A Phase III Study to Evaluate the Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Overactive Bladder
Phase: PHASE3
Conditions: Urinary Bladder, Overactive
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase III study to evaluate the efficacy and safety of GSK1358820 
(botulinum toxin type A) in patients with overactive bladder
Compound Number:
GSK1358820
Development Phase:
III
Effective Date:
17-Apr-2017
Protocol Amendment Number: 03
Author (s):
Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2016N273767_00
20-Apr-2016
Original
2016N273767_01
12-May-2016
Amendment Number 01

Delete the contraceptive methods which can not be used in Japan based on the indication by the 
Pharmaceuticals and Medical Device Agency.
2016N273767_02
20-Jun-2016
Amendment Number 02

Change the criteria to perform the urine culture/sensitivity test

Change the definition of urinary tract infection partially in this study

Change the adverse event term at increased residual urine volume
2016N273767_03
17-Apr-2017
Amendment Number 03

Change the day of re-treatment criteria regarding urinalysis partially

Add the cholinesterase inhibitor for the treatment of urinary disturbance as the prohibited
medication

Change the schedule of sample collection for neutralizing antibody partially

Clarify the timing for the initiation of antibiotic treatment
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying 
or use of this information is prohibited.
PPD

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SPONSOR SIGNATORY：
Yotaro Numachi
Glaxo Smith Kline K.K.
The head of Neurosciences TA Office, Medicines Development
Date

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Phone 
Number
Fax Number
Site Address
Medical 
Monitor
 MD, 
Ph.D
Glaxo Smith Kline K.K.
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-
8566 JAPAN
SAE contact  
information
GSK1358820 Section, 
Clinical Operation 
Department
Glaxo Smith Kline K.K. 
6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-
8566 JAPAN
Emergency Contact Information
Sponsor’s Emergency Contact Information (10:00-18:00, Monday to Friday, except national holidays 
and year-end and new-year holidays);
GSK1358820 Section, Clinical Operation Department, GlaxoSmithKline K.K.
TEL：
FAX：
Contact Information at Night and on Holidays (Monday through Friday: 18:00-10:00, Saturdays, 
Sundays, national holidays, year-end and new-year holidays)
BI Medical, Inc.
Responsible Person:
TEL：
toll-free）
FAX：
toll-free）
Sponsor Legal Registered Address:
GlaxoSmithKline K.K（GSK）
6-15, Sendagaya 4-chome, Shibuya-ku, Tokyo 151-8566 JAPAN
Study Director: 
The head of Neurosciences TA Office, Medicines Development
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol number: 204947

I confirm agreement to conduct the study in compliance with the protocol, as amended by this 
protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or 
supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study.
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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Table of Contents
Page
1.
PROTOCOL SYNOPSIS FOR STUDY 204947 ..............................................................9
2.
INTRODUCTION............................................................................................................13
2.1.
Study Rationale....................................................................................................13
2.2.
Brief Background.................................................................................................13
3.
OBJECTIVE(S) AND ENDPOINT(S).............................................................................14
4.
STUDY DESIGN.............................................................................................................15
4.1.
Overall Design......................................................................................................16
4.2.
Treatment Arms and Duration............................................................................16
4.3.
Type and Number of Subjects............................................................................16
4.4.
Design Justification.............................................................................................17
4.5.
Dose Justification................................................................................................17
4.6.
Benefit: Risk Assessment...................................................................................17
4.6.1.
Risk Assessment ........................................................................................18
4.6.2.
Benefit Assessment....................................................................................21
4.6.3.
Overall Benefit: Risk Conclusion..............................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA.................21
5.1.
Inclusion Criteria..................................................................................................21
5.2.
Exclusion Criteria ................................................................................................23
5.3.
Re-treatment Criteria...........................................................................................26
5.4.
Screening Failures...............................................................................................27
5.5.
Withdrawal/Stopping Criteria .............................................................................27
5.5.1.
Liver Chemistry Stopping Criteria.............................................................28
5.5.1.1.
Study Treatment Restart or Rechallenge.........................................29
5.5.2.
QTc Stopping Criteria.................................................................................29
5.6.
Subject and Study Completion ..........................................................................30
6.
STUDY TREATMENT ....................................................................................................30
6.1.
Investigational Product and Other Study Treatment.......................................30
6.1.1.
Investigational Product ..............................................................................30
6.1.2.
Treatment Administration ..........................................................................30
6.1.2.1.
Antibiotics ...........................................................................................30
6.1.2.2.
Use of Anesthesia ..............................................................................31
6.1.2.3.
Treatment Procedure .........................................................................31
6.2.
Treatment Assignment........................................................................................32
6.2.1.
Re-registration of subject ..........................................................................32

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6.3.
Blinding.................................................................................................................33
6.4.
Packaging and Labeling......................................................................................33
6.5.
Preparation/Handling/Storage/Accountability..................................................34
6.6.
Compliance with Study Treatment Administration..........................................34
6.7.
Treatment of Study Treatment Overdose..........................................................34
6.8.
Treatment after the End of the Study ................................................................35
6.9.
Concomitant Medications and Non-Drug Therapies .......................................35
6.9.1.
Permitted Medications and Non-Drug Therapies ....................................35
6.9.2.
Prohibited Medications and Non-Drug Therapies...................................35
7.
STUDY ASSESSMENTS AND PROCEDURES ...........................................................36
7.1.
Time and Events Table........................................................................................37
7.2.
Screening and Critical Baseline Assessments ................................................41
7.3.
Efficacy .................................................................................................................41
7.3.1.
Methods of assessments ...........................................................................41
7.3.1.1.
Bladder diary.......................................................................................41
7.3.1.2.
Health outcome questionnaires........................................................42
7.3.1.2.1.
King’s Health Questionnaire (KHQ).........................................42
7.3.1.2.2.
Overactive Bladder Symptom Score (OABSS).......................43
7.3.1.2.3.
Treatment Benefit Scale (TBS).................................................43
7.4.
Safety ....................................................................................................................43
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................44
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................44
7.4.1.2.
Method of Detecting AEs and SAEs.................................................44
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................44
7.4.1.4.
Cardiovascular and Death Events....................................................44
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................45
7.4.2.
Pregnancy....................................................................................................45
7.4.3.
Physical Exams...........................................................................................45
7.4.4.
Vital Signs....................................................................................................45
7.4.5.
Electrocardiogram (ECG) ...........................................................................45
7.4.6.
Clinical Safety Laboratory Assessments .................................................46
7.4.6.1.
Hematology and chemistry ...............................................................46
7.4.6.2.
Urinalysis.............................................................................................47
7.4.6.2.1.
Urinalysis using a urine reagent strip .....................................47
7.4.6.2.2.
Urinalysis, Culture and Sensitivity ..........................................48
7.4.6.2.3.
Urinary cytology.........................................................................48

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7.4.6.3.
Prostate-specific antigen...................................................................48
7.4.6.4.
Pregnancy test....................................................................................48
7.4.7.
Post-void residual (PVR) urine volume ....................................................48
7.4.8.
Kidney and bladder ultrasound.................................................................51
7.5.
Other endpoints ...................................................................................................52
7.5.1.
Immunogenicity Testing.............................................................................52
8.
DATA MANAGEMENT ..................................................................................................52
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................52
9.1.
Hypotheses...........................................................................................................52
9.2.
Sample Size Considerations ..............................................................................53
9.2.1.
Sample Size Assumptions .........................................................................53
9.2.2.
Sample Size Sensitivity ..............................................................................53
9.2.3.
Sample Size Re-estimation or Adjustment...............................................54
9.3.
Data Analysis Considerations............................................................................54
9.3.1.
Analysis Populations..................................................................................54
9.3.2.
Interim Analysis ..........................................................................................54
9.4.
Key Elements of Analysis Plan ..........................................................................54
9.4.1.
Primary Analyses........................................................................................54
9.4.2.
Secondary Analyses...................................................................................55
10. STUDY GOVERNANCE CONSIDERATIONS ..............................................................57
10.1.
Posting of Information on Publicly Available Clinical Trial Registers...........57
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process..................................................................................................57
10.3.
Quality Control (Study Monitoring)....................................................................57
10.4.
Quality Assurance ...............................................................................................58
10.5.
Study and Site Closure .......................................................................................58
10.6.
Records Retention...............................................................................................58
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................59
11. REFERENCES...............................................................................................................59
12. Appendices ...................................................................................................................62
12.1.
Appendix 1: Abbreviations and Trademarks....................................................62
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................64
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................67
12.3.1.
Definition of Adverse Events.....................................................................67

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12.3.2.
Definition of Serious Adverse Events.......................................................68
12.3.3.
Definition of Cardiovascular Events.........................................................69
12.3.4.
Recording of AEs and SAEs......................................................................69
12.3.5.
Evaluating AEs and SAEs..........................................................................70
12.3.6.
Reporting of SAEs to GSK.........................................................................71
12.4.
Appendix 4: Collection of Pregnancy Information...........................................72
12.5.
Appendix 5: Management guideline of PVR .....................................................73
12.6.
Appendix 6: COUNTRY SPECIFIC REQUIREMENTS (JAPAN) .......................74
12.6.1.
Study Conduct Considerations .................................................................74
12.6.1.1.
Regulatory and Ethical Considerations...........................................74
12.6.1.2.
Informed Consent...............................................................................74
12.6.1.3.
Study Period........................................................................................74
12.6.1.4.
Study Administrative Structure ........................................................74
12.6.2.
Nonaproved Medical Devices in Japan ....................................................74
12.6.2.1.
Documenting Medical Device Incidents...........................................75
12.6.2.2.
Transmission of Medical Device Incident Reports.........................75
12.6.2.3.
Time Period of Detecting Medical Device Incident.........................76
12.6.2.4.
Follow-up of Medical Device Incidents ............................................76
12.6.2.5.
Post-Study Medical Device Incidents...............................................76
12.6.2.6.
Regulatory Reporting Requirements for Medical Devices ............76
12.6.3.
Exhibits ........................................................................................................76
12.7.
Appendix 7：Protocol Changes.........................................................................77
12.7.1.
Changes from Original (Effective Date: 20-Apr-2016) to 
Amendment 01.............................................................................................77
12.7.2.
Changes from Amendment 01 (Effective Date: 12-May-2016) to 
Amendment 02.............................................................................................78
12.7.3.
Changes from Amendment 02 (Effective Date: 20-Jun-2016) to 
Amendment 03.............................................................................................80

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1.
PROTOCOL SYNOPSIS FOR STUDY 204947
Rationale
GSK1358820 (botulinum toxin type A) has already been approved for the treatment of overactive 
bladder (OAB) in overseas countries including the US and EU; however, it has not been approved for 
OAB treatment in Japan. Therefore, this study has been planned to evaluate the efficacy and safety of 
GSK1358820 in Japanese patients with OAB with urinary incontinence whose symptoms have not 
been adequately managed with medications for OAB*
This study design has been planned based on the results of the consultation meetings with the 
Pharmaceuticals and Medical Device Agency (ie, additional consultation meeting held on February 23, 
2015, and additional consultation meeting in writing by February 29, 2016).
As a result of being examined at the MHLW’s “Review meeting on unapproved or off-label drugs 
with of high medical need”, GSK1358820 for OAB was evaluated to have high medical needs and its 
development was requested by the MHLW on May 21, 2015.
*: Anticholinergic and beta-3 adrenergic receptor agonist have indication for patients with OAB
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To evaluate the superiority of a 
single dose treatment of 
GSK1358820 100 U compared 
with placebo

Change from baseline in the daily average 
number of urinary incontinence episodes a at 
week 12 after the first treatment.
Secondary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
100 U compared with placebo

To evaluate the efficacy of 
repeated dose treatment of 
GSK1358820 100 U
Major Secondary

Change from baseline in the average volume 
voided per micturition at week 12 after the first 
treatment.
Other Secondary

Changes from baseline and percentage change 
from baseline in the following endpoints

Daily average number of urinary 
incontinence episodes a

Daily average number of urinary urgency 
incontinence episodes a

Daily average number of voids a

Average volume voided per micturition a

Daily average number of urgency episodes a

Daily average number of nocturia episodes 
(voids that interrupt night sleep) a

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
Urgency intensity

Change from baseline in daily average 
number of urgency episodes by each 
urgency intensity category a

Proportions of patients with maximum 
urgency intensity a

Change from baseline of maximum urgency 
intensity a

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily 
average of urinary incontinence episodes

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily 
average of urinary urgency incontinence episodes

Duration of treatment effect after 1st treatment

Time to qualification for retreatment

Time to request for retreatment

Health outcome

Changes from baseline in King's Health 
Questionnaire (KHQ) domain scores

Proportion of patients with positive 
response on the Treatment Benefit Scale 
(TBS)

Changes from baseline in Overactive 
Bladder Symptom Score (OABSS) total 
score
a：Daily frequency calculated by 3-day dairy
Safety

To evaluate the safety of a single 
dose treatment of GSK1358820 
100 U compared with placebo

To evaluate the safety of repeated 
dose treatment of GSK1358820 
100 U

Adverse events

Safety parameter

Vital signs and physical examination

Clinical laboratory (hematology, blood 
chemistry and urinalysis)

Urine culture and sensitivity

Post void residual (PVR) urine volume

Use of clean intermittent catheterization 
(CIC) for urinary retention / elevated PVR

Kidney and bladder ultrasound

Pregnancy test

Twelve-lead electrocardiogram (ECG)

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Other

To evaluate the existence of toxin-
neutralizing antibody after the 
treatment of GSK1358820 100U

Neutralizing antibody measurement
Overall Design
This study includes a Screening phase, a Treatment phase 1(double-blind treatment phase), and a 
Treatment phase 2 (open-label treatment phase). The study design of each treatment phase is shown 
below.

Treatment phase 1: Multicenter, randomized, double-blind, placebo-controlled, parallel-
group comparison design

Treatment phase 2: Multicenter, open-label design
Treatment Arms and Duration
This study consists of a Screening phase (within 28 days period before first treatment), a Treatment 
phase 1 (double-blind treatment phase: 12 to 48 weeks period after first treatment), and a Treatment 
phase 2 (open-label treatment phase: 12 to 36 weeks period after first treatment). The duration of 
overall treatment phase is 48 weeks.
Following the Screening phase, patients meeting the eligibility criteria will be randomly assigned by 
the registration center to one of the 2 treatment arms (either 100 U GSK1358820 or placebo) in a ratio 
of 1:1. Subsequently, in Treatment phase 1, patients will receive single treatment with the allocated 
study drug (20 injections each of 0.5 mL) which will be injected into the detrusor muscle of bladder. 
At the randomization, patients will be stratified according to the number of urinary urgency 
incontinence episodes reported prior to initiation of treatment phase 1 (Week 0), ≤ 9 or ≥ 10 episodes, 
over the consecutive 3-day diary completed during the screening phase.
Subjects who meet the criteria for re-treatment (referred to the section 5.3 Re-treatment criteria) 
between 12 to 36 weeks after 1st treatment will enter to Treatment phase 2 to receive re-treatment. 
Patients are permitted to receive re-treatment until up to 36 weeks after 1st treatment and at most 2 
times (Note: a minimum of 12 weeks need to be elapsed since the previous study treatment). Subjects 
who did not receive re-treatment will remain in Treatment phase 1 and continue to visit at the 
scheduled study visits. Patients who complete the evaluation at 48 weeks after 1st treatment are 
regarded as the patients who complete the study, regardless of whether the subject was re-treated or 
not.
Type and Number of Subjects

Study population: Patients with OAB and urinary incontinence whose symptoms have not been 
adequately managed with medications for OAB (anticholinergic and beta-3 adrenergic receptor 
agonist)

Number of subjects (randomized subjects): 240 (120 per group)
Analysis
As primary analysis for efficacy, the change from baseline in the daily average number of urinary 
incontinence episodes will be analyzed using a mixed model for repeated measures (MMRM). This 

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model will include the treatment group, visit, and treatment-by-visit interaction as fixed factors, 
baseline values and baseline-by-visit as covariates. An unstructured variance structure will be used to 
model the within-subject errors, shared across treatments. Analysis will be done with the MIXED 
procedure in SAS®, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. Significant tests will be based on least-squares means using a two-sided 5% 
significance level (two-sided 95% confidence intervals). The dataset including only data until week 12 
after the first treatment will be used for MMRM.
All AEs that occur during the study will be recorded and classified using the current Medical 
Dictionary for Regulatory Activities (MedDRA). Events will be summarized overall, by treatment 
cycle and for the first 12 week of 1st treatment phase (adverse event that occurs ≤84 days from 1st 
treatment). Frequencies of AEs will be presented by system organ class and preferred term. 
Summaries of treatment-related AEs (study drug-related and injection procedure-related), AEs leading 
to discontinuation, AEs by intensity, and SAEs also will be provided.

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2.
INTRODUCTION
2.1.
Study Rationale
GSK1358820 (botulinum toxin type A) has already been approved for the treatment of overactive 
bladder (OAB) in overseas countries including the US and EU; however, it has not been approved for 
OAB treatment in Japan. Therefore, this study has been planned to evaluate the efficacy and safety of 
GSK1358820 in Japanese patients with OAB with urinary incontinence whose symptoms have not 
been adequately managed with medications for OAB*
This study design has been planned based on the results of the consultation meetings with the 
Pharmaceuticals and Medical Device Agency (ie, additional consultation meeting held on February 23, 
2015, and additional consultation meeting in writing by February 29, 2016).
As a result of being examined at the MHLW’s “Review meeting on unapproved or off-label drugs 
with of high medical need”, GSK1358820 for OAB was evaluated to have high medical needs and its 
development was requested by the MHLW on May 21, 2015.
*: Anticholinergic and beta-3 adrenergic receptor agonist have indication for patients with OAB
2.2.
Brief Background
OAB is defined by the International Continence Society (ICS) as the storage symptoms of “urgency 
with or without urge incontinence, usually with frequency and nocturia” [Abrams, 2010]. Symptoms 
of OAB such as urgency, urinary frequency and urinary urgency incontinence (UUI) significantly 
affect physical and social activities [Abrams, 2000; Goto, 2004]. OAB with UUI is characterized by 
more marked impairment of QOL compared with OAB without urinary incontinence [The Japanese 
Continence Society, 2005].
The mainstream of treatment for OAB is initial behaviour therapy / lifestyle guidance followed by 
pharmacotherapy, of which anticholinergics are considered to be the most important [the Japanese 
Continence Society, 2015]. However, some patients are resistant to anticholinergics [Fujimura, 2009; 
Yokoyama, 2008], and anticholinergics are frequently associated with adverse reactions such as dry 
mouth and constipation [Chapple, 2008], which may result in poor treatment compliance by patients 
and cessation of treatment due to intolerability by physicians [Abrams, 1998; Drutz, 1999; Aplle, 
1997; Kreder, 2002].
Currently, there are few acceptable alternative treatment options for patients with OAB who do not 
benefit from anticholinergic therapy or other pharmacotherapies, and there exists a significant unmet 
medical need for an effective and safe treatment option to bridge the gap in the treatment algorithm.
GSK1358820 is a sterile, purified botulinum neurotoxin A complex that inhibits the release of 
acetylcholine as a neurotransmitter, whereby causing the effect such as muscle relaxation. It was first 
approved for the treatment of strabismus and blepharospasm in the US in 1989 and then has been 
approved for various indications. In Japan, it is approved for the indications of blepharospasm, 
hemifacial spasm, cervical dystonia, upper limb spasticity, lower limb spasticity, equinus foot due to 
lower limb spasticity in juvenile cerebral palsy patients aged 2 years or older, severe primary axillary 
hyperhidrosis and strabismus. It is expected that injection of GSK1358820 into the detrusor muscle of 
bladder for the treatment of OAB can inhibit the parasympathetic stimulated contraction of the 
detrusor muscle, and furthermore, it is also suggested that GSK1358820 inhibits other 
neurotransmitters within the bladder associated with OAB. GSK1358820 is expected to be an 

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effective therapy in patients with OAB who have not been adequately managed with anticholinergic-
based pharmacotherapy [Yokoyama, 2008; Sekido, 2009; Giannantoni, 2004].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate the superiority of a 
single dose treatment of 
GSK1358820 100 U compared 
with placebo

Change from baseline in the daily average 
number of urinary incontinence episodes a at 
week 12 after the first treatment.
Secondary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
100 U compared with placebo

To evaluate the efficacy of 
repeated dose treatment of 
GSK1358820 100 U
Major Secondary

Change from baseline in the average volume 
voided per micturition at week 12 after the first 
treatment.
Other Secondary

Changes from baseline and percentage change 
from baseline in the following endpoints

Daily average number of urinary 
incontinence episodes a

Daily average number of urinary urgency 
incontinence episodes a

Daily average number of voids a

Average volume voided per micturition a

Daily average number of urgency episodes a

Daily average number of nocturia episodes 
(voids that interrupt night sleep) a

Urgency intensity

Change from baseline in daily average 
number of urgency episodes by each 
urgency intensity category a

Proportions of patients with maximum 
urgency intensity a

Change from baseline of maximum urgency 
intensity a

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily 
average of urinary incontinence episodes

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily 
average of urinary urgency incontinence episodes

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
Duration of treatment effect after 1st treatment

Time to qualification for retreatment

Time to request for retreatment

Health outcome

Changes from baseline in King's Health 
Questionnaire (KHQ) domain scores

Changes from baseline in Overactive
Bladder Symptom Score (OABSS) total 
score

Proportion of patients with positive 
response on the Treatment Benefit Scale 
(TBS)
a：Daily frequency calculated by 3-day dairy
Safety

To evaluate the safety of a single 
dose treatment of GSK1358820 
100 U compared with placebo

To evaluate the safety of repeated 
dose treatment of GSK1358820 
100 U

Adverse events

Safety parameter

Vital signs and physical examination

Clinical laboratory (hematology, blood 
chemistry and urinalysis)

Urine culture and sensitivity

Post void residual (PVR) urine volume

Use of clean intermittent catheterization 
(CIC) for urinary retention / elevated PVR

Kidney and bladder ultrasound

Pregnancy test

Twelve-lead electrocardiogram (ECG)
Other

To evaluate the existence of toxin-
neutralizing antibody after the 
treatment of GSK1358820 100U

Neutralizing antibody measurement
4.
STUDY DESIGN
This study includes a Screening phase, a Treatment phase 1(double-blind treatment phase), and a 
Treatment phase 2 (open-label treatment phase). The study design of each treatment phase is shown 
below.

Treatment phase 1: Multicenter, randomized, double-blind, placebo-controlled, parallel-
group comparison design

Treatment phase 2: Multicenter, open-label design

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4.1.
Overall Design
4.2.
Treatment Arms and Duration
This study consists of a Screening phase (within 28 days period before first treatment), a Treatment 
phase 1 (double-blind treatment phase: 12 to 48 weeks period after first treatment), and a Treatment 
phase 2 (open-label treatment phase: 12 to 36 weeks period after first treatment). The duration of 
overall treatment phase is 48 weeks.
Following the Screening phase, patients meeting the eligibility criteria will be randomly assigned by 
the registration center to one of the 2 treatment arms (either 100 U GSK1358820 or placebo) in a ratio 
of 1:1. Subsequently, in Treatment phase 1, patients will receive single treatment with the allocated 
study drug (20 injections each of 0.5 mL) which will be injected into the detrusor of the bladder. At 
the randomization, patients will be stratified according to the number of urinary urgency incontinence 
episodes reported prior to initiation of treatment phase 1 (Week 0), ≤ 9 or ≥ 10 episodes, over the 
consecutive 3-day diary completed during the screening phase.
Subjects who meet the criteria for re-treatment (referred to the section 5.3 Re-treatment criteria) 
between 12 to 36 weeks after 1st treatment can enter to Treatment phase 2 to receive re-treatment
(GSK1358820 100 U). Patients are permitted to receive re-treatment until up to 36 weeks after 1st 
treatment and at most 2 times (Note: a minimum of 12 weeks need to be elapsed since previous study 
treatment). Subjects who did not receive re-treatment will remain in Treatment phase 1 and continue 
to visit at the scheduled study visits. Patients who complete the evaluation at 48 weeks after 1st 
treatment are regarded as the patients who complete the study, regardless of whether the subject was 
re-treated or not.
4.3.
Type and Number of Subjects

Study population: Patients with OAB and urinary incontinence whose symptoms have not been 
adequately managed with medications for OAB symptoms (anticholinergic and beta-3 adrenergic 
receptor agonist)

Number of subjects (randomized subjects): 240 (120 per group)

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4.4.
Design Justification
Screening phase:
To confirm patients meet inclusion criteria and are not applicable to any of the exclusion criteria and 
to evaluate the condition of the subject’s primary disease, a screening phase within 28 days before 1st 
treatment has been set up.
In addition, to eliminate influences of the medications or therapies for OAB symptoms and to evaluate 
the efficacy and safety of GSK1358820 appropriately, use of these medications or therapies is 
prohibited at least 7 days before the start of the Screening phase.
Treatment phase:
To evaluate the efficacy and safety of GSK1358820 objectively, placebo will be used as a control.
To maintain the balance of the degree of symptom (i.e.: incontinence) due to OAB between the 
treatment groups, stratified randomization, according to the number of urinary urgency incontinence 
episodes (≤ 9 or ≥ 10 episodes) over the consecutive 3-day diary completed during the Screening 
phase, will be used.
Twelve weeks after 1st treatment is chosen as the primary time point based on results in the Phase III 
studies 191622-095 and 191622-520 conducted by Allergan, Inc., where significant and sustained 
reductions from baseline in urinary incontinence episodes were observed at 12 weeks after treatment 
of GSK1358820 100U compared to the placebo.
Since re-treatment may be required in the actual medical settings, the subjects are permitted to receive 
re-treatment of GSK1358820 100 U up to 2 times (i.e.: for a maximum of 3 treatments including 1st 
treatment) and are followed for up to 48 weeks after 1st treatment for the evaluation of safety and 
efficacy. In addition, in the case of re-treatment, at least 12 weeks from the prior injection are required, 
similar to the case in overseas countries.
4.5.
Dose Justification
Since GSK1358820 100U was approved for the indication of OAB as the optimal dose in overseas 
countries, GSK1358820 100U is deemed to be a dose in the range of optimal dose for Japanese OAB 
patients by the reasons as shown below. Therefore, GSK will examine the efficacy and safety of 
GSK1358820 at the dose of 100 U in Japanese patients with OAB.

Diagnosis and principles of treatment of OAB are considered to be substantially similar between 
Japan and overseas.

GSK1358820 is expected that racial differences in responsiveness are unlikely to occur from the 
characteristics of the metabolism and mode of action of the drug. In fact, no racial difference has 
been noted in dosage and administration of GSK1358820 for the already approved indications.

Efficacy and safety are reported in clinical experiences with GSK1358820 100U in Japanese
OAB patients.
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with GSK1358820 can 
be found in the Investigator’s Brochure and product label. The following section outlines the risk 
assessment and mitigation strategy for this protocol:

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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP)：GSK1358820
Urinary tract infections (UTI)
As the result of integrated data with 1 completed 
phase 2 study (191622-077), 2 completed pivotal 
phase3 study (191622-095 and 191622-520) and 
an interim cut of the long-term extension study 
(191622-096), the frequency of UTI as an adverse 
event, which was occurred in 26.4% of patients in 
the 100 U BOTOX group and 10.1% of patients in 
the placebo group (refer to IB section 5.2.4.2
Overactive Bladder).
The following potential factors that may have 
facilitated the occurrence of UTI were:
1) Elevated PVR urine volume post treatment
2) Initiation of clean intermittent catheterization 
for bladder emptying purposes when urinary 
retention occurred.
3) Patients ≥ 65 years are more predisposed to 
development of UTIs overall regardless of any 
treatment
4) Cystoscopy for study drug administration 
procedure (intradetrusor injection) during study 
participation.
Patients with potential risk for these events will be 
excluded from this study (refer to Protocol section 
5.2 exclusion eriteria 4, 5, 17 and 26 ) 
Urinalysis, urine culture and sensitivity test will be 
performed at each visits. If bacterial infection is 
confirmed, treatment with antibiotics will be 
administered in the opinion of the 
investigators/subinvestigators. The patiens are not 
allowed to receive the injection of the 
investigational product until bacterial infection is 
negative (refer to Protocol section 
7.4.6.2.Urinalysis).
Treatment with antibiotics will be administered to 
prevent bacterial infection before / after the 
injection of the investigational product (refer to 
Protocol section 6.1.2.1.Antibiotics) 

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Urinary retention
As the result of integrated data with 1 completed 
phase 2 study (191622-077), 2 completed pivotal 
phase3 study (191622-095 and 191622-520) and 
an interim cut of the long-term extension study 
(191622-096), the frequency of urinary retention 
as an adverse event occurred in 7.1% of patients in 
the 100 U BOTOX group and 0.5% of patients in 
the placebo group (refer to IB section 5.2.4.2 
Overactive Bladder).
Intradetrusor injection of BOTOX causes a 
detrusor muscle relaxation that leads to a decrease 
in the contractions of the detrusor muscle. This 
detrusor muscle relaxation may lead to an inability 
of the detrusor muscle to effectively contract 
during voiding in some patients thus causing a 
residual accumulation of urine in the bladder 
evident as an increased PVR volume, or may 
manifest as a patient’s inability to void due to 
urinary retention (refer to IB section 5.2.5 Clinical 
Safety in the published literature ).
Patients with potential risk for these events will be 
excluded fromo this study (refer to Protocol 
section 5.2 exclusion eriteria 22, 23 and 26 ) 
PVR urine volume will be assessed at each visit. 
Clean intermittent catheterization (CIC) and 
additional follow-up visit will be performed 
dependent on the PVR as well as subject's 
symptoms (refer to Protocol section 7.4.7.Post-
void residual urine volume and Appendix 5
Management guideline of PVR).
Pyelonephritis
In OAB clinical studies, pyelonephritis as an AE 
was also very uncommon and was reported as a
non-serious adverse event in one patient during 
placebo-controlled treatment cycle 1. However, 
based on the patient population who will be 
receiving instrumentation to deliver intradetrusor 
injections of BOTOX, and a potential temporary 
increase in PVR urine post treatment, mainly in 
Please refer to the mitigation strategy UTIs.

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the first 12 weeks, patients with bladder disorders 
with urinary incontinence who have a prior UTI 
may potentially progress from UTI to 
pyelonephritis.
Other
Use of the cystoscopy
It is possible that the cystoscopy required for the 
administration of the BOTOX injections could
result in perforation or tear anywhere along the 
urinary tract (urethra, bladder or ureter), urinary
obstruction due to temporary swelling of the 
urethra, urinary retention, temporary weakness of
the detrusor from bladder distention, bleeding, and 
infection (Su and Sosa, 2002). (refer to IB section 
6.1 Warnings and Precautions).
The investigators/subinvestigators will be required 
to complete the training for administration of 
investigational drug.
Regarding other risks associated with the treatment of GSK1358820, refer to the investigational brochure (General and Overactive bladder version) and the 
package insert.

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4.6.2.
Benefit Assessment
For OAB patients with urinary incontinence who do not have benefit by pharmacotherapy such as 
anticholinergic, the remaining treatment options are surgical interventions, etc. GSK1358820 is a 
promising drug to bridge the gap in the treatment algorithm between pharmacotherapy and surgical 
interventions, and has already been widely used for the treatment of OAB in the US, EU and other 
countries.
In overseas phase III studies conducted in OAB patients with urinary incontinence, who had not been 
adequately managed with anticholinergic therapy (Studies 191622-095 and 191622-520), Botox 100 U 
demonstrated improvement in OAB-related symptoms / parameters (such as frequency of urinary 
incontinence and volume voided per micturition) compared to placebo. Improvement in these 
symptoms / parameters with GSK1358820 is also expected in Study 204947.
Although Study 204947 is a placebo-controlled study, all subjects may be treated with GSK1358820 
since 100 U of GSK1358820 will be the treatment received if subjects satisfy the criteria for re-
treatment regardless of the treatment group they were randomized to for treatment 1.
4.6.3.
Overall Benefit: Risk Conclusion
Given the assessments to mitigate the risk to subjects enrolled in this study, the known potential risk 
of GSK1358820 is justified by the benefits that will be obtained to subjects with OAB.
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, and other 
pertinent information on the GSK investigational product that may impact subject eligibility is 
provided in the IB, product label, and other pertinent documents.
Deviations from inclusion and exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
NOTE: Verification at Screening and reconfirmation at the initiation of Treatment phase 1 (Week 0) 
are required, unless otherwise specified.
AGE
1.
Aged ≥20 years at the time of signing the informed consent
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Patient has symptoms of OAB (frequency and urgency) with urinary incontinence for a period of 
at least 6 months immediately prior to screening, determined by documented patient history
3.
Patient has not been adequately managed with one or more medications (i.e.: anticholinergics or 
beta-3 adrenergic receptor agonist) for treatment of their OAB symptom. Not adequately 
managed is defined as:
1）An inadequate response after at least a 4-week period of OAB medication(s) on an 
optimized dose(s)a, i.e., patient is still incontinent despite medication(s) for OAB, or

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2）Limiting side effects (i.e.: condition that subject reduced dosage or discontineued the 
medication due to side effect) after at least a 2-week period of OAB medication(s) on an 
optimized dose(s)a
4.
Patient who experiences all of the following, in the 3-day patient bladder diary completed during 
the screening phase
1）≥ 3 episodes of urinary urgency incontinence, with no more than one urgency incontinence-
free day
2）urinary frequency (defined as an average of ≥ 8 micturitions (toilet voids) per day, i.e., a 
total ≥ 24 micturitions)
5.
Patient is willing to use CIC to drain urine if it is determined to be necessary by the investigator 
(or subinvestigator)
a: approved dose for the indication of OAB in Japan.
6.
Body weight ≥40 kg at screening
SEX
7.
Males or females：

Male subjects with female partners of child bearing potential must comply with the following 
contraception requirements from the time of first dose of study medication until the study exit.
1）Vasectomy with documentation of azoospermia.
2）Male condom plus partner use of one of the contraceptive options below:

Intrauterine device or intrauterine system that meets the SOP effectiveness criteria 
including a <1% rate of failure per year, as stated in the product label [Hatcher, 2007]

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007]
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.

Female subject : is eligible to participate if she is not pregnant (as confirmed by a negative urine 
or serum human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the 
following conditions applies:
1）Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of 
bilateral tubal occlusion

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 

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one of the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal 
status prior to study enrolment.
2）Reproductive potential and agrees to follow one of the options listed below in the GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study 
medication and until the study exit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)*
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle 
or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long 
term and persistent basis.
1.
Intrauterine device or intrauterine system that meets the SOP effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Hatcher, 2007]
2.
Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007]
3.
Male partner sterilization with documentation of azoospermia prior to the female subject's entry 
into the study, and this male is the sole partner for that subject [Hatcher, 2007]
*: Contraceptive methods approved in Japan are shown
These allowed methods of contraception are only effective when used consistently, correctly and in 
accordance with the product label. The investigator is responsible for ensuring that subjects 
understand how to properly use these methods of contraception.
INFORMED CONSENT
8.
Patient has given signed informed consent, including compliance with the requirements and 
restrictions listed in the consent form and in this protocol (e.g., using the toilet without 
assistance, complete bladder diaries and questionnaires, is able to collect volume voided per 
micturition measurements over a 24-hour period, and attend all study visits in the opinion of the 
investigator(or subinvestigator)
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
NOTE: Verification at Screening and reconfirmation at the initiation of Treatment phase 1 (Week 0) 
are required, unless otherwise specified.
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER FUNCTION AND QTc 
INTERVAL)
1.
Patient has symptoms of OAB due to any known neurological reason (e.g., spinal cord injury, 
multiple sclerosis, cerebrovascular accident, Alzheimer’s disease, Parkinson’s disease, etc)
2.
Patient has a predominance of stress incontinence determined by patient history.
3.
Patient has a history or evidence of any diseases, functional abnormalities or bladder surgery, 
other than OAB, that may have affected bladder function including but not limited to:

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1）Bladder stones (including bladder stone surgery) within 6 months prior to screening or 
confirmed occurrence of bladder stones at the screening phase
2）Surgery (including minimally invasive surgery) within 1 year of screening for stress 
incontinence or pelvic organ prolapse
3）Current use of an electrostimulation / neuromodulation device for treatment of urinary 
incontinence. Note: Use of any implantable device is prohibited within 4 weeks prior to 
initiation of screening phase and throughout the study period. Use of any external device is 
prohibited within 7days prior to the start of the screening phase
4）History of interstitial cystitis, in the opinion of the investigator (or subinvestigator)
5）Past or current evidence of hematuria due to urological / renal pathology or uninvestigated 
hematuria b
6）Past or current history of bladder cancer or other urothelial malignancy, positive result of 
urine cytology or uninvestigated suspicious urine cytology results c at the Screening phase.
7）An active genital infection, other than genital warts, either concurrently or within 4 weeks 
prior to Screening
8）Male with previous or current diagnosis of prostate cancer or a prostate specific antigen 
(PSA) level of >10 ng/mL at Screening d
9）Evidence of urethral and/or bladder outlet obstruction, in the opinion of the investigator (or 
subinvestigator)
4.
Patient has a history of 2 or more urinary tract infections (UTIs) within 6 months of initiation of 
Treatment phase 1 (Week 0) or current administration of prophylactic antibiotics to prevent 
chronic UTIs
5.
Patient has a positive urine dipstick reagent strip test at initiation of Treatment phase 1 (Week 0) 
for nitrites or leukocyte esterase, or who are considered by the investigator (or subinvestigator) to 
have UTI
6.
Patient has a serum creatinine level >2 times the upper limit of normal (ULN) at screening
7.
ALT > 2xULN; and bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%) at screening
8.
Patient has current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator assessment)
NOTES:

Stable chronic liver disease should generally be defined by the absence of ascites, 
encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or 
persistent jaundice, or cirrhosis

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen (HBsAg) or 
positive hepatitis C antibody (HCVAb) test result within 3 months prior to first dose of 
study treatment) are acceptable if subject otherwise meets entry criteria
9.
QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block from the result of 
ECG at screening
Notes:

The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), 
Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read

The specific formula that will be used to determine eligibility and discontinuation for an 

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individual subject should be determined prior to initiation of the study. In other words, 
several different formulae cannot be used to calculate the QTc for an individual subject and 
then the lowest QTc value used to include or discontinue the subject from the trial
10. Patient has hemophilia or other clotting factor deficiencies or disorders that cause bleeding 
diathesis
b: Patients with investigated hematuria may enter the study if urological / renal pathology has been 
ruled out to the satisfaction by the investigator (or subinvestigator)
c: Suspicious urine cytology abnormalities required that bladder cancer or other urothelial malignancy 
has been ruled out to the satisfaction of the investigator according to local site practice
d: Patients with a PSA level of ≥ 4 ng/mL but ≤ 10 ng/mL must have prostate cancer ruled out to the 
satisfaction of the investigator (or subinvestigator) according to local site practice
CONCOMITANT MEDICATIONS
11. Patient receive anticholinergic, beta-3 adrenergic receptor agonist or any other medications or 
therapies to treat symptoms of OAB, including nocturia, within 7 days prior to the start of the 
screening phase
12. Patient has been treated with any intravesical pharmacologic agent (e.g., capsaicin, 
resiniferatoxin) for OAB symptoms within 12 months prior to initiation of Treatment phase 1 
(Week 0)
13. Patient has previous or current use of botulinum toxin therapy of any serotype for the treatment 
of any urological condition
14. Patient has previous use within 12 weeks prior to initiation of Treatment phase 1 (Week 0) or 
current use of botulinum toxin therapy of any serotype for any non-urological condition or 
beauty care
15. Patient has been immunized for botulinum toxin of any serotype
16. Patient cannot withhold any antiplatelet or anticoagulant therapy or medications with 
anticoagulative effects for 3 days e prior to initiation of Treatment phase 1 (Week 0)
17. Patient has not initiated appropriate antibiotic medication 1 to 3 days prior to the initiation of 
Treatment phase 1 (Week 0)
e: Some medications may need to be withheld for > 3 days, per clinical judgment of the investigator 
(or subinvestigator)
RELEVANT HABITS
18. Patient use CIC or indwelling catheter to manage their urinary incontinence
CONTRAINDICATIONS
19. Patient has a history of sensitivity to any of the study medications, medications used in the study 
(including anesthesia), or their components or a history of drug or other allergy that, in the 
opinion of the investigator or Medical Monitor, contraindicates their participation
20. Patient has any medical condition that may put them at increased risk with exposure to 
GSK1358820 including diagnosed myasthenia gravis, Eaton-Lambert syndrome, or amyotrophic 

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lateral sclerosis
21. Females who are pregnant, nursing or planning a pregnancy during the study
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
22. Patient has a PVR urine volume of >100 mL f at screening phase
23. Patient has had urinary retention or an elevated PVR urine volume g within 6 months of 
screening that has been treated with an intervention (such as catheterization)
24. Patient has a 24-hour total volume of urine voided >3000 mL of urine collected over 24 
consecutive hours during the 3-day bladder diary collection period in the Screening phase
25. Patient is currently participating in or has previously participated in another therapeutic study 
within 30 days prior to the start of the Screening phase
26. Patient has any condition or situation which, in the investigator’s (or subinvestigator’s) opinion, 
puts the patient at significant risk, may confound the study results, or may interfere significantly 
with the patient’s participation in the study
f: The PVR measurement can be repeated once; the patient is to be excluded if the repeated measure is 
above 100 mL
g: Voiding difficulties as a result of surgical procedures that resolved within 24 hours are not 
exclusionary
5.3.
Re-treatment Criteria
Patients can be considered for re-treatment beginning at the week 12 visit following the initial 
treatment or the week 12 visit following any re-treatment. The following re-treatment criteria must be 
used for the qualification of patient.
Qualification for re-treatment criteria:
1）Patient must have initiated request for re-treatment
2）Patient experienced ≥ 2 episodes of urinary urgency incontinence, with no more than one 
urgency incontinence-free day, as determined by the 3-day patient bladder diary completed 
in the week prior to the Qualification for Treatment visit
3）PVR urine volume must have been < 200 mL
4）Investigator deemed re-treatment appropriate and no condition or situation existed which, in 
the investigator’s opinion (or sub-investigator’s opinion), put the patient at significant risk 
from receiving a repeat treatment
Once these criteria are met, the patient who qualifies should be treated within 21 days of qualification, 
provided that all the following re-treatment criteria are met on the day of re-treatment.
Day of re-treatment criteria:
1）Central laboratory urine analysis for possible UTI using the sample collected at qualification 
for re-treatment visit had been reviewed by investigator (or sub-investigator)
2）Negative urine dipstick reagent strip test (for nitrites and leukocyte esterase) 
3）Patient was asymptomatic for a UTI, in the opinion of the investigator (or sub-investigator)

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4）Patient had discontinued any antiplatelet or anticoagulant therapy or medications with 
anticoagulative effects 3 days prior to re-treatment. Some medications may need to have 
been withheld for > 3 days per clinical judgment of the investigator (or sub-investigator)
5）Negative urine pregnancy test for women of childbearing potential. 
6）Patient had initiated appropriate antibiotic medication 1 to 3 days prior to re-treatment
7）No occurrence of bladder stones since entry into the study
8）A minimum of 12 weeks (84 days) must have elapsed since the previous treatment
9）Period after 1st treatment did not exceed 36 weeks
10）Investigator (or sub-investigator) continued to deem a repeat treatment was appropriate and 
no condition or situation existed which in the investigator’s opinion put the patient at 
significant risk from receiving a repeat treatment
5.4.
Screening Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but are never 
subsequently randomized. In order to ensure transparent reporting of screen failure subjects, meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse Events.
5.5.
Withdrawal/Stopping Criteria
If one of the following events 1) - 6) occurs in a subject, the investigator (or subinvestigator) should 
withdraw that subject from the study.
1）when the subject is lost to follow-up
2）when the subject wishes to withdraw from the study
3）when it is confirmed that the subject is pregnant
4）when the subject is found to meet the liver chemistry stopping criteria (referred to section 
5.5.1 Liver Chemistry Stopping Criteria)
5）when the subject is found to meet the stopping criteria regarding to QTc (referred to section 
5.5.2 QTc Stopping Criteria)
6）when the study is prematurely terminated for other reasons not directly related to the study
If one of the following events 7) - 11) occurs in a subject, the investigator (or subinvestigator) may 
withdraw that subject from the study in his / her judgement.
7）when it is difficult to continue the study due to an adverse event(s)
8）when a protocol deviation is found
9）when it is difficult to continue the study due to exacerbation of the primary disease or a 
complication
10）when subject needs to use prohibited medications / treatments
11）when the investigator (or subinvestigator) considers necessary to withdraw the subject from 
the study for other reasons

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The following actions must be taken in relation to a subject who fails to attend the clinic for a required 
study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit schedule 
and ascertain whether or not the subject wishes to and/or should continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and if necessary 
a certified letter to the subject’s last known mailing address or equivalent methods). These 
contact attempts should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”.
A subject may withdraw from study treatment at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or administrative 
reasons. If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.
5.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety 
guidance).
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin=2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’sLaw
ALT=3xULN
ALT
=8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value  n ot applicable to subjects on  anticoagulants 
ALT 
=3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT=3xULN and  Bilirubin=2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 12.2.

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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for 
ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in Appendix 12.2. 
5.5.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart after liver chemistry stopping criteria are met by any subject participating in 
this study is not allowed.
5.5.2.
QTc Stopping Criteria
A subject who meets either of the bulleted criteria below will be withdrawn from the study:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
Note:

The same QT correction formula must be used for each individual subject to determine eligibility 
for and discontinuation from the study.  This formula may not be changed or substituted once 
the subject has been enrolled.

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
For example, if a subject is eligible for the protocol based on QTcB, then QTcB must be 
used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the same 
formula must continue to be used for that subject for all QTc data being collected for data 
analysis.  Safety ECGs and other non-protocol specified ECGs are an exception.  
5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
6.1.1.
Investigational Product
The term ‘study treatment’ is used throughout the protocol to describe any combination of products 
received by the subject as per the protocol design. Study treatment may therefore refer to the 
individual study treatments or the combination of those study treatments.
Study Treatment
Investigational 
product name:
GSK1358820
(Non-proprietary name: botulinum toxin type A)
Placebo
Formulation 
description:
Botulinum toxin type A, 100 U
Sodium chloride, 0.9 mg
Human serum albumin, 0.5 mg
Sodium chloride, 0.9 mg
Dosage form:
Injections
Injections
Unit dose 
strength(s)
100 U
-
Route of 
administration:
Injecion into the detrusor muscle
Dosing 
instructions:
Under local anesthesia, via cystoscopyusing an injection needle for 
cystoscopy, inject into the detrusor musclevia  (0.5 mL evenly distributed 
into 20 sites, avoiding the trigone and bladder dome)
6.1.2.
Treatment Administration
6.1.2.1.
Antibiotics
Patients should begin prophylactic antibiotic therapy 1 to 3 days prior to administration of study
treatment, on the day of treatment and should continue for 1 to 3 days following the procedure.
Prophylactic antibiotic therapy should be initiated as close to 24 hours prior to the study treatment
injection as reasonably possible. For example, if the injection procedure is scheduled for the morning, 
the patient should begin antibiotic therapy the morning prior to the procedure.
All antibiotics that have been approved for the indication of UTIs may be used at the discretion of the 
investigator with the exceptions of those in the class of aminoglycosides (e.g.: amicin sulfate, 

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gentamycin sulfate, kanamycin, tobramycin, streptomycin). Patients requiring an aminoglycoside 
antibiotic during the trial must have any study treatment delayed until the aminoglycoside antibiotic 
therapy is completed. Use of aminoglycoside antibiotics should be avoided for 8 weeks after study 
treatment.
6.1.2.2.
Use of Anesthesia
The use of anesthesia during the treatment administration is determined by the investigator (or sub-
investigator). The following are permitted to facilitate the insertion of the cystoscope: 

Lubricating gel

Local anesthesia to the urethra: intraurethral lidocaine gel (or similar local anesthetic gel)
The following are the only anesthesia options that are permitted during treatment administration:

Local anesthesia to the bladder wall:
i)
instillation into the bladder of 1-2% lidocaine (or similar acting local anesthetic) prior 
to the procedure.
ii)
The instillation solution should remain in the bladder for at least 15 minutes in order to 
achieve sufficient anesthesia.
iii)
The bladder will then be drained of lidocaine, rinsed with saline and drained again.

Sedatives may also be administered according to local site practice if deemed medically 
necessary.
6.1.2.3.
Treatment Procedure
A flexible or rigid cystoscope may be used for study treatment administration. The bladder should be 
instilled with a sufficient amount of saline in order to achieve adequate visualization for the study 
injections.
The investigator (or subinvestigator) will prepare one 10 mL syringe pre-filled with 10 mL of study 
medication and one 1 mL syringe pre-filled with saline. The 10 mL of study drug will be administered 
as 20 injections each of 0.5 mL. Under direct cystoscopic visualization, injections should be 
distributed evenly across the detrusor wall and spaced approximately 1 cm apart. To avoid injecting 
the trigone and bladder dome the injections should be at least 1 cm above the trigone and 
approximately 3 cm below the dome. The injection needle should be inserted approximately 2 mm 
into the detrusor for each injection. For the final injection site, a sufficient amount of saline (from the 
1 mL syringe) will be flushed through the injection needle to deliver the small amount of study 
medication remaining in the needle. This will ensure that the entire volume of study medication is 
delivered to the patient.
After the injections are given, the saline used for visualization should not be drained from the bladder, 
so that patients may demonstrate their ability to void prior to leaving the clinic. Patients should remain 
in the clinic under observation for at least 30 minutes and until a spontaneous void has occurred. Prior 
to leaving the study clinic, patients will be instructed to contact the study site if they experience any 
adverse events post-treatment.

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Figure 1    Study medication injection
6.2.
Treatment Assignment
After completion of all screening / baseline assessments, subjects who satisfy the inclusion / exclusion 
criteria will be assigned a randomization number by the registration center, and assigned to a 
GSK1358820 100 U arm or a placebo arm. The assigned randomization number cannot be reassigned. 
The allocation table will be generated by a GSK computer using the RandAll system.
At the time of subject assignment, patients will be stratified according to the number of urinary urge
incontinence episodes (≤ 9 or ≥ 10 episodes), over the 3 consecutive days of bladder diary completion 
period.
The subjects who meet the criteria for re-treatment will enter Treatment period 2 and can receive the 
re-treatment (see section 5.3 Re-treatment Criteria). In the case of re-treatment, GSK1358820 100 U
will be injected to all subjects.
Other details will be provided in study reference manual (SRM).
6.2.1.
Re-registration of subject
If a subject is positive for nitrite or leukocyte esterase in urinalysis using a urine dipstick at initiation 
of Treatment phase 1 or an infectious disease is suggested, the subject should be withdrawn from the 
study and the screen failure should be resistered to the registration center. After appropriate tests /
treatments are performed (See section 7.4.6.2 Urinalysis) and urinalysis using a urine dipstick reveals 
that the subject is negative for bacterial infection, the subject may undergo a re-screening procedure. 
In addition, a re-screening procedure may be performed only once for when a medical monitor permits 
re-screening in cases such as imperfect entry in the bladder diary. The subject should be re-registered 
to the registration center when a re-screening procedure is started.
See SRM for procedures regarding failure / re-registration of subjects.

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6.3.
Blinding
This will be a study with double blind phase and follwing open-label phase. During the double blind 
phase, the following will apply.
Roles of Person Responsible for Allocation
The person responsible for allocation will prepare a procedure specifying the method of allocation of 
investigational products and perform its duties in accordance with this document. The person 
responsible for allocation will confirm the indistinguishability of study treatments (test drug and 
control drug) and their packages, and indicate the drug number on an investigational product container. 
The indistinguishability of study treatments (test drug and control drug) and their packages should be 
checked again after completion of the study. Furthermore, the person responsible for allocation will 
prepare a procedure for case of an emergency that knowledge of the study treatment is essential, and 
break the key code of only the treatment concerned, as per request.
Emergency Key Code Unblinding

The investigator or treating physician may unblind a subject’s treatment assignment only in the 
case of an emergency OR in the event of a serious medical condition when knowledge of the 
study treatment is essential for the appropriate clinical management or welfare of the subject as 
judged by the investigator. 

Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical Monitor or 
appropriate GSK study personnel to discuss options before unblinding the subject’s treatment 
assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must notify GSK as 
soon as possible after unblinding, but without revealing the treatment assignment of the
unblinded subject, unless that information is important for the safety of subjects currently in the 
study. 

The date and reason for the unblinding must be fully documented in the CRF

A subject will be withdrawn if the subject’s treatment code is unblinded by the investigator or 
treating physician. The primary reason for discontinuation (the event or condition which led to 
the unblinding) will be recorded in the CRF.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment 
assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report 
be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s 
treatment assignment, may be sent to investigators in accordance with local regulations and/or 
GSK policy.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory requirements.

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6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of investigational product, and
deactivation of used vial of investigational product and used materials for preparation / treatment of 
investigational product will be detailed in SRM.

Only subjects enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e. 
receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment are provided in 
the SRM.

Under normal conditions of handling and administration, study treatment is not expected to pose 
significant safety risks to site staff.  Take adequate precautions to avoid direct eye or skin 
contact and the generation of aerosols or mists. In the case of unintentional occupational 
exposure notify the monitor, Medical Monitor and/or GSK study contact.

Information describing occupational hazards and recommended handling precautions will be 
provided to the investigator, where this is required by local laws, or is available upon request 
from GSK.
6.6.
Compliance with Study Treatment Administration
GSK1358820 will be administered to the detrusor of subject at the site. Administration will be 
documented in the source documents and reported in the CRF.
6.7.
Treatment of Study Treatment Overdose
GSK does not recommend specific treatment for an overdose. Should accidental overdose be 
suspected, the patient should be medically monitored for up to several weeks for progressive signs or 
symptoms of systemic muscular weakness which could be local, or distant from the site of injection 
which may include ptosis, diplopia, dysphagia, dysarthria, generalized weakness or respiratory failure.
In the event of an overdose the investigator should:
1.
contact the Medical Monitor immediately
2.
closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) and 
laboratory abnormalities during the study. 
3.
document the quantity and the date of the excessive dose in the CRF.
Decisions regarding dose plan will be made by the investigator in consultation with the Medical 
Monitor based on the clinical evaluation of the subject.

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6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the study because the 
indication being studied is not life threatening or seriously debilitating and/or other treatment options 
are available.
The investigator is responsible for ensuring that consideration has been given to the post-study care of 
the subject’s medical condition, whether or not GSK is providing specific post-study treatment.
6.9.
Concomitant Medications and Non-Drug Therapies
Concomitant medications and non-drug therapies during the screening phase (within 28 days) and 
Treatment phase (48 weeks) is specified as follow.
6.9.1.
Permitted Medications and Non-Drug Therapies
Therapy considered necessary for the patient’s welfare can be given at the discretion of the 
investigator. In that event, patients are to maintain a stable dose during the study, whenever possible.
6.9.2.
Prohibited Medications and Non-Drug Therapies
Use of following medications or therapy is prohibited during the Screening phase, Treatment phase 
and given period by exclusion criteria.

Administration of botulinum toxin other than the study drug

Immunization to botulinum toxin

Treatment of symptoms of OAB including nocturia (anticholinergics, beta-3 adrenergic 
receptor agonist) or any other medications or therapies used for the treatment of symptoms 
of OAB

Intravesical pharmacologic agent for OAB symptom (e.g., capsaicin or resiniferatoxin)

Use of electrical stimulation and neuromodulation devices (implanted and external) for the 
treatment of OAB

Cholinesterase inhibitor for the treatment of urinary disturbance
The following medications are prohibited for a minimum of 3 days (or longer according to the clinical 
judgment of the investigator) prior to any study treatment and must not be recommenced until the day 
following treatment.

Anticoagulant medications (e.g., warfarin and other coumadin derivatives)

Antiplatelet medications (e.g., clopidogrel and aspirin [including low dose])

Any other medications with anticoagulative effects (e.g., non-steroidal anti-inflammatory 
drugs)
Note: Low molecular weight heparins (eg, enoxaparin) are permitted up to 24 hours prior to study 
drug treatment according to the clinical judgment.
Use of following medication is to be avoided for 8 weeks after study treatment. Patients requiring 
following medications during the trial are required to have any study treatment delayed until the 
following therapy is completed.

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
Aminoglycoside antibiotics

Curare-like agents (e.g., rocuronium)
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Time and 
Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The exact timing 
of each assessment is listed in the Time and Events Table Section 7.1.

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7.1.
Time and Events Table
Table 1    Time and Events Table (Screening to Treatment phase 1)
Screening
Treatment phase 1
All subjects
If subject was not re-treated
Withdrawal
Week (After 1st treatment)
Within 28 
days
0
2
6
12
18
24
30
36
42
48
(Study exit)
Window
3 d
7 d
7 d
7 d
7 d
7 d
7 d
7 d
7 d
Patient characteristics etc.
Informed consent
X
Medical history / demographics
X
Xa
Inclusion / exclusion criteria
X
Xa
Neutralizing antibody
Xl
X
X
Efficacy
Check of bladder diaryb
Xa
X
X
X
X
X
X
X
X
X
X
KHQ, OABSS
Xa
X
X
X
X
X
TBS
X
X
X
X
X
X
X
Safety
Adverse eventsc
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
Height, Weight
X
Xd
Xd
Vital signs
X
Xa
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
X
Clinical laboratory (hematology and blood chemistry)
X
X
X
X
HBsAg and HCVAb (for subjects who receive or plan 
to receive immunosuppressants)
X
Urinalysis (dipstick)
X
Xa
X
X
X
X
X
X
X
X
X
X
Urinalysis (clinical laboratory) / 
Urine culture / sensitivity e
X
Xa
X
X
X
X
X
X
X
X
X
X
PVR
Xf
X
X
X
X
X
X
X
X
X
X
Ultrasound (kidney / bladder)
X
X
X
X
Urine cytology
X
PSA (Only male)
X
Urine pregnancy test (Only females of 
reproductive potential)g
X
Xa
X
X
X
X
X
X
X
X
X
X
Investigational product
Treatment of antibiotich
X
Treatment of investigational product
X
Confirmation of qualification for re-treatment criteriai,j
X
X
X
X
X
Concomitant meds / therapies
Xk
X
X
X
X
X
X
X
X
X
X
X

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d = day (s)
(a) Performed prior to treatment
(b) Bladder diary must have been completed for any 3 consecutive days in the week prior to the visit (for screening phase only, it could have been completed for 3 consecutive
days at any time within 28 days). The volume voided is recorded by subjects for one 24-hour period during the 3 day diary collection period.
(c) Only serious adverse events assessed as related to study participation or GSK product will be recorded from the time when a subject consents.
(d) Measured only body weight
(e) Urine culture and sensitivity is performed by the central laboratory when urinalysis (dipstick) results were suggestive of a urinary tract infection
(f) Could be performed during the screening phase excluding diary data collection days
(g) If the result of urne pregnancy is suspicious, investigator (or sub-investigator) is able to conduct serum pregnancy test by central laboratory.
(h) First dose to be administered 1 (approximately 24 hours) to 3 days prior to study injection and continued for 1 to 3 days post injection (including the day of injection)
(i) If qualification for re-treatment criteria was met, the patient will undergo the exams specified in Table 2, column marked “If qualification for re-treatment criteria was met”. 
(j) Subjects who are not re-treated will remain in treatment phase 1 and continue to visit at the scheduled study visit.
(k) Patients must have stopped medication (i.e.: anticholinergic and beta-3 adrenergic receptor agonist indicated for patients with OAB, or other medications) or therapies for OAB for 
at least 7 days prior to start of screening procedures
(l) Samples may be colleced during the screening period through Day 1 (prior to randomization)

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Table 2    Time and Events Table [Treatment phase 1 (if qualification for re-treatment criteria was met) to treatment phase 2]
Treatment 
phase 1
Treatment phase 2
Week
If 
qualification 
for re-
treatment 
criteria was 
met
(Within 
21days prior 
to re-
treatment)
1st re-
treatment
Re-treatment (1st)
2nd re-
treatment
Re-treatment (2nd)
With
drawa
l
2
6
12
18a
24a
30a
Study exit 
(48 weeks 
after 1st 
treatment)
If 
qualification 
for re-
treatment 
criteria was 
met
(Within 
21days prior 
to re-
treatment)
2
6
12a
18a
Study exit 
(48 weeks 
after 1st 
treatment)
Window
0
3 d
7 d
7 d
7 d
7 d
7 d
7 d
0
3 d 7 d 7 d 7 d
7 d
Patient characteristics etc.
Neutralizing antibody
X
X
X
Efficacy
Check of bladder diaryb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
KHQ, OABSS
X
X
X
X
X
X
X
X
TBS
X
X
X
X
X
X
X
X
X
X
X
X
Safety
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
Height, Weight
Xc
Xc
Xc
Xc
Xc
Vital signs
X
Xd
X
X
X
X
X
X
X
X
Xd
X
X
X
X
X
X
ECG
Xe
X
X
Xe
X
X
X
Clinical laboratory 
(hematology and blood 
chemistry)
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
Xd
X
X
X
X
X
X
X
X
Xd
X
X
X
X
X
X
Urinalysis (clinical 
laboratory) / Urine 
culture / sensitivity f
X
Xd
X
X
X
X
X
X
X
X
Xd
X
X
X
X
X
X
PVR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ultrasound 
(kidney/bladder)
Xe
X
X
Xe
X
X
X
Pregnancy test (Only 
females of reproductive 
potential)g
X
Xd
X
X
X
X
X
X
X
X
Xd
X
X
X
X
X
X

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Treatment 
phase 1
Treatment phase 2
Week
If 
qualification 
for re-
treatment 
criteria was 
met
(Within 
21days prior 
to re-
treatment)
1st re-
treatment
Re-treatment (1st)
2nd re-
treatment
Re-treatment (2nd)
With
drawa
l
2
6
12
18a
24a
30a
Study exit 
(48 weeks 
after 1st 
treatment)
If 
qualification 
for re-
treatment 
criteria was 
met
(Within 
21days prior 
to re-
treatment)
2
6
12a
18a
Study exit 
(48 weeks 
after 1st 
treatment)
Window
0
3 d
7 d
7 d
7 d
7 d
7 d
7 d
0
3 d 7 d 7 d 7 d
7 d
Investigational product
Treatment of antibiotich
X
X
Confirmation of day of 
re-treatment criteriai
X
X
Treatment of 
investigational product
Xj
Xj
Confirmation of 
qualification for 
re-treatment criteriai,k
X
X
X
Concomitant 
meds / therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
d = day (s)
(a) Visit should not have occurred later than 48 weeks after 1st treatment. At 48 weeks after 1st treatment, study exit visit will be conducted.
(b) Bladder diary must have been completed for any 3 consecutive days in the week prior to the visit. The volume voided is recorded by subjects for one 24-hour period during the 3 day 
diary collection period.
(c) Measured only body weight
(d) Performed prior to treatment
(e) These examination can be completed at the Qualification for re-treatment visit or at any time prior to re-treatment
(f) Urine culture and sensitivity is performed by the central laboratory when urinalysis (dipstick) results were suggestive of a urinary tract infection
(g) If the result of urne pregnancy is suspicious, investigator (or sub-investigator) is able to conduct serum pregnancy test by central laboratory.
(h) First dose to be administered 1 (approximately 24 hours) to 3 days prior to study injection and continued for 1 to 3 days post injection (including the day of injection)
(i) Subjects who are not retreated will continue to visit at the scheduled study visit.
(j)Re-treatment must be ocuured after a minimum of 12 weeks (84 days) have elapsed since the previous treatment Re-treatment should not have occurred later than 36 weeks after 1st 
treatment 
(k) If qualification for re-treatment criteria was met, the patient will undergo the exams specified in Table 2, column marked “If qualification for re-treatment criteria was met” 

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7.2.
Screening and Critical Baseline Assessments
Following information should be collected from each subjectand entered in the CRF. 
Screening phase: within 28 days of the initiation of Treatment phase 1

Demographics: birth year, sex, race and ethnicity

Height, body weight

Medical history, complications

Cardiovascular history / risk factors (detailed in the CRF)

Duration of OAB

History of OAB medication/reason for OAB medication not considered to be adequately 
managed with the symptom (such as adverse drug reactions, insufficient efficacy)
Initiation of Treatment phase 1

Bladder diary

King's Health Questionnaire (KHQ)

Overactive Bladder Symptom Score (OABSS)
7.3.
Efficacy
7.3.1.
Methods of assessments
7.3.1.1.
Bladder diary
The subjects will be instructed to enter data on the bladder diary over 3 consecutive days as specified 
below. When receiving the diary, the subjects will be instructed and trained on the use of the diary and 
the data to be collected (See SRM and bladder diary). The subjects are instructed to bring their diary 
to each clinic visit. The diary data will also be used to satisfy eligibility requirements for study entry 
as well as to qualify the subject for re-treatment. The bladder diary will be treated as a source 
document and archived with the medical record. The staff involved in the study at the study site will 
send the copy of bladder diary to the sponsor after confirming that no personal information is contain 
in the diary (see SRM for method of forwarding).
[Period to enter data in the bladder diary]

Screening phase: Enter data on the bladder diary over 3 consecutive days during the screening 
phase within 28 days prior to Treatment phase 1. However, the day of initiation of Treatment 
phase 1 (week 0) should not be included in the data-entry period.

Treatment phase 1 and Treatment phase 2: Enter data on the bladder diary over 3 consecutive 
days within a week prior to each scheduled visit. However, the day of scheduled visit should not 
be included in the data-entry period.
The diary will capture the following information:

Date and time of urinary episode (including urinary incontinence) 

Episodes of micturition (toilet voids)

Episodes of urinary incontinencea

Episodes of urgency

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
Intensity of urgency
In answer to the question “how would you rate your need to urinate (urgency)?” in the bladder 
diary, the subjects will be asked to select one of the following 4 options:
0 – No urgency. I felt no need to empty my bladder, but did so for other reasons.
1 – Mild urgency. I could postpone urinating as long as necessary without fear of wetting 
myself.
2 – Moderate Urgency. I could postpone urinating for a short while without fear of wetting 
myself.
3 – Severe Urgency. I could not postpone urinating, but had to rush to the toilet in order not to 
wet myself.

Episodes of nocturia (voids that interrupt night sleep)

Use of CIC

Urine volume
The total volume voided will be measured and recorded by subjects over one 24-hour period 
during the 3-day bladder diary collection period (urine volume of urinary incontinence will not 
be measured and recorded). To perform this measurement, urine collection containers provided 
by the sponsor will be used. The volume voided per micturitionb will be determined by the 
sponsor from the total urine volume measured by the subjects divided by the number of 
micturitions (excluding urinary incontinence episode).
If a subject has symptoms of a urinary tract infection, the diary data will not be collected during this 
period because the data may have influence on the bladder diary data.
a: used for evaluation of primary endpoint (Change from baseline in the daily average number of 
urinary incontinence episodes a at week 12 after the first treatment)
b: used for evaluation of major secondary endpoint (Change from baseline in the average volume 
voided per micturition at week 12 after the first treatment)
7.3.1.2.
Health outcome questionnaires
The subject's perception of the level of impairment in work and other regular daily activities, etc.
associated with the symptoms of OAB with urinary incontinence will be assessed using patient-
completed questionnaires as specified below. Questionnaires should be administered in accordance 
with the study schedule and prior to study treatment on initiation of Treatment phase 1 (week 0). The 
investigators / subinvestigators or the persons assisting with the trial will ensure that the subjects 
answer all the questions. The questionnaires will be treated as source documents and archived with the 
medical record.
7.3.1.2.1.
King’s Health Questionnaire (KHQ)
Impact of urinary incontinence on QOL will be assessed using KHQ in accordance with the study 
schedule.

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KHQ was developed by Kelleher et al. as questionnaire to assess impact of urinary incontinence on 
QOL. [Kelleher, 1997] The KHQ was translated into Japanese by Honma et al., and its 
appropriateness was verified in Japanese patients with urinary incontinence. [Honma, 1999; Honma, 
2002]
KHQ is a questionnaire with 21 items and consisted by 9 domains: (i) General health, (ii) Incontinence 
impact, (iii) Role Limitations, (iv) Physical limitations, (v) Social limitations, (vi) Personal 
relationships, (vii) Emotion, (viii) Sleep/energy, (ix) Severity measure. The scores are summated 
according to an algorithm provided by Kelleher et al. [Kelleher, 1997]
Investigators/subinvestigators or the persons assisting with the trial will provide a KHO questionnaire 
and instruct subjects to select the one most appropriate answer for each question.
7.3.1.2.2.
Overactive Bladder Symptom Score (OABSS)
Symptoms of frequency, nocturia, urinary urgency, and urge incontinence will be assessed with 
OABSS in accordance with the study schedule.
OABSS was developed by Honma et al. as questionnaire to comprehensively assess OAB symptoms, 
and its appropriateness was verified in Japanese OAB patients. [The Japanese Continence Society, 
2005; Honma, 2006]
Investigators/sub-investigators or the persons assisting with the trial will provide an OABSS 
questionnaire including 4 questions for subjects and instruct subjects to select the one most 
appropriate answer for each question.
7.3.1.2.3.
Treatment Benefit Scale (TBS)
Treatment benefit of GSK1358820 will be assessed with TBS in accordance with the study schedule.
TBS was developed by Colman et al. as questionnaire for a patient-based treatment benefit assessment 
for OAB, and its appropriateness was verified in OAB patients. [Colman, 2008]
Investigators/sub-investigators or the persons assisting with the trial will provide a questionnaire 
including 1 question on TBS for subjects and instruct subjects to select the one most appropriate 
answer for each question.
Answer the following question after considering your present symptoms (issues of the urinary system, 
urine incontinence ) in comparison with those before treatments in this study.
In the course of the treatment, my symptoms is:
1.
greatly improved
2.
improved
3.
not changed
4.
worsened
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table (Section 7.1.).  
Additional time points for safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.

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7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and their designees are responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs will be collected from the start of Study Treatment until the study exit (see Section7.4.1.3), 
at the timepoints specified in the Time and Events Table (Section 7.1.).

Medical occurrences that begin prior to the start of study treatment but after obtaining informed 
consent may be recorded on the Medical History/Current Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be recorded from 
the time a subject consents to participate in the study up to study exit.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study subjects. However, 
if the investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK are provided in Appendix 3.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about AE occurrence.  
Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in Section
4.6.1.) will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.5.). Further information on 
follow-up procedures is given in Appendix 3.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden cardiac 
death) and non-cardiovascular death. 

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The CV CRFs are presented as queries in response to reporting of certain CV MedDRA terms. The 
CV information should be recorded in the specific cardiovascular section of the CRF within one week 
of receipt of a CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is reported. Initial 
and follow-up reports regarding death must be completed within one week of when the death is 
reported.
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even for non-
interventional post-marketing studies) is essential so that legal obligations and ethical responsibilities 
towards the safety of subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. GSK will comply with country 
specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according 
to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and if indicated female partners of male subjects 
will be collected after the start of dosing and until the study exit.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of 
the pregnancy and should follow the procedures outlined in Appendix 4.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the Cardiovascular, 
Respiratory, Gastrointestinal and Neurological systems. Height and weight will also be measured 
and recorded.

Investigators (or subinvestigator) should pay special attention to clinical signs related to previous 
serious illnesses
7.4.4.
Vital Signs
Temperature, systolic and diastolic blood pressure and pulse rate will be measured in seated position 
after 5 minutes rest.
7.4.5.
Electrocardiogram (ECG)
Single 12-lead ECGs will be obtained at each timepoint during the study using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS and QT. The QTc value is machine-read 
or manually over-read. If Qtc is prolonged, QTc should be based on averaged QTc values of triplicate 

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electrocardiograms which are evaluated same day. Refer to Section 5.2 for exclusion criteria and 
Section 5.5.2 for QTc withdrawal criteria.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in accordance 
with the Laboratory Manual, and Protocol Time and Events Schedule. Laboratory requisition forms 
must be completed and samples must be clearly labelled with the subject number, protocol number, 
site/centre number, and visit date. Details for the preparation and shipment of samples will be 
provided by the laboratory and are detailed in the SRM OR the laboratory manual. Reference ranges 
for all safety parameters will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in subject management or are considered clinically significant by the 
investigator (e.g., SAE or AE or dose modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate and/or 
additional blood draws. 
Table 3    Laboratory Assessments
Hematology
Platelet, RBC, WBC, Hemoglobin, Hematocrit, RBC morphology
Differential WBC count：Neutrophil, Band, Lymphocyte, Monocyte, Eosinophil, 
Basophil,
Chemistry1
Bun, Creatinine, Glucose, Potassium, Sodium, Calcium, Chloride, AST (SGOT), ALT 
(SGPT), Alkaline phosphatise, Uric acid, Total bilirubin and direct bilirubin, Total 
protein, Albumin
Routine 
Urinalysis

Urine dipstick reagent strip tests: nitrite, leukocyte esterase

Urine analysis: appearance, color, pH, specific gravity, ketones, protein, 
glucose, nitrite, leukocyte esterase, urobilinogen, occult blood, microscopic 
sediment (WBCs, RBCs, casts, bacteria, and crystals)

Urine culture and sensitivity (if UTI is suggested)
Other Screening 
Tests

HBsAg and HCVAb : for subjects who receive or plan to receive 
immunosuppressants at screening

Urine or serum hCG pregnancy test (only women of childbearing potential)
1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after 
liver stopping or monitoring event are given in Section 5.5.1 and Appendix 2.
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline. If such 
values do not return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
7.4.6.1.
Hematology and chemistry
Hematologic and chemistry evaluations will be centrally performed at the central laboratory.

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7.4.6.2.
Urinalysis
7.4.6.2.1.
Urinalysis using a urine reagent strip
Urine samples will be obtained at all study visits and a urine analysis with a urine reagent strip will be 
performed at each study site. If post-void residual (PVR) urine volume at scheduled visits is ≥ 200 mL 
and an additional follow-up visit occurs 1 week later, a urine analysis with a urine reagent strip will be 
performed (see 7.4.7 Post-void Residual (PVR) Urine Volume).
A urine analysis with a urine reagent strip will be performed to evaluate subjects for the possibility of 
urinary tract infection, in which the investigators/subinvestigators can receive the analysis results 
immediately (see 7.4.6.2.2 Urinalysis, culture and sensitivity for the definition of AE urinary tract 
infection). If the results of the urine analysis with a urine reagent strip suggest urinary tract infection
(i.e.: positive nitrites or leukocyte esterase), treatment with antibiotics can be administered in the 
opinion of the investigators/subinvestigators. If the urinary tract infection is suggested, in addition to 
samples necessary for urinalysis which is performed at all study visit, samples for urine culture and 
sensitivity test must be sent to the central laboratory.

Screening period
If a urine analysis with a urine reagent strip is positive for nitrites or leukocyte esterase or bacterial 
infection is confirmed by urinalysis, urine culture and sensitivity test at the central laboratory (with the 
presence of bacteriuria with 105 CFU [colony forming unit] per mL or more and leukocyturia with 
more than 5 per high power field), treatment with antibiotics will be administered in the opinion of the 
investigators/subinvestigators.

Initiation of Treatment phase 1 (Week 0)
If a urine analysis with a urine reagent strip at initiation of treatment phase 1 (Week 0) is positive for 
nitrites or leukocyte esterase, or bacterial infection is confirmed by urinalysis, urine culture and 
sensitivity test at the central laboratory, treatment with antibiotics will be administered in the opinion 
of the investigators/subinvestigators. The subjects may return for a rescheduled initiation of treatment 
phase 1 (Week 0) and be treated once a dipstick confirms a negative result for infection and criteria 
are fulfilled (see 5.1 Inclusion Criteria and 5.2 Exclusion Criteria).

At the time of reinjection
If a urine analysis with a urine reagent strip at the time of reinjection is positive for nitrites or 
leukocyte esterase, or bacterial infection is confirmed by urinarysis, urine culture and sensitivity test at 
the central laboratory, treatment with antibiotics will be administered in the opinion of the 
investigators/subinvestigators. In this case, if a subsequent urine analysis with a urine reagent strip 
confirms negativity for bacterial infection, the subjects who meet the criteria for reinjection are 
allowed to receive reinjection (see 5.3 Re-treatment Criteria).

At a visit after the injection of the investigational drug
If a urine analysis with a urine reagent strip at a visit after the injection of the investigational drug is 
positive for nitrites or leukocyte esterase, or bacterial infection is confirmed by urinalysis, urine 
culture and sensitivity test at the central laboratory, treatment with antibiotics will be administered in 
the opinion of the investigators/subinvestigators.

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7.4.6.2.2.
Urinalysis, Culture and Sensitivity
Urinalysis, culture and sensitivity will be centrally performed at the central laboratory.A urine culture 
and sensitivity test will be performed when urinalysis results with a urine reagent strip are suggestive 
of a UTI (positive nitrites or leukocyte esterase) (see below for the definition of AE urinary tract 
infection).
If PVR at scheduled visits is ≥ 200 mL and an additional follow-up visit occurs 1 week later, 
urinalysis, urine culture and sensitivity test at the central laboratory will be performed (see 7.4.7 Post-
void residual (PVR) urine volume).

Definition of AE urinary tract infection
If both of the following criteria are fulfilled, urinary tract infection is recorded as an adverse event, 
irrespective of symptoms:
1）The result of urine culture is positive (with the presence of bacteriuria with 105 CFU/mL)
2）Leukocyturia with  > 5 per high power field is noted.
If subjects report urinary tract infection, which is diagnosed by a physician at a medical institution 
other than study sites (i.e., a family doctor or critical care physician), the results of urinalysis, urine 
culture, and sensitivity test should be obtained as far as possible.
7.4.6.2.3.
Urinary cytology
Urinary cytology will be performed at screening period.
Urinary cytology will be centrally performed at the central laboratory.
7.4.6.3.
Prostate-specific antigen
In male subjects, the level of prostate specific antigen (PSA) will be measured at screening period.
Measurement of PSA will be centrally performed at the central laboratory.
7.4.6.4.
Pregnancy test
Urine pregnancy test will be performed in female subjects of childbearing potential according to the 
study schedule. In addition, pregnancy test is not required for female subjects of non-childbearing 
potential. Female subjects of non-childbearing potential are defined as postmenopausal women 
(women 12 months or more after menopause) or women who have undergone hysterectomy or 
bilateral oophorectomy. The test will be performed at each study site. Subjects are not allowed to 
receive the injection of the investigational drug, unless the tests at the start of treatment period 1 or at 
the time of reinjection are negative. If the result of urne pregnancy is suspicious, investigator (or sub-
investigator) is able to conduct serum pregnancy test by central laboratory.
7.4.7.
Post-void residual (PVR) urine volume
PVR urine volume will be assessed by ultrasound or bladder scan after subjects perform a voluntary 
void according to the study schedule. PVR urine volume can be assessed at any other time depending 
on clinical need. PVR measurements will not be done by catheterization.

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Should a PVR urine volume indicate a clinically meaningful elevation, subjects should be asked to 
void once again (allowing the subjects sufficient time to void) and the PVR urine volume will then be 
reassessed. For subjects who have a PVR urine volume measurement repeated, only the repeat value 
should be recorded in the case report form (CRF).
If increased PVR is noted at a scheduled visit or at an unscheduled visit, proper procedures should be 
conducted according to the Guidance about the Management of PVR Urine Volume (Appendix 5). 
The details of the Guidance about the Management of PVR Urine Volume are described below. Post-
treatment PVR is divided into 3 categories:

< 200 mL

≥ 200 mL and < 350 mL

≥ 350 mL
The need for an additional assessment visit is assessed based on the PVR category mentioned above. 
The need for clean intermittent catheterization (CIC) is also dependent on the PVR as well as subject's 
symptoms. The objective of the guidance is to ensure that subjects are appropriately followed up and 
CIC is only initiated when required (while also ensuring that any unnecessary intervention is limited). 
However, the guidance does not preclude further actions if the investigators/subinvestigators deem the 
actions to be necessary.
The details are as follows:
1.
PVR < 200 mL
No protocol required action needs to be taken. Subjects will continue to be assessed as per the 
schedule of visits and procedures.
2.
PVR ≥ 200 mL and < 350 mL
If a PVR of ≥ 200 mL but < 350 mL is identified at any post-treatment visit, the 
investigators/subinvestigators will assess the subject for any spontaneously reported associated 
symptoms (such as voiding difficulties or sensation of bladder fullness), with the resulting action to be 
as follows:
a.
If a subject reports associated symptoms that in the opinion of the investigators/subinvestigators 
require CIC to be initiated, then CIC should be initiated and managed according to the Guidance 
about the Management of PVR Urine Volume.
b.
If a subject does not report any associated symptoms or if they report associated symptoms that, 
in the opinion of the investigators/subinvestigators, do not require CIC, the subject will be seen at 
an additional visit 1 week later, when the PVR and any associated symptoms will be reassessed. 
In addition, a urine analysis with a urine reagent strip as well as urinalysis, urine culture and 
sensitivity test at the central laboratory will be performed. Based on the test results at this visit, 
the following procedures will be conducted:
1）If the PVR is increasing and is associated with symptoms, that in the opinion of the 
investigators/subinvestigators require CIC, then CIC should be initiated and managed 
according to the Guidance about the Management of PVR Urine Volume.
2）If the PVR is ≥ 350 mL then CIC should be initiated and managed according to the 
Guidance about the Management of PVR Urine Volume.

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3）If the PVR is increasing but is not associated with symptoms or is associated with symptoms 
that in the opinion of the investigators/subinvestigators do not require CIC, then the subject 
will be seen 1 week later to determine if CIC has become warranted based on PVR and/or 
any associated symptoms. The following procedures will be conducted at this additional 
visit:

A urine reagent strip, and urinalysis, urine culture and sensitivity test at the central 
laboratory will be collected.

If the investigators/subinvestigators judge that CIC should be initiated, then CIC 
should be initiated and managed according to the Guidance about the Management of 
PVR Urine Volume.

If CIC is not initiated and PVR continues to increase, the 
investigators/subinvestigators will determine whether the subject will be followed at 
regularly scheduled study visits or whether additional visits should occur.
4）If the PVR is decreasing or is unchanged then the subject will continue to be assessed per 
the schedule of visits and procedures
3.
PVR ≥ 350 mL
If a PVR of ≥ 350 mL is identified at any post-treatment visit (regardless of symptoms) then CIC will 
be initiated according to the Guidance about the Management of PVR Urine Volume.
Clean intermittent catheterization (CIC)
The following guidance should be used for the initiation and cessation of CIC in this study. Sterile, 
single-use intermittent catheters should be used. Indwelling catheters should not be used in this study 
and therefore, investigator (or sub-investigator) should discuss with medical monitors from the 
sponsor if an indwelling catheter is necessary.
Whether CIC is performed or not and, if CIC is performed, the dates of the initiation and completion 
of CIC and the reasons for CIC should be recorded in the CRF.
Initiation of CIC
CIC should only be initiated when one of the following criteria is fulfilled:

PVR is ≥ 350 mL at any post treatment visit, regardless of reports of associated symptoms by 
subjects; or

PVR is ≥ 200 mL and < 350 mL and the subject spontaneously reports associated symptoms 
(e.g., voiding difficulties and sensation of bladder fullness) that in the opinion of the 
investigators/subinvestigators require CIC.
The following will occur when initiating CIC:
1）CIC should be performed using sterile, single-use catheters.
2）An adverse event of urinary retention should be recorded.
3）A urine analysis with a urine reagent strip as well as urinalysis, urine culture and sensitivity 
test at the central laboratory should be performed. In addition, these tests and analyses will 
be performed at scheduled visits after CIC is initiated.
4）The subject should be seen at a follow-up visit 1 week later, when the results of PVR 
measurement, associated symptoms, and a urine analysis with a urine reagent strip are 

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reassessed while urinalysis, urine culture and sensitivity test are performed for reassessment 
at the central laboratory. The investigators/subinvestigators will determine whether the 
subject should then be followed at regularly scheduled study visits or whether additional 
visits should occur.
Cessation of CIC
CIC should only be discontinued when both of the following criteria are fulfilled:

The subject does not have any associated symptoms which in the opinion of the 
investigators/subinvestigators require CIC; and

The PVR is < 350 mL.
Upon discontinuing CIC, the subject will be seen at a follow-up visit 1 week later, when the results of 
PVR measurement, associated symptoms, and a urine analysis with a urine reagent strip are reassessed 
while urinalysis, urine culture and sensitivity test are performed for reassessment at the central 
laboratory. The investigators/subinvestigators will determine whether the subject can then be followed 
at regularly scheduled study visits or whether additional visits should occur based on PVR and/or 
associated symptoms.
Definition of AE urinary retention
An adverse event of urinary retention should only be recorded according to the following criteria 
when a subject has a raised PVR that requires protocol-specified intervention with CIC:

Subject has a PVR of ≥ 350 mL (regardless of symptoms); or

Subject has a PVR ≥ 200 mL and < 350 mL and the subject reports associated symptoms (e.g., 
voiding difficulties and sensation of bladder fullness) that in the opinion of the 
investigators/subinvestigators require CIC.
Definition of AE residual urine volume increased
An adverse event of residual urine volume increased should be recorded if, in the opinion of the 
investigators/subinvestigators, the raised PVR is clinically significant but does not fulfill the above 
definition for urinary retention.
7.4.8.
Kidney and bladder ultrasound
The kidney and bladder ultrasound study will be performed according to the study schedule. In order 
to assess the presence of stones in the kidneys and bladder, an ultrasound of these structures (with the 
bladder at least half full) will be performed.
Subjects will be excluded from this study if the screening ultrasound demonstrates the presence of 
bladder stones. In the case of unclear findings in an ultrasound study, other diagnostic measures (e.g., 
x-ray) may be required in order to confirm the presence of bladder stones. If a stone is detected in 
subjects after the injection of the investigational product, the event must be recorded as an adverse 
event in the CRF. Subjects developing stones while on study should be followed and treated according 
to the standard procedure at each study site.

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7.5.
Other endpoints
7.5.1.
Immunogenicity Testing
The investigators/subinvestigators will collect blood samples for neutralizing antibody testing 
according to the study schedule. Immunogenicity testing will be centrally performed at the central 
laboratory to which GSK outsources the analysis (Intertek Pharmaceutical Services and Pacific 
BioLabs).The samples will be stored at the central laboratory and sent to a laboratory in USA (Intertek 
Pharmaceutical Services) when samples in the screening period are collected from all subjects. At the 
laboratory, screening test will be performed to measure binding antibody (BaB). Positive BaB samples, 
determined based on the result of the measurement, will be sent to USA (Pacific BioLabs) separately, 
where a further test for definitive neutralizing antibody (NaB) positivity is performed. Similarly, when 
samples at the end of the study are collected from all subjects, immunogenicity testing will be 
performed according to the above-mentioned procedures.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to 
GSK or designee and combined with data provided from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable GSK standards and 
data cleaning procedures to ensure the integrity of the data, e.g., removing errors and 
inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA (Medical 
Dictionary for Regulatory Activities) and an internal validated medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the 
investigator to maintain as the investigator copy.  Subject initials will not be collected or 
transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES
9.1.
Hypotheses
The primary objective of this study is to evaluate the superiority of a single dose treatment of 
GSK1358820 100 U compared with placebo. The primary efficacy endpoint is the change from 
baseline in the daily average number of urinary incontinence episodes at week 12 after the first 
treatment. The major secondary efficacy endpoint is the change from baseline in the average volume 
voided per micturition at week 12 after the first treatment.
The primary null hypothesis is that there is no difference in the change from baseline of the daily 
average number of urinary incontinence episodes when treated with GSK1358820 compared to 
placebo. The primary two-sided alternative hypothesis is that there is a difference between two 
treatment groups.
The secondary null hypothesis is that there is no difference in the change from baseline of the average 
volume voided per micturition when treated with GSK1358820 compared to placebo. The secondary 
two-sided alternative hypothesis is that there is a difference between two treatment groups.

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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The samples size for this study is hypothesized based on the observed treatment difference in the 
change from baseline of the daily average number of urinary incontinence episodes and the average 
volume voided per micturition at Week 12 from the integrated data of studies 191622-095/191622-520. 
It is assumed that the mean differences in the daily average number of urinary incontinence episodes 
and the average volume voided per micturition between GSK1358820 and placebo are -1.79 
episodes/day and 30 mL from these studies results. Using the two sample t-test, 240 subjects in total 
(120 subjects for each treatment group) is required to achieve at least 89% power at the two-sided 
significance level of 5% to detect the assumed treatment differences for the daily average number of 
urinary incontinence episodes and the average volume voided per micturition simultaneously when 
common standard deviations (SD) are 3.5 episodes/day in the daily average number of urinary 
incontinence episodes and 70 mL in the average volume voided per micturition. This power is 
calculated by using power of each endpoint and Bonfferoni inequality. Using above assumed values, 
power is 98% for the daily average number of urinary incontinence episodes and 91% for the average 
volume voided per micturition at the two-sided significance level of 5%. In this case, joint power is 
expected at least 89% (=98 + 91 -100) calculated by Bonfferoni inequality.
The minimum detectable effect (i.e., the smallest observed effect size that could be statistically 
significant) based on the two sample t-test is a -0.9 episodes/day in the daily average number of 
urinary incontinence episodes and a 17.8mL in the average volume voided per micturition, 
respectively, when common standard deviations are 3.5 episodes/day in the daily average number of 
urinary incontinence episodes and 70 mL in the average volume voided per micturition.
9.2.2.
Sample Size Sensitivity
In order to check sample size sensitivity, power of this study is calculated with a sample size of 120 
subjects per treatment group in the following cases.
The mean difference of the daily average number of urinary incontinence episodes at week 12 
between GSK1358820 and placebo of -1.69 to -1.89 episodes/day, and SD of 3 to 4 episodes/day 
under the condition that the mean difference and SD of the average volume voided per micturition is 
fixed as 30 mL and 70 mL (Table 4)
The mean difference of the average volume voided per micturition at week 12 between GSK1358820 
and placebo of 25 to 35 mL, and SD of 60 to 80 mL under the condition that the mean difference and 
SD of the daily average number of urinary incontinence episodes is fixed as -1.79 episodes/day and 
3.5 episodes/day (Table 5)
Table 4    Power of this study under the condition of fixed mean difference and SD of 
the average volume voided per micturition
Mean difference of the daily average 
number of urinary incontinence episodes 
between GSK1358820 and placebo
SD of the daily average number of urinary incontinence episodes between 
GSK1358820 and placebo
3.0
3.5
4.0
-1.69
90%
88%
82%
-1.79
91%
89%
85%
-1.89
91%
90%
87%

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Table 5    Power of this study under the condition of fixed mean difference and SD of 
the daily average number of urinary incontinence episodes
Mean difference of the average volume 
voided per micturition between 
GSK1358820 and placebo
SD of the average volume voided per micturition between GSK1358820 
and placebo
60
70
80
25
87%
77%
66%
30
95%
89%
81%
35
97%
95%
90%
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
In this study, the subjects are permitted to receive re-treatment up to 2 times. When analyzing the 2nd 
treatment cycle, the population will be consist of the subjects who had a 1st and 2nd treatment. When 
analyzing the 3rd treatment cycle, the population will be consist of the subjects who had a 1st, 2nd and 
3rd treatment.
Full Analysis Set (FAS)
The FAS will be defined as all randomized subjects who have at least 1 post-baseline efficacy 
assessment. The FAS will be the primary population for all the efficacy analyses. The subjects will be 
analyzed according to the treatment group to which they were randomized.
Safety
The Safety Population will be defined as all randomized subjects who received at least one dose of 
study drug. The Safety Population will be the population for all the safety analyses. The subjects will 
be analyzed according to the treatment group which they actually received.
Per-Protocol (PP)
The PP Population will be defined as the subset of subjects in the FAS who do not have any major 
protocol violations. Details will be provided in the Reporting and Analysis Plan (RAP). The PP 
population will be only used to analyze until week 12 after first treatment, because the objective to use 
the PP population is to check the robustness of the primary and secondary efficacy endpoints.
9.3.2.
Interim Analysis
When all the subjects complete treatment phase 1 or week 24 of treatment phase 1 (except for the 
premature withdraw) data up to week 24 of treatment phase 1 may be locked, unblinded and analyzed 
for the regulatory submission.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The primary endpoint in this study is the change from baseline in the daily average number of urinary 
incontinence episodes at week 12 after the first treatment.

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This will be analyzed using a mixed model for repeated measures (MMRM). This model will include 
the treatment group, site, visit, and treatment-by-visit interaction as fixed factors, baseline values and 
baseline-by-visit as covariates. An unstructured variance structure will be used to model the within-
subject errors, shared across treatments. Analysis will be done with the MIXED procedure in SAS®, 
using the Kenward-Roger option to estimate denominator degrees of freedom and standard errors. 
Significant tests will be based on least-squares means using a two-sided 5% significance level (two-
sided 95% confidence intervals). The dataset including only data until week 12 after the first treatment 
will be used for MMRM.
Sensitivity analysis under the assumption of missing not at random for missing data will be performed, 
because MMRM is valid only under the assumption of missing at random. This will be documented in 
RAP.
9.4.2.
Secondary Analyses
Efficacy
The major secondary endpoint in this study is the change from baseline in the average volume voided 
per micturition at week 12 after the first treatment.
This will be analyzed using MMRM as well as the primary endpoint. This model will include the 
treatment group, a stratification factor, site, visit, and treatment-by-visit interaction as fixed factors, 
baseline values and baseline-by-visit as covariates. An unstructured variance structure will be used to 
model the within-subject errors, shared across treatments. Analysis will be done with the MIXED 
procedure in SAS®, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. Significant tests will be based on least-squares means using a two-sided 5% 
significance level (two-sided 95% confidence intervals). The dataset including only data until week 12 
after the first treatment will be used for MMRM.
The following endpoints until week 12 after the first treatment will be analyzed using MMRM. This 
model will include the same factors as the model for major secondary endpoint. The treatment 
differences after week 12 after the first treatment will be analyzed using analysis of covariance 
(ANCOVA) model at each visit. This model will include the treatment group, site and a stratification 
factor as fixed factors, and baseline values as a covariate. Note that for daily average number of 
urinary incontinence episodes and daily average number of urinary urgency incontinence episodes, 
MMRM and ANCOVA will not include a stratification factor as fixed factors because the strong 
correlation is expected between baseline values and a stratification factor.

Change from baseline and percent change from baseline:

Daily average number of urinary incontinence episodes (except for change from 
baseline at week 12 after the first treatment)

Average volume voided per void (except for change from baseline at week 12 after the 
first treatment)

Daily average number of urinary urgency incontinence episodes

Daily average number of voids

Daily average number of urgency episodes

Daily average number of nocturia episodes (voids that interrupt night sleep)

Change from baseline

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
Daily average number of urgency episodes by each urgency intensity category

Maximum urgency intensity
The following endpoints will be analyzed using ANCOVA model at each visit. This model will 
include the treatment group, site and a stratification factor as fixed factors, and baseline values as a 
covariate.

Change from baseline

Overactive Bladder Symptom Score (OABSS) total score

King's Health Questionnaire (KHQ) domain score
The following endpoints will be analyzed by using the Cochran-Mantel-Haenszel test stratified by a 
stratification factor. Missing data will be imputed by multiple imputation strategy.

Proportion of subjects attaining 100%, ≥75% and ≥50% reduction from baseline in the daily 
average of urinary incontinence episodes

Proportion of subjects attaining 100%, ≥75% and ≥50% reduction from baseline in the daily 
average of urinary urgency incontinence episodes

Proportion of patients with positive response on the TBS
Duration of treatment effect will be evaluated for each treatment group in 2 different ways.

Time to the subject’s first request for 2nd treatment from the day of 1st  treatment  
(regardless of fulfilment of the re-treatment criteria)

Time to the subject’s first qualification for 2nd treatment from the day of 1st treatment
The time to event will be graphically displayed as Kaplan-Meier curves. The endpoints will be tested 
using a log-rank test stratified by a stratification factor. Time to request/qualification for 2nd and 3rd 
treatment will not be analyzed.
No adjustment for multiplicity will be made for major secondary endpoint and other secondary 
endpoints.
Safety
All AEs that occur during the study will be recorded and classified using the current Medical 
Dictionary for Regulatory Activities (MedDRA). Events will be summarized overall, by treatment 
cycle and for the first 12 week of 1st treatment phase (≤84 days from 1st treatment). Frequencies of 
AEs will be presented by system organ class and preferred term.  Summaries of treatment-related 
AEs (study drug-related and injection procedure-related), AEs leading to discontinuation, AEs by 
intensity, and SAEs also will be provided.
ANCOVA for change from baseline in PVR urine volume will be performed at each visit. This model 
will include the treatment group, site and a stratification factor as fixed factors, baseline PVR urine 
volume as a covariate. The proportion of patients who will have a change from baseline in PVR 

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category (urine volume of < 100 mL, ≥ 100 to < 200 mL, ≥ 200 to < 350 mL, and ≥ 350 mL) will be 
summarized by visit. 
The proportion of subjects using CIC (for urinary retention or elevated PVR) post-treatment will be 
summarized by PVR category. Time to start of CIC from most recent treatment, duration of CIC and 
PVR volume at the time of initiation of CIC will be also presented.
The observed value of clinical laboratory test and its change from baseline will be summarized by 
treatment group. The number of subjects with values outside of normal range by visit will be tabulated 
by treatment group to evaluate the changes in clinical laboratory tests.
The observed value of vital signs and changes from baseline will be summarized by treatment group.  
Also the ECG findings by visit will be summarized by treatment group.
10. STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial Registers
Study information from this protocol will be posted on publicly available clinical trial registers before 
enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the Informed Consent 
Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the appropriate 
regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and 
applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, and with GSK 
policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), all applicable 
subject privacy requirements, and the guiding principles of the current version of the Declaration of 
Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and amendments as 
applicable

Signed informed consent to be obtained for each subject before participation in the study (and for 
amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or both.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include identification, 
agreement and documentation of data items for which the CRF will serve as the source 
document.
GSK will monitor the study and site activity to verify that the:

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
Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other study 
agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor 
direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a 
quality assurance assessment and/or audit of the site records, and the regulatory agencies may 
conduct a regulatory inspection at any time during or after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) must agree to 
grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to 
allocate their time and the time of their staff to discuss the conduct of the study, any 
findings/relevant issues and to implement any corrective and/or preventative actions to address 
any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with applicable 
regulations including GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time 
for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For 
multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking such action 
with the investigator or the head of the medical institution (where applicable).  When feasible, 
GSK will provide advance notification to the investigator or the head of the medical institution, 
where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will promptly 
inform all investigators, heads of the medical institutions (where applicable) and/or institution(s) 
conducting the study. GSK will also promptly inform the relevant regulatory authorities of the 
suspension or premature discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical institution 
(where applicable) must inform the IRB/IEC promptly and provide the reason for the suspension 
or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations to 
be maintained elsewhere), in a safe and secure location.  

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
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK 
audit or regulatory inspection) and must be available for review in conjunction with assessment 
of the facility, supporting systems, and relevant site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these records can 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution needs to be exercised before such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and accurate copy of 
the original and meet accessibility and retrieval standards, including re-generating a hard copy, if 
required.  Furthermore, the investigator must ensure there is an acceptable back-up of these 
reproductions and that an acceptable quality control process exists for making these 
reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all 
applicable regulatory requirements.  The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or local 
laws or regulations, GSK standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, including, but not 
limited to, archival at an off-site facility or transfer of ownership of the records in the event the 
investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of Information on 
Publically Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an investigator signatory will be identified for 
the approval of the clinical study report.  The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the complete 
study results at a GSK site or other mutually-agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The investigator is 
encouraged to share the summary results with the study subjects, as appropriate.
GSK will provide the investigator with the randomization codes for their site only after completion of 
the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for development of a 
manuscript for publication will be in accordance with GSK Policy.
11. REFERENCES
Abrams P, Freeman R, Anderstrom C, et al. Tolterodine, a new antimuscarinic agent: as effective but 
better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol. 1998;81:801-10.
Abrams P, Kelleher CJ, Kerr LA, et al. Overactive bladder significantly affects quality of life. Am J 
Manag Care. 2000 ;6(Suppl 11) :S580-90.
Abrams P, Andersson KE, Birder L, Fourth international consultation on incontinence 
recommendations of the international scientific committee: evaluation and treatment of urinary 
incontinence, pelvic organ prolapse, and fecal incontinence, Neurourol Urodyn. 2010:29:213-40.

2016N273767_03
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Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: a pooled 
analysis. Urology. 1997;50(Suppl 6A):90-6 ; discussion 97-9.
Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in overactive 
bladder: an update of a systematic review and meta-analysis. Eur Urol. 2008;54:543-62.
Colman S, Chapple C, Nitti V, et al. Validation of treatment benefit scale for assessing subjective 
outcomes in treatment of overactive bladder. Urology. 2008;72:803-7
Committee for Preparation of the Clinical Guideline for Overactive Bladder, the Japanese Continence 
Society. Clinical Guideline for Overactive Bladder. Blackwell Publishing. Tokyo. 2005.
Committee for Preparation of the Clinical Guideline for Overactive Bladder, the Japanese Continence 
Society. Clinical Guideline for Overactive Bladder (version. 2). RichHill Medical Inc. Tokyo. 2015.
Drutz HP, Appell RA, Gleason D, et al. Clinical efficacy and safety of tolterodine compared to 
oxybutynin and placebo in patients with overactive bladder. Int Urogynecol J. 1999;10:283-9.
Fujimura T, Homma Y. Botulinum toxin injection into the bladder wall. Jpn J of Urological Surgery.
2009;22:1493-7.
Giannantoni A, Di Stasi SM, Stephen RL, et al. Intravesical resiniferatoxin versus botulinum-A toxin 
injections for neurogenic detrusor overactively: A prospective randomized study. J Urol. 
2004 ;172 :240-3.
Goto M. Overactive bladder and QOL. Voiding Disorders Digest. 2004;12(3):226-32.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. Contraceptive 
Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2.
Homma Y, Yoshida M, Seki N, et al. Symptom assessment tool for overactive bladder syndrome –
overactive bladder symptom score. Urology. 2006;68:318-23.
Homma Y, Goto M, Ando T, et al. Development of Japanese version of QOL questionnaires for 
urinary incontinence. NBS. 1999;10:225-36.
Homma Y, Ando T, Yoshida M, et al. Validation of the Japanese version of QOL questionnaires for 
urinary incontinence. NBS. 2002;13:247-57.
Kelleher CJ, Cardozo LD, Khullar V, et al. A new questionnaire to assess the quality of life of urinary 
incontinent women, Br J Obstet Gynaecol, 1997;104:1374-9

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- 61 -
Kreder K, Mayne C, Jonas U. Long-term safety, tolerability and efficacy of extended release 
tolterodine in the treatment of overactive bladder. Eur Urol. 2002;41:588-95.
Su LM and Sosa RE. Ureteroscopy and retrograde urethral access. In Walsh PC, Retik AB, Vaughan 
ED Jr, Wein AJ (eds): Campbell’s Urology, 8th ed, vol 4. Philadelphia, PA: WB Saunders; 
2002;3306-3319.
Sekido N. Botulinum toxin injection into the bladder wall for the treatment of refractory overactive 
detrusor. Japanese Medical Journal. 2009;No.4451:116-7.
Yokoyama M. Botulinum toxin therapy in urology. Prog Med. 2008;28:1151-5.

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12. Appendices
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
AST
Asparate aminotransferase
CFU
Colony Forming Unit
CIC
Clean Intermittent Catheterization
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine Phosphokinase
CT
Computer Tomography
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
GSKDrug
GSKDrug (dictionary used for Clinical coding)
HBsAg
Hepatitis B surface Antigen
hCG
human Chorionic Gonadotropin
HCVAb
Hepatitis C Virus Antibody
hpf
high power field
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
ICS
International Continence Society
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
KHQ
King’s Health Questionnaire
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measures
MRI
magnetic resonance imaging
OAB
Overactive Bladder
OABSS
Overactive Bladder Symptom Score
PP
Per Protocol

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PSA
Prostatic Specific Antigen
PT
Preferred Term
QOL
Quality of Life
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SOC
System Organ Class
SRM
Study Reference Manual
TBS
Treatment Benefit Scale
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BOTOX®
SAS®
InForm™

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12.2.
Appendix 2: Liver Safety Required Actions and Follow up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to  
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted

If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) and 
quantitative hepatitis B DNA 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 

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hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  
24-72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin 
on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value 
stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody or Hepatitis E RNA
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and 
<8xULN to ≥3xULN but <5xULN, continue to 
monitor liver chemistries weekly. 

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
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.

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12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, Follow-
Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may 
have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication (overdose per se will not be reported as an AE/SAE unless this is an 
intentional overdose taken with possible suicidal/self-harming intent. This should be reported 
regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfil the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen.

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12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of 
disease, etc).
Serious Adverse Event (SAE) is defined as 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 subject 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.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or out-patient setting.  Complications that 
occur during hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.

This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute 
a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is appropriate 
in other situations, such as important medical events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above definition.  These 
should also be considered serious.

Examples of such events are invasive or malignant cancers, 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.

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* Serum bilirubin fractionation should be performed if testing is available; if unavailable, measure 
urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN and total bilirubin 
2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to subjects receiving 
anticoagulants.  If INR measurement is obtained, the value is to be recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the following AEs 
and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by GSK.  
In this instance, all subject identifiers, with the exception of the subject number, will be blinded 
on the copies of the medical records prior to submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE 
and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection of AE data 
are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will be treated in 
accordance with standard scoring and statistical procedures detailed by the scale’s developer.

The use of a single question from a multidimensional health survey to designate a cause-effect 
relationship to an AE is inappropriate.

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12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed as severe 
will not be confused with an SAE. Severity is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment / injection 
procedure and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study treatment will be considered 
and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for 
marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal information 
to include in the initial report to GSK.  However, it is very important that the investigator 
always make an assessment of causality for every event prior to the initial transmission of 
the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as 
fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

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
If a subject dies during participation in the study or during a recognized follow-up period, the 
investigator will provide GSK with a copy of any post-mortem findings, including 
histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated reporting time 
frames.
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE 
data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it becomes 
available.

The investigator will be required to confirm review of the SAE causality by ticking the 
‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., InForm 
system) will be taken off-line to prevent the entry of new data or changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, the site 
can report this information on a paper SAE form or to the Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the Sponsor/Medical 
Monitor Contact Information page.

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12.4.
Appendix 4: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 weeks of 
learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator will collect 
follow up information on mother and infant, which will be forwarded to GSK.  Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or absence of 
anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as such.  

Any SAE occurring as a result of a post-study pregnancy which is considered reasonably related 
to the study treatment by the investigator, will be reported to GSK as described in Appendix
12.3. While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting.

Investigator will attempt to collect pregnancy information on any female partner of a male study 
subject who becomes pregnant while participating in this study.  This applies only to subjects 
who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner directly, the 
investigator will record pregnancy information on the appropriate form and submit it to GSK 
within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  
Any termination of the pregnancy will be reported regardless of fetal status (presence or absence 
of anomalies) or indication for procedure.
Any female subject who becomes pregnant while participating 

will be withdrawn from the study.

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12.5.
Appendix 5: Management guideline of PVR
PVR <200 mL
PVR 200 mL, <350 mL
PVR 350 mL
Usual study 
visit
No symptoms needing CIC*
or patient has associated symptom* but not requiring CIC 
by investigator (or sub-investigator)
Symptoms requiring
CIC* by investigator 
(or sub-investigator)
Commence CIC
Re-assessment in 1 week
Further follow-up determined by
investigator
Re-assessment in approx. 1 week
PVR 350 
mL
Decreased
or 
unchanged
PVR
Increased PVR
Commence CIC
Symptoms
requiring CIC* 
by investigator 
(or sub-
investigator)
No symptoms needing CIC*
or patient has associated symptom* 
but not requiring CIC 
by investigator (or sub-investigator)
Re-assessment in 1 week
Further follow-up
determined by
investigator (or sub-
investigator)
Re-assessment in approx. 1 week
PVR 350 
mL
Decreased 
or 
unchanged 
PVR
Increased PVR
Symptoms
requiring CIC* 
by investigator 
(or sub-
investigator)
No symptoms 
needing CIC* or 
patient has 
associated 
symptom* but not 
requiring CIC 
by investigator (or 
sub-investigator)
Commence CIC
Re-assessment in 1 week
Further follow-up
determined by investigator
(or sub-investigator)
Usual study 
visit
Further follow-
up determined 
by investigator
(or sub-
investigator)
Usual study visit
At each visit:
- PVR and associated patient symptoms
- urine dipstick
- central lab urine analysis
(with culture/sensitivity)
Record as AE of urinary retention
Record as AE of residual urine volume increased
CIC, if applicable, discontinued when:
- PVR < 350 mL
- No associated patient symptoms 
requiring CIC
Follow-up visit 1 week after
discontinuation of CIC
*: such as voiding difficulties or sensation of bladder fullness

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12.6.
Appendix 6: COUNTRY SPECIFIC REQUIREMENTS (JAPAN)
12.6.1.
Study Conduct Considerations
12.6.1.1.
Regulatory and Ethical Considerations
The study will be conducted in accordance with “the Ministerial Ordinance on the Standards for the 
Conduct of Clinical Trials of Medicinal Products (MHW Notification No.28 dated 27th March, 1997)” 
and 80-2 of theLaw for Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices.
GSK will submit the CTN to the regulatory authorities in accordance with Article 80-2 of the Law for 
Ensuring the Quality, Efficacy, and Safety of Drugs and Medical Devices before conclusion of any 
contract for the conduct of the study with study sites.
12.6.1.2.
Informed Consent
Prior to participation in the study, the investigator (or subinvestigator) should fully inform the 
potential subject of the study including the written information. The investigator (or subinvestigator) 
should provide the subject ample time and opportunity to inquire about details of the study. The 
subject should sign and personally date the consent form. If the subject wishes to consider the content 
of the written information at home, he/she may sign the consent form at home. The person who 
conducted the informed consent discussion and the study collaborator giving supplementary 
explanation, where applicable, should sign and personally date the consent form. If an impartial 
witness is required, the witness should sign and personally date the consent form. The investigator (or 
subinvestigator) should retain this signed and dated form (and other written information) together with 
the source medical records, such as clinical charts (in accordance with the rules for records retention, 
if any, at each medical institution) and give a copy to the subject.
12.6.1.3.
Study Period
July, 2016 to Novemver, 2018
12.6.1.4.
Study Administrative Structure
Sponsor information is included in Exhibit 1. List of Medical Institutions and Investigators is included 
in Exhibit 2.
12.6.2.
Nonaproved Medical Devices in Japan
Medical devices that are approved in other countries but not approved in Japan (Nonapproved Medical 
Devices in Japan) will be provided by GSK for use in this study.
Nonapproved Medical Device in Japan incidents, including those resulting from malfunctions of the 
device, must be detected, documented, and reported by the (sub)investigator throughout the study.
<Nonapproved Medical Devices in Japan>
General Name
Manufacturer Name
Product Name
Biopsy needles for single use
Coloplast Manufacturing France 
S.A.S.
BONEE Needle of bladder 
injection

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Incident – Any malfunction or deterioration in the characteristics and/or performance of a device, as 
well as any inadequacy in the labeling or the instructions for use which, directly or indirectly might 
lead to or might have led to the death of a patient, or user or of other persons or to a serious 
deterioration in their state of health.
Not all incidents lead to death or serious deterioration in health. The non-occurrence of such a result 
might have been due to other fortunate circumstances or to the intervention of health care personnel.
Incidents include the followings:

An incident associated with a device happened and

The incident was such that, if it occurred again, it might lead to death or serious deterioration in 
health
A serious deterioration in state of health can include:

A life-threatening illness (a)

Permanent impairment of body function or permanent damage to a body structure (b)

A condition necessitating medical or surgical intervention to prevent (a) or (b)

Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic (IVD) test 
results when used within the manufacturer’s instructions for use

Fetal distress, fetal death or any congenital abnormality or birth defects
Malfunction – A failure of a device to perform in accordance with its intended purpose when used in 
accordance with the manufacturer’s instructions.
12.6.2.1.
Documenting Medical Device Incidents
Any medical device incident occurring during the study will be documented in the subject’s medical 
records, in accordance with the (sub)investigator’s normal clinical practice, and on the “Medical 
Device Incident Report Form”. In addition, for incidents fulfilling the definition of an AE or an SAE, 
the appropriate AE/SAE data collection tool in the CRF will be completed as previously described.
The form will be completed as thoroughly as possible and signed by the (sub) investigator before 
transmittal to GSK. It is very important that the (sub)investigator provides his/her assessment of 
causality to the medical device provided by GSK at the time of the initial report, and describes any 
corrective or remedial actions taken to prevent recurrence of the incident.
12.6.2.2.
Transmission of Medical Device Incident Reports
Immediate facsimile transmission of the Medical Device Incident Report Form is the preferred method 
to transmit this information to GSK.
In the absence of facsimile equipment, notification by telephone is acceptable for incidents, with a 
copy of the Medical Device Incident Report Form sent by overnight mail or delivery service.
Initial Report
Follow-up Information on a Previous Report
Type of Event
Time 
Frame
Documents
Time Frame
Documents
Medical device 
incident
24 hours
Medical Device 
Incident Report Form
24 hours
Updated Medical Device 
Incident Report Form

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12.6.2.3.
Time Period of Detecting Medical Device Incident
Medical device incidents will be collected from the start of the study until the follow-up contact.
12.6.2.4.
Follow-up of Medical Device Incidents
All medical device incidents involving an AE will be followed until resolution of the event, until the 
condition stabilizes, until the condition is otherwise explained, or until the subject is lost to follow-up.  
This applies to all subjects, including those withdrawn prematurely. The (sub) investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as may be indicated 
to elucidate as completely as practical the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed form with all changes 
signed and dated by the (sub) investigator.
12.6.2.5.
Post-Study Medical Device Incidents
The (sub) investigators are not obligated to actively seek reports of medical device incidents in former 
subjects.  However, if the (sub) investigator learns of any incident at any time after a subject has 
been discharged from the study, and such incident is reasonably related to a GSK medical device 
provided for the study, the (sub) investigator will promptly notify GSK.
12.6.2.6.
Regulatory Reporting Requirements for Medical Devices
The (sub) investigator will promptly report all incidents occurring with any GSK medical device 
provided for use in the study to GSK. GSK notifies appropriate regulatory bodies and other entities 
about certain safety information relating to medical devices being used in clinical studies. Prompt 
notification of incidents by the (sub) investigator to GSK is essential in order to meet legal obligations 
and ethical responsibility towards the safety of subjects.
The (sub) investigator or head of corresponding clinical institute, will comply with the applicable local 
regulatory requirements relating to the reporting of incidents and near-incidents to the IRB/IEC.
12.6.3.
Exhibits
Exhibit 1: Sponsor information
Exhibit 2: List of medical institutions and investigators

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12.7.
Appendix 7：Protocol Changes
12.7.1.
Changes from Original (Effective Date: 20-Apr-2016) to Amendment 01
Corresponding 
part (described 
part before the 
changes)
Before
After
Reason for the 
changes
5.1.Inclusion 
Criteria, # 7
(Page 22)
7. Males or females:
•Male subjects with female partners 
of child bearing potential must 
comply with the following 
contraception requirements from the 
time of first dose of study 
medication until the study exit.
1) Vasectomy with documentation of 
azoospermia.
2) Male condom plus partner use of 
one of the contraceptive options 
below:
•Contraceptive subdermal implant 
that meets the SOP effectiveness 
criteria including a <1% rate of 
failure per year, as stated in the 
product label
•Intrauterine device or intrauterine 
system that meets the SOP 
effectiveness criteria including a 
<1% rate of failure per year, as 
stated in the product label [Hatcher, 
2007]
•Oral Contraceptive, either 
combined or progestogen alone 
[Hatcher, 2007]
•Injectable progestogen [Hatcher, 
2007]
•Contraceptive vaginal ring 
[Hatcher, 2007]
•Percutaneous contraceptive patches 
[Hatcher, 2007]
7. Males or females:
•Male subjects with female partners 
of child bearing potential must 
comply with the following 
contraception requirements from the 
time of first dose of study 
medication until the study exit.
1) Vasectomy with documentation of 
azoospermia.
2) Male condom plus partner use of 
one of the contraceptive options 
below:
•Intrauterine device or intrauterine 
system that meets the SOP 
effectiveness criteria including a 
<1% rate of failure per year, as 
stated in the product label [Hatcher, 
2007]
•Oral Contraceptive, either 
combined or progestogen alone 
[Hatcher, 2007]
To delete the 
contraceptive 
methods which 
have not been 
approved in Japan 
based on the 
indication by the 
Pharmaceuticals 
and Medical 
Device Agency.
5.1.Inclusion 
Criteria, # 7
(Page 23)
GSK Modified List of Highly 
Effective Methods for Avoiding 
Pregnancy in Females of 
Reproductive Potential (FRP)
This list does not apply to FRP with 
same sex partners, when this is their 
preferred and usual lifestyle or for 
subjects who are and will continue to 
be abstinent from penile-vaginal 
intercourse on a long term and 
persistent basis.
1. Contraceptive subdermal implant 
that meets the SOP effectiveness 
criteria including a <1% rate of 
failure per year, as stated in the 
product label
2. Intrauterine device or intrauterine 
system that meets the SOP 
effectiveness criteria including a 
<1% rate of failure per year, as 
stated in the product label [Hatcher, 
2007]
3. Oral Contraceptive, either 
GSK Modified List of Highly 
Effective Methods for Avoiding 
Pregnancy in Females of 
Reproductive Potential (FRP)*
This list does not apply to FRP with 
same sex partners, when this is their 
preferred and usual lifestyle or for 
subjects who are and will continue to 
be abstinent from penile-vaginal 
intercourse on a long term and 
persistent basis.
1. Intrauterine device or intrauterine 
system that meets the SOP 
effectiveness criteria including a 
<1% rate of failure per year, as 
stated in the product label [Hatcher, 
2007]
2. Oral Contraceptive, either 
combined or progestogen alone 
[Hatcher, 2007]
3. Male partner sterilization with 
documentation of azoospermia prior 
to the female subject's entry into the 
To delete the 
contraceptive 
methods which 
have not been 
approved in Japan 
based on the 
indication by the 
Pharmaceuticals 
and Medical 
Device Agency.

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Corresponding 
part (described 
part before the 
changes)
Before
After
Reason for the 
changes
combined or progestogen alone 
[Hatcher, 2007]
4. Injectable progestogen [Hatcher, 
2007]
5. Contraceptive vaginal ring 
[Hatcher, 2007]
6. Percutaneous contraceptive 
patches [Hatcher, 2007]
7. Male partner sterilization with 
documentation of azoospermia prior 
to the female subject's entry into the 
study, and this male is the sole 
partner for that subject [Hatcher, 
2007]
study, and this male is the sole 
partner for that subject [Hatcher, 
2007]
*: Contraceptive methods approved 
in Japan are shown
12.7.2.
Changes from Amendment 01 (Effective Date: 12-May-2016) to Amendment 
02
Corresponding part 
(described part 
before the changes)
Before
After
Reason for the 
changes
7.1. Time and 
Events Table, Table 
1 footnote (e)
(Page 38)
Table 2 footnote (f)
(Page 40)
Urine culture and sensitivity is 
performed by the central laboratory 
when urinalysis (clinical 
laboratory) results were suggestive 
of a urinary tract infection
Urine culture and sensitivity is 
performed by the central laboratory 
when urinalysis (dipstick) results 
were suggestive of a urinary tract 
infection
Change the 
sentence in
consideration of 
operability in 
central
laboratory
7.4.6.2.1.Urinalysis 
using a urine 
reagent strip
(Page 47)
If the results of the urine analysis 
with a urine reagent strip suggest 
urinary tract infection, treatment 
with antibiotics can be administered 
in the opinion of the 
investigators/subinvestigators. In 
this case, samples for urinalysis, 
urine culture and sensitivity test 
must be sent to the central 
laboratory.
A urine analysis with a urine 
reagent strip will be conducted, in 
parallel with urine analysis, urine 
culture, and sensitivity test at the 
central laboratory.
If the results of the urine analysis 
with a urine reagent strip suggest 
urinary tract infection (i.e.: positive 
nitrites or leukocyte esterase), 
treatment with antibiotics can be 
administered in the opinion of the 
investigators/subinvestigators. If 
the urinary tract infection is 
suggested, in addition to samples 
necessary for urinalysis which is 
performed at all study visit, 
samples for urine culture and 
sensitivity test must be sent to the 
central laboratory.
Change the 
sentences in 
consideration of 
operability in 
central 
laboratory
7.4.6.2.1.Urinalysis 
using a urine 
reagent strip
(Page 47)
If a urine analysis with a urine 
reagent strip is positive for nitrites 
or leukocyte esterase or bacterial 
infection is confirmed by 
urinalysis, urine culture and 
sensitivity test at the central 
laboratory (with the presence of 
bacteriuria with more than 105 CFU 
[colony forming unit] per mL and 
leukocyturia with more than 5 per 
high power field), treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
If a urine analysis with a urine 
reagent strip is positive for nitrites 
or leukocyte esterase or bacterial 
infection is confirmed by urinalysis, 
urine culture and sensitivity test at 
the central laboratory (with the 
presence of bacteriuria with 105
CFU [colony forming unit] per mL 
or more and leukocyturia with more 
than 5 per high power field), 
treatment with antibiotics will be 
administered in the opinion of the 
investigators/subinvestigators.
Change the 
sentences in 
consideration of 
test result values 
in central 
laboratory

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Corresponding part 
(described part 
before the changes)
Before
After
Reason for the 
changes
7.4.6.2.2.Urinalysis, 
Culture and 
Sensitivity
(Page 48)
A urine culture and sensitivity test 
will be performed when central 
laboratory urine results are 
suggestive of a UTI (positive 
leukocyte esterase, nitrites, blood 
and/or microscopic sediments such 
as white blood cells (WBCs), red 
blood cells (RBCs) and/or bacteria) 
(see below for the definition of AE 
urinary tract infection).
A urine culture and sensitivity test 
will be performed when urinalysis
results with a urine reagent strip are 
suggestive of a UTI (positive 
nitrites or leukocyte esterase) (see 
below for the definition of AE 
urinary tract infection).
Change the 
sentence in 
consideration of 
operability in 
central 
laboratory
7.4.6.2.2.Urinalysis, 
Culture and 
Sensitivity
(Page 48)
•Definition of AE urinary tract 
infection
If both of the following criteria are 
fulfilled, urinary tract infection is 
recorded as an adverse event, 
irrespective of symptoms:
1)
The result of urine culture is 
positive (with the presence of 
bacteriuria with > 105
CFU/mL)
2)
Leukocyturia with > 5 per 
high power field is noted.
•Definition of AE urinary tract 
infection
If both of the following criteria are 
fulfilled, urinary tract infection is 
recorded as an adverse event, 
irrespective of symptoms:
1)
The result of urine culture is 
positive (with the presence of 
bacteriuria with 105
CFU/mL)
2)
Leukocyturia with > 5 per 
high power field is noted.
Change the 
sentences in 
consideration of 
test result values 
in central 
laboratory
7.4.7.Post-void 
residual (PVR) 
urine volume
(Page 51)
Definition of AE residual urine 
volume
An adverse event of residual urine 
volume should be recorded if, in 
the opinion of the 
investigators/subinvestigators, the 
raised PVR is clinically significant 
but does not fulfill the above 
definition for urinary retention.
Definition of AE residual urine 
volume increased
An adverse event of residual urine 
volume increased should be 
recorded if, in the opinion of the 
investigators/subinvestigators, the 
raised PVR is clinically significant 
but does not fulfill the above 
definition for urinary retention.
Change the 
sentences to be 
able to use more 
appropriate AE 
term when the 
increased 
residual urine 
volume is 
reported as AE. 
12.5.Appendix 5 
Management 
guideline of PVR
(Page 73)
Action based on each residual urine 
volume when the residual urine 
volume is ≥200 mL and < 350 mL
at scheduled visit and the residual 
urine volume is evaluated at the 
additional visit:
Decreased PVR: Usual study visit
Action based on each residual urine 
volume when the residual urine 
volume is ≥200 mL and < 350 mL
at scheduled visit and the residual 
urine volume is evaluated at the 
additional visit:
Decreased or unchanged PVR: 
Usual study visit
Modified to be 
consistence with 
the contents 
described in 
7.4.7.Post-void 
residual (PVR) 
urine volume
12.5.Appendix 5 
Management 
guideline of PVR, 
Footnote
(Page 73)
Record as AE of residual urine 
volume
Record as AE of residual urine 
volume increased
Change the 
wording to be 
able to use more 
appropriate AE 
term when the 
increased 
residual urine 
volume is 
reported as AE.

2016N273767_03
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12.7.3.
Changes from Amendment 02 (Effective Date: 20-Jun-2016) to Amendment 
03
Corresponding part 
(described part after
the changes)
Before
After
Reason for the 
changes
Author (s)
(Page 1)
Due to the 
Change of 
person in charge.
Contact 
Information at 
Night and on 
Holidays
(Page 3)
Bell Medical Solutions, Inc.
BI Medical Solutions, Inc.
The name of the 
company was 
changed
5.3. Re-treatment 
Criteria, Day of re-
treatment criteria 1
(Page 26)
Central laboratory urine analysis 
and urine culture and sensitivity 
results for possible UTI using the 
sample collected at qualification for 
re-treatment visit had been 
reviewed by investigator (or sub-
investigator)
Central laboratory urine analysis
results for possible UTI using the 
sample collected at qualification for 
re-treatment visit had been 
reviewed by investigator (or sub-
investigator)
To modify so as 
to be a realistic 
and safety-
maintained 
procedure in 
consideration of 
long interval to 
obatain the test 
results.
6.9.2. Prohibited 
Medications and 
Non-Drug 
Therapies
(Page 35)
－
Cholinesterase inhibitor for the 
treatment of urinary disturbance
Newly set as 
prohibited 
medication 
7.1. Time and 
Events Table, 
footnote (l) (Page 
37, 38)
－
Samples may be colleced during the 
screening period through Day 1 
(prior to randomization)
To be able to 
collect the 
sample prior to 
the dosing of 
investigational 
product on Day 1
7.4.6.2.1. Urinalysis 
using a urine 
reagent strip
(Page 47)
•Initiation of Treatment phase 1 
(Week 0)
If a urine analysis with a urine 
reagent strip at initiation of 
treatment phase 1 (Week 0) is 
positive for nitrites or leukocyte 
esterase and infection is suggested, 
the subject are not allowed to 
receive the injection of the 
investigational product until the 
results of urinalysis, urine culture 
and sensitivity test at the central 
laboratory are received. If bacterial 
infection is confirmed by 
urinalysis, urine culture and 
sensitivity test at the central 
laboratory, treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
•Initiation of Treatment phase 1 
(Week 0)
If a urine analysis with a urine 
reagent strip at initiation of 
treatment phase 1 (Week 0) is 
positive for nitrites or leukocyte 
esterase, or bacterial infection is 
confirmed by urinalysis, urine 
culture and sensitivity test at the 
central laboratory, treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
To clarify the 
timing for 
initiation of 
antibiotic 
treatment
PPD
PPD

2016N273767_03
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Corresponding part 
(described part after
the changes)
Before
After
Reason for the 
changes
7.4.6.2.1. Urinalysis 
using a urine 
reagent strip
(Page 47)
•At the time of reinjection
Subjects in whom infection is 
suggested because a urine analysis 
with a urine reagent strip at the 
time of reinjection is positive for 
nitrites or leukocyte esterase are 
not allowed to receive the 
injection of the investigational 
product until the results of 
urinalysis, urine culture and 
sensitivity test at the central 
laboratory are received. If 
bacterial infection is confirmed, 
treatment with antibiotics will be 
administered in the opinion of the 
investigators/subinvestigators.
•At the time of reinjection
If a urine analysis with a urine 
reagent strip at the time of 
reinjection is positive for nitrites 
or leukocyte esterase, or bacterial 
infection is confirmed by 
urinarysis, urine culture and 
sensitivity test at the central 
laboratory, treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
To clarify the 
timing for 
initiation of 
antibiotic 
treatment
7.4.6.2.1. Urinalysis 
using a urine 
reagent strip
(Page 47)
•At a visit after the injection of the 
investigational drug
If urinary tract infection is 
suggested because a urine analysis 
with a urine reagent strip at a visit 
after the injection of the 
investigational drug is positive for 
nitrites or leukocyte esterase, will 
be confirmed by the central 
laboratory urine analysis and urine 
culture/sensitivity test which is 
also performed at every study 
visit. If bacterial infection is 
confirmed, treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
•At a visit after the injection of the 
investigational drug
If a urine analysis with a urine 
reagent strip at a visit after the 
injection of the investigational 
drug is positive for nitrites or 
leukocyte esterase, or bacterial 
infection is confirmed by 
urinalysis, urine culture and 
sensitivity test at the central 
laboratory, treatment with 
antibiotics will be administered in 
the opinion of the 
investigators/subinvestigators.
To clarify the 
timing for 
initiation of 
antibiotic 
treatment