests at the registration in the 
observation period as a baseline, and the evaluation in the treatment period will be performed 
using the observations and tests at the registration in the treatment period as a baseline.
The principal investigator or subinvestigators will notify the sponsor of any adverse event or 
serious medical event including death which is reported or observed by a physician after the 
end of the follow-up examination and whose causal relationship with the investigational 
product cannot be ruled out.
12.1.6
Follow-up of Adverse Events
If an adverse event occurs, the principal investigator or subinvestigator will immediately take 
appropriate measures and follow up the event until it is confirmed to have resolved or to be 
resolving. However, if follow-up of the adverse event cannot be continued for any of the 
following reasons, the reason will be entered in the eCRF:
•
The causal relationship with the investigational product cannot be evaluated because 
other treatment was performed.
•
The follow-up becomes difficult due to transfer to another hospital, etc.
•
The patient refuses to be followed.
•
The patient dies.
•
Although the adverse event has not resolved or is not resolving, the principal investigator 
or subinvestigator considers that the adverse event is stable or no further improvement is 
expected.
12.2
Serious Adverse Events
12.2.1
Definitions of Serious Adverse Events
An adverse event that results in one of the following at any dose is a serious adverse event:
(a)
Results in death;
(b)
Is life-threatening;
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe.


66
(c)
Requires inpatient hospitalization or prolongation of existing hospitalization for 
treatment. The following are not considered hospitalizations for the purposes of 
assessing seriousness:
-
Emergency room visits < 24 hours;
-
Pre-planned hospitalization;
-
Hospitalization for study-related tests.
(d)
Results in persistent or significant disability/incapacity.
(e)
Is a congenital anomaly/birth defect (if exposure to a product just before conception or 
during pregnancy resulted in an adverse outcome in the child).
(f)
Other medically important conditions.
Note: Any other important medical event that based upon appropriate medical 
judgment may jeopardize the patient or may require medical or surgical intervention to 
prevent one of the other outcomes (a) to (e) listed in the definitions above. (eg, may 
not result in death, be life-threatening, or require hospitalization).
Examples of such events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, and blood dyscrasias, or convulsions that do not 
result in inpatient hospitalization, or development of drug dependency or drug abuse.
12.2.2
Reporting of Serious Adverse Events
A serious adverse event must be reported to the sponsor within 24 hours from the time the 
principal investigator or subinvestigator first becomes aware of the serious adverse event. 
Comprehensive information available at the time of initial reporting (including narrative 
description, medical history, and concomitant medications) needs to be provided with careful 
consideration regarding causality and serious criterion. The contact information for serious 
adverse events is shown below.
After the initial serious adverse event notification to the sponsor, all follow-up serious adverse 
event information will be submitted each time they become available (eg, diagnosis, outcome, 
causality assessment, results of specific investigations).
The principal investigator will submit further necessary information if it is requested by the 
sponsor, the head of the study site, or the IRB.
All serious adverse events occurring from the time of informed consent to the end of the 
follow-up examination will be reported to the sponsor. If any serious adverse event (including 
death) occurs outside the study period specified in the protocol, the principal investigator will 
report the serious adverse event to the sponsor only if he/she suspects it to be related to the 
investigational product.


67
Contact for serious adverse events
Clinical Development Department, Taiho Pharmaceutical Co., Ltd.
1-2-4 Uchikanda, Chiyoda-ku, Tokyo 101-047, Japan
(8:40 am to 5:30 pm, except for Saturdays, Sundays, holidays, and December 29 to 
January 4)
For hours other than the above, contact the product leader or clinical team leader.
For the contact information for the product leader and the clinical team leader, see the 
attachment to the protocol.
12.2.3
Follow-up of Serious Adverse Events
Serious adverse events should be followed up in the same manner as the follow-up of adverse 
events. The follow-up procedure for adverse events is described in Section 12.1.6. If the 
follow-up of a serious adverse event cannot be continued, the reason will be recorded in the 
serious adverse event report form as well.
12.2.4
Expectedness to Investigational Product
The expectedness (known, unknown) to the investigational product will be determined based 
on the description of the Investigator’s Brochure. If the nature and severity are consistent with 
the description, the event will be regarded as “known.” Even if the event is listed in the 
Investigator’s Brochure but if its nature and severity are not consistent with the description 
(eg, interstitial nephritis for acute renal failure, fulminant hepatitis for hepatitis), the event is 
regarded as “unknown.”
Since no serious adverse event for which a causal relationship cannot be ruled out has 
occurred so far with TAC-302, all serious adverse events occurring in this study will be 
handled as “unknown.”
12.3
Adverse Events of Special Interest
12.3.1
Definition of Adverse Events of Special Interest
Adverse events of special interest are not defined in this study.
12.4
Adverse Reactions
12.4.1
Definition of Adverse Reactions
Adverse events (including abnormal laboratory values) occurring during or after the treatment 
period for which a causal relationship with the investigational product is assessed as 
“reasonably possibility” by the principal investigator or subinvestigator are considered to be 
adverse reactions.


68
12.5
Other Information
12.5.1
Pregnancy
In this study, female patients of reproductive potential are required to practice contraception 
during the study period and for 30 days after the completion of investigational product 
administration. Male patients are required to practice contraception during the study period 
and for 90 days after the end of investigational product administration.
If obtaining pregnancy information such as pregnancy of a patient or the patient’s partner 
during the specified contraception period, the principal investigator or subinvestigator will 
report the pregnancy information of the patient within 24 hours after he or she initially 
learned the pregnancy or the outcome of pregnancy. Pregnancy information will be recorded 
on a Pregnancy Form and reported to the sponsor by e-mail or fax. New and/or corrected 
information must be entered into the Pregnancy Form and submitted to the sponsor via email 
or fax.
The principal investigator or subinvestigator will follow the pregnancy of the patient and 
report the outcome. If the outcome of the pregnancy is a stillbirth, congenital anomaly/birth 
defect, or a serious event in the mother, it should be reported as a serious adverse event to the 
sponsor. Live births will be followed up by the principal investigator or subinvestigator, and 
any information that may be associated with the investigational product should be reported to 
the sponsor even after study completion.
12.5.2
Medication Errors
In this study, a medication error is defined as any unintentional error in prescribing, 
dispensing, or administering the drug used in the study while the drug is in the control of the 
healthcare professional or patient. The error may be related to the administration of a wrong 
drug, the nature of a drug, the route of administration, the dosage or frequency of 
administration specified in this protocol.
The following procedures should be followed:
•
Any medication error with the investigational product should be reported to the sponsor 
immediately regardless of the occurrence of an adverse event (even if it does not fulfill 
the definition of a serious adverse event).
•
There is no known antidote available for an investigational product overdose. Patients 
should be carefully monitored, and aggressive treatment should be performed with 
prophylactic and symptomatic therapies to prevent or treat possible adverse reactions.


69
13. STATISTICAL CONSIDERATIONS
Statistical analyses will be performed according to the following plan. Details will be 
specified in a separately prepared statistical analysis plan. The first version of the statistical 
analysis plan will be prepared before unblinding.
13.1
Analysis Plan
13.1.1
Timing of Statistical Analysis
Statistical analysis will be performed after completion of the study in all patients in this study. 
Before unblinding, preliminary investigation (blind review) of the distribution of efficacy and 
safety measurements or endpoints and the relationships between items will be performed, and 
details such as the handling of patient data and the method of statistical analysis will be 
finalized.
13.1.2
Analysis Sets and Criteria for Handling Patient Data
13.1.2.1
Analysis set
The definitions of the analysis sets in this study are as follows.
Table 13.1.2.1-1  Definition of Analysis Sets
Analysis set
Definition
Screening patients
The set of all patients who provided informed consent
All enrolled patients in 
the observation period
The set of all patients who were enrolled in the observation period
All enrolled patients in 
the treatment period
The set of all patients who were enrolled in the treatment period
All treated patients in 
the observation period
The set of patients enrolled in the observation period who took the 
investigational drug at least once
All treated patients in 
the treatment period
The set of patients enrolled in the treatment period who took the 
investigational drug at least once
Full analysis set(FAS)
The set of patients enrolled in the treatment period who took the 
investigational drug for the treatment period at least once and who 
had at least 1 efficacy endpoint measurement before the start of the 
treatment period and in the treatment period
Per protocol set(PPS)
The set of patients in the full analysis set (FAS), excluding patients 
who met any of the following criteria:
(1) Being discovered to have a violation of the inclusion criteria
(2) Being discovered to meet any of the exclusion criteria (criteria 
affecting efficacy evaluation)
(3) A compliance rate for the treatment period of < 80%


70
(4) Being administered prohibited concomitant drugs or prohibited 
concomitant therapy considered likely to influence efficacy 
evaluation
(5) No evaluation of the primary endpoint at week 12 of the 
treatment period
If there are patients in unforeseen situations with respect to whether they belong to analysis 
sets, the sponsor will decide how to handle these patients after discussion with personnel 
including the medical expert, before unblinding.
13.1.2.2
Criteria for Handling Patient Data
The criteria for handling patient data in this study are as follows.
If there are patients with problems associated with the handling of patient data in this study 
other than those below, the sponsor will decide how to handle these patients after discussion 
with personnel including the medical expert, before unblinding.
(1) Handling of missing values and abnormal values
-
The handling of missing values for efficacy endpoints will be designated 
separately for each analysis.
-
Missing values for safety endpoints will not be imputed, and when percentages 
such as the incidence of adverse events are calculated, in analysis of the 
observation period, the analysis set will be used as the denominator, and in 
analysis of the treatment period, the patients in the analysis set who take the 
investigational drug for the treatment period at least once will be used as the 
denominator.
-
All measured data will be used in analysis except for abnormal values for which 
there is an obvious reason, such as laboratory values affected by hemolysis at the 
time of blood collection. If any abnormal values are excluded from analysis, 
these values will be identified and the reasons for excluding them will be shown.
(2) Handling of data from patients administered treatment for a group different from the 
group they are assigned to
-
In analysis of all treated patients and the PPS, data from patients administered 
treatment for a group different from the group they are assigned to will be 
handled as data for the group with the regimen actually administered.
-
For analyses using the FAS, data will be handled as data from the randomized 
assigned group.
13.1.3
Methods of Statistical Analysis
The methods of primary statistical analysis of the primary objective and secondary objectives 
in this study are as follows.
13.1.3.1
Patient Disposition and Patient Backgrounds
(1) Patient disposition


71
-
The numbers of patients enrolled in each group (including a breakdown by sex) 
will be tabulated so that the patients belonging to each analysis set can be seen, 
and a list of patients excluded from analysis sets with the reasons for exclusion 
will also be displayed.
(2) Patient backgrounds
-
In the PPS, information including distributions of the major patient background 
data and disease characteristics will be summarized.
13.1.3.2
Analysis of the Primary Endpoint
The primary endpoint, BCI (males) or PIP1 (females), will be analyzed as follows.
(1)
Primary analysis
-
Summary statistics and 95% confidence intervals at each evaluation time point 
will be calculated by group in the PPS.
(2)
Sensitivity analysis of the primary analysis
-
(1) will be evaluated in the FAS.
(3)
Secondary analysis of the primary endpoint
The following analysis will be performed in the FAS and PPS.
-
Time course plots at each evaluation time point will be prepared by group.
-
Paired t-tests for the values at baseline (week 0) and week 12 of the treatment 
period will be performed by group.
-
Summary statistics and 95% confidence intervals for the change and percentage 
change at week 12 of the treatment period relative to baseline (week 0) will be 
calculated by group.
-
The treatment effect in the TAC-302 group relative to the placebo group will be 
estimated using model analysis of the change and percentage change at week 12 
of the treatment period relative to baseline (week 0).
13.1.3.3
Analysis of Secondary Endpoints
13.1.3.3.1
Analysis of Efficacy
The following analysis will be performed by group in the FAS and PPS.
(1) PFS parameters (filling phase) [Evaluation time points: week 0, week 12]
1)
Volume at first desire to void
2)
Maximum bladder volume
3)
Bladder compliance
4)
Appearance of bladder involuntary contraction
5)
Bladder volume up to appearance of bladder involuntary contraction
-
For 1), 2), 3), and 5), summary statistics and 95% confidence intervals for the 
measured values at each evaluation time point, and for the change and percentage 
change at week 12 of the treatment period relative to baseline (week 0), will be 
calculated.


72
-
For 4), the frequency of involuntary bladder contractions at each evaluation time 
point (weeks 0 and 12) will be tabulated.
(2) PFS parameters (voiding phase) [Evaluation time points: week 0, week 12]
1)
Detrusor pressure at start of voiding (Pdet open)
2)
Maximum detrusor pressure (Pdet max)
3)
Maximum flow rate (Qmax)
4)
Average flow rate (Qave)
5)
Detrusor pressure at maximum flow (PdetQmax)
6)
Duration of bladder contraction
7)
Voided volume
8)
Post void residual
-
Summary statistics and 95% confidence intervals for the measured values at each 
evaluation time point, and for the change and percentage change at week 12 of the 
treatment period relative to baseline (week 0), will be calculated.
(3) Uroflowmetry parameters [Evaluation time points: weeks 0, 4, 8, 12]
1)
Maximum flow rate (free Qmax)
2)
Average flow rate (free Qave)
3)
Voided volume
4)
Voiding time
-
Summary statistics and 95% confidence intervals for the measured values at each 
evaluation time point, and for the change and percentage change at weeks 4, 8 and 
12 of the treatment periods relative to baseline (week 0), will be calculated.
(4) Post void residual measured by ultrasonography [Evaluation time points: at 
registration in observation period, weeks 0, 4, 8, 12]
-
Summary statistics and 95% confidence intervals for the measured values at each 
evaluation time point, and for the change and percentage change at weeks 4, 8 and 
12 of the treatment periods relative to baseline (week 0), will be calculated.
(5)
BVE [Voided volume / (voided volume + post void residual)] [Evaluation time points: 
weeks 0, 4, 8, 12]
Calculated from the voided volume measured by uroflowmetry and the post void 
residual measured by ultrasonography
-
Summary statistics and 95% confidence intervals for the measured values at each 
evaluation time point, and for the change and percentage change at weeks 4, 8 and 
12 of the treatment periods relative to baseline (week 0), will be calculated.
(6)
Change in IPSS score at weeks 4, 8, and 12 of the treatment periods relative to 
baseline (week 0)
1)
IPSS total score
2)
IPSS storage symptoms score
3)
IPSS voiding symptoms score
4)
IPSS QOL score
-
Summary statistics at each evaluation time point will be calculated by group.


73
(7)
Change in IPSS score at weeks 4, 8, and 12 of the treatment periods relative to 
baseline (week 0)
-
Summary statistics at each evaluation time point will be calculated by group.
(8)
Change in the KHQ score (by domain) at week 12 of the treatment period relative to 
baseline (week 0)
-
Summary statistics at each evaluation time point will be calculated by group.
(9)
Change in bladder diary record data at weeks 4, 8, and 12 of the treatment periods 
relative to baseline (week 0)
1)
Average number of micturition per 24 hours
2)
Average number of urgency urinary incontinence episodes per 24 hours
3)
Average number of urinary urgency episodes per 24 hours
4)
Average voided volume per urination
5)
Average number of nocturnal urinations
-
Summary statistics at each evaluation time point will be calculated by group.
The relationships between each endpoint will be investigated exploratively for the primary 
endpoint and secondary endpoints (efficacy). The investigated endpoints are specified in the 
statistical analysis plan.
13.1.3.3.2
Treatment Status
The following analysis will be performed by group in patients treated in the observation 
period and patients treated in the treatment period.
(1) Treatment Status
-
The treatment status (cumulative dose and total duration of treatment) for each 
patient will be summarized.
(2) Treatment completion status
-
Summary statistics for treatment compliance will be calculated for each patient.
-
Whether patients are discontinued from the study and the reasons for 
discontinuation will be tabulated.
13.1.3.3.3
Safety Analysis
The following analysis will be performed by group in the patients treated in the treatment 
period.
(1) Adverse events
The following analyses will be performed:
-
The incidences of adverse events will be calculated.
-
For each adverse event item, the numbers of patients who experience adverse 
events and the incidences of adverse events will be displayed by severity.
-
Incidences will be calculated by time of onset of adverse events in the treatment 
period.
-
A list of the adverse event term, severity, date of onset, action taken, outcome of 
the adverse event, causal relationship with the investigational drug and comment 


74
about the adverse events will be prepared for each adverse event item by patient, 
for all adverse events occurring from the start of administration of the 
investigational drug to the date of the end of the follow-up examination.
(2)
Adverse reactions
-
Adverse reactions will be analyzed in a similar manner to adverse events (except 
the preparation of lists).
(3)
Blood pressure, pulse rate, and body temperature
-
Summary statistics for blood pressure, pulse rate and body temperature at each 
evaluation time point will be calculated.
-
For blood pressure and pulse rate, summary statistics for the change in the 
measured value at each evaluation time point relative to directly before the start 
of administration of the investigational drug for the treatment period will be 
calculated.
(4)
12-lead electrocardiography
The QT interval corrected with the Fridericia method (QTcF), which is an examination 
item in 12-lead electrocardiography, will be used.
-
For the QTcF interval and heart rate, summary statistics for measured values will 
be calculated for each evaluation time point.
-
For the QTcF interval and heart rate, summary statistics for the change in the 
measured value at each evaluation time point relative to directly before the start 
of administration of the investigational drug for the treatment period will be 
calculated.
-
For the QTcF interval, the measured values at each evaluation time point were 
divided into categories and their frequencies will be tabulated.
-
For the QTcF interval, the change in the measured value at each evaluation time 
point relative to directly before the start of administration of the investigational 
drug for the treatment period were divided into categories and their frequencies 
will be tabulated.
(5)
Laboratory Values
-
Summary statistics at each evaluation time point will be calculated for each 
laboratory test.
13.1.4
Target Sample Size and Rationale for the Sample Size
 
 
 
 


75
14. RATIONALES
14.1
Rationale for the Endpoints
 
 
 
 
 
 
 
 
 
14.2
Rationale for the Method of Administration
 
 
 
 
 
 
 
 
 
14.3
Rationale for the Inclusion/Exclusion Criteria
14.3.1
Rationale for the Inclusion Criteria
14.3.1.1
Registration in the Observation Period
 
 
 
 


76
14.3.1.2
Registration in the Treatment Period
 
 
 
 
 
14.3.2
Rationale for the Exclusion Criteria
14.3.2.1
Registration in the Observation Period
 
 
 
 
 
 
 
 
 
 
 
14.3.2.2
Registration in the Treatment Period
 
 
 
14.4
Rationale for Prohibited Concomitant Medications


77
 
 
14.5
Rationale for Prohibited Concomitant Therapies
14.6
Rationale for the Contraception Period
 
 
 
 
 


78
15. CASE REPORT FORMS
In this study, the sponsor will provide electronic case report forms (eCRFs) and an electronic 
data capture (EDC) system. To protect eCRF data, data will be transmitted from study sites 
via an SSL system on the Internet. Access to the EDC system will be limited only to the 
principal investigator, subinvestigator, and authorized personnel authenticated by IDs and 
passwords assigned to each user. IDs and passwords shall be kept confidential and shall never 
be shared with others. Monitors will be given access to the EDC system for source data 
verification. The monitors, data manager, auditors, etc of the sponsor will be given access to 
the EDC system with authority according to their roles. The monitors, data manager, auditors, 
etc will not be authorized to enter, correct, or electronically sign eCRFs.
15.1
eCRF Documentation
An eCRF will be completed for each patient enrolled in the observation period. All contents, 
except for special notes, will be entered in English. The principal investigator, 
subinvestigator, and study coordinator will enter, change, correct, or add data in eCRFs 
according to the “Manual for eCRF Completion/Change/Modification.” The principal 
investigator will confirm that there is no problem in the contents entered in each eCRF and 
electronically sign the eCRF.
The sponsor will check the contents of each eCRF and may issue queries for additional items 
to be checked. The principal investigator, subinvestigator, and study coordinator will check 
the contents of data that require verification, make modifications as necessary, and respond to 
the sponsor.
15.2
eCRF Completion Instructions
When completing eCRFs, the following points should be considered:
(1) The sponsor will distribute the “Manual for eCRF Completion/Change/Modification” 
to the principal investigator, subinvestigator, and study coordinator. The principal 
investigator or subinvestigator will enter, change, modify, or add data in eCRFs in 
accordance with the manual. The study coordinator can enter, change, modify, or add 
data in eCRFs based on source documents prepared by the principal investigator or 
subinvestigator according to the manual.
(2) Information used for personal authentication in the EDC system, such as IDs and 
passwords, should never be shared among the principal investigator, subinvestigator, 
and study coordinator from the viewpoint of preparing eCRFs based on appropriate 
personal authentication. To prevent unauthorized access to eCRFs by masquerading, 
information such as IDs and passwords used for personal authentication shall be stored 
so that it will not be leaked to others. The sponsor, principal investigator, 
subinvestigator, and study coordinator will check the audit trail of the EDC system as 
appropriate to confirm whether there is any unauthorized access or data manipulation 
by masquerading.


79
(3) When a modification or change is made to eCRF entries, the reason should also be 
entered. The reason for modification/change will be recorded as an audit trail together 
with the contents of modification/change.
(4) When a section to be filled out remains blank, if necessary, an expression to 
differentiate it from input omission should be entered as “MS (No Data).”
(5) The principal investigator will check eCRF entries against source data such as medical 
records (charts), confirm the contents, and electronically sign each eCRF.
(6) The electronic signature must be personally affixed by the principal investigator.


80
16. PROTOCOL COMPLIANCE, DEVIATIONS, AND AMENDMENTS
16.1
Protocol Compliance
The principal investigator will sign or seal and date the protocol or an alternative document to 
confirm agreement with the sponsor on the contents of the protocol and compliance with the 
protocol.
16.2
Protocol Deviations
Major protocol deviations include the following:
(1) Violation of the inclusion criteria, which may have a significant impact on the efficacy 
and safety evaluations of TAC-302
(2) Violation of the exclusion criteria, which may have a significant impact on the 
efficacy and safety evaluations of TAC-302
(3) Violation where a patient meets the discontinuation criteria but does not discontinue 
investigational product administration
(4) Deviation that leads to a serious GCP violation
If a change is made to the protocol, the principal investigator and the sponsor should agree on 
the change in writing in advance and obtain written approval of the IRB based on the 
preliminary review.
The principal investigator should promptly provide a written report on any change 
significantly affecting the conduct of the study or increasing the risk to patients to the 
sponsor, the head of the study site, and the IRB via the head of the study site.
If there is an inevitable medical reason such as avoidance of urgent risks to patients, the 
protocol may be deviated or modified without prior written agreement with the sponsor and 
prior approval of the IRB. In such a case, the principal investigator should promptly report the 
details and the reason for the deviation or change to the sponsor and the head of the study site 
and submit it to the IRB via the head of the study site to obtain written approval.
The principal investigator will record all protocol deviations, regardless of the reason.
16.3
Protocol Amendments
If considering it necessary to amend the protocol, the sponsor will submit a protocol 
amendment to the principal investigator. The principal investigator will thoroughly review the 
details of the amendment.
If the protocol is amended, the sponsor should obtain the agreement of the principal 
investigator. However, no new agreement is required for administrative amendments only (eg, 
change in the sponsor’s organization or system, change of the name of the study site or 
department, change of the address or telephone number of the study site or the sponsor, 
change of the principal investigator’s title, change of monitors).
The sponsor will submit the protocol amendment to the head of the study site and obtain 
approval from the IRB via the head of the study site. 


81
17. Access to Source Data/Documents
The principal investigator and the head of the study site will provide all study-related records 
such as source documents for direct access during study-related monitoring, audits, and 
inspections by the IRB and regulatory authorities.
17.1
Source Data/Documents
Source documents are original documents, data, and records (eg, informed consent forms, 
medical records, test notes, memoranda, drug prescription records, data and test results 
recorded by various automatic instruments, patient files, patient enrollment sheets, list of 
screened patients, investigational product control records, medication diaries, pressure flow 
study [PFS] results, uroflowmetry test results, IPSS, OABSS, KHQ, bladder diary records, 
and records kept at the pharmacy, laboratories, and medical technology departments involved 
in this study).
The following items are “data to be directly entered in eCRFs and regarded as source data.” If 
there is a record in a medical record, etc, the medical record, etc will be the source document. 
If data are not recorded in a medical record and directly entered in eCRFs, the principal 
investigator or subinvestigator will enter the data.
•
Past history and complications considered to significantly affect the study by the 
principal investigator or subinvestigator
•
Purpose of concomitant medications and therapies
•
Name, purpose, and duration of concomitant medications and therapies prescribed at 
other hospitals
•
Presence or absence of adverse events, seriousness, severity, outcome, reason for 
completion of follow-up, causal relationship with the investigational product
•
Presence or absence of discontinuation/dropout and the reason
•
Comments, reason for completion of follow-up
17.2
Direct Access
The sponsor’s monitor will check the eCRFs against the source documents to confirm the 
following: If there is any inconsistency with a source document, a record explaining the 
reason shall be obtained from the principal investigator.
•
Data required by the protocol are accurately recorded in the eCRFs and serious adverse 
event reports and are consistent with the source documents.
•
All changes in the TAC-302 dosing regimen or dosing method, if any, have been entered 
in the eCRFs.
•
Adverse events have been entered into the eCRFs as per protocol.
•
All withdrawals and dropouts of enrolled patients have been entered in the eCRFs and the 
reasons are explained.


82
18. QUALITY CONTROL AND QUALITY ASSURANCE IN THE STUDY
The sponsor will implement the following quality control and quality assurance duties 
according to the sponsor’s SOPs.
18.1
Quality Control in the Study
The sponsor will control the quality of the study according to the individual SOPs relating to 
the conduct of the study and the monitoring plan for this study. The main duties are as 
follows:
•
Explaining matters such as the method of selecting patients and the method of 
investigating and evaluating efficacy and safety, through holding events such as meetings 
to explain the protocol to the principal investigator, subinvestigators or study coordinator.
•
Performing periodic monitoring of study sites to check that the study is being conducted 
in compliance with the protocol and GCP.
•
Viewing the source data to check that the contents entered into the electronic case report 
forms (eCRFs) are accurate. Preparing the “Manual for eCRF 
Completion/Change/Modification” and requesting the principal 
investigator/subinvestigator to modify it when a change or a modification becomes 
necessary.
•
Inspecting the contents entered into the eCRFs.
•
Checking that the required documents to be stored at study sites are stored appropriately.
•
Making records and reports about the running of the study, the collection of data, data 
management, statistical analysis and analysis of data such as adverse events, according to 
the sponsor’s SOPs, and inspecting and checking them.
18.2
Sponsor’s Auditing and Regulatory Inspection
The principal investigator will permit auditing by the sponsor and inspection by regulatory 
authorities for the purpose of ensuring compliance with the protocol, GCP, and applicable 
regulatory requirements.
The principal investigator will agree to allow the auditors and inspectors direct access to study 
records. The personnel performing these activities will not disclose any personal identity or 
personal medical information assessed.
The principal investigator will make every effort to help with the performance of the audits 
and inspections, giving access to all necessary facilities, data, and documents pertaining to the 
study. The principal investigator should contact the sponsor immediately when being notified 
of a planned inspection by the regulatory agency or the IRB. Any results arising from such an 
inspection will be immediately communicated by the principal investigator to the sponsor. 
The principal investigator will take appropriate measures required by the sponsor and take 
corrective actions for all findings and observations found during audits and/or inspections.


83
19. DATA HANDLING AND RECORD KEEPING
19.1
Handling of Data
All information provided to the principal investigator by the sponsor, including the protocol, 
eCRFs, Investigator’s Brochure, and results obtained during the course of the study, is 
confidential. Persons involved in the conduct of this study will agree not to mention such 
information in any way without prior written consent of the sponsor.
The patient’s personal data and the principal investigator’s and subinvestigator’s personal data 
which may be included in the sponsor’s database will be treated in compliance with all 
applicable laws and regulations.
When processing and retaining the patient’s personal data and the principal investigator’s and 
subinvestigator’s personal data, the sponsor will take all appropriate measures to safeguard 
and prevent access to these data by any unauthorized third party.
19.2
Retention of Records
19.2.1
Principal Investigator and Study Site
The principal investigator and the study site will be responsible for the retention of all study 
documents according to applicable regulatory requirements and GCP.
The principal investigator and the study site will agree to inform the sponsor in writing of the 
intention to remove or destroy any study-related records. Prior to contacting the sponsor, the 
principal investigator and the study site will ensure that the applicable regulatory 
requirements have been satisfied. The sponsor will permit the principal investigator and the 
study site in writing to destroy such records.
In the event that all requirements for record retention have been fulfilled but the sponsor 
requests that the principal investigator and the study site maintain the records for a longer 
period of time, additional arrangements will be made.
19.2.2
Sponsor
The sponsor shall retain all sponsor-specific essential documents in conformance with the 
applicable regulatory requirements of the countries where the product is approved and where 
the sponsor intends to apply for approvals. 
If discontinuing the clinical development of the investigational product, the sponsor shall 
maintain essential documents to be retained by the sponsor in conformance with the 
applicable regulatory requirements.


84
20. COMPENSATION FOR HEALTH INJURY
The sponsor is insured according to applicable regulatory requirements and provide a 
summary of compensation to the study site.
Except for claims that have arisen due to medical malpractice or negligence, in preparation for 
compensation claims arising out of cases which no legal responsibility is clearly identified, 
the sponsor will specify the compensation policy and payment procedure for summary of 
compensation in case of a health injury related to the study.
When patients receive compensation, summary of compensation should be complied with.


85
21. PUBLICATION AND SECONDARY USE OF DATA
21.1
Publication
The sponsor will retain the right to use the results of this study for submission to government 
and regulatory authorities of each country.
The results of this study will be reviewed by the sponsor in accordance with applicable 
publication guidelines and financial agreement guidelines and published in scientific journals.
The timing of publication, presenter, etc will be determined in consultation between the 
coordinating investigator and the sponsor.
21.2
Secondary Use of Data
The sponsor will reserve the right to secondary use of the study data. Secondary use of data 
refers to the use (including external provision) of collected data for purposes other than this 
study.
Major examples of secondary use of data are as follows:
•
Use in other clinical studies
•
Integrated analysis with relevant clinical studies
•
Independent analysis by regulatory authorities and information sharing between 
regulatory authorities
•
Use for epidemiological studies


86
22. ETHICS
22.1
Ethical Conduct of the Study
It is mandatory that all considerations regarding the protection of patients by complying with 
the protocol, the ICH GCP Guidelines, the ethical principles that have their origin in the 
Declaration of Helsinki, and all applicable regulatory requirements and grasping the latest 
information.
22.2
Approval by the Institutional Review Board
The study must be approved by an appropriately constituted IRB, as required by ICH 
guidelines (E6 Part 3). The conduct of this study must be reviewed and approved by the IRB 
and then approved by the head of the study site.
During the course of the study, the principal investigator will be responsible for obtaining 
continued review of the study. The timeframe for renewal is based on IRB requirements, but 
at least annually is required by regulations. At the end of the study, the IRB will be notified of 
the study completion and its outcome.
22.3
Procedure for Obtaining Informed Consent
Informed consent must be obtained in compliance with the guidelines provided in the 
Declaration of Helsinki, ICH Guideline (E6), and applicable regulatory requirements.
The principal investigator or subinvestigator will fully inform each patient of all pertinent 
aspects of the study in simple text.
Prior to the participation in the study, the informed consent form must be signed and dated by 
the patient and by the person giving an explanation about informed consent. A copy of the 
signed informed consent form will be given to the patient. The informed consent form 
approved by the IRB will be used.
By signing and dating the informed consent form prior to any study procedure specified in 
this protocol, the patient will be deemed to have consented to participate in the study.
The principal investigator will prepare an informed consent form based on a draft informed 
consent form provided by the sponsor. When the revision is necessary, the principal 
investigator will discuss with the sponsor, prepare the revised version, and use the version 
approved by the IRB.


87
23. STUDY ADMINISTRATIVE STRUCTURE
Details are described in the attachment.


88
24. REFERENCES
1.
Honma Y, Nishizawa O, Yamaguchi O. Terminology criteria for lower urinary tract 
function: Report from the standardization subcommittee of the International Continence 
Society. Journal of the Japanese Continence Society. 2003;14:278-289.
2.
Honma Y, Kakizaki H, Goto M, Takei M, Yamanishi T, Hayashi K. Epidemiological 
study on urination. Journal of the Japanese Continence Society. 2003;14:266-277.
3.
Ponholzer A, Temml C, Wehrberger C, Marszalek M, Madersbacher S. The association 
between vascular risk factors and lower urinary tract symptoms in both sexes. Eur Urol. 
2006;50:581-586.
4.
Thomas AW, Cannon A, Bartlett E, Ellis-Jones J, Abrams P. The natural history of lower 
urinary tract dysfunction in men: minimum 10-year urodynamic followup of transurethral 
resection of prostate for bladder outlet obstruction. J Urol. 2005;174:1887-1891.
5.
Abarbanel J, Marcus EL. Impaired detrusor contractility in community-dwelling elderly 
presenting with lower urinary tract symptoms. Urology. 2007;69:436-440.
6.
Greenland JE, Hvistendahl JJ, Andersen H, Jörgensen TM, McMurray G, Cortina-Borja 
M, et al. The effect of bladder outlet obstruction on tissue oxygen tension and blood flow 
in the pig bladder. BJU Int. 2000;85:1109-1114.
7.
Harrison SC, Hunnam GR, Farman P, Ferguson DR, Doyle PT. Bladder instability and 
denervation in patients with bladder outflow obstruction. Br J Urol. 1987;60:519-522.
8.
Brading AF. A myogenic basis for the overactive bladder. Urology. 1997;50(Suppl 
6A):57-67.
9.
Ameda K, Sullivan MP, Bae RJ, Yalla SV. Urodynamic characterization of 
nonobstructive voiding dysfunction in symptomatic elderly men. J Urol. 1999;162:142-
146.
10. Written and edited by Goto M. Lower urinary tract dysfunction and lower urinary tract 
symptoms: Approach to lower urinary tract dysfunction. Tokyo: Chugai-Igakusha; 2007. 
p.2-8.
11. Seki N. Current status and problems of drugs for the treatment of dysuria. Folia 
Pharmacologica Japonica. 2007;129:368-373.
12. Andersson K.E. Pharmacological treatment of underactive bladder. In: Chapple CR, Wein 
AJ, Osman NI, editors. Underactive Bladder. Springer; 2016. p.39-48.
13. Edited by the Japanese Urological Association, the Japanese Continence Society, the 
Japanese Society of Geriatric Urology, and the Urination Function Examiner System 
Committee. Practical training: Urinary function test. Tokyo: Blackwell Publishing Co., 
Ltd.; 2007. p.68.
14. Homma Y, Yamaguchi O, Hayashi K. An epidemiological survey of overactive bladder 
symptoms in Japan. BJU Int. 2005;96:1314-1318.
15. Gammie A, Kaper M, Dorrepaal C, Kos T, Abrams P. Signs and symptoms of detrusor 
underactivity: an analysis of clinical presentation and urodynamic tests from a large 
group of patients undergoing pressure flow studies. Eur Urol. 2016;69:361-369.


89
16. Nitti VW. Pressure flow urodynamic studies: the gold standard for diagnosing bladder 
outlet obstruction. Rev Urol. 2005;7 (Suppl 6):S14-S21.
17. Guidelines for Clinical Evaluation of Drugs for Overactive Bladder: Notification No. 
0628001 of the Evaluation and Licensing Division, PFSB (June 28, 2006)
18. European Medicines Agency. Guideline on the clinical investigation of medicinal 
products for the treatment of urinary incontinence. June 2013.
19. U.S. Department of Health and Human Services. FDA. CDRH. Guidance for industry and 
food and drug administration staff. Clinical investigations of devices indicated for the 
treatment of urinary incontinence. March 2011.
20. Yamaguchi O, Yoshida M, Okumura H, Kato D, Yasuda D. Efficacy and safety of drugs 
for the treatment of overactive bladder in Japanese patients with overactive bladder-Meta-
analysis of placebo-controlled randomized comparative studies-. Japanese Journal of 
Urological Surgery. 2014;27:1731-1744.
21. Drake MJ, Williams J, Bijos DA. Voiding dysfunction due to detrusor underactivity: an 
overview. Nat Rev Urol. 2014;11:454-464.
22. Choice of Control Group and Related Issues in Clinical Trials: Notification No. 136 of 
the Evaluating and Licensing Division, PMSB (February 27, 2001)
23. Edited by the Japanese Continence Society, Clinical Practice Guideline for Overactive 
Bladder Writing Committee. Clinical Practice Guideline for Overactive Bladder (2nd 
Edition). Tokyo: RichHill Medical Inc.; 2015. p.104-105, p.114-117.
24. Becher E, Roehrborn CG, Siami P, Gagnier RP, Wilson TH, Montorsi F. The effects of 
dutasteride, tamsulosin, and the combination on storage and voiding in men with benign 
prostatic hyperplasia and prostatic enlargement: 2-year results from the Combination of 
Avodart and Tamsulosin study. Prostate Cancer Prostatic Dis. 2009;12:369-374.
25. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder 
voiding efficiency: three simple indices to define bladder voiding function. BJU Int. 
1999;84:14-15.
26. Tan TL, Bergmann MA, Griffiths D, Resnick NM. Stop test or pressure-flow study? 
Measuring detrusor contractility in older females. Neurourol Urodyn. 2004;23:184-189.
27. Osman NI, Chapple CR, Abrams P, Dmochowski R, Haab F, Nitti V, et al. Detrusor 
underactivity and the underactive bladder: a new clinical entity? A review of current 
terminology, definitions, epidemiology, aetiology, and diagnosis. Eur Urol. 2014;65:389-
398.
28. General Considerations for Clinical Trials. Notification No. 380 of the Evaluating and 
Licensing Division, PMSB (April 21, 1998)


90
25. APPENDICES
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                           
 
 
 
 
 
                           
 







SAP_001.pdf: 
TAIHO Pharmaceutical Co., Ltd. 
 
 
Date2020/1/8 
TAC-302 Protocol: 10054040 
1 
Statistical Analysis Plan 
Version 2.0 
Name of investigational 
product 
TAC-302 
Study title 
A Phase 2a Study of TAC-302 in Detrusor Underactivity Patients with 
Overactive Bladder 
Protocol number 
10054040 
Date of preparation or 
revision 
08 January 2020 
Author 
 
History of preparation and revision 
Date 
Author 
Reason for preparation or revision 
29 November 2019 
 
Preparation of the first version 
08 January 2020 
 
Before unblinding, the analyses were changed based 
on the results of the blind review. 
Date and signature 
 
Person in charge of statistical 
analysis 
DD Month YYYY 
 
 
Person responsible for 
statistical analysis 
DD Month YYYY 
 
Taiho Pharmaceutical Co., 
Ltd. 
Statistical team leader 
DD Month YYYY 
 
 
 
 


TAIHO Pharmaceutical Co., Ltd. 
 
 
Date2020/1/8 
TAC-302 Protocol: 10054040 
2 
Changes in Statistical Analysis Plan 
Version 1.0 (29 November 2019) to Version 2.0 (08 January 2020) 
Item 
Before change 
After change 
Reason for change 
6.2.1 
Table 6-
3 
< 65 years, ≥ 65 years 
< 60 years, ≥ 60 years 
< 65 years, ≥ 65 years 
< 70 years, ≥ 70 years 
< 75 years, ≥ 75 years 
The other categories 
have been added 
based on the results of 
the blind review. 
7.3 
Analysis of covariance with age 
(< 65 years, ≥ 65 years) as a 
covariate 
By age (< 60 years and ≥ 60 years 
in males and < 70 years and ≥ 70 
years in females), the above 
analysis excluding time course 
plots and analysis of covariance 
will be performed. 
Separate age 
categories for men and 
women were specified 
based on the results of 
the blind review. 
Text was moved from 
8.1.11. 
8.1.11 Analysis of the primary 
endpoint and secondary 
endpoints (7.3 and 8.1.1 to 
8.1.9) 
Analysis of secondary endpoints 
(8.1.1 to 8.1.9) 
Text was moved to 
7.3. 
Secondary endpoints will be 
analyzed by sex (8.1.1 to 8.1.9). 
In analysis of covariance and 
analysis using an MMRM, sex 
will be excluded from the 
covariates. 
Analysis will be performed as for 
analysis of secondary endpoints by 
sex (8.1.1 to 8.1.9). In analysis of 
covariance and analysis using an 
MMRM, values at baseline and age 
(< 60 years and ≥ 60 years in males 
and < 70 years and ≥ 70 years in 
females) will be used as covariates. 
Separate categories for 
men and women were 
specified based on the 
results of the blind 
review. 
8.3.1 
≥ 65 years, < 65 years 
≥ 65 years, < 65 years 
A typographical error 
was corrected. 
The numbers of patients who 
experienced adverse events and 
the incidences of adverse events 
will be displayed. Similar 
analysis will be performed for 
adverse reactions. Similar 
analysis will also be performed 
by age (≥ 65 years and < 65 
years). 
The numbers of patients who 
experienced adverse events and the 
incidences of adverse events will 
be displayed. Similar analysis will 
be performed for adverse reactions. 
Similar analysis will also be 
performed by age (≥ 65 years and 
< 65 years). 
In addition, similar analysis will be 
performed by age (≥ 75 years and 
< 75 years). 
Tabulation by age was 
added based on the 
results of the blind 
review. 
- 
For each adverse event item, the 
numbers of patients who 
experienced adverse events and the 
incidences of adverse events will 
be displayed. Similar analysis will 
be performed for adverse reactions. 
Similar analysis will also be 
performed by age (≥ 65 years and 
< 65 years). 
In addition, similar analysis will be 
performed by age (≥ 75 years and 
< 75 years).  
This was added to 
make the description 
more detailed. 
Tabulation by age (≥ 
75 years and < 75 
years) was added 
based on the results of 
the blind review. 


TAIHO Pharmaceutical Co., Ltd. 
 
 
Date2020/1/8 
TAC-302 Protocol: 10054040 
3 
For each adverse event item, the 
numbers of patients who 
experienced adverse events and 
the incidences of adverse events 
will be displayed by severity. 
Similar analysis will be 
performed for adverse reactions. 
Similar analysis will also be 
performed by age (≥ 65 years 
and < 65 years). 
For each adverse event item, the 
numbers of patients who 
experienced adverse events and the 
incidences of adverse events will 
be displayed by severity. Similar 
analysis will be performed for 
adverse reactions.  
This text was deleted 
because analysis by 
age will not be 
performed in analysis 
by severity. 
 
 
 


TAIHO Pharmaceutical Co., Ltd. 
 
 
Date2020/1/8 
TAC-302 Protocol: 10054040 
4 
TABLE OF CONTENTS 
1. 
SCOPE AND OBJECTIVES ........................................................................................... 7 
1.1 
Primary Objective ..................................................................................................... 7 
1.2 
Secondary Objectives ................................................................................................ 7 
2. 
STUDY DESIGN AND TARGET SAMPLE SIZE ........................................................ 7 
2.1 
Study Design ............................................................................................................. 7 
2.1.1 
Primary Endpoint ............................................................................................ 7 
2.2 
Target Sample Size .................................................................................................... 7 
2.2.1 
Target Sample Size .......................................................................................... 7 
2.2.2 
Rationale for the Sample Size ......................................................................... 7 
3. 
Data and Analysis Sets to Be Used for Statistical Analysis ........................................... 8 
3.1 
Documents and Data Other Than Case Report Forms .............................................. 8 
3.2 
Analysis Sets ............................................................................................................. 9 
4. 
METHODS OF STATISTICAL ANALYSIS ................................................................ 10 
5. 
TIMING OF STATISTICAL ANALYSIS ..................................................................... 10 
6. 
ENDPOINTS AND COMMON ITEMS IN STATISTICAL ANALYSIS .................. 11 
6.1 
Endpoints ................................................................................................................ 11 
6.1.1 
Efficacy Endpoints ........................................................................................ 11 
6.1.1.1 
Pressure Flow Study (PFS) ................................................................. 11 
6.1.1.2 
Uroflowmetry ...................................................................................... 11 
6.1.1.3 
Evaluation of Symptom Scores ........................................................... 11 
6.1.1.4 
King's Health Questionnaire (KHQ) ................................................... 12 
6.1.1.5 
Bladder Diary Records ........................................................................ 12 
6.1.2 
Safety Endpoints ........................................................................................... 12 
6.1.2.1 
Adverse Events and Adverse Reactions .............................................. 12 
6.1.3 
Endpoints for Treatment Compliance ........................................................... 12 
6.1.3.1 
Compliance Rate ................................................................................. 12 
6.2 
Common Items in Statistical Analysis .................................................................... 13 
6.2.1 
Patient Backgrounds ..................................................................................... 13 
6.2.2 
Statistical Methods ........................................................................................ 14 
6.2.2.1 
Summary Statistics of Continuous Variables ...................................... 14 
6.2.2.2 
Estimation Method .............................................................................. 14 
6.2.3 
Allocation Adjustment Factors to Be Used for Analysis .............................. 14 
6.2.4 
Statistical Analysis Software ......................................................................... 14 
7. 
Primary Endpoint Analyses ........................................................................................... 14 
7.1 
Primary Analysis Corresponding to the Primary Objective .................................... 14 
7.2 
Sensitivity Analysis of Primary Analysis ................................................................ 14 
7.3 
Secondary Analyses of the Primary Endpoint......................................................... 14 
8. 
Secondary Endpoint Analyses ........................................................................................ 16 
8.1 
Analysis of Efficacy ................................................................................................ 16 
8.1.1 
Pressure Flow Study (PFS) Parameters (Filling Phase) ................................ 16 
8.1.2 
Pressure Flow Study (PFS) Parameters (Voiding Phase) .............................. 16 
8.1.3 
Uroflowmetry Parameters ............................................................................. 17 
8.1.4 
Post Void Residual Measured by Ultrasonography ....................................... 17 
8.1.5 
BVE [Voided Volume / (Voided Volume + Post Void Residual)] ................. 18 
8.1.6 
IPSS Score .................................................................................................... 18 
8.1.7 
OABSS Score ................................................................................................ 19 
8.1.8 
KHQ Score (by Domain) .............................................................................. 19 
8.1.9 
Bladder Diary Records .................................................................................. 20 
8.1.10 
Relationship Between Efficacy Endpoints .................................................... 20 
8.1.11 
Analysis by Allocation Factor ....................................................................... 22 
8.1.12 
Analysis by Severity Score ........................................................................... 22 


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8.1.13 
Analysis by Post Void Residual .................................................................... 22 
8.1.14 
Analysis by Appearance of Bladder Involuntary Contraction ...................... 22 
8.1.15 
Analysis of UDS Data Subset ....................................................................... 22 
8.2 
Analysis of Administration Status .......................................................................... 22 
8.2.1 
Study Drug Administration ........................................................................... 22 
8.2.2 
Status of Administration Completion ............................................................ 23 
8.3 
Safety Analysis ........................................................................................................ 23 
8.3.1 
Adverse Events and Adverse Reactions ........................................................ 23 
8.3.2 
Laboratory Test Values .................................................................................. 24 
8.3.3 
12-lead Electrocardiogram ............................................................................ 24 
8.3.4 
Blood Pressure, Pulse Rate, and Body Temperature ..................................... 24 
9. 
Other Analyses ................................................................................................................. 24 
9.1 
Analysis Sets ........................................................................................................... 24 
9.2 
Deviations ............................................................................................................... 24 
9.3 
Patient Backgrounds ............................................................................................... 24 
10. REVIEW AND REVISION OF THE STATISTICAL ANALYSIS PLAN ................ 25 
11. STATISTICAL ISSUES .................................................................................................. 25 
11.1 
Adjustment for Covariates ...................................................................................... 25 
11.2 
Handling of Dropouts or Missing Data ................................................................... 25 
11.3 
Interim Analysis and Data Monitoring ................................................................... 25 
11.4 
Multicenter Studies ................................................................................................. 25 
11.5 
Multiple Comparison/Multiplicity .......................................................................... 25 
11.6 
Use of an "Efficacy Subset" of Patients .................................................................. 25 
11.7 
Active-Control Studies Intended to Show Equivalence .......................................... 25 
11.8 
Examination of Subgroups ...................................................................................... 25 
12. PREPARATION OF REPORT ANALYSIS PLAN ..................................................... 26 
13. REFERENCES ................................................................................................................ 26 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviations and terms used in the statistical analysis plan are defined below. 
Abbreviation (term) 
Description (definition) 
BCI 
Bladder Contractility Index 
BMI 
Body mass index 
BOO 
Bladder Outlet Obstruction 
BVE 
Bladder Voiding Efficiency 
CIC 
Clean Intermittent Catheterization 
DU 
Detrusor Underactivity 
FAS 
Full analysis set 
ICH-E3 Guideline 
"Guideline for Structure and Content of Clinical Study Reports"1) 
IPSS 
International Prostate Symptom Score 
KHQ 
King's Health Questionnaire 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect Models for Repeated Measures 
OAB 
Overactive Bladder 
OABSS 
Overactive Bladder Symptom Score 
PFS 
Pressure Flow Study 
PIP 
Projected Isovolumetric Pressure 
PPS 
Per protocol set 
free Qave 
Average flow rate 
free Qmax 
Maximum flow rate 
QOL 
Quality of life 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
 
 




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3. Data and Analysis Sets to Be Used for Statistical Analysis 
3.1 
Documents and Data Other Than Case Report Forms 
A list of documents and data necessary for statistical analysis other than case report forms is shown in 
Table 3-1. 
Table 3-1: Documents or Data Necessary for Statistical Analysis Other Than Case Report 
Forms 
Item 
Documents or data 
Remarks 
Attribution of 
patients 
Flag of attribution of each patient 
to each analysis set 
To identify the attribution of each patient to 
each analysis set. 
List of patients excluded from 
analysis sets and reasons for 
exclusion 
To list patients excluded from analysis sets. 
UDS data subset and CIC status 
To analyze by UDS data subset and by CIC 
status. 
The definition of UDS data subset is shown 
in 8.1.15. 
Assignment 
information 
Key code and allocation 
adjustment factors at the time of 
enrollment 
To identify treatment groups and analyze 
using allocation adjustment factors. 
Deviation 
information 
Description of deviation and 
deviation flag 
To provide a list of patients with deviations. 
Conversion to 
MedDRA terms 
Correspondence table between 
verbatim terms of adverse events 
and MedDRA terms 
To tabulate the incidence of adverse events 
using standardized terms. 
Correspondence table between 
medical history and complication 
terms and MedDRA terms 
To list medical history and complications 
using MedDRA terms. 
Institutional 
reference value 
Institutional reference values of 
laboratory values 
To assess normal/abnormal laboratory 
values. 
Drug name 
Correspondence table between 
verbatim terms of concomitant 
drugs and WHO Drug Dictionary 
To tabulate concomitant drugs in groups 
and specify the order. 
Centralized 
assessment 
results 
Results of centralized assessment 
of pressure flow study and 
uroflowmetry 
For analysis of pressure flow study (only in 
patients enrolled in the treatment period) 
and uroflowmetry. 
However, for the results of pressure flow 
study in patients who are enrolled in the 
observation period and do not proceed to 
the treatment period, eCRF data (evaluation 
by the study site) will be used because there 
are no results of centralized assessment. 
Efficacy 
evaluation 
Efficacy evaluation data handling 
table 
To additionally specify the handling of 
efficacy evaluation data 
 
 


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3.2 
Analysis Sets 
The analysis sets and their definitions are shown in Table 3-2. If there are patients for whom attribution 
to analysis sets is problematic based on factors other than the criteria shown below, handling of such 
patients will be determined by discussion between the sponsor and medical expert, etc. The primary 
efficacy analysis set will be PPS, and the primary safety analysis set will be all treated patients in the 
treatment period. 
Table 3-2 Definition of Analysis Sets 
Analysis Sets 
Definition 
Screening Patients 
All patients who gave informed consent 
All enrolled patients in the 
observation period 
The set of all patients who were enrolled in the observation period 
All enrolled patients in the 
treatment period 
The set of all patients who were enrolled in the treatment period 
All treated patients in the 
observation period 
The set of patients enrolled in the observation period who took the 
investigational drug at least once 
All treated patients in the 
treatment period 
The set of patients enrolled in the treatment period who took the 
investigational drug at least once 
Full Analysis Set(FAS) 
The set of patients enrolled in the treatment period who took the 
investigational drug for the treatment period at least once and who had 
at least 1 efficacy endpoint measurement before the start of the 
treatment period and in the treatment period 
Per Protocol Set(PPS) 
The set of patients in the FAS, excluding patients who met any of the 
following criteria: 
(1) Being discovered to have a violation of the inclusion criteria 
(2) Being discovered to meet any of the exclusion criteria (criteria 
affecting efficacy evaluation) 
(3) A compliance rate for the treatment period of < 80% 
(4) Being administered prohibited concomitant drugs or prohibited 
concomitant therapy considered likely to influence efficacy evaluation 
(5) No evaluation of the primary endpoint at Week 12 of the 
treatment period 
 
 
 
 


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4. METHODS OF STATISTICAL ANALYSIS 
The objective of the primary analysis is to evaluate the efficacy of TAC-302. As the primary analysis, 
summary statistics and the 95% confidence interval of BCI (males) or PIP1 (females) at Weeks 0 and 12 of 
the treatment period will be calculated at each evaluation time point by treatment group. 
5. TIMING OF STATISTICAL ANALYSIS 
Statistical analysis will be performed after completion of the study in all patients in this study. Before 
unblinding, preliminary examination (blind review) of the measurement of efficacy and safety, distribution 
of endpoints, relationship among items, and other aspects will be performed to make decisions regarding 
the handling of patient data, statistical analysis methods, and other points. 
 
 


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6. ENDPOINTS AND COMMON ITEMS IN STATISTICAL ANALYSIS 
6.1 
Endpoints 
The efficacy and safety endpoints are defined below. 
6.1.1 
Efficacy Endpoints 
6.1.1.1 
Pressure Flow Study (PFS) 
The volume at first desire to void, maximum bladder volume, bladder compliance, appearance of bladder 
involuntary contraction, and bladder volume up to appearance of bladder involuntary contraction will be 
evaluated based on the pressure flow study (filling phase). The detrusor pressure at start of voiding (Pdet 
open), maximum detrusor pressure (Pdet max), maximum flow rate (Qmax), average flow rate (Qave), maximum 
detrusor pressure at peak urine flow (PdetQmax), duration of bladder contraction, voided volume, and post 
void residual will be evaluated based on the pressure flow study (voiding phase). 
For the duration of bladder contraction, the duration of bladder contraction for urination including Qmax 
is defined as the duration of bladder contraction-1 and the duration of bladder contraction for all evaluable 
urinations during the voiding phase is defined as the duration of bladder contraction-2. 
In the summary of patient backgrounds and the analysis by appearance of bladder involuntary 
contraction, patients judged to have bladder involuntary contraction at any of the evaluation time points 
(Weeks 0 and 12/at discontinuation) will be handled as those with bladder involuntary contraction. For the 
results at each evaluation time point (Weeks 0 and 12/at discontinuation), patients judged to have no 
bladder involuntary contraction at all time points will be handled as those without bladder involuntary 
contraction. Patients without data on presence/absence will be excluded from the analysis. 
6.1.1.2 
Uroflowmetry 
The maximum flow rate (free Qmax), average flow rate (free Qave), voided volume, and voiding time will 
be evaluated based on uroflowmetry. 
DeltaQ is defined as follows3): 
DeltaQ=free Qmax-free Qave 
6.1.1.3 
Evaluation of Symptom Scores 
The endpoints to be used for the evaluation of symptom scores are IPSS, QOL score, and OABSS. 
6.1.1.3.1 
IPSS and QOL Score 
Voiding symptoms and storage symptoms will be evaluated using the IPSS and QOL score. 
The IPSS total score will be the total score of questions 1 to 7, and a score of 0 to 7 points will be 
classified as mild, a score of 8 to 19 points will be classified as moderate, and a score of 20 to 35 points 
will be classified as severe. The total of the scores for question 1 on post-micturition symptoms and 
questions 3, 5, and 6 on voiding symptoms will be taken to be the IPSS voiding symptoms score, and the 
total of the scores for questions 2, 4, and 7 on storage symptoms will be taken to be the score for IPSS 
storage symptoms. 
The score for the question “If you were to spend the rest of your life with your urinary condition as it is 
right now, how would you feel about that?” will be taken to be the IPSS QOL score, and a score of 0 to 1 
points will be classified as mild, a score of 2 to 4 points will be classified as moderate, and a score of 5 to 6 
points will be classified as severe. 
6.1.1.3.2 
Overactive Bladder Symptoms Score (OABSS) 
The OAB symptoms will be evaluated using OABSS. 


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The total OABSS score is defined as the total score of all questions. A score of 5 points or less is 
considered mild, a score of 6 to 11 points is considered moderate, and a score of 12 points or more is 
considered severe. 
6.1.1.4 
King's Health Questionnaire (KHQ) 
The QOL in DU patients with OAB will be evaluated using the KHQ. The scoring method for each 
domain based on the Japanese version of KHQ is shown below. 
Table 6-1 Scoring Method for Each Domain Based on the Japanese Version of KHQ 
Each domain 
Scoring method 
General health 
(Q1 score − 1) / 4 x 100 
Incontinence impact 
(Q2 score − 1) / 3 x 100 
Restrictions on 
job/housework 
(Q3a + 3b − 2) / 6 × 100 
Limitation of physical 
activities 
(Q4a + 4b − 2) / 6 × 100 
Limitation of social activities 
If Q5c score is ≥ 1: 
(Q4c + 4d + 5c score − 3) / 9 x 100 
*If Q5c score is 0: 
(Q4c + 4d + 5c score − 2) / 6 x 100 
Personal relationships 
If Q5a + 5b ≥ 2: 
(Q5a+5b-2)/6×100 
If Q5a + 5b = 1: 
(Q5a+5b-1)/3×100 
If Q5a + 5b = 0: 
Handle the score as a missing value (not applicable) 
Emotions 
(Q6a + 6b + 6c score − 3) / 9 × 100 
Sleep/energy 
(Q7a + 7b score − 2) / 6 × 100 
Severity measures 
(Q8a + 8b + 8c + 8b + 8e score − 5) / 15 × 100 
6.1.1.5 
Bladder Diary Records 
The times of urination, times of urinary incontinence, whether urinary urgency is present, and voided 
volume for each urination will be evaluated using Bladder Diary records. 
The average number of daytime urinations is defined as follows. Nocturnal urination is defined as 
urination after bedtime on the day and before wake-up on the next day. 
Average number of daytime urinations = average number of micturitions per 24 hours – average number 
of nocturnal urinations 
6.1.2 
Safety Endpoints 
6.1.2.1 
Adverse Events and Adverse Reactions 
An adverse event is any untoward medical occurrence in a patient participating in the study. Adverse 
events for which a causal relationship with the investigational product is assessed as “reasonably possible” 
are considered to be adverse reactions. 
6.1.3 
Endpoints for Treatment Compliance 
6.1.3.1 
Compliance Rate 
The definition of compliance rate in the observation and treatment periods is shown below. 


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[1] Observation period 
Compliance rate during the observation period (%) = (number of doses with no dose 
modification/interruption during the observation period) / (prescribed number of doses from the first 
dose of investigational product during the observation period to the last dose of investigational product 
during the observation period) × 100 
[2] Treatment period 
Compliance rate during the treatment period (%) = (number of doses with no dose 
modification/interruption during the treatment period) / (prescribed number of doses from the first 
dose of investigational product during the treatment period to the last dose of investigational product 
during the treatment period) × 100 
6.2 
Common Items in Statistical Analysis 
6.2.1 
Patient Backgrounds 
A list of patient backgrounds to be measured at enrollment is shown in Table 6-2. The details of 
categories when the background factors of continuous values among the background factors shown in Table 
6-2 are divided by category are shown in Table 6-3. 
Table 6-2 Background Factors 
Item 
Factor 
Patient backgrounds 
Sex, age, height, body weight, presence or absence of medical history, 
presence or absence of complications, race, ethnicity, and BMI 
Disease characteristics 
Timing of onset of lower urinary tract symptoms, presence or absence 
of pelvic visceral surgery, presence or absence of radiotherapy, presence 
or absence of drug therapy for the primary disease, bladder outlet 
obstruction index (males) (PdetQmax − 2Qmax), prostate volume 
measurement (males), free Qmax, voiding time, voided volume 
(uroflowmetry), post void residual measured by ultrasonography, BVE 
(voided volume / [voided volume + post void residual] × 100), PdetQmax, 
Qmax, BCI (males), PIP1 (females), IPSS total score, IPSS storage 
symptoms score, IPSS voiding symptoms score, IPSS (Q1, Q3, Q5, and 
Q6), presence or absence of CIC, presence or absence of bladder 
involuntary contraction, severity based on IPSS total score, severity 
based on IPSS QOLS score, and severity based on OABSS score 
Table 6-3 Details of Categories 
Category 
Definition 
Age category 
< 60 years, ≥ 60 years 
< 65 years, ≥ 65 years 
< 70 years, ≥ 70 years 
< 75 years, ≥ 75 years 
Race 
Asian/Oriental, Other 
Ethnicity 
Japanese, .Other 
 
 


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6.2.2 
Statistical Methods 
6.2.2.1 
Summary Statistics of Continuous Variables 
Summary statistics of continuous variables will be presented together with the sample size, minimum, 
maximum, first quartile, median, third quartile, mean, and standard deviation. 
6.2.2.2 
Estimation Method 
(1) Confidence interval of proportion 
The confidence interval of proportion will be determined by an exact method based on F 
distribution.2) 
The upper confidence limit PU and the lower confidence limit PL will be estimated using the 
following formula. P is the proportion, X is the number of patients with events, N is the number of 
patients in the analysis set, and α is the two-sided significance level. 
X
X
N
F
P
X
N
X
F
F
P
N
X
P
L
U
2
)
1
(
2
,
)
2
/
(
)
(
2
)
1
(
2
,
)
2
/
(
)
2
/
(
/
2
1
,
1
2
2
2
1
,
1
2
,
1
2
1
2
1
2
1
































 
6.2.3 
Allocation Adjustment Factors to Be Used for Analysis 
In the analysis using allocation adjustment factors, the data of allocation adjustment factors at the time of 
enrollment will be used. 
Allocation adjustment factors are shown below. 
• Sex (male or female) 
• Age at informed consent (< 65 years or ≥ 65 years) 
6.2.4 
Statistical Analysis Software 
In this study, all statistical processing will be performed using SAS Version 9.4 (SAS/STAT 14.2). 
7. Primary Endpoint Analyses 
The items to be analyzed for the primary endpoint are summarized below. 
7.1 
Primary Analysis Corresponding to the Primary Objective 
For BCI (males) and PIP1 (females), summary statistics and 95% confidence intervals for each 
evaluation time point (Weeks 0 and 12) were calculated by group in the PPS. 
7.2 
Sensitivity Analysis of Primary Analysis 
The primary analysis will be performed in the FAS. 
7.3 
Secondary Analyses of the Primary Endpoint 
For BCI (males) and PIP1 (females), the following analyses will be performed in the FAS and PPS. 
• Time course plots at each evaluation time point (Weeks 0 and 12) will be prepared by group. 
• Paired t-tests for the measured values at baseline (Week 0) and Week 12 of the treatment period will be 
performed by group. 
• Summary statistics and 95% confidence intervals for the change and percentage change at Week 12 of 
the treatment period relative to baseline (Week 0) will be calculated by group. 


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• For the measured values at each evaluation time point (Weeks 0 and 12) and the change and percentage 
change from baseline (Week 0) to Week 12 of the treatment period, the 95% confidence interval for the 
difference between the placebo group and the TAC-302 group will be calculated. 
• For the change and percentage change from baseline (Week 0) to Week 12 of the treatment period, 
student's t test will be performed using the placebo group as the control. 
• Analysis of covariance of the change and percentage change from baseline (Week 0) to Week 12 of the 
treatment period will be performed using treatment group, baseline value, and age (< 60 years or ≥ 60 
years in males, < 70 years or ≥ 70 years in females) as covariates, and the least squares means in each 
treatment group, and the difference in least squares mean between the placebo group and the TAC-302 
group and its two-sided 95% confidence interval will be estimated. 
• By age (< 60 years and ≥ 60 years in males and < 70 years and ≥ 70 years in females), the above analysis 
excluding time course plots and analysis of covariance will be performed. 
 
 


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8. Secondary Endpoint Analyses 
The analyses of the secondary endpoints are outlined below. 
8.1 
Analysis of Efficacy 
In principle, the following analyses will be performed by treatment group in the FAS and PPS. 
8.1.1 
Pressure Flow Study (PFS) Parameters (Filling Phase) 
For the volume at first desire to void, maximum bladder volume, bladder compliance, and bladder 
volume up to appearance of bladder involuntary contraction, the following analyses 1) to 5) will be 
performed. In addition, the analysis in 6) will be performed. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0 and 12), and for the change and percentage change at Week 12 of the treatment period relative 
to baseline (Week 0), will be calculated. 
2) Paired t-test for the measured values at baseline (Week 0) and Week 12 of the treatment period will be 
performed. 
3) For the measured values at each evaluation time point (Weeks 0 and 12) and the change and percentage 
change from baseline (Week 0) to Week 12 of the treatment period, the 95% confidence interval for the 
difference between the placebo group and the TAC-302 group will be calculated. 
4) For the change and percentage change from baseline (Week 0) to Week 12 of the treatment period, 
student's t test will be performed using the placebo group as the control. 
5) Analysis of covariance of the change and percentage change from baseline (Week 0) to Week 12 of the 
treatment period will be performed using treatment group, baseline value, and age (< 65 years or ≥ 65 
years) as covariates, and the least squares means in each treatment group, and the difference in least 
squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval will be estimated.  
6) The frequency of involuntary bladder contractions at each evaluation time point (Weeks 0 and 12) will 
be tabulated. 
8.1.2 
Pressure Flow Study (PFS) Parameters (Voiding Phase) 
The following analyses will be performed for the detrusor pressure at start of voiding (Pdet open), 
maximum detrusor pressure (Pdet max), maximum flow rate (Qmax), average flow rate (Qave), detrusor 
pressure at maximum flow rate (PdetQmax), duration of bladder contraction, voided volume, and post 
void residual. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0 and 12), and for the change and percentage change at Week 12 of the treatment period relative 
to baseline (Week 0), will be calculated. 
2) Paired t-test for the measured values at baseline (Week 0) and Week 12 of the treatment period will be 
performed. 
3) For the measured values at each evaluation time point (Weeks 0 and 12) and the change and percentage 
change from baseline (Week 0) to Week 12 of the treatment period, the 95% confidence interval for the 
difference between the placebo group and the TAC-302 group will be calculated. 
4) For the change and percentage change from baseline (Week 0) to Week 12 of the treatment period, 
student's t test will be performed using the placebo group as the control. 
5) Analysis of covariance of the change and percentage change from baseline (Week 0) to Week 12 of the 
treatment period will be performed using treatment group, baseline value, and age (< 65 years or ≥ 65 
years) as covariates, and the least squares means in each treatment group, and the difference in least 


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squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval will be estimated. 
6) A scatter plot with Qmax on the vertical axis and PdetQmax on the horizontal axis will be prepared for each 
sex. 
8.1.3 
Uroflowmetry Parameters 
The following analyses will be performed for the maximum flow rate (free Qmax), average flow rate 
(free Qave), voided volume, and voiding time. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0, 4, 8, and 12), and for the changes and percentage changes at Weeks 0, 4, 8, and 12 of the 
treatment period relative to baseline (Week 0), will be calculated. 
2) Paired t-test for the measured values at baseline (Week 0) and Week 12 of the treatment period will be 
performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test will be performed using the placebo group as the control. 
5) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with the last observation carried forward (LOCF). 
8.1.4 
Post Void Residual Measured by Ultrasonography 
The following analyses will be performed for post void residual measured by ultrasonography. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0, 4, 8, and 12), and for the changes and percentage changes at Weeks 0, 4, 8, and 12 of the 
treatment period relative to baseline (Week 0), will be calculated. 
2) Paired t-tests for the measured values at baseline (Week 0) and Weeks 4, 8, and 12 of the treatment 
period will be performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test will be performed using the placebo group as the control. 
5) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with LOCF. 
6) The change and percentage change from baseline (Week 0) will be analyzed by MMRM using treatment 
group, evaluation time point (Weeks 4, 8, and 12 of the treatment period), and interaction between 
treatment group and evaluation time point as fixed effects and baseline value, sex, and age (< 65 years 
or ≥ 65 years) as covariates. The least squares means in each treatment group, and the difference in the 
least squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval at each evaluation time point will be estimated. Unstructured covariance structure will be 
assumed, and toeplitz type will be used if convergence is not achieved. If convergence is still not 
achieved, the first-order autoregressive, compound symmetry, and variance component will be used in 
this order. The Kenward-Roger method (2009)4) will be used to calculate degrees of freedom. 


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8.1.5 
BVE [Voided Volume / (Voided Volume + Post Void Residual)] 
The following analyses will be performed for BVE calculated from the voided volume measured by 
uroflowmetry and the post void residual measured by ultrasonography. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0, 4, 8, and 12), and for the changes and percentage changes at Weeks 0, 4, 8, and 12 of the 
treatment period relative to baseline (Week 0), will be calculated. 
2) Paired t-tests for the measured values at baseline (Week 0) and Weeks 4, 8, and 12 of the treatment 
period will be performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test will be performed using the placebo group as the control. 
5) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with LOCF. 
6) The change and percentage change from baseline (Week 0) will be analyzed by MMRM using treatment 
group, evaluation time point (Weeks 4, 8, and 12 of the treatment period), and interaction between 
treatment group and evaluation time point as fixed effects and baseline value, sex, and age (< 65 years 
or ≥ 65 years) as covariates. The least squares means in each treatment group, and the difference in the 
least squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval at each evaluation time point will be estimated. Unstructured covariance structure will be 
assumed, and toeplitz type will be used if convergence is not achieved. If convergence is still not 
achieved, the first-order autoregressive, compound symmetry, and variance component will be used in 
this order. The Kenward-Roger method (2009) will be used to calculate degrees of freedom. 
8.1.6 
IPSS Score 
The following analyses will be performed for the IPSS total score, IPSS storage symptoms score, 
IPSS voiding symptoms score, IPSS QOL score, Q1, Q3, Q5, and Q6. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0, 4, 8, and 12), and for the changes and percentage changes at Weeks 0, 4, 8, and 12 of the 
treatment period relative to baseline (Week 0), will be calculated. 
2) Paired t-tests for the measured values at baseline (Week 0) and Weeks 4, 8, and 12 of the treatment 
period will be performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test will be performed using the placebo group as the control. 
5) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with LOCF. 
6) The change and percentage change from baseline (Week 0) will be analyzed by MMRM using treatment 
group, evaluation time point (Weeks 4, 8, and 12 of the treatment period), and interaction between 
treatment group and evaluation time point as fixed effects and baseline value, sex, and age (< 65 years 
or ≥ 65 years) as covariates. The least squares means in each treatment group, and the difference in the 


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least squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval at each evaluation time point will be estimated. Unstructured covariance structure will be 
assumed, and toeplitz type will be used if convergence is not achieved. If convergence is still not 
achieved, the first-order autoregressive, compound symmetry, and variance component will be used in 
this order. The Kenward-Roger method (2009) will be used to calculate degrees of freedom. 
8.1.7 
OABSS Score 
The following analyses will be performed for the OABSS score. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0, 4, 8, and 12), and for the changes and percentage changes at Weeks 0, 4, 8, and 12 of the 
treatment period relative to baseline (Week 0), will be calculated. The same analysis will be performed 
by presence or absence of CIC. 
2) Paired t-tests for the measured values at baseline (Week 0) and Weeks 4, 8, and 12 of the treatment 
period will be performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. The same analysis will be performed by presence or absence of CIC. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test will be performed using the placebo group as the control. 
5) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with LOCF. 
6) The change and percentage change from baseline (Week 0) will be analyzed by MMRM using treatment 
group, evaluation time point (Weeks 4, 8, and 12 of the treatment period), and interaction between 
treatment group and evaluation time point as fixed effects and baseline value, sex, and age (< 65 years 
or ≥ 65 years) as covariates. The least squares means in each treatment group, and the difference in the 
least squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval at each evaluation time point will be estimated. Unstructured covariance structure will be 
assumed, and toeplitz type will be used if convergence is not achieved. If convergence is still not 
achieved, the first-order autoregressive, compound symmetry, and variance component will be used in 
this order. The Kenward-Roger method (2009) will be used to calculate degrees of freedom. 
8.1.8 
KHQ Score (by Domain) 
The following analyses will be performed for the score of each domain based on the Japanese 
version of KHQ. 
1) Summary statistics and 95% confidence intervals for the measured values at each evaluation time point 
(Weeks 0 and 12), and for the change and percentage change at Week 12 of the treatment period relative 
to baseline (Week 0), will be calculated. 
2) Paired t-test for the measured values at baseline (Week 0) and Week 12 of the treatment period will be 
performed. 
3) For the measured values at each evaluation time point (Weeks 0 and 12) and the change and percentage 
change from baseline (Week 0) to Week 12 of the treatment period, the 95% confidence interval for the 
difference between the placebo group and the TAC-302 group will be calculated. 
4) For the change and percentage change from baseline (Week 0) to Week 12, student's t-test will be 
performed using the placebo group as the control. 


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8.1.9 
Bladder Diary Records 
The following analyses will be performed for the average number of micturitions per 24 hours, 
average number of urgency urinary incontinence episodes per 24 hours, average number of urinary 
urgency episodes per 24 hours, average voided volume per urination, average number of daytime 
urinations, and average number of nocturnal urinations. 
1) Summary statistics will be calculated for the measured values at each evaluation time point (Weeks 0, 4, 
8, and 12) and the changes and percentage changes from baseline (Week 0) to Week 4, 8, and 12 of the 
treatment period. The same analysis will be performed by presence or absence of CIC. 
2) Paired t-tests for the measured values at baseline (Week 0) and Weeks 4, 8, and 12 of the treatment 
period will be performed. 
3) For the measured values at each evaluation time point (Weeks 0, 4, 8, and 12) and the changes and 
percentage changes from baseline (Week 0) to Weeks 4, 8, and 12 of the treatment period, the 95% 
confidence interval for the difference between the placebo group and the TAC-302 group will be 
calculated. The same analysis will be performed by presence or absence of CIC. 
4) For the changes and percentage changes from baseline (Week 0) to each evaluation time point (Weeks 
4, 8, and 12), student's t test, Wilcoxon rank sum test, and van Elteren test using the allocation adjustment 
factors as strata5) will be performed using the placebo group as the control. 
5) The proportion of patients with a ≤ –50% change in the average number of urgency urinary incontinence 
episodes per 24 hours will be calculated, and Fisher's exact test will be performed to compare the 
between-group difference. 
6) The same analyses as 1) to 4) will be performed for the case where missing data at Week 12 of the 
treatment period are imputed with LOCF. 
7) The change and percentage change from baseline (Week 0) will be analyzed by MMRM using treatment 
group, evaluation time point (Weeks 4, 8, and 12 of the treatment period), and interaction between 
treatment group and evaluation time point as fixed effects and baseline value, sex, and age (< 65 years 
or ≥ 65 years) as covariates. The least squares means in each treatment group, and the difference in the 
least squares mean between the placebo group and the TAC-302 group and its two-sided 95% confidence 
interval at each evaluation time point will be estimated. Unstructured covariance structure will be 
assumed, and toeplitz type will be used if convergence is not achieved. If convergence is still not 
achieved, the first-order autoregressive, compound symmetry, and variance component will be used in 
this order. The Kenward-Roger method (2009) will be used to calculate degrees of freedom. 
8.1.10 Relationship Between Efficacy Endpoints 
For the relationship of the change and percentage change from baseline (Week 0) to Week 12 of the 
treatment period between the efficacy endpoints, Pearson and Spearman correlation coefficients will be 
calculated, and scatter plots will be prepared. The combinations of endpoints to be evaluated are those for 
which a combination of diseases considered to be related (DU or DU-OAB) is specified in Figure 8-1. 




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8.1.11 Analysis by Allocation Factor 
• Analyses of secondary endpoints excluding analysis of covariance/analysis using an MMRM and scatter 
plots (8.1.1 to 8.1.9) will be performed by age group (< 65 years and ≥ 65 years). 
• Analysis will be performed as for analysis of secondary endpoints by sex (8.1.1 to 8.1.9). In analysis of 
covariance and analysis using an MMRM, values at baseline and age (< 60 years and ≥ 60 years in males 
and < 70 years and ≥ 70 years in females) will be used as covariates. 
8.1.12 Analysis by Severity Score 
The following analyses will be performed. The same analyses will be performed by sex. 
• Analyses of the primary and secondary endpoints excluding analysis of covariance/analysis using an 
MMRM and scatter plots (7.3 and 8.1.1 to 8.1.9) will be performed by IPSS total score at baseline (Week 
0). 
• Analyses of the primary and secondary endpoints excluding analysis of covariance/analysis using an 
MMRM and scatter plots (7.3 and 8.1.1 to 8.1.9) will be performed by IPSS QOL score at baseline 
(Week 0). 
• Analyses of the secondary endpoints excluding analysis of covariance/analysis using an MMRM and 
scatter plots (7.3 and 8.1.1 to 8.1.9) will be performed by OABSS score at baseline (Week 0). 
8.1.13 Analysis by Post Void Residual 
The following analyses will be performed. The same analyses will be performed by sex. 
• Analyses of the primary and secondary endpoints excluding analysis of covariance/analysis using an 
MMRM and scatter plots (7.3 and 8.1.1 to 8.1.9) will be performed by post void residual measured by 
ultrasonography (< 50 mL, ≥ 50 mL, < 100 mL, and ≥ 100 mL) at baseline (Week 0). 
8.1.14 Analysis by Appearance of Bladder Involuntary Contraction 
The following analyses will be performed in the PPS. The same analyses will be performed by sex. 
• Analyses of the primary and secondary endpoints (7.3 and 8.1.1 to 8.1.5) will be performed by 
appearance of bladder involuntary contraction. However, frequency tabulation of the appearance of 
bladder involuntary contraction and analysis of covariance/analysis using an MMRM in 8.1.1, 8.1.4, and 
8.1.5 will not be performed. 
8.1.15 Analysis of UDS Data Subset 
The following analyses will be performed in the PPS. The same analyses will be performed by sex. Cases 
raising queries were pointed out at the urodynamic study data review meeting, and as a result of 
consideration by the case review committee, the appropriate urodynamic study evaluation set, with cases 
raising queries excluded, was taken to be the UDS data subset. 
• Analyses of the primary and secondary endpoints (7.3 and 8.1.1 to 8.1.5) will be performed in the UDS 
data subset. However, frequency tabulation of the appearance of bladder involuntary contraction and 
analysis of covariance/analysis using an MMRM in 8.1.1, 8.1.4, and 8.1.5 will not be performed. 
8.2 
Analysis of Administration Status 
The following analyses will be performed by treatment group in patients treated in the observation period 
and patients treated in the treatment period. 
8.2.1 
Study Drug Administration 
Summary statistics for administration status (total dose and total duration of administration) will be 
presented for each patient. 


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8.2.2 
Status of Administration Completion 
• Summary statistics for treatment compliance will be calculated for each patient. 
• Whether patients are discontinued from the study and the reasons for discontinuation will be tabulated. 
8.3 
Safety Analysis 
The following analyses will be performed for each treatment group in patients treated in the treatment 
period. 
8.3.1 
Adverse Events and Adverse Reactions 
The following analyses will be performed at each time point. 
• The numbers of patients who experienced adverse events and the incidences of adverse events will be 
displayed. Similar analysis will be performed for adverse reactions. Similar analysis will also be 
performed by age (≥ 65 years and < 65 years). In addition, similar analysis will be performed by age (≥ 
75 years and < 75 years). 
• For each adverse event item, the numbers of patients who experienced adverse events and the incidences 
of adverse events will be displayed. Similar analysis will be performed for adverse reactions. Similar 
analysis will also be performed by age (≥ 65 years and < 65 years). In addition, similar analysis will be 
performed by age (≥ 75 years and < 75 years). 
• For each adverse event item, the numbers of patients who experienced adverse events and the incidences 
of adverse events will be displayed by severity. Similar analysis will be performed for adverse reactions. 
• The incidence of adverse events in the treatment period will be presented by time of onset (at or before 
Week 2 of the treatment period; after Week 2 of the treatment period and at or before Week 4 of the 
treatment period; after Week 4 of the treatment period and at or before Week 8 of the treatment period; 
after Week 8 of the treatment period and at or before Week 12 of the treatment period; after Week 12 of 
the treatment period; and follow-up observation). Similar analysis will be performed for adverse 
reactions. 
• All adverse events that occurred from the start of study treatment to the end date of the follow-up 
observation will be listed by the adverse event variable of each patient, together with the adverse event 
term, severity, date of onset, action, outcome, causal relationship with the study drug, and comments. 
• The incidence of serious adverse events will be calculated. Similar analysis will be performed for 
adverse reactions. 
• The incidence of adverse events leading to discontinuation/dose interruption will be calculated. Similar 
analysis will be performed for adverse reactions. 
 
 


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8.3.2 
Laboratory Test Values 
If the measured values of each laboratory test parameter (quantitative parameter) include "≤," the 
analysis will be performed using the numerical values excluding inequality. 
• For each laboratory test parameter (quantitative parameter), the time course of measured values will be 
shown in graphs. 
• Summary statistics for the laboratory test parameters (quantitative parameters) at each time point will be 
calculated. 
• The frequency of each laboratory test parameter (urinalysis parameter) at each evaluation time point will 
be tabulated. 
8.3.3 
12-lead Electrocardiogram 
• For QTcF interval and heart rate, summary statistics for measured values will be calculated for each 
evaluation time point. 
• For QTcF interval and heart rate, summary statistics for the change in the measured value at each 
evaluation time point relative to directly before the start of administration of the investigational drug for 
the treatment period will be calculated. 
• The measured value of QTcF interval at each evaluation time point will be divided into categories (≤ 450 
msec, > 450 msec and ≤ 480 msec, > 480 msec and ≤ 500 msec, and > 500 msec), and the frequency of 
each category will be tabulated. 
• For QTcF interval, the change in the measured value at each evaluation time point relative to directly 
before the start of administration of the investigational drug for the treatment period will be divided into 
categories (≤ 30 msec, > 30 msec and ≤ 60 msec, and > 60 msec) and their frequencies were tabulated. 
• A list of patients with abnormal 12-lead electrocardiogram changes will be prepared. 
8.3.4 
Blood Pressure, Pulse Rate, and Body Temperature 
• Summary statistics for blood pressure, pulse rate, and body temperature at each time point will be 
calculated. 
• For blood pressure and pulse rate, summary statistics for the change in the measured value at each 
evaluation time point relative to directly before the start of administration of the investigational drug for 
the treatment period will be calculated. 
9. Other Analyses 
9.1 
Analysis Sets 
The proportion of patients in each analysis set and the reasons for exclusion will be tabulated by 
treatment group. A list of patients excluded from the analysis sets will be provided with the reasons. 
9.2 
Deviations 
The presence or absence of deviations and items of deviations will be tabulated by treatment group. The 
details of patients with deviations will be listed. 
9.3 
Patient Backgrounds 
For each treatment group, summary statistics will be calculated or frequency tabulations will be 
performed to present appropriate summaries, depending on the data of each item of patient background. 
The same analysis will be performed by sex. Furthermore, for patients treated in the observation period and 
dropped out during the observation period, the same analysis will be performed in the subgroups of patients 
who did not meet the inclusion criterion (4) at enrollment in the treatment period and those who dropped 
out for other reasons. 
 
 


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10. REVIEW AND REVISION OF THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan will be finalized prior to unblinding. 
When the statistical analysis plan is revised, a record of changes in the statistical analysis plan/report 
analysis plan will be prepared, and the changes and reasons for the changes will be described. Analyses 
newly planned after unblinding will be distinguished from the analyses planned in advance and described in 
the change record. 
11. STATISTICAL ISSUES 
Explanations about the ICH-E3 guideline1) and other statistical issues are summarized below. 
11.1 Adjustment for Covariates 
Adjustment for covariates will be performed using analysis of covariance. Details of specific covariates 
will be provided separately. 
11.2 Handling of Dropouts or Missing Data 
Handling of missing values in efficacy endpoints is specified for each analysis. 
Missing data for safety endpoints will not be imputed. 
Other than abnormal values for which there is an obvious rationale, such as the effect of hemolysis due to 
blood collection on laboratory test values, all measured data will be used for analysis. If abnormal values 
are excluded from the analysis, they will be specified and the reasons for exclusion will be stated. 
In addition, in post-hoc exploratory analysis, for each analyzed item, the handling of missing values will 
be decided appropriately depending on the method of analysis and the characteristics of the endpoints being 
analyzed. 
11.3 Interim Analysis and Data Monitoring 
No interim analysis will be performed in this study. 
11.4 Multicenter Studies 
This is a multicenter study.  
11.5 Multiple Comparison/Multiplicity 
Not applicable in this study. 
11.6 Use of an "Efficacy Subset" of Patients 
This is not planned in this study, but it will be performed as necessary as additional analysis. 
11.7 Active-Control Studies Intended to Show Equivalence 
Not applicable in this study. 
11.8 Examination of Subgroups 
In this study, subgroup analyses by allocation adjustment factors, severity score, and post void residual 
are planned in some analyses. Additional analyses will be performed as necessary. 
 
 


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12. PREPARATION OF REPORT ANALYSIS PLAN 
Only the major analysis items are shown in the statistical analysis plan. All analysis items to be 
performed are shown in the separately prepared report analysis plan. 
13. REFERENCES 
(1) “Structure and Content of Clinical Study Reports” (PAB/ED Notification No. 335 dated 01 May 
1996) 
(2) Akira Sakuma, Medical Statistics Q & A, Tokyo, Kanehara & Co., Ltd.; 1987: p.75 
(3) Kwon Soo Lee, Phil Hyun Song, Young Hwii Ko. "Does uroflowmetry parameter facilitate 
discrimination between detrusor underactivity and bladder outlet obstruction?" Investig Clin Urol 
2016;57:437-441. 
(4) Kenward, M. G., and Roger, J. H. (2009). "An Improved Approximation to the Precision of Fixed 
Effects from Restricted Maximum Likelihood." Computational Statistics and Data Analysis 53:2583–
2595. 
(5) van Elteren, P. H. (1960). "On the combination of independent two-sample tests of Wilcoxon," 
Bulletin of the International Statistical Institute, 37, 351-361.