Conditions: Stress Urinary Incontinence
Keywords: Urinary Incontinence Urinary Incontinence, Stress Lower Urinary Tract Symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 337
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of TAS-303 in female patients with stress urinary incontinence.

Detailed description:
The main purpose of this study is to assess the efficacy of TAS-303 for 8 weeks in female patients with stress urinary incontinence (SUI) compared with placebo as measured by the percent change in incontinence episode frequency (IEF) from baseline.

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: TAS-303 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration for 8 weeks, once daily. intervention 2: Oral administration for 8 weeks, once daily.

Protocol document:
Prot_000.pdf: 
1 
An early phase II study of TAS-303 in female patients with 
stress urinary incontinence 
 
TAS-303 
 [investigational product] 
PROTOCOL No.:
FINALIZATION DATE:
AMENDMENT:
10060050 Ver.P02 
July 11, 2016 
August 16, 2016 
 
SPONSOR:  
Taiho Pharmaceutical Co., Ltd. 
1-27 Kandanishiki-cho, Chiyoda-ku, Tokyo 101-8444, Japan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical study will be conducted in accordance with International Conference on Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline on Good Clinical Practice 
(GCP) and the regulatory requirements in Japan. 
CONFIDENTIAL 
The information contained in this protocol is the property of Taiho Pharmaceutical Co., Ltd. 
and is strictly confidential. No part of this document may be published or disclosed without the 
prior written approval of Taiho Pharmaceutical Co., Ltd., except as a request by competent 
authorities and if necessary to obtain consent from persons who are considering participation 
in this study. 
 


2 
Table of Contents 
Table of Contents ..................................................................................................................... 2 
List of In-Text Figures ............................................................................................................ 6 
List of In-Text Tables ............................................................................................................. 6 
Abbreviations ........................................................................................................................... 7 
Synopsis ..................................................................................................................................... 9 
1. Background Information ................................................................................................ 18 
1.1 Introduction .................................................................................................................. 18 
1.2 TAS-303 
 [investigational drug] ............................................................ 20 
1.2.1 Mechanism of Action ............................................................................................ 20 
1.3 Placebo [Comparator] .................................................................................................. 20 
1.4 Known and Potential Benefits and Risks ..................................................................... 20 
1.4.1 TAS-303 ................................................................................................................ 20 
1.4.1.1 
Potential Benefits ........................................................................................... 20 
1.4.1.2 
Possible Safety Risks ..................................................................................... 21 
1.4.2 Drugs with Similar Mechanism of Action to That of TAS-303 ............................ 22 
1.4.3 Estimated Benefits and Risks for This Study ........................................................ 23 
1.5 Key Findings and Experiences ..................................................................................... 23 
1.5.1 Nonclinical Findings ............................................................................................. 23 
1.5.2 Clinical Experiences ............................................................................................. 23 
1.5.2.1 
Phase I single-dose study (Study 10060010) ................................................. 23 
1.5.2.2 
Phase I multiple-dose study (Study 10060020) ............................................. 24 
1.5.2.3 
Drug Interaction Study with Simvastatin/Midazolam (Study 10060030) ..... 25 
1.5.2.4 
Phase I Study in Patients with SUI (Study 10060040) .................................. 28 
1.6 Rationale for Study and Selection ................................................................................ 28 
1.6.1 Study Population ................................................................................................... 28 
1.6.2 Study Design ......................................................................................................... 28 
1.6.3 Selection of TAS-303 Doses ................................................................................. 29 
1.6.4 Selection of Placebo .............................................................................................. 29 
2. Objectives and Endpoints .............................................................................................. 30 
2.1 Primary Objective ........................................................................................................ 30 
2.2 Secondary Objectives ................................................................................................... 30 
2.3 Endpoints...................................................................................................................... 30 
2.3.1 Primary Endpoint .................................................................................................. 30 
2.3.2 Secondary Endpoints ............................................................................................. 30 
2.3.2.1 
Efficacy .......................................................................................................... 30 
2.3.2.2 
Safety ............................................................................................................. 31 
3. Overview of Study Design .............................................................................................. 32 
3.1 Study Status .................................................................................................................. 32 
3.1.1 Definition of Each Period for Each Patient ........................................................... 33 
3.2 Randomization and Blinding........................................................................................ 33 
3.2.1 Randomization ...................................................................................................... 33 
3.2.2 Blinding ................................................................................................................. 34 
4. Eligibility and Patient Discontinuation Criteria .......................................................... 35 
4.1 Inclusion Criteria .......................................................................................................... 35 


3 
4.1.1 At the time of enrollment in observation period ................................................... 35 
4.1.2 At the time of enrollment in treatment period ....................................................... 35 
4.2 Exclusion Criteria ......................................................................................................... 36 
4.2.1 At the time of enrollment in observation period ................................................... 36 
4.2.2 At the time of enrollment in treatment period ....................................................... 38 
4.3 Patient Discontinuation Criteria ................................................................................... 39 
5. Study Assessments ........................................................................................................... 41 
5.1 All Study Procedures.................................................................................................... 44 
5.1.1 Informed Consent .................................................................................................. 44 
5.1.2 Patient Background ............................................................................................... 44 
5.1.3 Patient enrollment ................................................................................................. 44 
5.1.4 Subjective and Objective Findings ....................................................................... 44 
5.1.5 Vital Signs ............................................................................................................. 44 
5.1.6 Compliance with treatment with study drugs ....................................................... 44 
5.1.7 Concomitant medications and therapies ............................................................... 44 
5.1.8 12-lead Electrocardiography ................................................................................. 45 
5.1.9 Laboratory Findings .............................................................................................. 45 
5.1.9.1 
Hematology .................................................................................................... 45 
5.1.9.2 
Serum chemistry ............................................................................................ 45 
5.1.9.3 
Urinalysis ....................................................................................................... 45 
5.1.10 Pregnancy Test ...................................................................................................... 45 
5.1.11 Evaluation of symptom scores .............................................................................. 46 
5.1.11.1 ICIQ-SF .......................................................................................................... 46 
5.1.11.2 PGI-I .............................................................................................................. 46 
5.1.12 Evaluation of QOL Scores .................................................................................... 46 
5.1.13 Urination Record (Bladder Diary) ........................................................................ 46 
5.1.14 Pad Test ................................................................................................................. 46 
5.1.15 Urinary Flow Test ................................................................................................. 46 
5.1.16 Measurement of Residual Urine Volume .............................................................. 46 
5.1.17 Evaluation of Adverse Events ............................................................................... 46 
5.2 Assessments by Visit .................................................................................................... 46 
6. Study Drugs ..................................................................................................................... 47 
6.1 Overview of the Study Drugs ....................................................................................... 47 
6.2 Packaging and Labeling ............................................................................................... 47 
6.3 Accountability .............................................................................................................. 48 
6.4 Patients Instruction on Proper Using............................................................................ 48 
6.5 Implementation of Allocation Confirmation Study ...................................................... 48 
7. Study Drug Regimens ..................................................................................................... 49 
7.1 Administration Procedure ............................................................................................ 49 
7.1.1 Administration Regimens ..................................................................................... 49 
7.1.1.1 
Observation period ......................................................................................... 49 
7.1.1.2 
Treatment period ............................................................................................ 49 
7.2 Total Blood Volume ..................................................................................................... 49 
7.3 Restrictions ................................................................................................................... 50 
7.3.1 Contraception ........................................................................................................ 50 
7.3.2 Food and Drink ..................................................................................................... 50 


4 
7.4 Concomitant medications and therapies....................................................................... 50 
7.4.1 Prohibited Concomitant Medications and Therapies ............................................ 50 
7.4.2 Concomitant Medications and Therapies Requiring Precautions ......................... 51 
8. Pharmacokinetics and Pharmacodynamics .................................................................. 53 
9. Pharmacogenomic Analysis ........................................................................................... 53 
10. Discontinuation and Study Completion ........................................................................ 54 
10.1 Criteria for Discontinuation of the Study at Individual Study Sites ............................ 54 
10.2 Criteria for Termination of the Entire Study ................................................................ 54 
11. Efficacy Evaluation ......................................................................................................... 55 
11.1 Evaluation of symptom scores ..................................................................................... 55 
11.1.1 ICIQ-SF ................................................................................................................. 55 
11.1.2 PGI-I ...................................................................................................................... 55 
11.2 Evaluation of QOL Scores ........................................................................................... 55 
11.3 Urination Record (Bladder Diary) ............................................................................... 56 
11.4 1-hour Pad Test ............................................................................................................. 56 
12. Safety Evaluation ............................................................................................................ 57 
12.1 Adverse Events............................................................................................................. 57 
12.1.1 Definition of Adverse Events ................................................................................ 57 
12.1.2 Severity of Adverse Events ................................................................................... 57 
12.1.3 Causal Relationship with the Study Drug ............................................................. 58 
12.1.4 Outcome of Adverse Events .................................................................................. 58 
12.1.5 Reporting of Adverse Events ................................................................................ 59 
12.1.6 Follow-up of Adverse Events ................................................................................ 59 
12.2 Serious Adverse Events ................................................................................................ 59 
12.2.1 Definition of Serious Adverse Events ................................................................... 59 
12.2.2 Reporting of Serious Adverse Events ................................................................... 60 
12.2.3 Follow-up of Serious Adverse Events ................................................................... 61 
12.2.4 Possibility of Prediction of Serious Adverse Events in Use of Study Drugs ........ 61 
12.3 Adverse Events of Special Interest .............................................................................. 61 
12.3.1 Definition of Adverse Events of Special Interest .................................................. 61 
12.4 Adverse Reactions ........................................................................................................ 61 
12.4.1 Definition of Adverse Reactions ........................................................................... 61 
12.5 Other Information ......................................................................................................... 61 
12.5.1 Pregnancy .............................................................................................................. 61 
12.5.2 Medication Errors ................................................................................................. 62 
13. Statistical Analysis .......................................................................................................... 63 
13.1 Statistical Plan .............................................................................................................. 63 
13.1.1 Timing of Statistical Analysis ............................................................................... 63 
13.1.2 Analysis Populations and Criteria for Handling Patient Data ............................... 63 
13.1.2.1 Analysis Population ....................................................................................... 63 
13.1.2.2 Criteria for Handling of Patient Data ............................................................. 63 
13.1.3 Statistical Analysis Methods ................................................................................. 64 
13.1.3.1 Patient Disposition and Demographic Characteristics ................................... 64 
13.1.3.2 Primary Endpoint Analysis ............................................................................ 64 
13.1.3.3 Secondary Endpoint Analysis ........................................................................ 65 
13.1.4 Target Number of Patients and Sample Size Justification .................................... 69 


5 
14. Rationales ........................................................................................................................ 70 
14.1 Rationale for Endpoints................................................................................................ 70 
14.2 Rationale for Administration Methods ......................................................................... 70 
14.3 Rationale for Inclusion and Exclusion Criteria ............................................................ 70 
14.3.1 Rationale for Inclusion Criteria ............................................................................. 70 
14.3.1.1 At the Time of Enrollment in Observation Period ......................................... 70 
14.3.1.2 At the Time of Enrollment in Treatment Period ............................................ 70 
14.3.2 Rationale for Exclusion Criteria ........................................................................... 71 
14.3.2.1 At the Time of Enrollment in Observation Period ......................................... 71 
14.3.2.2 At the Time of Enrollment in Treatment Period ............................................ 71 
14.4 Rationale for Prohibited Concomitant Medications and Therapies ............................. 71 
14.5 Rationale for Concomitant Medications and Therapies Requiring Precautions .......... 72 
14.6 Rationale for Contraception Period .............................................................................. 72 
14.7 Rationale for Restriction on Food and Beverages ........................................................ 72 
15. Case Report Form (eCRF) ............................................................................................. 73 
15.1 Recording of Case Report Forms ................................................................................. 73 
15.2 Completing Case Report Forms ................................................................................... 73 
16. Protocol Compliance, Deviations and Amendments .................................................... 75 
16.1 Protocol Compliance .................................................................................................... 75 
16.2 Protocol Deviations ...................................................................................................... 75 
16.3 Protocol Amendments .................................................................................................. 75 
17. Direct Access to Source Documents ............................................................................... 77 
17.1 Source Documents ....................................................................................................... 77 
17.2 Direct Access ................................................................................................................ 77 
18. Quality Control and Quality Assurance ....................................................................... 78 
18.1 Quality Control............................................................................................................. 78 
18.2 Sponsor’s Audits and Regulatory Inspections .............................................................. 78 
19. Data Handling and Recordkeeping ............................................................................... 79 
19.1 Data Handling .............................................................................................................. 79 
19.2 Responsibilities of Recordkeeping ............................................................................... 79 
19.2.1 Investigator and Study Site ................................................................................... 79 
19.2.2 Sponsor .................................................................................................................. 79 
20. Compensation for Health Injury ................................................................................... 80 
21. Publication Policy and Secondary Use of Data ............................................................ 81 
21.1 Publication Policy ........................................................................................................ 81 
21.2 Secondary Use of Data ................................................................................................. 81 
22. Ethics ................................................................................................................................ 82 
22.1 Ethical Considerations ................................................................................................. 82 
22.2 Institutional Review Board .......................................................................................... 82 
22.3 Informed Consent Procedure........................................................................................ 82 
23. Study Administrative Structure ..................................................................................... 83 
24. References ........................................................................................................................ 84 
25. Appendices ....................................................................................................................... 86 
APPENDIX 1  ICIQ-SF ....................................................................................................... 86 
APPENDIX 2  Patient Global Impression-Improvement: PGI-I .................................... 87 


6 
APPENDIX 3  I-QOL .......................................................................................................... 88 
APPENDIX 4  1-hour Pad Test ........................................................................................... 89 
 
List of In-Text Figures 
Figure 3-1  Study Design ................................................................................................... 32 
 
 
List of In-Text Tables 
Table 1.4.2-1  Main Adverse Reactions to Atomoxetine Hydrochloride .......................... 22 
Table 1.4.2-2  Main Adverse Reactions to Amezinium Metilsulfate ................................ 22 
Table 5-1  Evaluation and Test Items ................................................................................ 41 
Table 5-2  Observation and Test Schedule ........................................................................ 42 
Table 6.1-1  Overview of TAS-303
 [Investigational Drug] ...................... 47 
Table 6.1-2  Overview of placebo [Comparator] ............................................................... 47 
Table 7.1.1.1-1  Number of Tablets of Study Drug Taken per Administration (observation 
period) ......................................................................................................................... 49 
Table 7.1.1.2-1  Number of Tablets of Study Drug Taken per Administration (treatment 
period) ......................................................................................................................... 49 
Table 7.2-1  Volume of Blood Collected during Study Participation Period .................... 49 
Table 13.1.2.1-1  Definitions of Analysis Populations ...................................................... 63 
 
 
 


7 
Abbreviations 
Abbreviation 
Definition 
A/G 
albumin/globulin ratio 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC0-24 hr 
area under the plasma concentration versus time curve from time zero to 24 hr 
AUC0-inf 
area under the plasma concentration versus time curve from time zero to infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to t (where t = the 
final time of detection) 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CPK 
creatine kinase, creatine phosphokinase 
Cmax 
maximum plasma concentration 
CRP 
C-reactive protein 
CYP 
cytochrome P450 
C0 
initial plasma concentration 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
γ-GTP 
γ-glutamyltransferase 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for human use 
ICIQ-SF 
International Consultation on Incontinence Questionnaire-Short Form 
I-QOL 
Incontinence-Quality of Life 
INR 
international normalized ratio 
IRB 
institutional review board 
ISD 
intrinsic sphincter deficiency 
IWRS 
Interactive Web Response System 
LDH 
lactate dehydrogenase 
LOCF 
last observation carried forward 
LPP 
leak point pressure 
MMRM  
mixed-effect models for repeated measures 
MUI 
mixed urinary incontinence 


8 
Abbreviation 
Definition 
NA 
noradrenaline 
6-OHF 
6β-Hydroxycortisol 
PGI-I 
Patient Global Impression-Improvement 
POP 
pelvic organ prolapse 
PPS 
Per Protocol Set 
PT-INR 
prothrombin time-international normalized ratio 
free Qave 
Average urinary flow rate 
free Qmax 
Maximum urinary flow rate 
QOL 
quality of life 
QTcF 
QT corrected for heart rate by Fridericia's formula 
SOP 
standard operating procedure 
SUI 
stress urinary incontinence 
t1/2 
elimination half-time 
tmax 
time to maximum plasma concentration 
TOT 
Trans-Obturator Tape 
TVT 
Tension-free Vaginal Tape 
ULN 
upper limit of normal 
UUI 
urgency urinary incontinence 
VD 
vaginal distention 
Vdss 
distribution volume at steady state 
X6-OHF/XF 
ratio of urinary 6β-hydroxycortisol to cortisol 
X6-OHF/AUCF 
ratio of urinary 6β-hydroxycortisol to cortisol area under the plasma concentration 
versus time curve (AUC) 






11 
• 
The amount of urinary incontinence exceeds 2.0 g in a 1-hour pad 
test at the time of the enrollment in the observation period. 
Inclusion Criteria at the Time of Enrollment in Treatment Period: 
• 
Fulfillment of all the following conditions has been indicated in the 
information in the urination record for 7 days immediately before the 
enrollment in the treatment period. 
1) 1 or more mean number of urinary incontinence per 24 hours 
2) Number of SUI > number of urgency urinary incontinence (UUI)
3) Ten or less mean number of daytime urination per day and 2 or 
less mean number of night-time urination per day 
4) 70% or higher rate of entry in urination record (status of urinary 
incontinence) 
• 
Meet all the following conditions for ICIQ-SF at the time of the 
enrollment in the treatment period 
1) Selection of the answer, “about once a day” (3 points), or those 
with higher scores for Q1 
2) Selection of the answer, “small amount” (2 points), or those with 
higher scores for Q2 
3) Selection of the answer, leaks “when I cough or sneeze” or leaks 
“while I am moving my body or exercising” for Q4 
Main Exclusion Criteria at the Time of Enrollment in Observation 
Period: 
• 
Symptoms of UUI were considered by the Investigator or 
Sub-investigator to be more predominant than those of SUI 
• 
History of surgical treatment for urinary incontinence 
(Trans-Obturator Tape [TOT] procedure, Tension-free Vaginal Tape 
[TVT] procedure, etc.) 
• 
Have accompanying pelvic organ prolapse quantification (POP-Q) 
stage II or more severe pelvic organ prolapse (POP) or underwent 
surgical repair of POP within 180 days before the enrollment in the 
observation period 
• 
Accompanying lower urinary tract obstruction 
• 
Accompanying urinary tract infection (cystitis, etc.), urolithiasis 
(ureteral calculus, urethral calculus, vesical calculus, etc.), urethral 
diseases (urethral polyp, urethral diverticulum, etc.) or interstitial 
cystitis, or a history of recurrent urinary tract infection (3 or more 
incidents within 180 days before the consent) 
• 
Diagnosis of neurogenic bladder 
• 
Difficulty in undergoing pad test (going up and down stairs, etc.) 
• 
Accompanying central nervous system disorders (dementia, etc.) that 
make it impossible to answer the questionnaire 
• 
Accompanying angle-closure glaucoma 
• 
100 mL or more residual urine volume measured at the time of the 
enrollment in the observation period 
• 
Delivery within 1 year before the enrollment in the observation period 
• 
Started physical therapy (pelvic floor muscle training, feedback 
training, biofeedback training, vaginal cone, bladder training, electric 
stimulation therapy, magnetic stimulation therapy, etc.) within 30 
days before the enrollment in the observation period 
• 
Pregnant or nursing women, or women of childbearing potential with 


12 
positive pregnancy test (urine or serum) within 7 days before the 
enrollment in the observation period 
• 
Fertile patients who do not agree to practice contraception during 
their participation in the study and for 40 days after the completion 
of the treatment with the study drugs 
Main Exclusion Criteria at the Time of Enrollment in Treatment Period:
• 
Less than 80% compliance with the treatment with the study drugs 
during the observation period 
• 
Urinary incontinence symptoms at the time of enrollment in the 
treatment period were considered by the Investigator or 
Sub-investigator to have improved greatly compared with those at 
the time of the enrollment in the observation period (50% or greater 
improvement in the mean number of urinary incontinence per 24 
hours, etc.). 
• 
Symptoms of UUI were considered by the Investigator or 
Sub-investigator to be more predominant than those of SUI based on 
the information in the urination record for 7 days immediately before 
the enrollment in the treatment period. 
• 
100 mL or more residual urine volume measured at the time of the 
enrollment in the treatment period 
• 
Pregnant or nursing women, or women of childbearing potential with 
a positive pregnancy test (urine or serum) within 7 days before the 
enrollment in the treatment period 
Administration Regimens: 
Observation Period: 
Placebo is orally administered once daily for 3 weeks. 
Treatment Period: 
Three or 6 mg of TAS-303, or placebo is orally administered once daily for 8 
weeks. 
Study Participation Period: 
Study Participation Period: 
Period from the acquisition of written consent to the completion of the 
follow-up observation period 
Observation Period: 
Period from the enrollment in the observation period up to the enrollment in 
the treatment period (the enrollment in the treatment period is implemented 3 
weeks after the enrollment in the observation period) 
Treatment Period: 
Period from the enrollment in the treatment period to the visit at Week 8 in 
the treatment period 
Follow-up Observation Period: 
Period after the visit at Week 8 in the treatment period to the completion of 
the follow-up observation (implemented 2 to 4 weeks after the completion of 
Week 8 of the treatment period) 




14 
incontinence per 24 hours for each week was analyzed using 
mixed-effect models for repeated measures (MMRM) to estimate 
the therapeutic effect of TAS-303 at Week 8 of the treatment 
period. 
- 
In PPS and FAS, intergroup comparison is performed by 
Wilcoxon rank sum test. Missing values are imputed by LOCF. 
(4) Analysis by allocation factor 
- 
The primary endpoint is analyzed for each condition of urinary 
incontinence (SUI and mixed urinary incontinence [MUI]). 
- 
The primary endpoint is analyzed for each category of mean 
number of urinary incontinence per 24 hours (less than 2/day and 
2 or more/day). 
Sample Size Justification: 
Target number of patients: 250 to be enrolled in the treatment period 
This study is the first study that evaluates the efficacy of TAS-303 for the 
treatment of urinary incontinence. The number of subjects was determined, 
assuming that efficacy comparable to that of duloxetine can be expected 
based on the results of nonclinical studies. 
Based on the mean rate of change in the number of urinary incontinence of 
-62.28% in the duloxetine group and -41.86% in the placebo group from the 
data of a clinical trial of duloxetine, 
 
 the difference between the TAS-303 6 mg or 3 mg group and the 
placebo group in the rate of change in the number of urinary incontinence, 
which is the primary endpoint of the present study, was assumed to be -20%. 
From the standard deviation of 33.73% in the duloxetine group and 32.08% in 
the placebo group in the above study data, the standard deviation common in 
two groups was assumed to be 35%. Using the two-sided significance level of 
the entire test of 5% and the two-sided significance level of each test of 2.5% 
by Bonferroni’s method, when the statistical power is specified as 90% and 
the rate of withdrawal in the treatment period as about 5%, the number of 
subjects necessary for the confirmation of a significant difference between the 
TAS-303 group and the placebo group is approximately 250 (83 per group). 
 
 
 


15 
Table 1  Evaluation and Test Items 
Acquisition of consent 
 
Date of acquisition of consent 
Patient background 
 
Gender 
Date of birth 
Age*1 
 
Race 
Height 
Body weight 
 
BMI*2 
History of clinical trial participation (within past 90 days) 
 
Past history (within past 180 days) 
Complication 
 
Onset timing of SUI (year) 
Condition of urinary incontinence (SUI/MUI)*3 
 
Presence or absence of menopause 
Number of delivery (natural/cesarean section) 
 
History of previous treatment 
Menstrual cycle 
 
Presence or absence of use of incontinence pad 
History of POP surgical repair 
Patient enrollment 
 
Patient identification code 
Patient number 
Drug number 
Subjective and objective findings 
Vital signs 
 
Pulse rate 
Blood pressure (systolic, diastolic) 
Body temperature 
Compliance with treatment with study drugs 
Concomitant medications and therapies 
12-lead electrocardiography 
 
Heart rate 
QTcF interval 
 
Hematological tests 
 
Red blood cell count 
Hemoglobin 
Hematocrit 
Platelet count 
 
White blood cell count 
Neutrophil 
Eosinophil 
Basophil 
 
Lymphocyte 
Monocyte 
PT-INR 
 
Serum chemistry 
 
AST 
ALT 
ALP 
BUN  
 
Albumin 
Creatinine 
Na 
Cl 
 
K 
T-Bil 
Direct bilirubin 
Total protein 
 
CRP 
CPK 
LDH 
γ-GTP 
 
Blood sugar 
Triglyceride 
Total cholesterol 
A/G 
Urinalysis 
 
Protein 
Occult blood 
Glucose 
Urobilinogen 
Pregnancy test*4 
 
Serum or urinary β-human chorionic gonadotropin 
Evaluation of symptom scores 
 
ICIQ-SF 
PGI-I 
 
 
Evaluation of QOL score 
 
I-QOL 
 
 
 
Urination record 
 
Status of urinary incontinence, time and date 
Presence or absence of pad change 
 
Urination time and date 
 
Pad test 
 
1-hour pad test 
 
 
 
Measurement of urinary flow 
 
Maximum urinary flow rate (free Qmax) 
Average urinary flow rate (free Qave) 
 
Voided volume 
Time of voiding 
Measurement of residual urine volume 
Evaluation of adverse events 
*1: Automatically calculated from date of birth 
*2: Automatically calculated from height and body weight 
*3: Determined from the content of Q4 of ICIQ-SF 
*4: Required. When at least 1 year has passed after menopause or when the possibility of pregnancy is medically denied, 
the test is not necessary. 


16 
Table 2  Observation and Test Schedule 
Timing 
At 
enrollment 
in 
observation 
period 
Observation 
period5) 
At 
enrollment 
in treatment 
period 
Treatment period6) 
Follow-up 
observation7)
At 
discontinuation8) 
7 days before 
enrollment in 
treatment 
period 
7 days 
before 
Week 4 
visit 
Week 4 
7 days 
before 
Week 8 
visit 
Week 8 
Visit 
1 
2 
3 
4 
5 
Week  
-3 
1 
4 
8 
10 to 12 
Acquisition of consent 
X1) 
 
 
 
 
 
 
 
Patient background survey 
X 
 
X 
 
 
 
 
 
 
Enrollment 
X 
 
X 
 
 
 
 
 
 
Study drugs Prescription 
X 
 
X 
 
X 
 
 
 
Collection of remaining drugs 
 
 
X 
 
X 
 
X 
 
X 
 
Confirmation of compliance 
 
 
X 
 
X 
 
X 
 
X 
Subjective and objective findings 
X 
 
X 
 
X 
 
X 
X 
X 
Blood pressure, pulse rate and body 
temperature measurement 
X9) 
 
X 
 
X 
 
X 
X 
X 
12-lead electrocardiography 
X9) 
 
X 
 
 
X 
X 
X 
Laboratory test2) 
X9) 
 
X 
 
X 
 
X 
X 
X 
Pregnancy test3) 
X 
 
X 
 
 
 
X 
X 
Urination record Distribution 
X 
 
X 
 
X 
 
 
 
 
Collection 
 
 
X 
 
X 
 
X 
 
X 
 
Confirmation of entry 
 
 
X 
 
X 
 
X 
 
X 
Record of status of urinary incontinence 
 
 
 
 
 
 
Record of number of used pads 
 
 
 
 
 
 
Record of number of urinations 
 
 
 
 
 
 
1-hour pad test 
X 
 
X 
 
 
 
X 
 
X 
ICIQ-SF evaluation 
X 
 
X 
 
X 
 
X 
 
X 
PGI-I evaluation 
 
 
X 
 
X 
 
X 
 
X 
I-QOL evaluation 
 
 
X 
 
X 
 
X 
 
X 
Urinary flow test 
 
 
X 
 
 
 
X 
 
X 
Measurement of residual urine volume by 
ultrasonography 
X9) 
 
X 
 
 
 
X 
 
X 
Concomitant drugs and therapies4) 
 
 
 
 
 
X 
Evaluation of adverse events4) 
 
 
 
 
 
X 
1. 
Acquisition of consent: Consent is obtained within 28 days before the enrollment in the observation period.  
2. 
Laboratory test: Hematological tests, serum chemistry and urinalysis are performed. 
3. 
Pregnancy test: Required. When at least 1 year has passed after menopause or when the possibility of pregnancy is medically denied, the test is not necessary. The pregnancy test (serum or urine) 
before the enrollment must be negative. 


17 
4. 
Concomitant drugs/therapies, evaluation of adverse events: Investigated from the acquisition of consent to the completion of the follow-up observation period. 
5. 
Acceptable range of observation period: Observation period is 3 weeks in principle, but up to 4 weeks is permitted. 
6. 
Acceptable range of timings of visits in treatment period: Week 4 and Week 8 visits ± 3 days from the scheduled dates are permitted. 
7. 
Follow-up observation: Observation is performed 2 to 4 weeks after the completion of Week 8 of the treatment period. When the treatment is discontinued, it is performed 2 to 4 weeks after the last 
administration of the study drugs. 
8. 
In cases of discontinuation: Specified observation and tests are performed as much as possible. 
9. 
When the specified observation and tests were performed within 14 days before the enrollment, even if it was before the consent, the results can be used as the data at the time of the enrollment in 
the observation period. 
 


18 
1. Background Information 
1.1 Introduction 
Urinary incontinence is a complaint of involuntary leak of urine.1) When it becomes 
serious, urinary incontinence markedly lowers quality of life (QOL) by discouraging patients 
from going out or making them always concerned about urination. There are various types of 
urinary incontinence, which can be roughly divided into urgency urinary incontinence (UUI), 
stress urinary incontinence (SUI) and mixed urinary incontinence (MUI). UUI is a complaint 
of involuntary leak of urine at the same time or immediately after urgency.1) SUI is a 
complaint of involuntary leak of urine at the time of exertion or exercise, or during sneezing 
or coughing.1) MUI is a symptom in which UUI and SUI are observed. It is a complaint of 
involuntary leak of urine associated not only with urgency, but also with exercise, exertion, 
sneezing and cough. 
No full-scale epidemiological survey of urinary incontinence has been conducted in Japan 
and therefore, exact prevalence is unknown. On urinary incontinence in women, some studies 
of its prevalence have been conducted and the results have been reported since around 1986. 
The prevalence of urinary incontinence in otherwise healthy women without disorders other 
than urinary incontinence has been reported to be 10% to 46%.2),3),4),5) SUI is more prevalent 
than UUI and the frequency of UUI increases with age. In Japan, MUI is observed in 
approximately 20% of women. Moreover, in an epidemiological study of people aged 40 
years or older by the Japanese Continence Society, SUI occurred once a week or more 
frequently in 12.6% and 3.0% of women and men, respectively, confirming that SUI is more 
common in women. When women were analyzed by generation, SUI peaked in their forties 
and fifties and decreased after that.6) In contrast, the prevalence of MUI rose sharply at the 
age of no less than 60 years, at which SUI started to decrease.6) These results suggest that 
symptoms of SUI are universal among people aged 40 years or older. In addition, along with 
nocturia, SUI is considered to lower the QOL most greatly among urination disorders in 
women. This tendency is prominent in women in their forties to sixties.6) Therefore, women 
in these generations who are actively involved in the society are speculated to be bothered 
especially by SUI. As the society ages and women make more advances in society, treatment 
of SUI is considered to have a greater social significance. 
The factor for onset of SUI is decrease in urethral resistance and resulting increase in 
intravesical pressure in response to abdominal pressure to the level exceeding urethral 
resistance. Thus, urine leaks without bladder contraction. The main pathological conditions 
that cause decrease in urethral resistance are urethral hypermobility and intrinsic sphincter 
deficiency (ISD). In urethral hypermobility, pelvic floor muscles that support pelvic viscera 
relax, the bladder neck droops down and the support by pubourethral ligament becomes 
insufficient. Therefore, urethra tends to dilate when there is abdominal pressure, resulting in 
urinary leak. In ISD, urinary sphincter itself becomes weak, bladder neck and proximal 
urethra dilate even at rest and mild increase in bladder pressure in response to abdominal 
pressure causes urinary incontinence. ISD may be caused by atrophy of urethral mucosa due 
to postmenopausal decrease in estrogen or changes in urethra due to surgical treatment of 
urinary incontinence or gynecological surgery. However, the causes are unknown in many 
cases. ISD is also considered to be caused by disorders of external urethral sphincter that are 
iatrogenic or based on traumas or neurological diseases.5) The smooth muscles in bladder 
























30 
2. Objectives and Endpoints 
2.1 Primary Objective 
To examine the efficacy of TAS-303 using the rate of change in the number of urinary 
incontinence as an index and placebo as control, in female patients with SUI 
2.2 Secondary Objectives 
(1) To examine the efficacy of TAS-303 using the changes in the variables including 
ICIQ-SF score or I-QOL score as indices and placebo as control, in female patients 
with SUI 
(2) To examine the dose response of TAS-303 in improvement of urinary incontinence in 
female patients with SUI in an exploratory manner 
(3) To examine the safety of TAS-303 using the status of onset of adverse events and 
other indices in female patients with SUI 
2.3 Endpoints 
2.3.1 
Primary Endpoint 
Rate of change in mean number of urinary incontinence per 24 hours (Week 8 in treatment 
period) 
2.3.2 
Secondary Endpoints 
2.3.2.1 
Efficacy 
(1) Mean number of urinary incontinence per 24 hours 
1) Rate of change (Week 4 in treatment period) 
2) Amount of change (Week 4 and Week 8 in treatment period) 
3) Proportion of subjects with 50% or greater improvement (Week 4 and Week 8 in 
treatment period) 
4) Value at each evaluation time point (at the time of enrollment in treatment period, 
Week 4, Week 8) 
(2) Amount of urinary incontinence by 1-hour pad test 
1) Proportion of subjects with continence (2.0 g or less) (Week 8 in treatment 
period) 
2) Proportion of subjects with 50% or greater improvement (Week 8 in treatment 
period) 
3) Value at each evaluation time point (at the time of enrollment in observation 
period, at the time of enrollment in treatment period, Week 8) 
4) Rate of change (Week 8 in treatment period) 
5) Amount of change (Week 8 in treatment period) 


31 
(3) Mean number of used pads per 24 hours 
1) Value at each evaluation time point (at the time of enrollment in treatment period, 
Week 4, Week 8) 
2) Rate of change (Week 4 and Week 8 in treatment period) 
3) Amount of change (Week 4 and Week 8 in treatment period) 
(4) ICIQ-SF score 
1) Total score at each evaluation time point (at the time of enrollment in observation 
period, at the time of enrollment in treatment period, Week 4, Week 8) 
2) Score for each item at each evaluation time point (at the time of enrollment in 
observation period, at the time of enrollment in treatment period, Week 4, Week 
8) 
(5) Patient Global Impression-Improvement (PGI-I) 
1) Proportion for 7-point scale evaluation at each evaluation time point (at the time 
of enrollment in treatment period, Week 4, Week 8) 
2) Proportion of improvement (“very much better”, “much better”, “a little better”) 
at each evaluation time point (at the time of enrollment in treatment period, Week 
4, Week 8) 
(6) I-QOL score 
1) Total score at each evaluation time point (at the time of enrollment in treatment 
period, Week 4, Week 8) 
2) Score of each area at each evaluation time point (at the time of enrollment in 
treatment period, Week 4, Week 8) 
2.3.2.2 
Safety 
(1) Status of onset of adverse events and adverse reactions 
(2) Vital signs (blood pressure, pulse rate, body temperature), 12-lead electrocardiogram, 
laboratory tests 
(3) Urinary flow test parameters 
Maximum urinary flow rate: Free Qmax, average urinary flow rate: free Qave, voided 
volume, time of voiding (at the time of enrollment in treatment period, Week 8) 
(4) Residual urine volume (at the time of enrollment in observation period, at the time of 
enrollment in treatment period, Week 8) 
(5) Mean number of urinations per 24 hours in urination record (at the time of enrollment 
in treatment period, Week 4, Week 8) 
 
 




33 
3.1.1 
Definition of Each Period for Each Patient 
Each period specified in the protocol of this study is defined as follows: 
Study participation period: 
Period from the acquisition of written consent to the 
completion of the follow-up observation 
Observation period: 
Period from the enrollment in the observation period 
up to the enrollment in the treatment period (the 
enrollment in the treatment period is implemented 3 
weeks after the enrollment in the observation period) 
Treatment period:  
Period from the enrollment in the treatment period to 
the visit at Week 8 in the treatment period 
Follow-up observation period: Period after the visit at Week 8 in the treatment period 
to the completion of the follow-up observation 
(implemented 2 to 4 weeks after the completion of 
Week 8 of the treatment period) 
3.2 Randomization and Blinding 
3.2.1 
Randomization 
This study is a randomized study to be conducted by central enrollment using an 
interactive web response system (IWRS). Data are entered in accordance with the written 
procedures for IWRS. 
The Investigator or Sub-investigator obtains written consent after providing an 
explanation to the patients. Patient numbers are 6-digit (eg., 500101). The first digit 
represents the protocol number (5). The following 3 digits indicate a healthcare facility code. 
The last 2 digits represent the order of consent at each healthcare facility. These patient 
numbers are used throughout the entire study. The Investigator or Sub-investigator confirms 
that the subjects meet the inclusion criteria and do not meet the exclusion criteria for the 
enrollment in the observation period. Then, the patients concerned are enrolled in the 
observation period through IWRS. Similarly, for the enrollment in the treatment period, the 
patients concerned are enrolled in the treatment period through IWRS after the confirmation 
that they meet the inclusion criteria and do not meet the exclusion criteria for the enrollment 
in the treatment period. At the time of enrollment in the treatment period, subjects are 
randomly assigned to 3 mg of TAS-303, 6 mg of TAS-303 or placebo with a ratio of 1:1:1 
through IWRS based on the stochastic minimization method. 
Patients are stratified using the following allocation adjustment factors. 
 
Mean number of urinary incontinence per 24 hours at the time of enrollment in the 
treatment period (less than 2/day and 2 or more/day) 
 
Condition of urinary incontinence (SUI/MUI) 
Through IWRS, a study drug is assigned to each patient, the study site is informed of the 
drug number assigned to the patient and the instructions regarding the prescription of the 
study drug are given. For details, see written procedures for IWRS. 


34 
If by any chance the study drug different from the drug number assigned by IWRS is 
dispensed to a patient, the Sponsor must be contacted immediately. The study site must 
record the cause of the error in prescription or dispensing of the study drug. If administration 
of the study drug was started in the group different from the assigned one, the administration 
is continued. 
When the “Section 4.3 Patient Discontinuation Criteria” are met, the items related to the 
discontinuation are promptly entered into IWRS. 
3.2.2 
Blinding 
This study is a double-blind study. All patients, Investigator, Sub-investigator, Clinical 
Research Coordinator and Sponsor will remain blinded to treatment groups during the study. 
Key codes are prepared and the study treatment is unblinded in accordance with the written 
procedures for allocation of the study drugs. The person responsible for study drug 
assignment retains and manages the key codes until unblinding. 
The following items are presented in the written procedures for allocation of study drugs, 
the written procedures for emergency unblinding, the written procedures for unblinding or 
other documents. 
 
Method for assuring indistinguishability (timing, person in charge, items, etc.) 
 
Method for storage, management and handling of key codes and emergency key codes 
and specification of the person in charge of storage 
 
Procedures for emergency unblinding 
 
Timing and procedures for unblinding after data lock 
 
 


35 
4. Eligibility and Patient Discontinuation Criteria 
4.1 Inclusion Criteria 
The patients who meet all the following inclusion criteria at the time of each enrollment 
are the subjects of this study. 
The rationale for the criteria is presented in Section 14.3. 
4.1.1 
At the time of enrollment in observation period 
(1) Female outpatients who gave written consent by themselves 
(2) Aged 20 years or older and younger than 80 years at the time of consent 
(3) Have symptoms of SUI for at least 12 weeks before enrollment in the observation 
period 
(4) Considered by the Investigator or Sub-investigator to be able to go to the bathroom 
and keep an accurate urination record by themselves 
(5) Meet all the following conditions for ICIQ-SF at the time of the enrollment in the 
observation period 
1) Selection of the answer, “about once a day” (3 points), or those with higher 
scores for Q1 
2) Selection of the answer, “small amount” (2 points), or those with higher scores 
for Q2 
3) Selection of the answer, leaks “when I cough or sneeze” or leaks “while I am 
moving my body or exercising” for Q4 
(6) The amount of urinary incontinence exceeds 2.0 g in a 1-hour pad test at the time of 
the enrollment in the observation period 
4.1.2 
At the time of enrollment in treatment period 
(1) Fulfillment of all the following conditions has been indicated in the information in the 
urination record for 7 days immediately before the enrollment in the treatment period 
1) 1 or more mean number of urinary incontinence per 24 hours 
2) Number of SUI > number of UUI 
3) Ten or less mean number of daytime urination per day and 2 or less mean number 
of night-time urination per day 
4) 70% or higher rate of entry in urination record (status of urinary incontinence) 
(2) Meet all the following conditions for ICIQ-SF at the time of the enrollment in the 
treatment period 
1) Selection of the answer, “about once a day” (3 points), or those with higher 
scores for Q1 


36 
2) Selection of the answer, “small amount” (2 points), or those with higher scores 
for Q2 
3) Selection of the answer, leaks “when I cough or sneeze” or leaks “while I am 
moving my body or exercising” for Q4 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria at the time of each enrollment are 
excluded from this study. 
The rationale for the criteria is presented in Section 14.3. 
4.2.1 
At the time of enrollment in observation period 
(1) Symptoms of UUI were considered by the Investigator or Sub-investigator to be more 
predominant than those of SUI 
(2) History of surgical treatment for urinary incontinence (Trans-Obturator Tape [TOT] 
procedure, Tension-free Vaginal Tape [TVT] procedure, etc.) 
(3) Have accompanying pelvic organ prolapse quantification (POP-Q) stage II or more 
severe pelvic organ prolapse (POP) or underwent surgical repair of POP within 180 
days before the enrollment in the observation period 
(4) Accompanying lower urinary tract obstruction 
(5) Accompanying urinary tract infection (cystitis, etc.), urolithiasis (ureteral calculus, 
urethral calculus, vesical calculus, etc.), urethral diseases (urethral polyp, urethral 
diverticulum, etc.) or interstitial cystitis, or a history of recurrent urinary tract 
infection (3 or more incidents within 180 days before the consent) 
(6) Diagnosis of neurogenic bladder 
(7) Accompanying overflow incontinence 
(8) Absence of urge to urinate 
(9) Difficulty in undergoing pad test (going up and down stairs, etc.) 
(10) Accompanying central nervous system disorders (dementia, etc.) that make it 
impossible to answer the questionnaire 
(11) Accompanying angle-closure glaucoma 
(12) Clinically problematic complications (including symptoms and findings) including 
severe liver diseases (viral hepatitis, chronic hepatic failure, hepatic cirrhosis, etc.), 
renal and urologic disease (acute renal failure, glomerulonephritis, interstitial 
nephritis, etc.), cardiovascular diseases (congestive cardiac failure, angina pectoris, 
serious arrythmia, etc.), hematologic diseases (pancytopenia, leukopenia, etc.), 
respiratory diseases (serious bronchial asthma, chronic bronchitis, etc.), 
gastrointestinal disease (serious peptic ulcer, reflux esophagitis, etc.), 
neuropsychiatric diseases (schizophrenia, dementia, etc.), immune diseases (collagen 


37 
disorder, etc.), metabolic and endocrine system diseases or malignant tumors 
(13) History of hypersensitivity to the ingredients of the investigational products 
(14) 100 mL or more residual urine volume measured at the time of the enrollment in the 
observation period 
(15) Fulfillment of the following conditions in laboratory tests performed within 14 days 
before the enrollment in the observation period 
1) Aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) 
2) ALT >3×ULN 
3) T-Bil >2×ULN 
4) Serum creatinine > 2.0 mg/dL 
(16) Delivery within 1 year before the enrollment in the observation period 
(17) The following surgery or therapy within 180 days before the enrollment in the 
observation period 
1) Surgery of pelvic viscera that damages hypogastric nerve and pudendal nerve 
(radical hysterectomy, radical operation for rectal cancer, extensive dissection of 
pelvic lymph nodes, etc.) 
2) Radiation therapy that may influence urinary function 
(18) Treatment with other investigational products within 90 days before the enrollment in 
the observation period 
(19) Started physical therapy (pelvic floor muscle training, feedback training, biofeedback 
training, vaginal cone, bladder training, electric stimulation therapy, magnetic 
stimulation therapy, etc.) within 30 days before the enrollment in the observation 
period 
(20) Pregnant or nursing women, or women of childbearing potential with positive 
pregnancy test (urine or serum) within 7 days before the enrollment in the observation 
period 
Note) Women without childbearing potential are those who underwent 
hysterectomy or postmenopausal women who did not have menstruation for 
1 year or longer without medical reasons including use of contraceptive 
drugs. 
(21) Fertile patients who do not agree to practice contraception during their participation in 
the study and for 40 days after the completion of the treatment with the study drugs 
Note) The Investigator or Sub-investigator instructs practicing contraception using 
the double barrier method (condom and diaphragm), intrauterine device or 
other methods during the study participation period and the contraception 


38 
period. Because the possibility that the study drugs inhibit the metabolism of 
oral contraceptive drugs cannot be denied, use of oral contraceptive drugs is 
not considered appropriate. 
(22) Other patients considered by the Investigator or Sub-investigator to be inappropriate 
as subjects of this study 
4.2.2 
At the time of enrollment in treatment period 
(1) Less than 80% compliance with the treatment with the study drugs during the 
observation period 
(2) Urinary incontinence symptoms at the time of enrollment in the treatment period were 
considered by the Investigator or Sub-investigator to have improved greatly compared 
with those at the time of the enrollment in the observation period (50% or greater 
improvement in the mean number of urinary incontinence per 24 hours, etc.). 
(3) Symptoms of UUI were considered by the Investigator or Sub-investigator to be more 
predominant than those of SUI based on the information in urination record for 7 days 
immediately before the enrollment in the treatment period 
(4) Accompanying POP-Q Stage II or more severe POP 
(5) Accompanying lower urinary tract obstruction 
(6) Accompanying urinary tract infection (cystitis, etc.), urolithiasis (ureteral calculus, 
urethral calculus, vesical calculus, etc.), urethral diseases (urethral polyp, urethral 
diverticulum, etc.) or interstitial cystitis 
(7) Diagnosis of neurogenic bladder 
(8) Accompanying overflow incontinence 
(9) Absence of urge to urinate 
(10) Difficulty in undergoing pad test (going up and down stairs, etc.) 
(11) Accompanying central nervous system disorders (dementia, etc.) that make it 
impossible to answer the questionnaire 
(12) Accompanying angle-closure glaucoma 
(13) Clinically problematic complications (including symptoms and findings) including 
severe liver diseases (viral hepatitis, chronic hepatic failure, hepatic cirrhosis, etc.), 
renal and urologic disease (acute renal failure, glomerulonephritis, interstitial 
nephritis, etc.), cardiovascular diseases (congestive cardiac failure, angina pectoris, 
serious arrythmia, etc.), hematologic diseases (pancytopenia, leukopenia, etc.), 
respiratory diseases (serious bronchial asthma, chronic bronchitis, etc.), 
gastrointestinal disease (serious peptic ulcer, reflux esophagitis, etc.), 
neuropsychiatric diseases (schizophrenia, dementia, etc.), immune diseases (collagen 
disorder, etc.), metabolic and endocrine system diseases or malignant tumors 
(14) 100 mL or more residual urine volume measured at the time of the enrollment in the 


39 
treatment period 
(15) Fulfillment of the following conditions in laboratory tests performed within 14 days 
before the enrollment in the treatment period 
1) AST >3×ULN 
2) ALT >3×ULN 
3) T-Bil >2×ULN 
4) Serum creatinine > 2.0 mg/dL 
(16) Pregnant or nursing women, or women of childbearing potential with positive 
pregnancy test (urine or serum) within 7 days before the enrollment in the treatment 
period 
Note) Women without childbearing potential are those who underwent 
hysterectomy or postmenopausal women who did not have menstruation for 
1 year or longer without medical reasons including use of contraceptive 
drugs. 
(17) Other patients considered by the Investigator or Sub-investigator to be inappropriate 
as subjects of this study 
4.3 Patient Discontinuation Criteria 
When patients meet the following conditions, administration of the study drugs is 
discontinued. Discontinuation criteria for individual patients are shown below. 
(1) When continuation of treatment is difficult because of onset of an adverse event 
(2) When the patient requested the withdrawal of consent 
(3) When a serious noncompliance with the study implementation procedures was noted 
(4) When continuation of the study became impossible due to a move, transfer to another 
hospital, busy schedule or other reasons of the patient 
(5) When a patient was found not to fulfill the criteria for subjects of this study (not 
meeting the inclusion criteria or meeting the exclusion criteria) 
(6) When the following liver damage for which a causal relationship with the study drugs 
of this study cannot be denied occurred 
1) AST (glutamic oxaloacetic transaminase [GOT]) or ALT (glutamic pyruvic 
transaminase [GPT]) > 8 × ULN 
2) AST (GOT) or ALT (GPT) > 5 × ULN persisting for 2 weeks or longer 
3) AST (GOT) or ALT (GPT) > 3 × ULN with total bilirubin (T-Bil) > 2 × ULN or 
international normalized ratio (INR) > 1.5 
4) AST (GOT) or ALT (GPT) > 3 × ULN and onset of malaise, nausea, vomiting, 


40 
right upper quadrant pain/tenderness, pyrexia, rash or eosinophilia (> 5%) 
(7) When a patient became pregnant 
(8) When the effect of the study drugs was insufficient or symptoms were exacerbated 
and the Investigator or Sub-investigator considered that the study should be 
discontinued 
(9) Other cases in which the Investigator or Sub-investigator considered the 
discontinuation of the study necessary 
 
 


41 
5. Study Assessments 
The evaluation and test items performed in this study are shown in Table 5-1 and the 
details of the implementation schedule in Table 5-2. 
All information specified in the protocol must be recorded. When the specified 
observation and tests were performed within 14 days before the enrollment, even if it was 
before the consent, the results can be used as the data at the time of the enrollment in the 
observation period. 
Table 5-1  Evaluation and Test Items 
Acquisition of consent 
 
Date of acquisition of consent 
 
Patient background 
 
Gender 
Date of birth 
Age*1 
 
Race 
Height 
Body weight 
 
BMI*2 
History of clinical trial participation (within past 90 days) 
Past history (within past 180 days) 
 
Complication 
Onset timing of SUI (year) 
Condition of urinary incontinence (SUI/MUI)*3 
 
Presence or absence of menopause 
Number of delivery (natural/cesarean section) 
History of previous treatment 
 
Menstrual cycle 
Presence or absence of use of incontinence pad 
History of POP surgical repair 
Patient enrollment 
 
 
 
Patient identification code 
Patient number 
Drug number 
Subjective and objective findings 
 
 
Vital signs 
 
 
 
Pulse rate 
Blood pressure (systolic, diastolic) 
Body temperature 
Compliance with treatment with study drugs 
Concomitant medications and therapies 
12-lead electrocardiography 
 
Heart rate 
QTcF interval 
 
Hematological tests 
 
Red blood cell count 
Hemoglobin 
Hematocrit 
Platelet count 
 
White blood cell count 
Neutrophil 
Eosinophil 
Basophil 
 
Lymphocyte 
Monocyte 
Prothrombin time-international normalized ratio (PT-INR)  
Serum chemistry 
 
AST 
ALT 
ALP 
BUN  
 
Albumin 
Creatinine 
Na 
Cl 
 
K 
T-Bil 
Direct bilirubin 
Total protein 
 
CRP 
CPK 
LDH 
γ-GTP 
 
Blood sugar 
Triglyceride 
Total cholesterol 
A/G 
Urinalysis 
 
Protein 
Occult blood 
Glucose 
Urobilinogen 
Pregnancy test*4 
 
Serum or urinary β-human chorionic gonadotropin 
 
Evaluation of symptom scores 
 
 
 
 
ICIQ-SF 
PGI-I 
 
 
Evaluation of QOL score 
 
 
 
 
I-QOL 
 
 
 
Urination record 
 
 
 
 
Status of urinary incontinence, time and date 
Presence or absence of pad change 
Urination time and date 
Pad test 
 
 
 
 
1-hour pad test 
 
 
 
Measurement of urinary flow 
 
 
 
 
Maximum urinary flow rate (free Qmax) 
Average urinary flow rate (free Qave) 
 
Voided volume 
Time of voiding 
 
Measurement of residual urine volume 
Evaluation of adverse events 
*1: Automatically calculated from date of birth 
*2: Automatically calculated from height and body weight 
*3: Determined from the content of Q4 of ICIQ-SF 
*4: Required. When at least 1 year has passed after menopause or when the possibility of pregnancy is medically denied, the test is not 
necessary. 
 


42 
Table 5-2  Observation and Test Schedule 
Timing 
At 
enrollment 
in 
observation 
period 
Observation 
period5) 
At 
enrollment 
in treatment 
period 
Treatment period6) 
Follow-up 
observation7)
At 
discontinuation8) 
7 days 
before 
enrollment 
in treatment 
period 
7 days 
before 
Week 4 
visit 
Week 4
7 days 
before 
Week 8 
visit 
Week 8
Visit 
1 
2 
3 
4 
5 
Week  
-3 
1 
4 
8 
10 - 12 
Acquisition of consent 
X1) 
 
 
 
 
 
 
 
Patient background survey 
X 
 
X 
 
 
 
 
 
 
Enrollment 
X 
 
X 
 
 
 
 
 
 
Study drugs Prescription 
X 
 
X 
 
X 
 
 
 
Collection of remaining drugs
 
 
X 
 
X 
 
X 
 
X 
 
Confirmation of compliance 
 
 
X 
 
X 
 
X 
 
X 
Subjective and objective findings 
X 
 
X 
 
X 
 
X 
X 
X 
Blood pressure, pulse rate and body 
temperature measurement 
X9) 
 
X 
 
X 
 
X 
X 
X 
12-lead electrocardiography 
X9) 
 
X 
 
 
X 
X 
X 
Laboratory test2) 
X9) 
 
X 
 
X 
 
X 
X 
X 
Pregnancy test3) 
X 
 
X 
 
 
 
X 
X 
Urination record Distribution 
X 
 
X 
 
X 
 
 
 
 
Collection 
 
 
X 
 
X 
 
X 
 
X 
 
Confirmation of entry 
 
 
X 
 
X 
 
X 
 
X 
Record of status of urinary incontinence 
 
 
 
 
 
 
Record of number of used pads 
 
 
 
 
 
 
Record of number of urinations 
 
 
 
 
 
 
1-hour pad test 
X 
 
X 
 
 
 
X 
 
X 
ICIQ-SF evaluation 
X 
 
X 
 
X 
 
X 
 
X 
PGI-I evaluation 
 
 
X 
 
X 
 
X 
 
X 
I-QOL evaluation 
 
 
X 
 
X 
 
X 
 
X 
Urinary flow test 
 
 
X 
 
 
 
X 
 
X 
Measurement of residual urine volume by 
ultrasonography 
X9) 
 
X 
 
 
 
X 
 
X 
Concomitant drugs and therapies4) 
 
 
 
 
 
X 
Evaluation of adverse events4) 
 
 
 
 
 
X 
1. 
Acquisition of consent: Consent is obtained within 28 days before the enrollment in the observation period. 
2. 
Laboratory test: Hematological tests, serum chemistry and urinalysis are performed. 


43 
3. 
Pregnancy test: Required. When at least 1 year has passed after menopause or when the possibility of pregnancy is medically denied, the test is
before the enrollment must be negative. 
4. 
Concomitant drugs/therapies, evaluation of adverse events: Investigated from the acquisition of consent to the completion of the follow-up obs
5. 
Acceptable range of observation period: Observation period is 3 weeks in principle, but up to 4 weeks is permitted. 
6. 
Acceptable range of timings of visits in treatment period: Week 4 and Week 8 visits ± 3 days from the scheduled dates are permitted. 
7. 
Follow-up observation: Observation is performed 2 to 4 weeks after the completion of Week 8 of the treatment period. When the treatment is d
administration of the study drugs. 
8. 
In cases of discontinuation: Specified observation and tests are performed as much as possible. 
9. 
When the specified observation and tests were performed within 14 days before the enrollment, even if it was before the consent, the results ca
the observation period. 
 


44 
5.1 All Study Procedures 
The following evaluation and tests must be recorded as source documents of each patient. 
5.1.1 
Informed Consent 
Consent is obtained within 28 days before the enrollment in the observation period and 
subsequently, eligibility is confirmed. 
5.1.2 
Patient Background 
All the items of patient background information shown in Table 5-1 are collected. 
5.1.3 
Patient enrollment 
Unique patient identification codes are assigned for screening at study sites and patient 
numbers are assigned by the time of enrollment in the observation period. At the time of 
enrollment in the treatment period, drug numbers are obtained. The allocation method is 
shown in Section 3.2. 
5.1.4 
Subjective and Objective Findings 
Subjective and objective findings are evaluated at the timing shown in Table 5-2. The 
information regarding signs and symptoms observed at the time of enrollment in the 
treatment period is collected as the information regarding baseline signs and symptoms. All 
the abnormal findings considered to be clinically significant compared with baseline must be 
recorded as adverse events. The evaluation methods of adverse events shown in Section 12 
are used. 
5.1.5 
Vital Signs 
As vital signs, blood pressure (systolic and diastolic), pulse rate and body temperature are 
measured at the timings shown in Table 5-2. At all measurement timings, they should be 
measured keeping the patients at rest, using the same site and method in each patient. 
The Investigator or Sub-investigator is responsible for assessing the changes in vital signs. 
If an abnormal result is obtained, measurement should be performed again immediately. 
Changes that are considered clinically significant based on the comparison with baseline 
must be recorded as adverse events. The evaluation methods of adverse events shown in 
Section 12 are used. 
5.1.6 
Compliance with treatment with study drugs 
Compliance with treatment with the study drugs is confirmed in every visit by checking 
the treatment diary and empty sheet of used study drugs, asking subjects questions and other 
methods from the start of the treatment with the study drugs to the completion of the 
treatment. 
5.1.7 
Concomitant medications and therapies 
The status of concomitant medications and therapies is confirmed and related information 
is collected at least in every visit by asking subjects questions or by other methods from the 
start of the treatment with the study drugs to the completion of the study participation period. 
The information regarding all the concomitant medications (prescription drugs and 
over-the-counter drugs) and therapies is collected from the time of consent to the completion 


45 
of the study participation period and the status of their use is recorded in the source 
documents. The concomitant medications and therapies include the therapeutic agents used to 
treat adverse events or serious adverse events. For the concomitant medications and therapies 
for the adverse events the observation of the course of which is required at the time of the 
follow-up observation, information is collected until the completion of the observation of the 
course and the status of their use is recorded in the source documents. However, test agents, 
diagnostic agents or fluids for the administration of injections do not have to be recorded in 
the case report form (eCRF). 
5.1.8 
12-lead Electrocardiography 
Twelve-lead electrocardiography is performed at the timings shown in Table 5-2. It should 
be performed keeping patients at rest, using the same method for each patient.  
The Investigator or Sub-investigator is responsible for assessing the results of 
electrocardiography. All the abnormal findings considered to be clinically significant 
compared with baseline must be recorded as adverse events. The evaluation methods of 
adverse events shown in Section 12 are used. 
5.1.9 
Laboratory Findings 
In laboratory tests, the items shown in Table 5-1 are evaluated. 
The Investigator or Sub-investigator must evaluate all the laboratory test values as to 
whether they are clinically significant events. When an event was considered to be a 
clinically significant event, its course must be observed as specified in the protocol and the 
event must be recorded as an adverse event. The evaluation methods of adverse events shown 
in Section 12 are used. When liver damage is suspected, hepatic function tests are performed. 
When the tests showed AST (GOT) > 3 × ULN, ALT (GPT) > 3 × ULN or T-Bil > 2 × ULN, 
at least AST (GOT), ALT (GPT), alkaline phosphatase (ALP) and T-Bil are tested once every 
2 to 3 days and the condition of the patient is observed in detail. 
5.1.9.1 
Hematology 
Blood samples for hematology will be collected at the time points shown in Table 5-2. 
5.1.9.2 
Serum chemistry 
Blood samples for serum chemistry will be collected at the time points shown in Table 
5-2. 
5.1.9.3 
Urinalysis 
Urine samples for urinalysis will be collected at the time points shown in Table 5-2. 
5.1.10 
Pregnancy Test 
Serum or urinary β-human chorionic gonadotropin is tested at the timings shown in Table 
5-2 in patients with childbearing potential to confirm that they are not pregnant. The test is 
unnecessary for patients without childbearing potential. 
Note) Women without childbearing potential are those who underwent hysterectomy or 
postmenopausal women who did not have menstruation for 1 year or longer 
without medical reasons including use of contraceptive drugs. 


46 
5.1.11 
Evaluation of symptom scores 
5.1.11.1 
ICIQ-SF 
As the evaluation of a symptom score, patients are asked to answer ICIQ-SF at the timings 
shown in Table 5-2. 
5.1.11.2 
PGI-I 
As the evaluation of patients’ impression of improvement of urinary incontinence, patients 
are asked to evaluate PGI-I at the timing shown in Table 5-2. 
5.1.12 
Evaluation of QOL Scores 
As the evaluation of QOL score, patients are asked to evaluate I-QOL at the timings 
shown in Table 5-2. 
5.1.13 
Urination Record (Bladder Diary) 
Urination record (bladder diary) is issued to patients and collected at the timings shown in 
Table 5-2 and the entry is confirmed. 
5.1.14 
Pad Test 
One-hour pad test is performed at the timings shown in Table 5-2 and the amount of 
urinary incontinence is evaluated. The test is performed in accordance with the written 
procedures for pad test. 
5.1.15 
Urinary Flow Test 
Urinary flow test is performed at the timings shown in Table 5-2 and the maximum 
urinary flow rate (free Qmax), average urinary flow rate (free Qave), voided volume and time 
of voiding are evaluated. The test is performed in accordance with the written procedures for 
urinary flow test. 
5.1.16 
Measurement of Residual Urine Volume 
Residual urine volume is measured at the timings shown in Table 5-2. 
5.1.17 
Evaluation of Adverse Events 
As shown in Table 5-2, it is checked whether there are untoward medical occurrences 
(adverse events or serious adverse events) including adverse reactions on each day of visit 
from the time of consent to the completion of study participation period. The evaluation 
methods of adverse events shown in Section 12 are used. 
5.2 Assessments by Visit 
The evaluation and tests shown in Table 5-1 are performed according to the schedule 
shown in Table 5-2. 
 
 




48 
6.3 Accountability 
The head of the study site or the person in charge of management of the study drugs 
manages all study drugs received at the study site in accordance with the written procedures 
for management and handling of study drugs. The details are specified in the written 
procedures for management and handling of study drugs. The entire history of prescription of 
study drugs is recorded in the table for management of study drugs. 
No study drug is to be used outside of this study. 
6.4 Patients Instruction on Proper Using 
The Investigator or Sub-investigator instructs patients to handle the study drugs using 
specified methods and record compliance with the treatment with study drugs in the 
treatment diary. The details of the instructions are specified in the written procedures for 
management and handling of study drugs and the treatment diary. When a patient does not 
comply with the specified methods, the Investigator or Sub-investigator can discontinue the 
study in the patient. Compliance is confirmed by checking the entry in the table for 
management of study drugs, the treatment diary and consistency with the source documents. 
6.5 Implementation of Allocation Confirmation Study 
This study is a double-blind controlled study. In order to confirm that the subjects are 
appropriately allocated to each treatment group (TAS-303 6 mg group, TAS-303 3 mg group 
and placebo group) after the allocation, the allocation confirmation study is conducted. 
 
 




50 
7.3 Restrictions 
7.3.1 
Contraception 
Patients practice contraception during the study participation period and for 40 days after 
the completion of the treatment with the study drugs. The Investigator or Sub-investigator 
instructs practicing contraception using the double barrier method (condom and diaphragm), 
intrauterine device or other methods during the study participation period and the 
contraception period. Because the possibility that the study drugs inhibit the metabolism of 
oral contraceptive drugs cannot be denied, use of oral contraceptive drugs is not considered 
appropriate. 
7.3.2 
Food and Drink 
During the treatment with the study drugs, patients should be instructed not to ingest food 
and beverages containing grapefruit or St. John's wort. Because ingestion of these food and 
beverages during the treatment with the study drugs may enhance or diminish the action of 
TAS-303, presence or absence of adverse events should be checked in cases of ingestion. 
7.4 Concomitant medications and therapies 
7.4.1 
Prohibited Concomitant Medications and Therapies 
The following concomitant medications and therapies are prohibited after the enrollment 
in the observation period until the day of Week 8 visit in the treatment period or the day of 
completion of treatment with the study drugs. The rationale is presented in Section 14.4. 
(1) Drugs and therapies for SUI 
 
Clenbuterol hydrochloride 
 
Chinese herbal medicine or other related products (Hochuekkito, processed food 
containing medicinal Cucurbita pepo seed extract and soy germ extract [PEP]) 
 
Tricyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, 
clomipramine hydrochloride, etc.) 
 
Estrogen 
 
α adrenergic receptor agonists (ephedrine, phenylpropanolamine, midodrine, 
methoxamine, etc.) 
 
Duloxetine 
 
Surgical treatment (TOT procedure, TVT procedure, etc.) 
 
Physical therapy (pelvic floor muscle training, feedback training, biofeedback 
training, vaginal cone, electric stimulation therapy, magnetic stimulation therapy, 
etc.) 
(2) Drugs and therapies for overactive bladder (OAB) 
 
Anticholinergics (oxybutynin hydrochloride, propiverine hydrochloride, 
tolterodine tartrate, solifenacin succinate, imidafenacin, fesoterodine fumarate, 


51 
propantheline bromide, etc.)  
 
β3 receptor agonist (mirabegron) 
 
Flavoxate hydrochloride 
 
Tricyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, 
clomipramine hydrochloride, etc.) 
 
Chinese medicine (Goshajinkigan, etc.) 
 
Estrogen 
 
Botulinum toxin 
 
Resiniferatoxin, capsaicin 
 
Antidiuretic hormone (desmopressin, etc.) 
 
Physical therapy (pelvic floor muscle training, feedback training, biofeedback 
training, bladder training, electric stimulation therapy, magnetic stimulation 
therapy, etc.) 
(3) Drugs and therapies for voiding dysfunction 
 
Bethanechol chloride, distigmine bromide 
 
α adrenergic receptor antagonists (urapidil, naftopidil, terazosin hydrochloride, 
etc.) 
(4) Other drugs speculated to affect the urinary function 
(5) Drugs that inhibit NA reuptake 
 
Atomoxetine hydrochloride 
 
Amezinium metilsulfate 
 
Milnacipran hydrochloride 
 
Venlafaxine hydrochloride 
 
Maprotiline hydrochloride 
(6) Other investigational drugs 
7.4.2 
Concomitant Medications and Therapies Requiring Precautions 
Concomitant medications and therapies requiring precautions are specified as follows for 
the period after the enrollment in the observation period until the day of Week 8 visit in the 
treatment period or the day of completion of treatment with the study drugs. The rationale is 
presented in Section 14.5. 
(1) Drugs with potent inhibitory action on CYP3A (itraconazole, voriconazole, 
clarithromycin, etc.) 




53 
 
8. Pharmacokinetics and Pharmacodynamics 
Pharmacokinetics and pharmacodynamics are not evaluated in this study. 
9. Pharmacogenomic Analysis 
Pharmacogenomic investigation is not performed in this study. 
 
 


54 
10. Discontinuation and Study Completion 
10.1 Criteria for Discontinuation of the Study at Individual Study Sites 
The Sponsor or Investigator may discontinue the study at a study site where major or 
continuous non-compliance with Good Clinical Practice (GCP) or the study protocol by the 
Investigator or Sub-investigator is found to have interfered or may have interfered with the 
proper conduct of the study. In such a case, the Sponsor or Investigator should promptly 
notify the IRB in writing, according to the standard operating procedure (SOP) of the study 
site. 
10.2 Criteria for Termination of the Entire Study 
The Sponsor reserves the right to discontinue the study for administrative reasons at any 
time. If the Sponsor should discover conditions arising during the clinical study that indicate 
it should be terminated, an appropriate schedule for termination of the entire or part of the 
study will be instituted. In such a case, the Sponsor will promptly notify the study site(s) lead 
with the reasons for study termination. Study site leads will promptly inform, in writing, the 
IRB and the Investigator. The Investigator or Sub-investigator should immediately advise the 
patients of the termination of the study and change the study treatment to other treatments. 
The Sponsor will promptly notify the Regulatory Authorities of the premature termination of 
the study. 
 
 


55 
11. Efficacy Evaluation 
11.1 Evaluation of symptom scores 
11.1.1 
ICIQ-SF 
The subjective symptoms of SUI (frequency of urine leakage, volume of urine leakage, 
impact on living and reason for urine leakage) are evaluated using ICIQ-SF. The content of 
ICIQ-SF is shown in APPENDIX 1  ICIQ-SF. 
The total score of ICIQ-SF is defined as the sum of the scores for Q1, Q2 and Q3. 
The Investigator or Sub-investigator instructs patients to enter the score corresponding to 
each subjective symptom at the evaluation time point. The Investigator or Sub-investigator 
should be careful not to bias the evaluation by, for example, being close to patients or talking 
to them while they are evaluating. 
11.1.2 
PGI-I 
The patients’ impression of improvement of urinary incontinence is evaluated using PGI-I. 
The content of PGI-I is shown in APPENDIX 2  Patient Global Impression-Improvement: 
PGI-I. 
The improvement of PGI-I is defined as the selection of “very much better”, “much better” 
or “a little better”. 
The Investigator or Sub-investigator instructs patients to evaluate the improvement of 
urinary incontinence at the evaluation time point using the following 7-point scale. The 
Investigator or Sub-investigator should be careful not to bias the evaluation by, for example, 
being close to patients or talking to them while they are evaluating. 
· 
Very much better 
· 
Much better 
· 
A little better 
· 
No change 
· 
A little worse 
· 
Much worse 
· 
Very much worse 
11.2 Evaluation of QOL Scores 
QOL associated with urinary incontinence is evaluated using I-QOL. The content of 
I-QOL is shown in APPENDIX 3  I-QOL. 
The total score of I-QOL is defined as the sum of the scores for all questions. In the 
evaluation of I-QOL scores for individual areas, 1) the score for “avoidance and limiting 
behavior” is defined as the sum of the scores for Questions 1, 2, 3, 4, 10, 11, 13 and 20, 2) the 
score for “psychosocial impacts” is defined as the sum of the scores for Questions 5, 6, 7, 9, 


56 
15, 16, 17, 21 and 22, and 3) the score for “social embarrassment” is defined as the sum of 
the scores for Questions 8, 12, 14, 18 and 19. 
The Investigator or Sub-investigator instructs patients to enter the score corresponding to 
each subjective symptom at the evaluation time point. The Investigator or Sub-investigator 
should be careful not to bias the evaluation by, for example, being close to patients or talking 
to them while they are evaluating. 
11.3 Urination Record (Bladder Diary) 
Time of voiding, presence or absence of urgency, time of urinary incontinence, reason for 
leakage and status of use of pads are evaluated using the urination record (bladder diary). 
The Investigator or Sub-investigator explains how to fill out the urination record (bladder 
diary) to patients. The details of the entry method are shown in the urination record (bladder 
diary). Patients are instructed to enter the time of voiding, presence or absence of urgency, 
time of urinary incontinence and reason for leakage during the 7 days before the day of the 
next visit in the urination record. 
The urination record is issued to patients at every visit and they are instructed to bring it in 
the next visit. The urination record is collected in the subsequent visit, in principle. 
11.4 1-hour Pad Test 
Amount of urinary incontinence is evaluated by 1-hour pad test. The details of the 1-hour 
pad test are shown in APPENDIX 4  1-hour Pad Test. 
The Investigator or Sub-investigator explains a 1-hour pad test to patients. The details of 
the method are shown in the written procedures of pad test. While patients are performing the 
pad test, it should be confirmed that they are carrying out the movements specified in the 
procedures. 
 
 


57 
12. Safety Evaluation 
12.1 Adverse Events 
12.1.1 
Definition of Adverse Events 
An AE is any untoward medical condition that occurs in a patient while participating in a 
clinical study and does not necessarily have a causal relationship with the study drug. 
A complete and specific clinical diagnosis should be provided as an AE term. If a 
diagnosis is not available, then report signs and symptoms. 
Symptoms or laboratory abnormalities associated with a pre-existing medical condition, 
SUI or other disease, should not be considered an AE. However, occurrences of new 
symptoms as well as worsening of pre-existing medical conditions are considered AEs. 
Any laboratory abnormality that is clinically significant or medically important must be 
reported as an AE, unless it is a result considered to be supporting a clinical diagnosis that is 
already reported as an AE. 
When a laboratory test value is handled as an adverse event: 
 
When intervention is required. 
 
When interruption or discontinuation of treatment with the study drugs or other 
measures are required. 
 
Additional tests were performed for diagnosis 
 
Any other events that are considered as medically important by the Investigator or 
Sub-investigator occur. 
The details of the entry method are presented in the guide for preparation, change and 
correction of case report form (CRF). 
Pregnancy and medication errors are described in Section 12.5. 
12.1.2 
Severity of Adverse Events 
The severity of adverse events is rated as one of the following (“;” means “or”). 
(1) Mild 
Mild; asymptomatic or mild symptoms; clinical or examination findings only; 
intervention not indicated 
(2) Moderate 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activity of daily living (ADL)* 
(3) Severe 
Severe or medically significant but not immediately life-threatening; hospitalization 
of prolongation of hospitalization indicated; disabling; limiting self-care ADL** 


58 
Moreover, life-threatening events, events requiring emergency treatment and deaths 
due to adverse events are included in severe events. 
*: 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using 
the telephone, managing money, etc. 
**: 
Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications and not bedridden. 
12.1.3 
Causal Relationship with the Study Drug 
Causal relationship between AE and the study drug will be assessed using the following 
2-point scale, taking into consideration factors including the patient’s condition, medical 
history, concomitant medications, and temporal relationship between study drug 
administration and onset of the AE. When the causal relationship with study drug was rated 
as being “No reasonable possibility”, the reason is entered in the CRF. 
(1) Select “Reasonable possibility (Related)” if the event follows a reasonable temporal 
sequence from study drug administration and any of the following conditions are true: 
− 
A positive Dechallenge. This means that the event improves or resolves after the 
study drug is stopped (temporarily or permanently). 
− 
A positive Rechallenge. This means that the event reappears after the study drug 
is restarted. 
− 
The event cannot be reasonably explained by the patient’s clinical state and/or 
other therapies administered. 
− 
A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (eg, angioedema, Stevens-Johnson syndrome). 
(2) Select “No reasonable possibility (Not related)” if there is no evidence to suggest a 
causal relationship between study drug and the AE. 
No reasonable possibility is selected if: 
− 
The event occurred prior to the study drug administration. 
− 
When the adverse event was possibly caused by the primary disease, 
complications, concomitant medications, predisposition of the patient or other 
factors 
12.1.4 
Outcome of Adverse Events 
Record the outcome of AEs as follows: 
(1) Recovered/resolved 
Symptom or finding disappeared or returned to the previous condition. 
(2) Recovering/resolving 
Symptom or finding almost disappeared or almost returned to the previous condition. 
(3) Not recovered/not resolved 
Symptom or finding neither resolved nor changed. 


59 
(4) Recovered/resolved with sequelae 
Symptom resolved, but dysfunction that interferes with daily life is considered to have 
been caused by the adverse event. 
(5) Fatal 
The patient died because of the adverse event. 
12.1.5 
Reporting of Adverse Events 
Adverse events are reported for the period from the acquisition of consent to the 
completion of the follow-up observation. All adverse events are entered in the source 
documents. In CRF, the adverse events that occurred in relation to this study from the 
acquisition of consent up to the start of the treatment with study drugs and the adverse events 
that have occurred since the start of the treatment with the study drugs are entered. 
When serious medical occurrences including adverse events and deaths were reported or 
observed by the Investigator or Sub-investigator after the completion of the follow-up 
observation and the causal relationship between these occurrences and the study drugs cannot 
be denied, the Investigator or Sub-investigator reports them to the Sponsor. 
12.1.6 
Follow-up of Adverse Events 
When an AE occurs, the Investigator or Sub-investigator will promptly provide 
appropriate measures and follow up the patient until the AE is confirmed to have resolved. If 
it is not possible to follow up an AE for any of the following reasons, this should be 
documented fully in the CRF as follows: 
· 
Another treatment is provided and it is therefore impossible to evaluate a causal 
relationship with the study drug. 
· 
It is difficult to follow up the patient due to transfer to another hospital. 
· 
The patient refuses follow up. 
· 
The patient dies. 
· 
Although the AE has not yet resolved, the Investigator or Sub-investigator considers 
that the AE is stable or no further improvement is expected. 
12.2 Serious Adverse Events 
12.2.1 
Definition of Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
(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. 


60 
(c) Requires inpatient hospitalization or prolongation of existing hospitalization. The 
following are not considered hospitalizations for the purposes of assessing 
seriousness: 
- 
Emergency room visits <24 hours. 
- 
Hospitalizations for preplanned procedures. 
- 
Hospitalization for study-related treatment and procedures. 
(d) Results in persistent or significant disability or incapacity. 
(e) Is a congenital anomaly/birth defect (if exposure to product just before conception or 
during pregnancy resulted in an adverse outcome in the child). 
(f) Other important medical event  
Note: That may not be immediately life-threatening, result in death or hospitalization 
but may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above.  
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse. 
12.2.2 
Reporting of Serious Adverse Events 
SAEs must be reported to the Sponsor within 24 hours from the time the Investigator or 
Sub-investigator first becomes aware of the SAE. Comprehensive information available at 
the time of initial reporting (eg, narrative description, medical history, concomitant 
medications) should be provided with careful consideration regarding causal relationship and 
serious criterion. The contact information for reporting the SAE are provided below. 
After the initial SAE notification to the Sponsor, follow up SAE information will be 
submitted each time that important follow-up information (eg, diagnosis, outcome, 
assessment of causal relationship, results of specific investigations) becomes available. 
The Investigator also must submit further information if it is required by the Sponsor, the 
director of study site or IRB. 
All the SAEs that occurred from the time of consent to the completion of the follow-up 
observation are reported to the Sponsor. When SAEs (including deaths) occurred outside the 
study participation period specified in the protocol, these SAEs are reported to the Sponsor 
only if the Investigator suspects a relationship between them and the study drugs. 
SAEs should be reported to: 
Clinical Development Division, Taiho Pharmaceutical Co., Ltd.  
1-2-4 Uchikanda, Chiyoda-ku, Tokyo 101-0047 
Phone 03-3293-2455 (direct number), Fax 03-3293-1271 
(from 8:40 a.m. to 5:30 p.m. except Saturdays, Sundays and national holidays and the 
period from December 29 to January 4) 
Outside the above time frame, the product leader or the clinical team leader should be 


61 
contacted. 
For the contact information of the product leader and the clinical team leader, see the 
document attached to the protocol. 
 
12.2.3 
Follow-up of Serious Adverse Events 
SAEs are followed up in the same way as the follow-up of adverse events. Follow-up of 
adverse events is described in Section 12.1.6. When the follow-up of SAEs cannot be 
continued, the reason is reported in the reports of SAEs. 
12.2.4 
Possibility of Prediction of Serious Adverse Events in Use of Study Drugs 
It is determined based on the description in the investigator’s brochure whether or not a 
serious adverse event can be predicted in association with the study drugs (known, unknown). 
When the characteristics and severity are consistent with the description, the event is 
considered to be “known”. Even if the event is listed in the brochure, its characteristics and 
severity are inconsistent with the description (acute kidney failure and nephritis interstitial, 
hepatitis and hepatitis fulminant, etc.), the event is considered to be “unknown”. 
Because SAEs for which a causal relationship cannot be denied have not occurred in the 
use of TAS-303, all SAEs that occurred in this study are handled as “unknown” events. 
12.3 Adverse Events of Special Interest 
12.3.1 
Definition of Adverse Events of Special Interest 
In this study, adverse events of special interest are not defined. 
12.4 Adverse Reactions 
12.4.1 
Definition of Adverse Reactions 
Among the adverse events that occurred during or after the treatment period, those for 
which a causal relationship with the study drugs was rated as being “reasonably possible” by 
the Investigator or Sub-investigator (including abnormal laboratory test values) are 
considered to be adverse reactions. 
12.5 Other Information 
12.5.1 
Pregnancy 
In this study, contraception during the study participation period and for 40 days after the 
completion of the treatment with the study drugs is required. 
If by any chance a patient becomes pregnant during the specified period for contraception, 
the Investigator or Sub-investigator reports the information about pregnancy of this patient 
within 24 hours from the time the Investigator or Sub-investigator first becomes aware of 
the pregnancy or its outcome. Information regarding pregnancy is entered in the Pregnancy 
Form and sent to the Sponsor by e-mail, fax or other methods. New and/or corrected 
information regarding the pregnancy obtained after submitting the Pregnancy Form must be 
submitted by emailing or faxing an updated Pregnancy Form to the Sponsor. 
The Investigator or Sub-investigator will follow the pregnancy and report the outcome. If 


62 
the outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious 
event in the mother, report as an SAE to the Sponsor. Live births will be followed up by the 
Investigator or Sub-investigator and any information that may be associated with the study 
drug should be reported to the Sponsor even after study completion. 
12.5.2 
Medication Errors 
A medication error is defined as any unintentional error in the prescribing, dispensing or 
administration of the study drug while the study drug is in the control of the healthcare 
professional or patient. The error may be related to the administration of a wrong drug, nature 
of the medication, route of administration, dosage or frequency of the treatment as specified 
in this protocol. 
The following procedures should be followed: 
 
Medication errors with the study drugs regardless of whether it is associated with an 
AE (even if not fulfilling a definition of SAE) are to be promptly reported to the 
Sponsor. 
 
No antidote that can be used for the overdose of the study drugs is known. While 
carefully monitoring the patient, proactive treatment is provided by prophylactic and 
symptomatic methods to prevent or treat possible adverse reactions. 
 
 




64 
For problematic cases the Sponsor and the Medical Experts will discuss and determine an 
approach prior to database lock. 
(1) Handling of missing values and abnormal values 
− 
Handling of missing values in efficacy endpoints is specified for each analysis. 
− 
Missing values in safety endpoints are not imputed. The proportion including that 
of subjects with adverse events is calculated using the analysis population as the 
denominator for the observation period and using the number of subjects who 
took the study drugs for the treatment period at least once among those in the 
analysis population as the denominator for the treatment period. 
− 
The analyses will include all measured data unless the laboratory tests (eg, the 
effect of hemolysis during blood collection, showed obvious abnormal values). If 
abnormal values are excluded from the analysis, they should be specified and the 
reasons for exclusion should be stated. 
(2) Handling of data of patients treated by study drug different from the assigned one 
− 
In the analysis of the subjects treated with the study drugs or PPS, the data of 
patients treated with the study drug of the treatment group different from the 
group they are allocated to are handled as the data of the treatment group for the 
study drug they actually received. 
− 
In the analysis of FAS, the data of these subjects are handled as the data in the 
allocated group. 
13.1.3 
Statistical Analysis Methods 
The main statistical methods to evaluate the primary and secondary objectives of this 
study are described below. 
13.1.3.1 
Patient Disposition and Demographic Characteristics 
(1) Patient disposition 
− 
The number of patients enrolled will be counted so that their attribution to each 
analysis population can be seen, and patients excluded from the analysis 
populations will be listed with the reasons. 
(2) Demographic characteristics of patients 
− 
Distribution of the main patient background, disease characteristics and other 
characteristics in PPS is summarized. 
13.1.3.2 
Primary Endpoint Analysis 
The following analyses are performed regarding the rate of change in mean number of 
urinary incontinence per 24 hours at Week 8 of the treatment period from baseline, which is 
the primary endpoint. 
(1) Main analysis 
− 
In PPS, the difference between the TAS-303 6 mg group and the placebo group 
and the difference between the TAS-303 3 mg group and the placebo group are 


65 
tested by t test using the two-sided significance level of the entire test of 5%. To 
consider multiplicity, the significance level for each comparison is adjusted by 
Hochberg’s method.14) 
(2) Sensitivity analysis of main analysis 
− 
The evaluation in (1) is performed in FAS. Missing values are imputed using last 
observation carried forward (LOCF). 
(3) Secondary analysis of primary endpoint 
The following analyses are performed in FAS and PPS. 
− 
Summary statistics are calculated for each treatment group. Missing values are 
not imputed. 
− 
The rate of change from baseline in mean number of urinary incontinence per 24 
hours for each week was analyzed using mixed-effect models for repeated 
measures (MMRM) to estimate the therapeutic effect of TAS-303 at Week 8 of 
the treatment period. 
− 
In PPS and FAS, intergroup comparison is performed by the Wilcoxon rank sum 
test. Missing values are imputed by LOCF. 
(4) Analysis by allocation factor 
− 
The primary endpoint is analyzed for each condition of urinary incontinence (SUI 
and MUI). 
− 
The primary endpoint is analyzed for each category of mean number of urinary 
incontinence per 24 hours (less than 2/day and 2 or more/day). 
13.1.3.3 
Secondary Endpoint Analysis 
13.1.3.3.1 
Efficacy Analysis 
The following analyses are performed for each treatment group in FAS and PPS. 
(1) Mean number of urinary incontinence per 24 hours 
− 
Summary statistics of measured values, rate of change from baseline and amount 
of change at each evaluation time point are calculated. 
− 
The rate of change from baseline is analyzed using MMRM and the therapeutic 
effect of TAS-303 at all evaluation time points is estimated. 
− 
The proportion of subjects with 50% or greater improvement in the rate of 
change from baseline and 95% CI at each evaluation time point are calculated. 
(2) Amount of urinary incontinence by 1-hour pad test 
− 
Summary statistics of measured values, rate of change from baseline and amount 
of change at each evaluation time point are calculated. 
− 
The proportion of subjects with 2.0 g or less measured values at Week 8 of the 
treatment period and 95% CI are calculated. 
− 
The proportion of subjects with 50% or greater improvement in the rate of 
change from baseline at Week 8 of the treatment period and 95% CI are 


66 
calculated. 
(3) Mean number of used pads per 24 hours (only in patients who used incontinence 
pads) 
− 
Summary statistics of measured values, rate of change from baseline and amount 
of change at each evaluation time point are calculated. 
(4) ICIQ-SF score 
− 
Summary statistics of total score and amount of change from baseline at each 
evaluation time point are calculated. 
− 
Summary statistics of the score for each item and amount of change from 
baseline at each evaluation time point are calculated. 
(5) Patient Global Impression-Improvement (PGI-I) 
− 
Proportion for each rating on 7-point scale at each evaluation time point is 
calculated. 
− 
Proportion of improvement (“very much better”, “much better”, “a little better”) 
at each evaluation time point and 95% CI are calculated. 
(6) I-QOL score 
− 
Summary statistics of total score and amount of change from baseline at each 
evaluation time point are calculated. 
− 
Summary statistics of the score of each area and amount of change from baseline 
at each evaluation time point are calculated. 
(7) Analysis by allocation factor 
− 
The secondary endpoints are analyzed for each condition of urinary incontinence 
(SUI and MUI). 
− 
The secondary endpoints are analyzed for each category of mean number of 
urinary incontinence per 24 hours (less than 2/day and 2 or more/day). 
(8) Mean number of SUI per 24 hours 
Among the incidents of urinary incontinence recorded in the urination record (bladder 
diary), the data of the incidents excluding those that occurred because patients “could 
not hold it in” are used in the following analyses. 
− 
Summary statistics of measured values, rate of change from baseline and amount 
of change at each evaluation time point are calculated. 
− 
The rate of change from baseline is analyzed using MMRM and the therapeutic 
effect of TAS-303 at all evaluation time points is estimated. 
− 
The proportion of subjects with 50% or greater improvement in the rate of 
change from baseline and 95% CI at each evaluation time point are calculated. 
(9) Mean number of UUI per 24 hours 
Among the incidents of urinary incontinence recorded in the urination record (bladder 


67 
diary), the data excluding those that occurred “while coughing, laughing, sneezing, 
movements including standing up or engaging in sports” are used in the following 
analyses. 
− 
Summary statistics of measured values, rate of change from baseline and amount 
of change at each evaluation time point are calculated. 
− 
The rate of change from baseline is analyzed using MMRM and the therapeutic 
effect of TAS-303 at all evaluation time points is estimated. 
− 
The proportion of subjects with 50% or greater improvement in the rate of 
change from baseline and 95% CI at each evaluation time point are calculated. 
13.1.3.3.2 
Administration Status 
In the subjects treated with the study drugs, the following analyses are performed for the 
observation period and the treatment period separately, and for each treatment group. 
(1) Administration status 
− 
The administration status (total dose and total duration of administration) for 
each patient is summarized. 
(2) Status of administration completion 
− 
Summary statistics of compliance with treatment with the study drugs are 
calculated for each patient. 
− 
Presence or absence of study discontinuation (including timing) and its reason are 
tabulated. 
13.1.3.3.3 
Safety Analysis 
In the subjects treated with the study drugs, the following analyses are performed for each 
treatment group. The analysis for the treatment period is performed in subjects treated in the 
treatment period. 
(1) AEs 
The following analyses are performed for the observation period and for the treatment 
period, separately. 
− 
The incidence of AEs is calculated. 
− 
The number of patients and the incidence are calculated for each adverse event 
for each severity. 
− 
The incidence of adverse events for each timing (Weeks 4 and 8 and follow-up 
observation) in the treatment period is calculated. 
− 
For all adverse events that occurred from the start of the treatment with the study 
drugs to the completion day of the follow-up observation, name of the event, 
severity, onset date, treatment, outcome, causal relationship with study drugs and 
comments are listed for each adverse event in each patient. 
(2) Adverse reactions 
− 
Analyses similar to those for adverse events are performed for adverse reactions 


68 
(except preparation of the list). 
(3) Blood pressure, pulse rate and body temperature 
− 
Summary statistics of blood pressure, pulse rate and body temperature are 
calculated for each evaluation time point. 
− 
Summary statistics of the amount of change in measured values of blood pressure 
and pulse rate from the values immediately before the start of the treatment with 
the study drugs are calculated for each evaluation time point. 
− 
For blood pressure and pulse rate, the amount of change in measured values at 
each evaluation time point from the values immediately before the start of the 
treatment with the study drugs is categorized and the frequency for each category 
is calculated. 
(4) 12-lead Electrocardiography 
A test item based on 12-lead electrocardiogram, QT interval corrected using 
Fridericia’s formula (QTcF) is used. 
− 
Summary statistics of measured values of QTcF and heart rate are calculated for 
each evaluation time point. 
− 
Summary statistics of the amount of change in measured values of QTcF and 
heart rate from the values immediately before the start of the treatment with the 
study drugs are calculated for each evaluation time point. 
− 
For QTcF, measured values at each evaluation time point are categorized and the 
frequency for each category is calculated. 
− 
For QTcF and heart rate, the amount of change in measured values at each 
evaluation time point from the values immediately before the start of the 
treatment with the study drugs is categorized and the frequency for each category 
is calculated. 
− 
Subjects with abnormal changes in 12-lead electrocardiogram are listed. 
(5) Laboratory test values 
− 
Summary statistics of each laboratory test item are calculated for each evaluation 
time point. 
(6) Urinary flow test 
− 
Summary statistics of each item of urinary flow test (maximum urinary flow rate 
[free Qmax], average urinary flow rate [free Qave], voided volume and time of 
voiding) are calculated for each evaluation time point. 
− 
Summary statistics of the amount of change in measured values of each urinary 
flow test item from the values immediately before the start of the treatment with 
the study drugs are calculated for each evaluation time point. 
(7) Residual urine volume 
− 
Summary statistics are calculated for each evaluation time point. 
− 
Summary statistics of the amount of change in measured values from the values 










73 
15. Case Report Form (eCRF) 
In this study, electronic case report form (eCRF) and Electronic Data Capture (EDC) 
system will be provided by the Sponsor. In order to protect eCRF data, eCRF data will be 
transmitted from study sites via SSL Internet communication, and access to the EDC system 
will be limited only to the Investigator, Sub-investigator and appropriate personnel 
authenticated by IDs and passwords unique to individuals, which should be maintained 
confidentially and never shared. Monitors will have the right to access to the EDC system for 
performing source data verification. Monitors, data managers, auditors and other relevant 
personnel of the Sponsor will receive a right to access to the EDC system according to their 
roles. These monitors, data managers, auditors or other relevant personnel will not have 
authority to enter or correct data or provide electronic signatures in eCRFs. 
15.1 Recording of Case Report Forms 
The eCRFs are prepared for the patients enrolled in the observation period. All the content 
except the special instructions is entered in English. The Investigator, Sub-investigator and 
Clinical Research Coordinators should input, change, correct or add data in eCRFs using the 
“eCRF Completion Guidelines” as a reference. In addition, the Investigator should check 
whether the contents of an eCRF are adequate and then electronically sign the eCRF. 
After verification of the eCRF by the Sponsor, the Sponsor may make queries on 
additional check items. The Investigator, Sub-investigator and Clinical Research 
Coordinators should check the details of data required to be verified, correct as necessary and 
return to the Sponsor. 
15.2 Completing Case Report Forms 
When completing an eCRF, the following should be considered: 
(1) The Sponsor should distribute the eCRF Completion Guidelines to the Investigator, 
Sub-investigator and Clinical Research Coordinators. The Investigator or 
Sub-investigator should enter, change, correct or add data in eCRFs in accordance 
with the Guidelines. The Clinical Research Coordinators may enter, change, correct or 
add data in eCRFs based on source documents prepared by the Investigator and 
Sub-investigator in accordance with the Guidelines. 
(2) Information used for personal authentication in the EDC system (eg, ID and 
passwords) shall never be shared among the Investigator, Sub-investigator and 
Clinical Research Coordinators from the perspective of preparation of eCRFs based 
on proper personal authentication. This information shall be retained in such a manner 
that it will not be leaked to other people for preventing improper access to eCRFs by 
masquerading. The Sponsor, Investigator, Sub-investigator and Clinical Research 
Coordinators should as necessary check an audit trail of the EDC system to verify 
whether or not there is unauthorized access or data manipulation by masquerading. 
(3) When corrections and/or changes are made, the reasons for the correction or change 
should be also entered. The reasons for corrections/changes will be recorded in an 
audit trail together with the details of the corrections/changes. 


74 
(4) When a section to be filled out remains blank, if necessary, an expression to 
differentiate it from input omission should be entered eg, “MS (No Data)”. 
(5) The Investigator should check information entered in the eCRF against source data 
(eg, medical records [charts]), confirm the information and electronically sign the 
eCRF. 
(6) The electronic signature must be personally affixed by the Investigator. 
 
The Investigator should record all the data on eCRFs in accordance with time limit in the 
following items (Except the Sponsor request to stop recording the data): 
· 
Patient background (condition of urinary incontinence, presence or absence of 
menopause, menstrual cycle): within 7 days after enrollment 
· 
ICIQ-SF and I-QOL: within 7 days after they are recorded 
· 
Urination record: within 7 days after collection day 
· 
1-hour pad test: within 7 days after it is performed 
· 
Adverse events (as much information as possible): Within 7 days after the time point 
the Investigator or Sub-investigator first became aware of their onset 
· 
Hematological tests, serum chemistry and urinalysis: Within 14 days after they are 
performed 
· 
Other items: Within 14 days after the completion day of the follow-up observation 
 
 


75 
16. Protocol Compliance, Deviations and Amendments 
16.1 Protocol Compliance 
The Investigator will agree with the Sponsor on the details of the protocol and the sample 
CRF, and will sign or affix the signature and seal on and date the protocol or an alternative 
document as an evidence of the agreement that the protocol should be complied with.  
In the case of amendment of the protocol and the sample CRF, and/or in the case of 
correction of the protocol and sample CRF by the direction of the Director of the study site 
based on the IRB, the same procedure should be followed. 
16.2 Protocol Deviations 
Severe protocol deviations are as follows: 
(1) Failure to fulfill the inclusion criteria, which has a significant impact on the efficacy 
and safety evaluation of TAS-303 
(2) Fulfillment of the exclusion criteria, which has a significant impact on the efficacy 
and safety evaluation of TAS-303 
(3) Met the criteria for drug administration discontinuation, but did not discontinue 
(4) Deviation that leads to significant noncompliance with GCP 
To modify the protocol, the Investigator and the Sponsor must prepare a written agreement 
in advance and obtain the written approval of the IRB based on the prior review. 
The Investigator should promptly provide written reports to the Sponsor, the director of 
study site, and the IRB via the director of study site on any change to the study that 
significantly affect the conduct of the study and/or increase the risk to patients. 
However, where it is necessary for some unavoidable medical reason, eg, to eliminate an 
immediate hazard(s) to patients, deviation from or changes to the protocol may be 
implemented without prior written agreement with the Sponsor and prior approval by the 
IRB. In such a case, the Investigator should promptly report the details and the reason for the 
deviation or change to the Sponsor and the director of study site, and provide written reports 
to the IRB via the director of study site. The written approval of the IRB must be obtained. 
The Investigator is to record any deviation from the protocol, irrespective of any reasons 
whatsoever. 
16.3 Protocol Amendments 
When the Sponsor considers that the protocol or the sample CRF requires an amendment, 
the Sponsor will submit the amended protocol or sample CRF to the Investigator. The 
Investigator will thoroughly review the details of amendment.  
In the case of amendment of the protocol or sample CRF, the Sponsor will obtain 
agreement from the Investigator. For administrative amendments only (eg, change in the 
Sponsor’s organization or system, change of name of the study site or department, change in 
the address or telephone number of the study site or the Sponsor, change of the Investigator’s 


76 
title, change of monitors, change in CRF layout), no new agreement is required. 
The Sponsor will submit the protocol or sample CRF to the director of study site, and 
obtain the approval of the IRB via the director of study site in a timely manner.  
 
 


77 
17. Direct Access to Source Documents 
The Investigator and the director of study site must make all study-related records (eg, 
source documents) available for direct access for study-related monitoring, audit, IRB review, 
and regulatory inspection. 
17.1 Source Documents 
Source documents are original documents, data and records (eg., consent form, medical 
record, test notes, memos, record of prescription of drugs, data recorded by various 
automated instruments, patient files, list of names for screening, record of management of 
study drugs, medication diary, ICIQ-SF, PGI-I, I-QOL, urination record, record of 1-hour pad 
test, urinary flow test data and records retained at pharmacies, laboratories and medical 
technology departments involved in this study). 
The following data will be recorded directly into the CRFs and will be considered source 
data: 
 
Previous and concurrent illnesses considered by the Investigator or Sub-investigator 
to have an important impact on the study 
 
Purpose of concomitant medications and therapies 
 
Names, purposes and treatment period of concomitant medications and therapies 
prescribed at other clinics 
 
Presence or absence, seriousness, severity and outcome of adverse events, reason for 
terminating follow-up investigation, causal relationship with the study drugs 
 
Presence or absence and reason of discontinuation and withdrawal 
 
Comments, reason for terminating the observation of course 
17.2 Direct Access 
The monitor of the Sponsor should cross-check the entries in the CRF and source 
documents to confirm that descriptions are accurate with regard to the following. If there are 
any discrepancies between the entries in CRF, etc., and source documents, the monitor will 
obtain from the Investigator records explaining such discrepancies. 
 
Data required by the protocol have been accurately recorded in the CRF and the 
report on SAEs, and are consistent with the descriptions in the source documents. 
 
All changes in dosage regimen or administration method, if any, have been recorded 
in the CRF for each patient. 
 
AEs have been recorded in the CRF in accordance with the protocol. 
 
All discontinued or drop-out cases among registered patients have been recorded in 
the CRF together with the reasons for discontinuation or drop-out. 
 
 


78 
18. Quality Control and Quality Assurance 
The following quality control and quality assurance tasks are implemented in accordance 
with the SOP of the Sponsor. 
18.1 Quality Control 
The Sponsor is responsible for controlling the quality of the clinical study through, the 
following procedures according to individual SOPs related to study implementation and the 
Monitoring Plan for this study: 
· 
The Sponsor will hold a meeting, etc. on the protocol to explain the study 
methodology (eg, patient selection, and investigation or assessment of the efficacy 
and safety to the Investigator, Sub-investigator or Clinical Research Coordinators). 
· 
The Sponsor will conduct study monitoring of the study sites periodically to ensure 
that the study is performed in compliance with the protocol and GCP. 
· 
The Sponsor will review the source documents to ensure that the entries in CRFs are 
accurate. In addition, the Sponsor will prepare the CRF Completion Guidelines and 
request the Investigator or Sub-investigator to make a correction in case that any 
change or correction is required. 
· 
The Sponsor will check the items to be recorded in CRFs. 
· 
The Sponsor will make sure that essential documents to be retained at the study sites 
are properly maintained. 
 
According to the Sponsor's SOPs, the Sponsor will complete recording and reporting 
pertaining to the operation of the study, data collection, DM, statistical analysis, and 
analyses of AEs, etc., and inspect them. 
18.2 Sponsor’s Audits and Regulatory Inspections 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory 
requirements, the Investigator will permit auditing by the Sponsor and inspections by 
Regulatory Authorities. 
The Investigator agrees to allow the auditors and inspectors to have direct access to the 
study records for review. The people performing these activities will not disclose any 
personal identity or personal medical information assessed. 
The 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 
clinical study. As soon as the Investigator is notified of a planned inspection by the 
Regulatory Authorities or IRB, the Investigator will inform the Sponsor. Any results arising 
from such inspections will be immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during audits and or inspections. 
 
 


79 
19. Data Handling and Recordkeeping 
19.1 Data Handling 
All information provided to the Investigator by the Sponsor, information produced during 
the clinical study included, but not limited to the protocol, CRF, investigator's brochure, and 
the results obtained during the course of the study is confidential. The members of the 
research team agree not to discuss such information in any way without prior written 
permission from the Sponsor. 
The patient’s personal data and Investigator’s or Sub-investigator’s personal data which 
may be included in the Sponsor’s database shall be treated in compliance with all applicable 
laws and regulations. 
When processing and archiving personal data pertaining to the Investigator, 
Sub-investigator and to the patients, the Sponsor shall take all appropriate measures to 
safeguard and prevent access to this data by any unauthorized third party. 
19.2 Responsibilities of Recordkeeping 
19.2.1 
Investigator and Study Site 
The Investigator and the study site are responsible for retaining all study documents in 
accordance with applicable regulatory requirements and GCP. 
The Investigator and the study site agree to inform the Sponsor in writing of the intention 
to remove or destroy any study-related records. Prior to contacting the Sponsor, the 
Investigator and study site must ensure that the applicable regulatory requirements have been 
satisfied. The Sponsor will provide authorization for destruction of such records to the 
Investigator and study site in writing. 
In the event that all retention of records requirements have been fulfilled, but the Sponsor 
requests that the Investigator and study site maintain the records for a longer period of time, 
additional arrangements will be made. 
19.2.2 
Sponsor 
The Sponsor must 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 the Sponsor discontinues the clinical development of the study drug, the Sponsor must 
maintain all sponsor-specific essential documents in conformance with the applicable 
regulatory requirements. 
 
 


80 
20. Compensation for Health Injury 
The clinical study is insured according to applicable regulatory requirements. A copy of 
the Compensation Policy Document will be provided to the study site by the Sponsor. 
For the compensation claims associated with this study except for those based on medical 
malpractice or negligence, for which the Sponsor was clearly shown not to have any liability, 
the Sponsor specifies the compensation policy and payment procedure for health injuries 
related to the study in the Compensation Policy Document. 
When patients receive compensation, the policies and payment procedure of compensation 
should comply with the Compensation Policy Document. 
 
 
 


81 
21. Publication Policy and Secondary Use of Data 
21.1 Publication Policy 
The Sponsor maintains the right to use the results of this study in their original form 
and/or in a global report for submission to governmental and Regulatory Authorities of any 
country. 
The results of the study may be presented during scientific symposia or published in a 
scientific journal only after review by the Sponsor in accordance with the guidelines set forth 
in the applicable publication or financial agreement. 
The timing, presenter and other matters are determined through discussion between the 
Coordinating Investigator and the Sponsor. 
21.2 Secondary Use of Data 
The Sponsor maintains the right to secondary use of data in this study. Secondary use of 
data describes the use of data from this study for other study/studies (including an external 
offering). 
Specifically, secondary use of data may include:  
 
Use for analysis of other study. 
 
Use for integrated analysis with data from one or more associated study/studies. 
 
Utilization to regulatory authorities for their own analysis and the sharing of 
information with other regulatory authorities. 
 
Use for epidemiology study. 
 
 
 


82 
22. Ethics 
22.1 Ethical Considerations 
It is mandatory that all considerations regarding the protection of patients be carried out in 
accordance with the latest versions of the protocol, GCP, ICH Guidelines, the ethical 
principles that have their origin in the Declaration of Helsinki, and all applicable regulatory 
requirements. 
22.2 Institutional Review Board 
The study must be approved by an appropriately constituted IRB, as required in GCP or 
ICH E6 Guidelines. Prior to conduct, the study must be reviewed and approved by the IRB of 
the study site, and approved by the director of study site. 
The Investigator is responsible for obtaining renewal of approval during the clinical study. 
Timeframes for renewal will be based on IRB requirements but renewal at least annually is 
required by regulations. At the end of the study, the Investigator will notify the IRB of the 
study site of the conclusion of the study and its outcome. 
22.3 Informed Consent Procedure 
Informed consent must be obtained in compliance with the guidelines provided in the GCP, 
Declaration of Helsinki, ICH E6 Guideline and local regulations. 
The Investigator and Sub-investigator must fully inform patients of all pertinent aspects of 
the study. All participants should be informed to the fullest extent possible about the study in 
a language and in terms they are able to understand. 
Prior to participation in the study, the written ICF is to be signed and personally dated by 
the patient and the person who provided the explanation for ICF. A copy of the signed and 
dated ICF must be given to the patient. The ICF used must have had prior approval by the 
IRB. 
By signing and dating the ICF prior to the implementation of the study procedures set 
forth in this protocol, the patient is deemed to have consented to participate in the study. 
Prior to the study enrollment, a copy of the ICF signed and dated by the patient must be 
given to him/her prior to any study-related procedures described in the ICF are undertaken. 
The Investigator must prepare the ICF using a proposed ICF provided by the Sponsor as 
reference. When the ICF needs to be revised, the Investigator must discuss with the Sponsor, 
prepare a revised version and use the version approved by the IRB. 
 
 


83 
23. Study Administrative Structure 
For details, see the attached document. 
 
 
 


84 
24. References 
1. Homma Y, Nishizawa O, Yamaguchi, O. The Standardisation of Terminology of 
Lower Urinary Tract Function: Report from the Standardisation Sub-committee of the 
International Continence Society.J.Neurogenic Bladder Soc. 2003;14:278-289.  
2. Kato K, Kondo A, Okamura K, Takaba H. Prevalence of Urinary Incontinence in 
Working Women. The Japanese Journal of Urology 1986;77:1501-1505.  
3. Takai K, Miyashita A, Mochizuki K. Actual Conditions of Female Stress 
Incontinence.Japanese Journal of Clinical Urology 1987;41:393-396.  
4. Umehara T, Matsukawa M, Tsukamoto T, Kumamoto Y. An incidence of stress 
urinary incontinence in healthy women-Analyses of 3020 questionares. Japanese 
Journal of Urological Surgery 1991;4:53-57.  
5. The Study Group on Standardization of Treatment in the Urological Field. Guideline 
for Evidence-based Management of Urinary Incontinence. Tokyo: Jiho, Inc.; 2004. p. 
9-11.  
6. Homma Y, Kakizaki H, Goto M, Takei M, Yamanishi T, Hayashi K. Epidemiological 
survey on lower urinary tract symptoms in Japan. J Neurogenic Bladder Soc. 
2003;14:266-277.  
7. Edited by Kato K. Care for Urinary Incontinence and Female Urological Disease. 
Osaka: Medicus Shuppan Publishers Co., Ltd. 2008.; p. 230-231.  
8. Committee for preparation of clinical guideline for female lower urinary tract 
symptoms, Ed. Clinical guideline for female lower urinary tract symptoms. Tokyo: 
RichHill Medical Inc. 2013. p. 128.  
9. Shimazaki J, Yasuda K, Imabayashi K, Takimoto Y, Toyoshima A, Morita T, et al. 
Dose finding study on clenbuterol in stress in incontinence - a dose finding study -. 
Japanese Journal of Urological Surgery 1992;5:933-945.  
 
11. European Medicines Agency. Guideline on the clinical investigation of medicinal 
products for the treatment of urinary incontinence. June 2013. 
12. U.S. Department of Health and Human Services. Food and Drug Administration. 
Guidance for industry. Clinical investigations of devices indicated for the treatment of 
urinary incontinence. March 2011. 
13. van Leeuwen JH, Castro R., Busse M, Bemelmans BL. The placebo effect in the 
pharmacologic treatment of patients with lower urinary tract symptoms. Eur Urol 
2006;50:440–453. 
14. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. 
Biometrika. 1988;75:800-802. 


85 
15. General Considerations for Clinical Trials. PMSB/ELD Notification No. 380 (April 
21, 1998) 
 
 




87 


88 



SAP_001.pdf: 
TAIHO Pharmaceutical Co., Ltd. 
 
Date2018/9/4 
TAS-303 Protocol: 10060050 
1 
STATISTICAL ANALYSIS PLAN 
Version 3.0 
Name of Investigational 
Product 
TAS-303 
Title of Study 
A phase IIa study of TAS-303 in female patients with stress urinary 
incontinence 
Protocol number 
10060050 
Date of preparation or 
revision 
September 4, 2018 
Author 
 
History of preparation and revision 
Date 
Author 
Reason for preparation or revision 
March 20, 2018 
 
Preparation of the first version 
May 29, 2018 
 
Prior to the key code breaking, details of analyses were 
changed according to results of blinded review. 
September 4, 2018 
 
Contents were added because it was an additional analysis. 
Date and Signature 
 
Person in charge of statistical analysis 
MM DD, YYYY 
 
 
Responsible person for statistical analysis 
MM DD, YYYY 
 
Taiho Pharmaceutical Co., Ltd. 
Statistical Team Leader 
MM DD, YYYY 
 
 


TAIHO Pharmaceutical Co., Ltd. 
 
Date2018/9/4 
TAS-303 Protocol: 10060050 
2 
Changes in Statistical Analysis Plan 
Version 1.0 (March 20, 2018) to Version 2.0 (May 29, 2018) 
Item 
Before change 
After change 
Reason for change 
5 
Blinded Review 
Blinded Review 
Japanese notation was 
changed. 
6.2.1 
Table 
6-2 
– 
Age Category 2 
< 60 years, ≥ 60 years 
Category was added 
according to results of 
blinded review. 
7.3 
8.1.1 
8.1.7 
8.1.8 
Baseline values and allocation 
adjustment factors (status of 
urinary incontinence, mean 
incontinence episode frequency 
(IEF) per 24 hours [≥ 2 per day, < 
2 per day]) were used as 
covariates. 
Allocation adjustment factors 
(status of urinary incontinence, 
mean IEF per 24 hours [≥ 2 per 
day, < 2 per day]), and age (< 60 
years and ≥ 60 years) were used as 
covariates. 
Covariates were 
changed according to 
results of blinded 
review. 
7.3 
Intergroup comparison will be 
conducted using the placebo group 
as the control by the van Elteren 
test5) using allocation adjustment 
factors as strata. 
Intergroup comparison will be 
conducted using the placebo group 
as the control by the van Elteren 
test5) using allocation adjustment 
factors and age (< 60 years and ≥ 
60 years) as strata. If any stratum 
includes a group with 0 patient, the 
test will be conducted by 
excluding age from the strata. The 
van Elteren test will be performed 
in two patterns, i.e., a pattern in 
which allocation adjustment 
factors at the time of enrollment 
are used as strata (analysis in the 
FAS only) and a pattern in which 
allocation adjustment factors 
recorded in CRF are used as strata. 
Stratification factors 
were added according 
to results of blinded 
review. Moreover, 
details of stratification 
factors were added. 
8.1.1 
The van Elteren test using 
allocation adjustment factors as 
strata will be conducted. 
The van Elteren test using 
allocation adjustment factors and 
age (< 60 years and ≥ 60 years) as 
strata will be conducted. If any 
stratum includes a group with 0 
patient, the test will be conducted 
by excluding age from the strata. 
The van Elteren test will be 
performed in two patterns, i.e., a 
pattern in which allocation 
adjustment factors at the time of 
enrollment are used as strata 
(analysis in the FAS only) and a 
pattern in which allocation 
adjustment factors recorded in 
CRF are used as strata.   
Stratification factors 
were added according 
to results of blinded 
review. Moreover, 
details of stratification 
factors were added. 


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Item 
Before change 
After change 
Reason for change 
8.1.7 
The van Elteren test using 
allocation adjustment factors as 
strata will be conducted. The van 
Elteren test will be performed in 
two patterns, i.e., a pattern in 
which allocation adjustment 
factors at the time of enrollment 
are used as strata and a pattern in 
which allocation adjustment 
factors recorded in CRF are used 
as strata. 
The van Elteren test using 
allocation adjustment factors and 
age (< 60 years and ≥ 60 years) as 
strata will be conducted. If any 
stratum includes a group with 0 
patient, the test will be conducted 
by excluding age from the strata. 
The van Elteren test will be 
performed in two patterns, i.e., a 
pattern in which allocation 
adjustment factors at the time of 
enrollment are used as strata 
(analysis in the FAS only) and a 
pattern in which allocation 
adjustment factors recorded in 
CRF are used as strata. 
Stratification factors 
were added according 
to results of blinded 
review. Moreover, 
details of stratification 
factors were added. 
8.1.8 
- 
For percent changes (Weeks 4 and 8 
of treatment) and changes (Weeks 4 
and 8 of treatment) from baseline to 
each time point of evaluation, 
student’s t-test, Wilcoxon’s rank sum 
test, and van Elteren test using 
allocation adjustment factors and 
age (< 60 years and ≥ 60 years) as 
strata will be conducted using the 
placebo group as the control. If any 
stratum includes a group with 0 
patient, the test will be conducted by 
excluding age from the strata. The 
van Elteren test will be performed in 
two patterns, i.e., a pattern in which 
allocation adjustment factors at the 
time of enrollment are used as strata 
(analysis in the FAS only) and a 
pattern in which allocation 
adjustment factors recorded in CRF 
are used as strata.   
Stratification factors 
were added according 
to results of blinded 
review. 
Since tests for the 
mean frequency of 
UUI episode per 24 
hours were not 
mentioned, they were 
added. 


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Version 2.0 (May 29, 2018) to Version 3.0 (September 4, 2018) 
Item 
Before change 
After change 
Reason for change 
8.1.1 
8.1.2 
8.1.5 
8.1.7 
8.1.8 
Fisher’s exact test will be 
conducted. 
Fisher’s exact test with placebo as 
control will be conducted. 
Since Fisher’s exact 
test uses the placebo 
as the control, the 
statement was added. 
8.1.5 
- 
The proportion of improvement 
(Very much better and Much 
better) at the time of enrollment 
and Weeks 4 and 8 of treatment 
and 95% CI will be calculated, and 
Fisher’s exact test with placebo as 
the control will be conducted. 
The statement was 
added because it was 
an additional analysis. 
8.1.10 
8.1.11 
8.1.12 
8.1.13 
8.1.14 
8.1.15 
8.1.16 
8.1.17 
- 
(Addition of items) 
Analytical items were 
added because it was 
an additional analysis. 
8.3.1 
- 
The number of patients and the 
incidence will be displayed by 
severity (incidence ≥ 2%) for each 
item of adverse event. ADRs will 
be analyzed in the same way. 
The statement was 
added because it was 
missing. 
8.3.3 
- 
The incidence of abnormal 
variations in 12-lead ECG will be 
calculated. 
The statement was 
added because it was 
missing. 
8.3.3 
- 
For amounts of changes in 
measured values of the QTcF 
interval and heart rate from values 
immediately before start of 
treatment to each evaluation time 
point, student’s t-test will be 
conducted using the placebo group 
as the control. 
The statement was 
added because it was 
an additional analysis. 
8.3.4 
- 
For amounts of changes in 
measured values of blood pressure 
and pulse rate from values 
immediately before start of 
treatment to each evaluation time 
point, student’s t-test will be 
conducted using the placebo group 
as the control. 
The statement was 
added because it was 
an additional analysis. 
 
 


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TABLE OF CONTENTS 
1. 
SCOPE AND PURPOSE .......................................................................................................9 
2. 
STUDY DESIGN AND TARGET SAMPLE SIZE ..............................................................9 
2.1. Study Design ......................................................................................................................9 
2.1.1. 
Primary Endpoint .....................................................................................................9 
2.2. Target Sample Size ............................................................................................................9 
2.2.1. 
Target Sample Size ...................................................................................................9 
2.2.2. 
Rationale for Sample Size Determination ................................................................9 
3. 
DATA AND ANALYSIS POPULATIONS USED FOR STATISTICAL 
ANALYSIS ..........................................................................................................................10 
3.1. Materials and Data Other Than Case Report Form .........................................................10 
3.2. Analysis Populations .......................................................................................................10 
4. 
STATISTICAL ANALYSIS POLICY.................................................................................11 
5. 
TIMING OF STATISTICAL ANALYSIS ..........................................................................11 
6. 
COMMON ITEMS BETWEEN ENDPOINTS AND STATISTICAL ANALYSES .........12 
6.1. Endpoints .........................................................................................................................12 
6.1.1. 
Efficacy Endpoints .................................................................................................12 
6.1.1.1. 
Evaluation of Symptom Score ........................................................................12 
6.1.1.2. 
Evaluation of QOL Score ...............................................................................12 
6.1.1.3. 
Bladder Diary ..................................................................................................12 
6.1.1.4. 
One-Hour Pad Test .........................................................................................12 
6.1.2. 
Safety Endpoints ....................................................................................................12 
6.1.2.1. 
Adverse Events and Adverse Drug Reactions ................................................12 
6.1.3. 
Treatment Compliance Endpoints ..........................................................................13 
6.1.3.1. 
Compliance Rate .............................................................................................13 
6.2. Common Items in Statistical Analysis .............................................................................13 
6.2.1. 
Patient Background ................................................................................................13 
6.2.2. 
Statistical Methods .................................................................................................14 
6.2.2.1. 
Summary Statistics of Continuous Volume ....................................................14 
6.2.2.2. 
Estimation Method ..........................................................................................14 
6.2.3. 
Allocation Adjustment Factors Used for Analysis .................................................14 
6.2.4. 
Statistical Analysis Software ..................................................................................15 
7. 
ANALYSES OF PRIMARY ENDPOINT ...........................................................................15 


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7.1. Primary Analysis for Primary Objective .........................................................................15 
7.2. Sensitivity Analysis of Primary Analysis ........................................................................15 
7.3. Secondary Analyses of Primary Endpoint .......................................................................15 
7.4. Analyses Based on Allocation Factors ............................................................................16 
8. 
ANALYSES OF SECONDARY ENDPOINT .....................................................................16 
8.1. Efficacy Analysis .............................................................................................................16 
8.1.1. 
Mean IEF per 24 Hours ..........................................................................................16 
8.1.2. 
Urinary Incontinence Amount in 1-Hour Pad Test ................................................17 
8.1.3. 
Mean Number of Pads Used per 24 Hours (Only for Patients Who Had 
Ever Used Incontinence Pads) ................................................................................17 
8.1.4. 
ICIQ-SF score ........................................................................................................17 
8.1.5. 
Patient Global Impression of Improvement (PGI-I) ..............................................18 
8.1.6. 
I-QOL Score ...........................................................................................................18 
8.1.7. 
Mean Frequency of SUI Episode per 24 Hours .....................................................18 
8.1.8. 
Mean Frequency of UUI Episode per 24 Hours .....................................................19 
8.1.9. 
Analyses Based on Allocation Factors ...................................................................20 
8.1.10. Mean Incontinence Episode Frequency per 24 Hours: Subgroup Analysis ...........20 
8.1.11. Mean Incontinence Episode Frequency per 24 Hours: Integrated TAS-303 
Group ......................................................................................................................21 
8.1.12. Mean Frequency of SUI Episode per 24 Hours 2 ..................................................22 
8.1.13. Mean Frequency of SUI Episode per 24 Hours 2: Subgroup Analysis ..................22 
8.1.14. Mean Frequency of UUI Episode per 24 Hours 2 ..................................................23 
8.1.15. Mean Frequency of UUI Episode per 24 Hours 2: Subgroup Analysis .................23 
8.1.16. Mean Frequency of Episodes of Micturition Urgency per 24 Hours .....................23 
8.1.17. Mean Leakage Amount per 24 Hours ....................................................................24 
8.2. Analysis of Administration Status ...................................................................................24 
8.2.1. 
Administration Status .............................................................................................24 
8.2.2. 
Status of Administration Completion .....................................................................24 
8.3. Safety Analysis ................................................................................................................24 
8.3.1. 
Adverse Events and Adverse Drug Reactions ........................................................24 
8.3.2. 
Laboratory Test Values ..........................................................................................25 
8.3.3. 
12-Lead ECG ..........................................................................................................25 
8.3.4. 
Blood Pressure, Pulse Rate, and Body Temperature ..............................................25 


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8.3.5. 
Uroflowmetry .........................................................................................................26 
8.3.6. 
Residual Urine Volume ..........................................................................................26 
8.3.7. 
Mean Frequency of Micturition per 24 Hours .......................................................26 
9. 
OTHER ANALYSES ...........................................................................................................27 
9.1. Analysis Populations .......................................................................................................27 
9.2. Deviation ..........................................................................................................................27 
10. 
REVIEW AND REVISION OF STATISTICAL ANALYSIS PLAN ................................27 
11. 
STATISTICAL ISSUES ......................................................................................................27 
11.1. Adjustments for Covariates .............................................................................................27 
11.2. Handling of Dropouts or Missing Data ...........................................................................27 
11.3. Interim Analyses and Data Monitoring ...........................................................................28 
11.4. Multicenter Studies ..........................................................................................................28 
11.5. Multiple Comparisons/Multiplicity .................................................................................28 
11.6. Use of an “Efficacy Subset” of Patients ..........................................................................28 
11.7. Active-Control Studies Intended to Show Equivalence ..................................................28 
11.8. Examination of Subgroups ..............................................................................................28 
12. 
PREPARATION OF TABLE AND FIGURE PLAN ..........................................................28 
13. 
REFERENCES .....................................................................................................................28 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviations and definitions used in the Statistical Analysis Plan are as shown below. 
Abbreviation (Term) 
Description (Definitions) 
BMI 
Body Mass Index 
FAS 
Full Analysis Set 
ICH-E3 Guideline 
“Structure and Content of Clinical Study Reports”1) 
ICIQ-SF 
International Consultation on Incontinence Questionnaire-Short Form 
I-QOL 
Incontinence-Quality of Life 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect Models for Repeated Measures 
MUI 
Mixed Urinary Incontinence 
PGI-I 
Patient Global Impression-Improvement 
POP 
Pelvic Organ Prolapse 
PPS 
Per Protocol Set 
free Qave 
free Qave 
free Qmax 
free Qmax 
QOL 
Quality of Life 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
SUI 
Stress Urinary Incontinence 
UUI 
Urgency Urinary Incontinence 
 
 


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1. 
SCOPE AND PURPOSE 
This plan specifies details of the statistical analysis plan for “a phase IIa study of TAS-303 in 
female patients with stress urinary incontinence” (Protocol No. 10060050). 
2. 
STUDY DESIGN AND TARGET SAMPLE SIZE 
2.1. 
Study Design 
This clinical trial is a multicenter, randomized, double-blind, placebo-controlled parallel-group 
study with central enrollment for examination of efficacy and safety of TAS-303 in female 
patients with SUI. This study consists of a single-blind observation period, a double-blind 
treatment period, and a follow-up observation period.  
2.1.1. 
Primary Endpoint 
Percent change in the mean incontinence episode frequency per 24 hours (Week 8 of treatment) 
2.2. 
Target Sample Size 
2.2.1. 
Target Sample Size 
250 to be enrolled in the treatment period 
2.2.2. 
Rationale for Sample Size Determination 
The number of patients was determined, assuming that efficacy comparable to that of duloxetine 
can be expected based on results of nonclinical studies. Based on the mean rate of change in the 
number of urinary incontinence of -62.28% in the duloxetine group and -41.86% in the placebo 
group from data of a clinical trial of duloxetine, Yentreve clinical study results, Trial ID #6231, 
the difference between the TAS-303 6-mg or 3 mg group and the placebo group in the rate of 
change in the number of urinary incontinence, which is the primary endpoint of the present study, 
was assumed to be -20%. From the standard deviation of 33.73% in the duloxetine group and 
32.08% in the placebo group in the above study data, the standard deviation common in two 
groups was assumed to be 35%. Using the two-sided significance level of the entire test of 5% 
and the two-sided significance level of each test of 2.5% by Bonferroni’s method, when the 
statistical power is specified as 90% and the rate of withdrawal in the treatment period as about 
5%, the number of patients necessary for confirmation of a significant difference between the 
TAS-303 group and the placebo group is approximately 250 (83 per group). 


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3. 
DATA AND ANALYSIS POPULATIONS USED FOR 
STATISTICAL ANALYSIS 
3.1. 
Materials and Data Other Than Case Report Form 
Materials and data necessary for statistical analysis other than the case report form are listed in 
Table 3-1. 
Table 3-1 
Materials or Data Necessary for Statistical Analysis Other than Case Report 
Form 
Item 
Materials or data 
Remarks 
Attribution of 
patients 
Flag for attribution of each patient to 
each analysis population 
To identify attribution of each patient to each 
analysis population. 
List of patients excluded from 
analysis populations with reasons 
To list patients excluded from analysis 
populations 
Information on 
randomization 
Key code, allocation adjustment 
factor at the time of allocation 
To identify the treatment group and for 
analyses with the allocation adjustment factor 
Information on 
deviation 
Details of deviation, significant 
deviation flag 
To list patients with deviations 
Coding to 
MedDRA terms 
Correspondence table between AEs 
by investigators and AEs in 
MedDRA terms (English to 
Japanese) 
To tabulate the incidence of AEs using 
standardized terms. 
Correspondence table with MedDRA 
terms for medical history and 
complications 
To list medical history and complications in 
MedDRA terms 
Institutional 
reference value 
Institutional reference values for 
laboratory test values 
To evaluate normal/abnormal laboratory values 
Drug name 
Correspondence table between 
concomitant medications by 
investigator and WHO Drug 
Dictionary 
To tabulate grouped concomitant medications 
and specify the order 
 
3.2. 
Analysis Populations 
The name of analysis populations and their definitions are shown in Table 3-2. The handling of 
patients with problems in terms of their attribution apart from the criteria shown below will be 
determined through discussion by the sponsor, the medical experts, and other personnel. The 
primary efficacy analysis population is PPS while the primary safety analysis population is all 
treated population. 


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Table 3-2 
Definition of Analysis Populations 
Analysis Populations 
Definition 
All screened population 
All patients who gave informed consent 
All observation period 
enrolled population 
All patients enrolled in the observation period of this study 
All treatment period enrolled 
population 
All patients enrolled in the treatment period of this study 
All treated population 
Patients in the all observation period enrolled population who have 
received at least 1 dose of the study drug. 
Full Analysis Set(FAS) 
Patients in the all treatment period enrolled population who have received 
at least 1 dose of the study drug for the treatment period and have at least 
1 available efficacy endpoint before start of the treatment period and 
during the treatment period. 
Per Protocol Set(PPS) 
Patients in FAS who have not met any of the following criteria: 
(1) Patients that have violated any inclusion criteria 
(2) Patients that have met any exclusion criteria (any criteria that affects 
the efficacy evaluation) 
(3) Patients whose compliance rate is < 80% during the treatment period 
(4) Patients whose rate of completion of Bladder diary (status of urinary 
incontinence) is < 70% at Week 8 of treatment 
(5) Patients that have received any prohibited concomitant medications or 
prohibited concomitant therapies that may affect the efficacy evaluation 
4. 
STATISTICAL ANALYSIS POLICY 
The purpose of the primary analysis is to evaluate efficacy of TAS-303. To compare the 
difference between TAS-303 6-mg group and placebo group and between the TAS-303 3 mg 
group and the placebo group as measured by the percent change in IEF at Week 8 of treatment. 
5. 
TIMING OF STATISTICAL ANALYSIS 
Statistical analysis is performed after completion of all patients’ study. Before unblinding, 
preliminary examination (blinded review) of measurement of efficacy and safety, distribution of 
endpoints, relationship among items, and other aspects will be performed to make decisions 
regarding handling of patient data, statistical analysis methods, and other points. 


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6. 
COMMON ITEMS BETWEEN ENDPOINTS AND STATISTICAL 
ANALYSES 
6.1. 
Endpoints 
The definition of efficacy and safety endpoints are as shown below. 
6.1.1. 
Efficacy Endpoints 
6.1.1.1. 
Evaluation of Symptom Score 
Endpoints used to evaluate symptom scores are ICIQ-SF and PGI-I. 
6.1.1.1.1. ICIQ-SF 
Subjective symptoms (frequency of urine leakage, volume of urine leakage, impact on living, 
and reason for urine leakage) will be evaluated using ICIQ-SF. The total score of ICIQ-SF is 
defined as the sum of scores for Q1, Q2, and Q3. 
6.1.1.1.2. PGI-I 
Patients’ impression of improvement of urinary incontinence will be evaluated using PGI-I. 
Improvement of PGI-I is defined as selection of “Very much better,” “Much better,” or “A little 
better.” 
6.1.1.2. 
Evaluation of QOL Score 
QOL associated with urinary incontinence will be evaluated using I-QOL. 
The total score of I-QOL is defined as the sum of scores for all questions. In evaluation of I-QOL 
scores for individual areas, (1) the score for “avoidance and limiting behavior” is defined as the 
sum of scores for Questions 1, 2, 3, 4, 10, 11, 13, and 20, (2) the score for “psychosocial impacts” 
is defined as the sum of scores for Questions 5, 6, 7, 9, 15, 16, 17, 21, and 22, and (3) the score 
for “social embarrassment” is defined as the sum of scores for Questions 8, 12, 14, 18, and 19. 
6.1.1.3. 
Bladder Diary 
Time of voiding, presence or absence of urgency, time of urinary incontinence, reason for 
leakage, and status of use of pads will be evaluated using Bladder diary. 
6.1.1.4. 
One-Hour Pad Test 
Amount of urinary incontinence will be evaluated by a 1-hour pad test. 
6.1.2. 
Safety Endpoints 
6.1.2.1. 
Adverse Events and Adverse Drug Reactions 
An AE is any untoward medical condition that have occurred in a patient while participating in 
this clinical study. Among adverse events, those for which a causal relationship with study drugs 
is rated as being “reasonably possible” will be considered to be ADRs. 


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6.1.3. 
Treatment Compliance Endpoints 
6.1.3.1. 
Compliance Rate 
The definition of compliance rate during observation and treatment periods is shown below. 
• Observation/Treatment periods discontinued patient 
If there is no dose Modification/Interruption/Discontinuation at all, the compliance rate is 
100%, and if “Yes” is selected for dose Modification/Interruption/Discontinuation, the 
following formula shall apply. 
[1] 
Observation period 
Observation period compliance rate (%) = 100*[Total Treatment Days (Dose Modification/ 
Interruption/ Discontinuation were not included)] / [The larger of 21 and (the last dose date 
in Observation Period - the first dose date in Observation Period + 1)] 
[2] 
Treatment period 
Treatment period compliance rate (%) = 100*[Total Treatment Days (Dose Modification/ 
Interruption/ Discontinuation were not included)] / [The larger of 56 and (the last dose date 
in Treatment Period - the first dose date in Treatment Period + 1)] 
6.2. 
Common Items in Statistical Analysis 
6.2.1. 
Patient Background 
The patient background information investigated at the time of enrollment is listed in Table 6-1. 
Depending on data of each item, appropriate summaries will be provided by calculation of 
summary statistics or frequency tabulation. Among patient background information shown in 
Table 6-1, details of the case where background factor of continuous values are categorized are 
shown in Table 6-2. 
Table 6-1 
Background Factors 
Item 
Factor 
Patient Background 
Gender, age, height, body weight, presence or absence of medical history, 
presence or absence of complication, race, ethnic group 
Disease Characteristics 
BMI, duration of SUI (years), type of urinary incontinence, menopause, 
delivery, number of deliveries (natural childbirth/caesarean section), 
menstrual cycle, use incontinence pads, have repair surgery for POP, 
average number of urinary incontinence episodes per 24 hours, 1-hour 
pad test 


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Table 6-2 
Detailed Category 
Category 
Description 
Age Category 1 
< 65 years, ≥ 65 years 
Age Category 2 
< 60 years, ≥ 60 years 
Race 
Asian/Oriental, Other 
Ethnic group 
Japanese, Other 
Status of urinary incontinence Stress Urinary Incontinence, Mixed Urinary Incontinence 
 
6.2.2. 
Statistical Methods 
6.2.2.1. 
Summary Statistics of Continuous Volume 
When summary statistics of continuous volume is provided, it should also show the sample size, 
minimum, maximum, first quartile, median, third quartile, mean, and standard deviation. 
6.2.2.2. 
Estimation Method 
(1) 
Confidence interval of percentage 
The confidence interval of the percentage will be calculated by an accurate method based 
on F-distribution2). 
The following formula will be used to estimate the upper limit of confidence interval PU 
and lower limit PL of confidence interval. P indicates the percentage, X indicates the 
number of patients with events, N indicates the analysis set, and α  indicates 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
=
+
−
=
+
=
−
=
+
=
+
=
=
ν
ν
α
ν
ν
ν
ν
ν
α
ν
ν
α
ν
ν
ν
ν
ν
ν
ν
 
6.2.3. 
Allocation Adjustment Factors Used for Analysis 
In analyses that use allocation adjustment factors, allocation adjustment factors recorded in CRF 
will be used for analyses in all treated population/PPS. Analyses in FAS will be performed in 
two patterns, i.e., a pattern in which allocation adjustment factors recorded in CRF are used and 
a pattern in which allocation adjustment factors entered in IWRS are used. 


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6.2.4. 
Statistical Analysis Software 
In this study, all statistical processing will be performed using SAS Version 9.4 and SAS/STAT 
14.2. 
7. 
ANALYSES OF PRIMARY ENDPOINT 
The below shows the summary of items to be analyzed for the primary endpoint. 
7.1. 
Primary Analysis for Primary Objective 
In PPS, the difference between the TAS-303 6 mg group and the placebo group and the 
difference between the TAS-303 3 mg group and the placebo group will be compared for percent 
change from the baseline to Week 8 in the average number of urinary incontinence episodes per 
24 hours using the student’s t-test with the level of significance set at two-sided 5% for the entire 
test. The significance level for each comparison will be adjusted by Hochberg’s method3), 
considering multiplicity  
7.2. 
Sensitivity Analysis of Primary Analysis 
The primary analysis will be performed in FAS. Any missing values will be imputed using the 
last observation carried forward (LOCF) method. Analyses will be performed in the same 
fashion if no imputation takes place. 
7.3. 
Secondary Analyses of Primary Endpoint 
Following analyses will be performed in FAS and PPS: 
• Summary statistics will be calculated for each treatment group. Missing values will 
not be imputed. 
• For percent change in the mean IEF per 24 hours from baseline at each week, 
mixed-effect models for repeated measures (MMRM) will be performed using 
treatment groups, evaluation time points (Week 4 and Week 8 of treatment), and 
interactions between the treatment group and the evaluation time point as fixed 
effects, and allocation factors (status of urinary incontinence [SUI or MUI], mean IEF 
per 24 hours [≥ 2 per day or < 2 per day]) and age (≥ 60 years or < 60 years) as 
covariates. Thus, the least mean square (LS Mean) in each treatment group and the 
difference in the LS mean between each dose group and the placebo group and the 
two-sided 95% CI will be estimated at Week 8 of treatment. Unstructured covariance 
structure will be assumed, and toeplitz type will be used in case of no convergence. If 
convergence is still not achieved, the First-order autoregressive → Compound 
symmetry → Variance component will be used in this order. The Kenward-Roger 
method (2009)4) will be used to calculate degrees of freedom.  
• Intergroup comparison will be conducted using the placebo group as the control by 
the van Elteren test5) using Wilcoxon rank sum test and allocation adjustment factors 
and age (< 60 years and ≥ 60 years) as strata. If any stratum includes a group with 0 
patient, the test will be conducted by excluding age from the strata. The van Elteren 


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test will be performed in two patterns, i.e., a pattern in which allocation adjustment 
factors at the time of enrollment are used as strata (analysis in the FAS only) and a 
pattern in which allocation adjustment factors recorded in CRF are used as strata. 
Missing data will be imputed using LOCF. 
• The time profile of percent change from the baseline will be graphically presented by 
treatment group. 
7.4. 
Analyses Based on Allocation Factors 
Following analyses will be performed in PPS: 
• Primary endpoints will be analyzed by status of urinary incontinence (SUI, MUI). 
• Primary endpoints will be analyzed by mean IEF per 24 hours (≥ 2 per day, < 2 per 
day). 
8. 
ANALYSES OF SECONDARY ENDPOINT 
The below shows the summary of analyses for secondary endpoints. A confidence coefficient of 
95% will be used to present the confidence interval. 
8.1. 
Efficacy Analysis 
Following analyses will be performed by treatment group in FAS and PPS: 
8.1.1. 
Mean IEF per 24 Hours 
• Summary statistics will be calculated for measured values at each evaluation time 
point (at the time of enrollment, Weeks 4 and 8 of treatment) and percent changes 
(Week 4 of treatment) as well as changes (Weeks 4 and 8 of treatment) from baseline. 
Summary statistics of the mean frequency of SUI episode per week will also be 
calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patient, the test will be conducted by 
excluding age from the strata. The van Elteren test will be performed in two patterns, 
i.e., a pattern in which allocation adjustment factors at the time of enrollment are used 
as strata (analysis in the FAS only) and a pattern in which allocation adjustment 
factors recorded in CRF are used as strata. 
• For percent change and changes from baseline at each week, MMRM will be 
performed using treatment groups, evaluation time points (Weeks 4 and 8 of 
treatment), and interactions between the treatment group and the evaluation time 
point as fixed effects, and allocation factors (status of urinary incontinence [SUI or 
MUI], mean IEF per 24 hours [≥ 2 per day or < 2 per day]) and age (≥ 60 years or < 
60 years) as covariates. Thus, the least mean square (LS Mean) in each treatment 


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group and the difference in the LS Mean between each dose group and the placebo 
group and the two-sided 95% CI will be estimated at overall evaluation time points. 
Unstructured covariance structure will be assumed, and toeplitz type will be used in 
case of no convergence. If convergence is still not achieved, the First-order 
autoregressive → Compound symmetry → Variance component will be used in this 
order. The Kenward-Roger method (2009)4) will be used to calculate degrees of 
freedom. 
• The percentage of patients with at least 50% reduction from baseline at each time 
point (Weeks 4 and 8 of treatment) and its 95% confidence interval (CI) will be 
calculated, and Fisher’s exact test with placebo as the control will be conducted. 
8.1.2. 
Urinary Incontinence Amount in 1-Hour Pad Test 
• Summary statistics will be calculated for measured values at each evaluation time 
point (at the time of enrollment in the treatment period and Week 8 of treatment) and 
percent changes (Week 8 of treatment) as well as changes (Week 8 of treatment) from 
baseline. 
• For percent change from baseline and change from baseline to each evaluation time 
point (Week 8 in the treatment period), student’s t-test will be conducted using the 
placebo group as the control. 
• The percentage of patients with an observed value of ≤ 2.0 g at Week 8 of treatment, 
and its 95% CI will be calculated. 
• The percentage of patients with at least 50% reduction from baseline at Week 8 of 
treatment and its 95% CI will be calculated, and Fisher’s exact test with placebo as 
the control will be conducted. 
8.1.3. 
Mean Number of Pads Used per 24 Hours (Only for Patients Who Had Ever 
Used Incontinence Pads) 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent change from baseline and change from baseline to each evaluation time 
point (Weeks 4 and 8 of treatment), student’s t-test will be conducted using the 
placebo group as the control. 
8.1.4. 
ICIQ-SF score 
• Summary statistics for the total score (at the time of enrollment in the observation 
period, at the time of enrollment in the treatment period, and Weeks 4 and 8 of 
treatment) and change (Weeks 4 and 8 of treatment) from baseline at each time point 
will be calculated. 
• Summary statistics for the subscale score (at the time of enrollment in the observation 
period, at the time of enrollment in the treatment period, and Weeks 4 and 8 of 


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treatment) and change (Weeks 4 and 8 of treatment) from baseline at each time point 
will be calculated. 
• For the change in the total score from baseline to each evaluation time point (Weeks 4 
and 8 of treatment), student’s t-test will be conducted using the placebo group as the 
control. 
• For the change in the subscale score from baseline to each evaluation time point 
(Weeks 4 and 8 of treatment), student’s t-test will be conducted using the placebo 
group as the control. 
8.1.5. 
Patient Global Impression of Improvement (PGI-I) 
• The percentage of patients by score on the 7-point scale assessment at the time of 
enrollment in the treatment period, and Weeks 4 and 8 of treatment will be calculated. 
• The percentage of patients with an improvement (patients selecting “Very much 
better,” “Much better,” or “A little better” or patients selecting “Very much better” or 
“Much better”) at the time of enrollment in the treatment period and Weeks 4 and 8 
of treatment and its 95% CI will be calculated, and Fisher’s exact test with placebo as 
the control will be conducted. 
• The proportion of improvement (“Very much better” and “Much better”) at the time 
of enrollment in the treatment period and Weeks 4 and 8 of treatment and 95% CI 
will be calculated, and Fisher’s exact test with placebo as the control will be 
conducted. 
8.1.6. 
I-QOL Score 
• Summary statistics for the total score (at the time of enrollment in the treatment 
period, and Weeks 4 and 8 of treatment) and change (Weeks 4 and 8 of treatment) 
from baseline at each time point will be calculated.  
• Summary statistics for the domain score (at the time of enrollment in the treatment 
period and Weeks 4 and 8 of treatment) and change (Weeks 4 and 8 of treatment) 
from baseline at each time point will be calculated. 
• For the change in the total score from baseline to each evaluation time point (Weeks 4 
and 8 of treatment), student’s t-test will be conducted using the placebo group as the 
control. 
• For the change in the domain score from baseline to each evaluation time point 
(Weeks 4 and 8 of treatment), student’s t-test will be conducted using the placebo 
group as the control. 
8.1.7. 
Mean Frequency of SUI Episode per 24 Hours 
Of urinary incontinence episodes documented in the Bladder diary, those excluding episodes 
because of “Leaks irrepressibly” will be used for following analyses. 


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• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patient, the test will be conducted by 
excluding age from the strata. The van Elteren test will be performed in two patterns, 
i.e., a pattern in which allocation adjustment factors at the time of enrollment are used 
as strata (analysis in the FAS only) and a pattern in which allocation adjustment 
factors recorded in CRF are used as strata. 
• For percent change and changes from baseline at each week, MMRM is performed 
using treatment groups, evaluation time points (Weeks 4 and 8 of treatment), and 
interactions between the treatment group and the evaluation time point as fixed 
effects, and allocation factors (status of urinary incontinence, mean IEF per 24 hours 
[≥ 2 per day or < 2 per day]) and age (≥ 60 years or < 60 years) as covariates. Thus, 
the least mean square (LS Mean) in each treatment group and the difference in LS 
Mean between each dose group and the placebo group and the two-sided 95% CI are 
estimated at overall evaluation time points. Unstructured covariance structure will be 
assumed, and the toeplitz type will be used in case of no convergence. If convergence is still 
not achieved, the First-order autoregressive → Compound symmetry → Variance component will be 
used in this order. The Kenward-Roger method (2009)4) will be used to calculate 
degrees of freedom. 
• The percentage of patients with at least 50% reduction from baseline at each time 
point (Weeks 4 and 8 of treatment) and its 95% confidence interval (CI) will be 
calculated, and Fisher’s exact test with placebo as the control will be conducted. 
8.1.8. 
Mean Frequency of UUI Episode per 24 Hours 
Of urinary incontinence episodes documented in the Bladder diary, those excluding episodes 
because of “Leaks when you do physical movements such as coughing, laughing, sneezing, 
standing, or doing sports” will be used for following analyses.  
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patient, the test will be conducted by 
excluding age from the strata. The van Elteren test will be performed in two patterns, 
i.e., a pattern in which allocation adjustment factors at the time of enrollment are used 


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as strata (analysis in the FAS only) and a pattern in which allocation adjustment 
factors recorded in CRF are used as strata. 
• For percent change and changes from baseline at each week, MMRM is performed 
using treatment groups, evaluation time points (Weeks 4 and 8 of treatment), and 
interactions between the treatment group and the evaluation time point as fixed 
effects, and allocation factors (status of urinary incontinence, mean IEF per 24 hours 
[≥ 2 per day or < 2 per day]) and age (≥ 60 years or < 60 years) as covariates. Thus, 
the least mean square (LS Mean) in each treatment group and the difference in LS 
Mean between each dose group and the placebo group and the two-sided 95% CI are 
estimated at overall evaluation time points. Unstructured covariance structure will be 
assumed, and toeplitz type will be used in case of no convergence. If convergence is 
still not achieved, the First-order autoregressive → Compound symmetry → Variance 
component will be used in this order. The Kenward-Roger method (2009)4) will be 
used to calculate degrees of freedom. 
• The percentage of patients with at least 50% reduction from baseline at each time 
point (Weeks 4 and 8 of treatment) and its 95% confidence interval (CI) will be 
calculated, and Fisher’s exact test with placebo as the control will be conducted. 
8.1.9. 
Analyses Based on Allocation Factors 
Following analyses will be performed in PPS: 
• Secondary endpoints will be analyzed by status of urinary incontinence (SUI, MUI) 
(8.1.1 to 8.1.8). 
• Secondary endpoints will be analyzed (8.1.1 to 8.1.8) by mean IEF per 24 hours (≥ 2 
per day, < 2 per day). 
8.1.10. 
Mean Incontinence Episode Frequency per 24 Hours: Subgroup Analysis 
Following analyses will be performed in PPS for each subgroup specified in Table 8. 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. Summary statistics of 
the mean frequency of SUI episode per week will also be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 


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Table 8 
Subgroup 
Item 
Details of subgroup 
By timing of enrollment in the 
treatment period: Quarters and 
pollen season 
“January to March,” “April to June,” “July to September,” “October 
to December” 
“January to February (pollen season)” 
By timing of enrollment in the 
treatment period: Number of 
patients enrolled 
Months prior to the month in which a half of the patients in the whole 
PPS are enrolled, 
Month in which a half of the patients in the whole PPS are enrolled 
and thereafter 
Mean IEF per 24 hours at baseline 
(≥ 2 per day or < 2 per day) × 
status of urinary incontinence 
“< 2 per day and SUI,” “< 2 per day and MUI,” “≥ 2 per day and 
SUI,” “≥ 2 per day and MUI 
By measured values in the 1 hour 
pad test at the time of enrollment 
in the treatment period 
≤ 5 g, > 5 g 
≤ 10 g, > 10 g 
≤ 50 g, > 50 g 
≤ 100 g, > 100 g 
> 5 g, ≤ 10 g, > 10 g, ≤ 50 g, > 50 g, ≤ 100 g 
By ICIQ-F score at the time of 
enrollment in the treatment period 
< 6, ≥ 6 
< 13, ≥ 13 
< 19, ≥ 19 
≥ 6 and < 13, ≥ 13 and < 19, ≥ 19 and ≤ 21 
By I-QOL score at the time of 
enrollment in the treatment period 
< 65, ≥ 65 
< 85, ≥ 85 
By baseline mean IEF per 24 
hours at the time of enrollment in 
treatment 
< 1.5 times/day, ≥ 1.5 times/day 
< 2.5 times/day, ≥ 2.5 times/day 
< 3 times/day, ≥ 3 times/day 
< 3.5 times/day, ≥ 3.5 times/day 
< 4 times/day, ≥ 4 times/day 
 
8.1.11. 
Mean Incontinence Episode Frequency per 24 Hours: Integrated TAS-303 
Group 
TAS-303 3 mg group and 6 mg group will be integrated, and following analyses will be 
performed in FAS and PPS: Similar analyses will be performed by mean IEF per 24 hours (< 2 
per day, ≥ 2 per day) and status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 


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treatment) from baseline at each time point will be calculated. Summary statistics of 
the mean frequency of SUI episode per week will also be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 
8.1.12. 
Mean Frequency of SUI Episode per 24 Hours 2 
In PPS, data on urinary incontinence only for the reason categorized as “Leaks when you do 
physical movements such as coughing, laughing, sneezing, standing, or doing sports” recorded in 
the Bladder diary will be used for following analyses. This will also be performed for the 
integrated TAS-303 3 mg group and 6 mg group. Similar analyses will be performed by mean 
IEF per 24 hours (< 2 per day, ≥ 2 per day) and status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 
8.1.13. 
Mean Frequency of SUI Episode per 24 Hours 2: Subgroup Analysis 
In PPS, data on urinary incontinence only for the reason categorized as “Leaks when you do 
physical movements such as coughing, laughing, sneezing, standing, or doing sports” recorded in 
the Bladder diary will be used for following analyses by subgroup specified in Table 8. Similar 
analyses will be performed by status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 


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8.1.14. 
Mean Frequency of UUI Episode per 24 Hours 2 
In PPS, data on urinary incontinence only for the reason categorized as “Leaks irrepressibly” 
recorded in the Bladder diary will be used for following analyses. This will also be performed for 
the integrated TAS-303 3 mg group and 6 mg group. Similar analyses will be performed by 
mean IEF per 24 hours (< 2 per day, ≥ 2 per day) and status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 
8.1.15. 
Mean Frequency of UUI Episode per 24 Hours 2: Subgroup Analysis 
In PPS, data on urinary incontinence only for the reason categorized as “Leaks irrepressibly” 
recorded in the Bladder diary will be used for following analyses by subgroup specified in Table 
8. Similar analyses will be performed by status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 
control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 
8.1.16. 
Mean Frequency of Episodes of Micturition Urgency per 24 Hours 
In PPS, data on “urgency” recorded in the Bladder diary will be used for following analyses. 
Similar analyses will be performed by mean IEF per 24 hours (< 2 per day, ≥ 2 per day) and 
status of urinary incontinence (SUI, MUI). 
• Summary statistics for the observed value (Weeks 4 and 8 of treatment), percent 
change (Weeks 4 and 8 of treatment) from baseline, and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. 
• For percent changes (Weeks 4 and 8 of treatment) and changes (Weeks 4 and 8 of 
treatment) from baseline to each time point of evaluation, student’s t-test, Wilcoxon’s 
rank sum test, and van Elteren test using allocation adjustment factors and age (< 60 
years and ≥ 60 years) as strata will be conducted using the placebo group as the 


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control. If any stratum includes a group with 0 patients, the test will be conducted 
only for the age stratum identified as a prognostic factor in the blinded review. If 
there is any group with 0 patient, the test will not be conducted. 
8.1.17. 
Mean Leakage Amount per 24 Hours 
Leakage amounts will be scored as Small = 2, Moderate = 4, and Large = 6, and summary 
statistics for the observed value (Weeks 4 and 8 of treatment) and change (Weeks 4 and 8 of 
treatment) from baseline at each time point will be calculated. For change from baseline to each 
evaluation time point (Weeks 4 and 8 of treatment), student’s t-test will be conducted using the 
placebo group as the control. Similar analyses will be performed by mean IEF per 24 hours (< 2 
per day, ≥ 2 per day) and status of urinary incontinence (SUI, MUI). 
8.2. 
Analysis of Administration Status 
In all treated population, following analyses will be performed by observation/treatment period 
and treatment group. 
8.2.1. 
Administration Status 
Summary statistics will be calculated for the status of administration (total dose and total 
duration of administration). 
8.2.2. 
Status of Administration Completion 
• Summary statistics of compliance with treatment with study drugs will be calculated 
for each patient. 
• The presence or absence of study discontinuation (including timing) and its reason 
will be tabulated. 
8.3. 
Safety Analysis 
Following analyses will be performed in the all-treated population at each treatment group. 
However, analyses for the treatment period will be performed in patients in the all-treated 
population who have received treatment during the treatment period. 
8.3.1. 
Adverse Events and Adverse Drug Reactions 
Following analyses will be performed for each of the observation and treatment periods: 
• The number of patients and the incidence will be calculated. ADRs will be analyzed 
in the same way. 
• The number of patients and the incidence will be displayed by severity for each item 
of adverse event. ADRs will be analyzed in the same way. 
• The number of patients and the incidence will be displayed by severity (incidence ≥ 
2%) for each item of adverse event. ADRs will be analyzed in the same way. 
• The incidence of AEs in the treatment period will be displayed by time of onset 
(Weeks 4 and 8 and follow-up). ADRs will be analyzed in the same way. 


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• All AEs that have occurred from the start of study treatment to the end date of the 
follow-up will be listed by AE variable of each patient, together with the AE term, 
severity, date of onset, action, outcome, causal relationship with the study drug, and 
comments. 
• The incidence of serious AEs will be calculated. ADRs will be analyzed in the same 
way. 
8.3.2. 
Laboratory Test Values 
• Changes in laboratory parameters (quantitative test) from the baseline will be 
graphically presented. 
• Summary statistics for laboratory test parameters (quantitative test) at each evaluation 
time point will be calculated. 
• Frequency of each laboratory parameter (urine qualitative test) at each evaluation 
time point will be tabulated. 
8.3.3. 
12-Lead ECG 
• Summary statistics for the observed value of the QTcF interval and heart rate at each 
evaluation time point will be calculated. 
• Summary statistics for change from baseline in the observed value of the QTcF 
interval and heart rate at each evaluation time point will be calculated. 
• For amounts of changes in measured values of the QTcF interval and heart rate from 
values immediately before the start of treatment to each evaluation time point, 
student’s t-test will be conducted using the placebo group as the control. 
• The observed value of the QTcF interval at each evaluation time point was divided 
into categories (≤ 450 msec, > 450 msec and ≤ 480 msec, > 480 msec, and ≤ 500 
msec, > 500 msec), and the frequency of each category will be tabulated. 
• Change from baseline in the observed value of the QTcF interval and heart rate at 
each evaluation time point was divided into categories (QTcF interval, ≤ 30 msec, > 
30 msec, and ≤ 60 msec, > 60 msec: heart rate <5 bpm, ≤ 5 bpm), and the frequency of 
each category will be tabulated. 
• The incidence of abnormal variations in 12-lead ECG will be calculated. 
• A list of patients with abnormal 12-lead ECG 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 
evaluation time point will be calculated. 
• Summary statistics for change from baseline in the observed value of blood pressure 
and pulse rate at each evaluation time point will be calculated. 


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• For amounts of changes in measured values of blood pressure and pulse rate from 
values immediately before the start of treatment to each evaluation time point, 
student’s t-test will be conducted using the placebo group as the control. 
• Change from baseline in the observed value of blood pressure and pulse rate at each 
evaluation time point will be divided into categories (blood pressure, < 10 mmHg, ≥ 
10 mmHg: pulse rate, < 5 bpm, ≥ 5 bpm), and the frequency of each category will be 
tabulated. 
8.3.5. 
Uroflowmetry 
• Summary statistics for uroflowmetry parameters (free Qmax, free Qave, voided volume, 
and voiding time) at the time of enrollment and Week 8 of treatment will be 
calculated. 
• Summary statistics for change from baseline in the observed value of uroflowmetry 
parameters at Week 8 of treatment will be calculated. 
• For amounts of changes in measured values of uroflowmetry parameters at Week 8 
from values immediately before the start of treatment to each evaluation time point, 
student’s t-test will be conducted using the placebo group as the control. 
8.3.6. 
Residual Urine Volume 
• Summary statistics at the time of enrollment in the observation period, at the time of 
enrollment in the treatment period, and Week 8 of treatment will be calculated. 
• Summary statistics for change from baseline in the observed value at Week 8 of 
treatment will be calculated. 
• For amounts of changes in measured values at Week 8 from values immediately 
before the start of treatment to each evaluation time point, student’s t-test will be 
conducted using the placebo group as the control. 
8.3.7. 
Mean Frequency of Micturition per 24 Hours 
• Summary statistics at the time of enrollment and Weeks 4 and 8 of treatment will be 
calculated. 
• Summary statistics for change from baseline in the observed value at Weeks 4 and 8 
of treatment will be calculated. 
• For amounts of changes in measured values at Weeks 4 and 8 from values 
immediately before the start of treatment to each evaluation time point, student’s 
t-test will be conducted using the placebo group as the control. 
• Above analyses will be performed by status of urinary incontinence (SUI, MUI). 


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9. 
OTHER ANALYSES 
9.1. 
Analysis Populations 
The proportion of each analysis population and reasons for exclusion will be tabulated by 
treatment group. Patients excluded from analysis populations will be listed along with reasons. 
9.2. 
Deviation 
The presence or absence of deviations and deviation items will be tabulated by treatment group. 
A detailed list of patients with deviations will be presented. 
10. 
REVIEW AND REVISION OF STATISTICAL ANALYSIS PLAN 
The statistical analysis plan will be finalized before key code breaking. 
If the statistical analysis plan is revised, the change log of Statistical Analysis Plan/Table and 
Figure Plan should be prepared to record the changed content and the reason. Analyses newly 
planned after key code breaking should be distinguished from those planned beforehand and 
recorded in the change log. 
11. 
STATISTICAL ISSUES 
Explanations on ICH-E3 Guidelines1) and other statistical issues are summarized below. 
11.1. 
Adjustments for Covariates 
Adjustments for covariates will be performed using MMRM. Details of covariates will be 
specified separately. 
11.2. 
Handling of Dropouts or Missing Data 
Handling of missing values in efficacy endpoints will be specified for each analysis. 
Missing values in safety endpoints will not be imputed. The proportion, including that of patients 
with adverse events, will be calculated using the analysis population as the denominator for the 
observation period and using the number of patients who have taken study drugs for the 
treatment period at least once among those in the analysis population as the denominator for the 
treatment period. 
Analyses will include all measured data, except for abnormal laboratory test values with obvious 
reasons, such as the effect of hemolysis during blood collection. If abnormal values are excluded 
from the analysis, they will be specified and reasons for exclusion will be stated. 
In the case of any post hoc exploratory analysis, the procedure for handling of missing data will 
be determined appropriately for each item to be analyzed according to the method of analysis 
and characteristics of items to be evaluated. 


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11.3. 
Interim Analyses and Data Monitoring 
Interim analyses will not be conducted in this study. 
11.4. 
Multicenter Studies 
This study is a multicenter study.  
11.5. 
Multiple Comparisons/Multiplicity 
In the analysis of the primary objective, the significance level for each comparison will be 
adjusted by the Hochberg’s method, considering multiplicity. 
11.6. 
Use of an “Efficacy Subset” of Patients 
Although not planned in this study, additional analyses may be performed as necessary. 
11.7. 
Active-Control Studies Intended to Show Equivalence 
Not applicable for this study 
11.8. 
Examination of Subgroups 
In this study, subgroup analyses by allocation adjustment factors are planned for some analyses. 
Additional analyses will be performed as necessary. 
12. 
PREPARATION OF TABLE AND FIGURE PLAN 
The statistical analysis plan only specifies major analysis items. All analysis items to be 
performed will be presented separately in the Table and Figure Plan. 
13. 
REFERENCES 
(1) 
“Structure and Content of. Clinical Study Reports” (PAB/ELD Notification No. 335 dated 
May 1, 1996) 
(2) 
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