Conditions: Urinary Bladder, Overactive
Keywords: Botulinum toxin type A Urinary Incontinence Neurogenic Detrusor Overactivity
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 21
Healthy volunteers: no

Brief summary:
This study will evaluate the efficacy and safety of GSK1358820 in Japanese patients with neurogenic detrusor overactivity (NDO) with urinary incontinence, whose symptoms have not been adequately managed with medications for urinary incontinence due to NDO.

This study consists of a screening phase up to 28 days followed by a double-blind Treatment phase 1 of 12 to 48 weeks wherein subjects will receive a single treatment of either GSK1358820 200 Units (U) injection or placebo injection. After the first treatment, subjects who meet the re-treatment criteria between 12 to 36 weeks can enter an open-label Treatment phase 2 to receive a second treatment with GSK1358820 200 U. Subjects will be permitted to receive re-treatment up to 2 times, and there should be a gap of minimum of 12 weeks since the previous treatment. The duration of overall treatment phases is 48 weeks. The total duration of participation for any subject will not exceed 52 weeks, including screening.

Detailed description:

Arms:
arm 1: Subjects will receive a single treatment with 200 U GSK1358820 injection (30 mL of study drug will be administered as 30 injections, each of 1.0 mL) in the detrusor of bladder, using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents. If the criteria for re-treatment between 12 to 36 weeks after first treatment are met, subjects will receive a second treatment with GSK1358820. Following this, subjects could receive another re-treatment up to 36 weeks after the first treatment, upon meeting the criteria, provided a minimum of 12 weeks elapse since previous treatment. arm 2: Subjects will receive a single treatment with placebo (30 injections, each of 1 mL) in the detrusor of bladder, using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents. If the criteria for re-treatment between 12 to 36 weeks after first treatment are met, subjects will receive treatment with GSK1358820. Following this, subjects could receive another re-treatment up to 36 weeks after the first treatment, upon meeting the criteria, provided a minimum of 12 weeks elapse since previous treatment

Interventions: intervention 1: GSK1358820 intervention 2: Placebo
Intervention descriptions: intervention 1: GSK1358820 injection contains botulinum toxin type A (100 U), sodium chloride (0.9 milligrams \[mg\]), and human serum albumin (0.5 mg). The 30 mL of study drug will be administered as 30 injections each of 1.0 mL, evenly distributed at 30 sites in the detrusor muscle, spaced approximately 1 centimeter (cm) apart. The injection will be administered using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents. intervention 2: Placebo injection contains sodium chloride (0.9 milligrams \[mg\]); 30 mL of the injection will be injected at 30 sites in the detrusor muscle, spaced approximately 1 centimeter (cm) apart. The injection will be administered using cystoscopy and under local anesthesia. General anesthesia may be used excluding neuromuscular blocking agents

Protocol document:
Prot_000.pdf: 
2016N276451_06
CONFIDENTIAL
GlaxoSmithKline group of companies
204948
- 1 -
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 urinary incontinence due to 
neurogenic detrusor overactivity
Compound Number:
GSK1358820
Development Phase:
III
Effective Date:
16-Nov-2017
Protocol Amendment Number: 06
Author (s):
Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2016N276451_00
28-Apr-2016
Original
2016N276451_01
13-May-2016
Amendment Number 01

Delete the contraceptive methods which can not be used in Japan.
2016N276451_02
24-Jun-2016
Amendment Number 02

Clarify the requirement for antibiotic administration which is needed before study treatment

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
2016N276451_03
07-Sep-2016
Amendment Number 03

Change the part of exclusion criteria for the use of intravesical pharmacological agent

Clarify the day of re-treatment criteria regarding the duration of antibiotic administration

Clarify the intravesical pharmacological agent as a prohibited medication

Clarify the initiation of clean intermittent catheterization and definition of urinary retention as an 
adverse event
2016N276451_04
14-Apr-2017
Amendment Number 04

Change the inclusion criteria, and add the exclusion criteria and the stratification factor since 
spinal cord injury patient with neurological injury level C5 to C8 is added as the new candidate
for this study.

Change the use of general anesthsia partially since spinal cord injury patient with neurological 
injury level C5 to C8 is added as the new candidate for this study.

Change the inclusion criteria since patient currently uses temporary indwelling balloon catheter 
is to be included in this study.
PPD


2016N276451_06
CONFIDENTIAL
GlaxoSmithKline group of companies
204948
- 2 -

Add the cholinesterase inhibitor for the treatment of urinary disturbance as the prohibited
medication

Change the schedule of sample collection for neutralizing antibody partially
2016N276451_05
20-Jul-2017
Amendment Number 05

Extend the study period
2016N276451_06
16-Nov-2017
Amendment Number 06

Change the medical monitor/sponsor information page

Extend the study period
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying 
or use of this information is prohibited.


2016N276451_06
CONFIDENTIAL
204948
- 3 -
SPONSOR SIGNATORY
Yotaro Numachi
Glaxo Smith Kline K.K.
The head of Neurosciences TA Office, Medicines Development
Date


2016N276451_06
CONFIDENTIAL
204948
- 4 -
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.
8-1, Akasaka 1-chome, 
Minato-ku, Tokyo 107-0052
JAPAN
SAE contact  
information
GSK1358820 Section, 
Clinical Operation 
Department
Glaxo Smith Kline K.K. 
8-1, Akasaka 1-chome, 
Minato-ku, Tokyo 107-0052
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）
8-1, Akasaka 1-chome, Minato-ku, Tokyo 107-0052 JAPAN
Study Director: 
 The head of Neurosciences TA Office, Medicines Development
PPD
PPD
PPD
PPD
PPD
PPD


2016N276451_06
CONFIDENTIAL
204948
- 5 -
INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol number: 204948

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


2016N276451_06
CONFIDENTIAL
204948
- 6 -
Table of Contents
Page
1.
PROTOCOL SYNOPSIS FOR STUDY 204948 ............................................................10
2.
INTRODUCTION............................................................................................................14
2.1.
Study Rationale....................................................................................................14
2.2.
Brief Background.................................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S).............................................................................15
4.
STUDY DESIGN.............................................................................................................16
4.1.
Overall Design......................................................................................................17
4.2.
Treatment Arms and Duration............................................................................17
4.3.
Type and Number of Subjects............................................................................17
4.4.
Design Justification.............................................................................................18
4.5.
Dose Justification................................................................................................18
4.6.
Benefit: Risk Assessment...................................................................................19
4.6.1.
Risk Assessment ........................................................................................20
4.6.2.
Benefit Assessment....................................................................................23
4.6.3.
Overall Benefit: Risk Conclusion..............................................................23
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA.................23
5.1.
Inclusion Criteria..................................................................................................23
5.2.
Exclusion Criteria ................................................................................................26
5.3.
Re-treatment Criteria...........................................................................................28
5.4.
Screening Failures...............................................................................................29
5.5.
Withdrawal/Stopping Criteria .............................................................................29
5.5.1.
Liver Chemistry Stopping Criteria.............................................................30
5.5.1.1.
Study Treatment Restart or Rechallenge.........................................32
5.5.2.
QTc Stopping Criteria.................................................................................32
5.6.
Subject and Study Completion ..........................................................................32
6.
STUDY TREATMENT ....................................................................................................32
6.1.
Investigational Product and Other Study Treatment.......................................32
6.1.1.
Investigational Product ..............................................................................32
6.1.2.
Treatment Administration ..........................................................................33
6.1.2.1.
Antibiotics ...........................................................................................33
6.1.2.2.
Use of Anesthesia ..............................................................................33
6.1.2.3.
Treatment Procedure .........................................................................34
6.2.
Treatment Assignment........................................................................................35
6.2.1.
Re-registration of subject ..........................................................................35


2016N276451_06
CONFIDENTIAL
204948
- 7 -
6.3.
Blinding.................................................................................................................36
6.4.
Packaging and Labeling......................................................................................36
6.5.
Preparation/Handling/Storage/Accountability..................................................37
6.6.
Compliance with Study Treatment Administration..........................................37
6.7.
Treatment of Study Treatment Overdose..........................................................37
6.8.
Treatment after the End of the Study ................................................................38
6.9.
Concomitant Medications and Non-Drug Therapies .......................................38
6.9.1.
Permitted Medications and Non-Drug Therapies ....................................38
6.9.2.
Prohibited Medications and Non-Drug Therapies...................................38
7.
STUDY ASSESSMENTS AND PROCEDURES ...........................................................39
7.1.
Time and Events Table........................................................................................40
7.2.
Screening and Critical Baseline Assessments ................................................44
7.3.
Efficacy .................................................................................................................44
7.3.1.
Methods of assessments ...........................................................................44
7.3.1.1.
Bladder diary.......................................................................................44
7.3.1.2.
Urodynamic test .................................................................................45
7.3.1.3.
Health outcome questionnaires........................................................45
7.3.1.3.1.
King’s Health Questionnaire (KHQ).........................................46
7.3.1.3.2.
Treatment Benefit Scale (TBS).................................................46
7.4.
Safety ....................................................................................................................46
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)....................46
7.4.1.1.
Time period and Frequency for collecting AE and SAE 
information..........................................................................................47
7.4.1.2.
Method of Detecting AEs and SAEs.................................................47
7.4.1.3.
Follow-up of AEs and SAEs ..............................................................47
7.4.1.4.
Cardiovascular and Death Events....................................................47
7.4.1.5.
Regulatory Reporting Requirements for SAEs...............................48
7.4.2.
Pregnancy....................................................................................................48
7.4.3.
Physical Exams...........................................................................................48
7.4.4.
Vital Signs....................................................................................................48
7.4.5.
Electrocardiogram (ECG) ...........................................................................48
7.4.6.
Clinical Safety Laboratory Assessments .................................................49
7.4.6.1.
Hematology and chemistry ...............................................................49
7.4.6.2.
Urinalysis.............................................................................................49
7.4.6.2.1.
Urinalysis using a urine reagent strip .....................................49
7.4.6.2.2.
Urinalysis, Culture and Sensitivity ..........................................50
7.4.6.2.3.
Urinary cytology.........................................................................50


2016N276451_06
CONFIDENTIAL
204948
- 8 -
7.4.6.3.
Prostate-specific antigen...................................................................50
7.4.6.4.
Pregnancy test....................................................................................51
7.4.7.
Post-void residual (PVR) urine volume ....................................................51
7.4.8.
Kidney and bladder ultrasound.................................................................54
7.4.9.
EDSS.............................................................................................................54
7.4.10.
Definition of AE MS exacerbation .............................................................54
7.5.
Other endpoints ...................................................................................................55
7.5.1.
Immunogenicity Testing.............................................................................55
8.
DATA MANAGEMENT ..................................................................................................55
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .....................................55
9.1.
Hypotheses...........................................................................................................55
9.2.
Sample Size Considerations ..............................................................................56
9.2.1.
Sample Size Assumptions .........................................................................56
9.2.2.
Sample Size Sensitivity ..............................................................................56
9.2.3.
Sample Size Re-estimation or Adjustment...............................................56
9.3.
Data Analysis Considerations............................................................................56
9.3.1.
Analysis Populations..................................................................................56
9.3.2.
Interim Analysis ..........................................................................................57
9.4.
Key Elements of Analysis Plan ..........................................................................57
9.4.1.
Primary Analyses........................................................................................57
9.4.2.
Secondary Analyses...................................................................................57
10. STUDY GOVERNANCE CONSIDERATIONS ..............................................................59
10.1.
Posting of Information on Publicly Available Clinical Trial Registers...........59
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process..................................................................................................59
10.3.
Quality Control (Study Monitoring)....................................................................59
10.4.
Quality Assurance ...............................................................................................60
10.5.
Study and Site Closure .......................................................................................60
10.6.
Records Retention...............................................................................................60
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................61
11. REFERENCES...............................................................................................................61
12. Appendices ...................................................................................................................63
12.1.
Appendix 1: Abbreviations and Trademarks....................................................63
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments........................................................................................................65


2016N276451_06
CONFIDENTIAL
204948
- 9 -
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ...................................................68
12.3.1.
Definition of Adverse Events.....................................................................68
12.3.2.
Definition of Serious Adverse Events.......................................................69
12.3.3.
Definition of Cardiovascular Events.........................................................70
12.3.4.
Recording of AEs and SAEs......................................................................70
12.3.5.
Evaluating AEs and SAEs..........................................................................71
12.3.6.
Reporting of SAEs to GSK.........................................................................72
12.4.
Appendix 4: Collection of Pregnancy Information...........................................73
12.5.
Appendix 5: Management guideline of PVR (in subjects who were 
not catheterizing at baseline).............................................................................74
12.6.
Appendix 6: COUNTRY SPECIFIC REQUIREMENTS (JAPAN) .......................75
12.6.1.
Study Conduct Considerations .................................................................75
12.6.1.1.
Regulatory and Ethical Considerations...........................................75
12.6.1.2.
Informed Consent...............................................................................75
12.6.1.3.
Study Period........................................................................................75
12.6.1.4.
Study Administrative Structure ........................................................75
12.6.2.
Nonaproved Medical Devices in Japan ....................................................75
12.6.2.1.
Documenting Medical Device Incidents...........................................76
12.6.2.2.
Transmission of Medical Device Incident Reports.........................76
12.6.2.3.
Time Period of Detecting Medical Device Incident.........................77
12.6.2.4.
Follow-up of Medical Device Incidents ............................................77
12.6.2.5.
Post-Study Medical Device Incidents...............................................77
12.6.2.6.
Regulatory Reporting Requirements for Medical Devices ............77
12.6.3.
Exhibits ........................................................................................................77
12.7.
Appendix 7：Protocol Changes.........................................................................78
12.7.1.
Changes from Original (Effective Date: 28-Apr-2016) to 
Amendment 01.............................................................................................78
12.7.2.
Changes from Amendment 01 (Effective Date: 13-May-2016) to 
Amendment 02.............................................................................................79
12.7.3.
Changes from Amendment 02 (Effective Date: 24-Jun-2016) to 
Amendment 03.............................................................................................81
12.7.4.
Changes from Amendment 03 (Effective Date: 07-Sep-2016) to 
Amendment 04.............................................................................................83
12.7.5.
Changes from Amendment 04 (Effective Date: 14-Apr-2017) to 
Amendment 05.............................................................................................85
12.7.6.
Changes from Amendment 05 (Effective Date: 20-Jul-2017) to 
Amendment 06.............................................................................................86


2016N276451_06
CONFIDENTIAL
204948
- 10 -
1.
PROTOCOL SYNOPSIS FOR STUDY 204948
Rationale
GSK1358820 (botulinum toxin type A) has already been approved for the treatment of urinary 
incontinence due to neurogenic detrusor overactivity (NDO) in overseas countries including the US 
and EU; however, it has not been approved for NDO treatment in Japan. Therefore, this study has 
been planned to evaluate the efficacy and safety of GSK1358820 in Japanese patients with NDO with 
urinary incontinence whose symptoms have not been adequately managed with medications for 
urinary incontinence due to NDO*
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, 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 NDO 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 overactive 
bladder (OAB) and are often used for NDO though not having a specific indication
Objective/Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
200 U

Change from baseline in the daily average 
number of urinary incontinence episodes a at 
week 6 after the first treatment.
Secondary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
200 U compared with placebo

To evaluate the efficacy of 
repeated dose treatment of 
GSK1358820 200 U

Changes from baseline at week 6 after the first 
treatment in the following endpoints by
urodynamic assessment

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the 
first involuntary detrusor contraction
(IDC)（PmaxIDC）

Volume at first IDC (VPmaxIDC)

Maximum detrusor pressure during the 
storage phase (PdetMax)

Changes from baseline and percentage change 
from baseline in the following endpoints

Daily average number of urinary 
incontinence episodes a

Daily average number of voids a


2016N276451_06
CONFIDENTIAL
204948
- 11 -

Average volume voided per void a

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily 
average of urinary 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 
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 
200 U compared with placebo

To evaluate the safety of a repeated 
dose treatment of GSK1358820 
200 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 [Only patients 
who are able to spontaneously void
(excluding mixed catheterization) at 
baseline]

Kidney and bladder ultrasound

Pregnancy test

Twelve-lead electrocardiogram (ECG)
Other

To evaluate the existence of toxin-
neutralizing antibody after the 
treatment of GSK1358820 200U

Neutralizing antibody measurement


2016N276451_06
CONFIDENTIAL
204948
- 12 -
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 the 28 day-period before first treatment), a Treatment 
phase 1 (double-blind treatment phase: 12 to 48 week period after first treatment), and a Treatment 
phase 2 (open-label treatment phase: 12 to 36 week 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 200 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 (30 injections each of 1.0 mL) which will be injected into the detrusor muscle of bladder. 
At the randomization, patients will be stratified according to NDO etiology (spinal cord injury [SCI]
with neurological injury level C5 to C8, SCI with neurological injury level T1 or below, or multiple 
sclerosis[MS])
Subjects who meet the criteria for re-treatment (referred Re-treatment criteria) between 12 to 36 
weeks after 1st treatment can enter to Treatment phase 2 to receive re-treatment (GSK1358820 200 U). 
Patients are permitted to receive re-treatment 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 the Treatment phase 1 and continue to visit at the scheduled 
study visit. Observation period will be the 48 week period after 1st treatment and 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 urinary incontinence due to NDO as a result of spinal 
cord injury or multiple sclerosis whose symptoms have not been adequately managed 
with medications for urinary incontinence due to NDO (anticholinergic ,and beta-3 
adrenergic receptor agonist)

Number of subjects (randomized subjects): 30 (15 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 
model will include the treatment group, visit, patient etiology 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 


2016N276451_06
CONFIDENTIAL
204948
- 13 -
freedom and standard errors. Least-squares mean and its two-sided 95% confidence intervals will be 
estimated. 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 (drug-related AEs, injection procedure related AEs), AEs leading 
to discontinuation, AEs by intensity, and SAEs also will be provided.


2016N276451_06
CONFIDENTIAL
204948
- 14 -
2.
INTRODUCTION
2.1.
Study Rationale
GSK1358820 (botulinum toxin type A) has already been approved for the treatment of urinary 
incontinence due to neurogenic detrusor overactivity (NDO) in overseas countries including the US 
and EU ; however, it has not been approved for NDO treatment in Japan. Therefore, this study has 
been planned to evaluate the efficacy and safety of GSK1358820 in Japanese patients with NDO with 
urinary incontinence whose symptoms have not been adequately managed with medications for 
urinary incontinence due to NDO*
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, 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 NDO 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 overactive 
bladder (OAB) and are often used for NDO though not having a specific indication
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] A definitive 
diagnosis of OAB due to detrusor overactivity, however can only be made based on an urodynamic 
finding of involuntary detrusor contractions. Specifically, detrusor overactivity is characterized by 
involuntary detrusor contractions during the filling phase that may be spontaneous or provoked and is 
divided into 2 categories: 1) Neurogenic Detrusor Overactivity (NDO) which is defined as 
overactivity due to a relevant neurological condition, and 2) Idiopathic Detrusor Overactivity, when 
there is no clear cause [Abrams, 2010]. Patients with urinary incontinence as a result of NDO due to 
spinal pathology (e.g., spinal cord injury or multiple sclerosis) report a decrease in quality of life 
(QOL) [Sekido, 2011]. These patients typically suffer from a loss of coordinated relaxation of the 
urethral sphincters that normally precedes micturition. This lack of coordinated activity can result not 
only in incontinence but also in vesico-ureteric reflux which if left untreated, can lead to potential 
renal damage.  Clean intermittent catheterization (CIC) is commonly used to drain the bladder and 
manage neurogenic incontinence in these patients who are not able to spontaneously void. 
Additionally, when they have urinary incontinence due to NDO, they are treated with
pharmacotherapy, indwelling catheter or surgery [The Japanese continence society/ Japan medical 
society of spinal cord lesion, 2011].
In pharmacotherapy, anticholinergics are considered to be the most important. However, some patients 
are resistant to anticholinergics [Igawa, 2012], 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; Appell, 1997; Kreder, 2002].
Currently, there are few acceptable alternative treatment options for patients with urinary incontinence 
due to NDO who do not benefit from anticholinergic therapy or other pharmacotherapies, and there 


2016N276451_06
CONFIDENTIAL
204948
- 15 -
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 urinary incontinence due to NDO 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 and NDO. GSK1358820 is 
expected to be an effective therapy in patients with urinary incontinence due to NDO who have not 
been adequately managed with anticholinergic-based pharmacotherapy [Yokoyama, 2008; Sekido, 
2009; Igawa, 2012].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
200 U

Change from baseline in the daily average 
number of urinary incontinence episodes a at 
week 6 after the first treatment.
Secondary

To evaluate the efficacy of a single 
dose treatment of GSK1358820 
200 U compared with placebo

To evaluate the efficacy of 
repeated dose treatment of 
GSK1358820 200 U

Changes from baseline at week 6 after the first 
treatment in the following endpoints by
urodynamic assessment

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the 
first involuntary detrusor contraction
(IDC)（PmaxIDC）

Volume at first IDC (VPmaxIDC)

Maximum detrusor pressure during the 
storage phase (PdetMax)

Changes from baseline and percentage change 
from baseline in the following endpoints

Daily average number of urinary 
incontinence episodes a

Daily average number of voids a

Average volume voided per void a

Proportion of patients attaining 100%, ≥75% and 


2016N276451_06
CONFIDENTIAL
204948
- 16 -
≥50% reduction from baseline in the daily 
average of urinary 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 
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 
200 U compared with placebo

To evaluate the safety of a repeated 
dose treatment of GSK1358820 
200 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 [Only patients 
who are able to spontaneously void
(excluding mixed catheterization) at 
baseline]

Kidney and bladder ultrasound

Pregnancy test

Twelve-lead electrocardiogram (ECG)
Other

To evaluate the existence of toxin-
neutralizing antibody after the 
treatment of GSK1358820 200U

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


2016N276451_06
CONFIDENTIAL
204948
- 17 -

Treatment phase 2: Multicenter, open-label design
4.1.
Overall Design
4.2.
Treatment Arms and Duration
This study consists of a Screening phase (within the 28 day-period before first treatment), a Treatment 
phase 1 (double-blind treatment phase: 12 to 48 week period after first treatment), and a Treatment 
phase 2 (open-label treatment phase: 12 to 36 week 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 200 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 (30 injections each of 1.0 mL) which will be injected into the detrusor of bladder. At the 
randomization, patients will be stratified according to NDO etiology (spinal cord injury [SCI] with 
neurological injury level C5 to C8, SCI with neurological injury level T1 or below, or multiple 
sclerosis[MS]).
Subjects who meet the criteria for re-treatment (referred Re-treatment criteria) between 12 to 36 
weeks after 1st treatment can enter to Treatment phase 2 to receive re-treatment (GSK1358820 200 U). 
Patients are permitted to receive re-treatment  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 the Treatment phase 1 and continue to visit at the scheduled 
study visit. Observation period will be the 48 week period after 1st treatment and 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 urinary incontinence due to NDO as a result of spinal 
cord injury or multiple sclerosis whose symptoms have not been adequately managed 
with medications for urinary incontinence due to NDO (anticholinergic and beta-3 
adrenergic receptor agonist)

Number of subjects (randomized subjects): 30 (15 per group)


2016N276451_06
CONFIDENTIAL
204948
- 18 -
4.4.
Design Justification
Screening phase:
To confirm patients meet inclusion criteria, are not applicable to any of the exclusion criteria and to 
evaluate the condition of the subject’s primary disease, the screening phase within the 28 day period 
before 1st treatment has been set up.
Concomitant use of the medications or therapies for urinary incontinence due to NDO is permitted. 
However, to eliminate influences of these medications or therapies and to evaluate the efficacy and 
safety of GSK1358820 appropriately, status of use of these medications or therapies should maintain 
from at least 7 days before the start of the screening phase and throughout Treatment phase 1. 
Treatment phase:
To evaluate the efficacy and safety of GSK1358820 objectively, placebo will be used as a control.
To maintain the balance of patient background between the treatment groups, stratified randomization, 
according to NDO etiology (SCI with neurological injury level C5 to C8, SCI with neurological injury 
level T1 or below, or MS), will be used.
Six weeks after 1st treatment is chosen as the primary time point based on results in the Phase III 
studies 191622-515 and 191622-516, where significant and sustained reductions from baseline in 
urinary incontinence episodes were observed at 6 weeks after treatment of GSK1358820 200U 
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 200 U at most 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, re-treatment cannot occur until at least 12 weeks from the prior injection has 
elapsed, similar to the case in overseas countries.
4.5.
Dose Justification
Since GSK1358820 200U was approved for the indication of urinary incontinence due to NDO as the 
optimal dose in overseas countries, GSK1358820 200U is deemed to be a dose in the range of optimal 
dose for Japanese patients by the reasons as shown below. Therefore, GSK will examine the efficacy 
and safety of GSK1358820 at the dose of 200 U in Japanese patients with urinary incontinence due to 
NDO.

Diagnosis and principles of treatment of NDO 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 200U in Japanese
NDO patients.


2016N276451_06
CONFIDENTIAL
204948
- 19 -
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:


2016N276451_06
CONFIDENTIAL
204948
- 20 -
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 2 completed 
phase 2 studies (Studies 191622-511 and 191622-
518), 2 completed pivotal phase3 studies (Studies 
191622-515 and 191622-516) and an interim cut 
of the long-term extension study (Study 191622-
094), the frequency of UTI as an adverse event on 
first treatment that patients received occurred in 
53.2% of patients in the 300 U BOTOX group, 
49.2% of patients in the BOTOX 200U group and 
35.7% in the placebo group (refer to IB section 
5.2.4.1 Neurogenic Detrusor Overactivity).
The following potential factors that may have
facilitated the occurrence of UTI were:
1) Routine, daily scheduled CIC for bladder
emptying purposes – both in patients who were 
already catheterizing and those patients in whom 
catheterization (clean, intermittent) was initiated to
manage emptying the bladder when urinary 
retention occurred.
2) Elevated PVR urine volume in patients who did 
not use catheterization pre- or post-treatment
3) Cystoscopy for study drug administration 
procedure (intradetrusor injection) and 
urodynamic evaluations for efficacy assessments 
during study participation.
Patients with potential risk for these events will be 
excluded from this study to reduce the risk of UTI
(refer to Protocol section 5.2 exclusion eriteria 
13、14、18 and 21)
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 patients are not 
allowed to receive the injection of the 
investigational product,if the patient is 
symptomatic for UTI (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)


2016N276451_06
CONFIDENTIAL
204948
- 21 -
Urinary retention
As the result of integrated data with 2 completed 
phase 2 studies (Studies 191622-511and191622-
518), 2 completed pivotal phase3 studies (Studies 
191622-515 and 191622-516) and an interim cut 
of the long-term extension study (Study 191622-
094), the frequency of urinary retention as an 
adverse event on first treatment that patients 
received occurred in 21.3% of patients in the 
BOTOX 300 U group, 17.2% in the BOTOX 
200U group and 2.9% of patients in the placebo 
group (refer to IB section 5.2.4.1 Neurogenic 
Detrusor Overactivity).
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 (IB section 5.2.5 Clinical Safety 
in the published literature).
Patients with potential risk for these events will be 
excluded from this study to reduce the risk of 
urinary retention (refer to Protocol section 5.2 
exclusion eriteria 18 and 21) 
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 NDO clinical studies, pyelonephritis as an AE 
was uncommon and was reported in one patient
(0.4%) in the BOTOX 300U group during 
placebo-controlled treatment cycle 1. However, 
based on the patient population who will be 
Please refer to the mitigation strategy UTIs


2016N276451_06
CONFIDENTIAL
204948
- 22 -
receiving instrumentation to deliver intradetrusor 
injections of BOTOX, and a potential temporary 
increase in PVR urine post treatment, mainly in 
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 
6.2 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.


2016N276451_06
CONFIDENTIAL
204948
- 23 -
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 urinary incontinence due to NDO
in the US, EU and other countries.
In overseas phase III studies conducted in NDO patients with urinary incontinence, who had not been 
adequately managed with anticholinergic therapy (Studies 191622-515 and 191622-516), Botox 200 U 
demonstrated improvement in NDO -related symptoms / parameters (such as frequency of urinary 
incontinence) compared to placebo. Improvement in these symptoms / parameters with GSK1358820 
is also expected in Study 204948.
Although Study 204948 is a placebo-controlled study, all subjects may be treated with GSK1358820 
since 200 U of GSK1358820 will be the treatment received if subjects satisfy the criteria for re-
treatment regardless of the treatment gourp they were randomize 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 NDO.
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 urinary incontinence as a result of neurogenic detrusor overactivity for a period of at 
least 3 months prior to screening as a result of spinal cord injury or multiple sclerosis, determined 
by documented patient history. In addition:

Spinal cord injury patients must have a stable neurological injury level at C5 or below
occurring ≥ 6 months prior to screening.

Multiple sclerosis patients must be clinically stable in the investigator’s opinion, for ≥ 


2016N276451_06
CONFIDENTIAL
204948
- 24 -
3 months prior to screening and have an Expanded Disability Status Scale (EDSS) 
score ≤ 6.5.
3.
Patient has NDO for a period of at least 3 months prior to screening, determined by documented 
patient history

The presence of an IDC must also be demonstrated during the urodynamic assessment 
during the screening period or Day 1 (prior to randomization).
4.
Patient has not been adequately managed with one or more medications (i.e.: anticholinergics or 
beta-3 adrenergic receptor agonist) for treatment of urinary incontinence due to NDO . Not 
adequately managed is defined as:

An inadequate response after at least a 4-week period of medication(s) for urinary 
incontinence due to NDO on an optimized dose(s)a, i.e., patient is still incontinent 
despite medication(s) for urinary incontinence due to NDO, or

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 medication(s) for 
urinary incontinence due to NDO on an optimized dose(s)a
5.
Patient has ≥ 6 episodes of urinary incontinence, with no more than one urgency incontinence-
free day in the 3-day patient bladder diary completed during the screening phase
6.
Patient currently uses clean intermittent catheterization (CIC) and/or temporary indwelling 
balloon catheter, or is willing to use clean intermittent catheterization (CIC) to empty the bladder 
(continuous indwelling catheter is not permitted). Patients currently on CIC should be willing to 
maintain a CIC schedule of at least 3 times per day throughout the study. Caregiver may perform 
CIC. Patients must not use temporary indwelling balloon catheter during the 3-day patient 
bladder diary collection period.
a: approved dose for the indication of OAB or neurogenic bladder (urinary frequency, urinary 
incontinence, etc) in Japan.
WEIGHT
7.
Body weight ≥40 kg at screening
SEX
8.
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.


2016N276451_06
CONFIDENTIAL
204948
- 25 -

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 
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
9.
Patient has given signed informed consent, including compliance with the requirements and 
restrictions listed in the consent form and in this protocol (e.g., complete bladder diaries and 
questionnaires, is able to collect volume voided per void measurements over a 24-hour period, 
and attend all study visits in the opinion of the investigator(or subinvestigator)


2016N276451_06
CONFIDENTIAL
204948
- 26 -
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 a history or evidence of any diseases, functional abnormalities or bladder surgery, 
other than NDO, that may have affected bladder function including but not limited to:
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 
discontinued at least 7days prior to the start of the screening phase
4）Current use of a baclofen pump
5）History of interstitial cystitis, in the opinion of the investigator (or subinvestigator)
6）Past or current evidence of hematuria due to urological / renal pathology or uninvestigated 
hematuria b
7）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.
8）An active genital infection, other than genital warts, either concurrently or within 4 weeks 
prior to Screening
9）Male with previous or current diagnosis of prostate cancer or a prostate specific antigen 
(PSA) level of >10 ng/mL at Screening d
10）Evidence of urethral and/or bladder outlet obstruction, in the opinion of the investigator (or 
subinvestigator)
2.
Patient has a serum creatinine level >2 times the upper limit of normal (ULN) at screening
3.
ALT > 2xULN; and bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%) at screening
4.
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


2016N276451_06
CONFIDENTIAL
204948
- 27 -
5.
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 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
6.
Patient has hemophilia or other clotting factor deficiencies or disorders that cause bleeding 
diathesis
7.
Patient has aspiration pneumonia, aspiration pneumonitis or acute respiratory failure within 12 
months prior to Screening.
8.
Patient currently requires or may require use of supplemental oxygen therapy and/or ventilatory 
support
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
9.
Patient change or initiate or discontinue anticholinergic, beta-3 adrenergic receptor agonist or any 
other medications or therapies to treat urinary incontinence due to NDO, within 6 days prior to 
the start of the screening phase
10. Patient has been treated with any intravesical pharmacologic agent for urinary incontinence due 
to NDO during following period: 

Capsaicin or resiniferatoxin: within 12 months prior to initiation of Treatment phase 1 
(Week 0)

Anticholinergic within 4 weeks prior to start of screening
11. Patient has previous or current use of botulinum toxin therapy of any serotype for the treatment 
of any urological condition
12. 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
13. Patient has been immunized for botulinum toxin of any serotype
14. Patient cannot withhold any antiplatelet or anticoagulant therapy or medications with 


2016N276451_06
CONFIDENTIAL
204948
- 28 -
anticoagulative effects for 3 days e prior to initiation of Treatment phase 1 (Week 0)
15. Patient without a UTI as determined from the urinalysis or urine culture and/or investigator 
opinion, has not initiated prophylactic antibiotic medication 1 to 3 days prior to the initiation of 
Treatment phase 1 (Week 0). Patient with a UTI as determined from the urinalysis or urine 
culture and/or investigator opinion, has not initiated antibiotic medication at least 5 days prior to 
the initiation of Treatment phase 1 (Week 0)
16. Patient is symptomatic for UTI on day of treatment
e: Some medications may need to be withheld for > 3 days, per clinical judgment of the 
investigator (or subinvestigator) 
CONTRAINDICATIONS
17. 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
18. 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 
lateral sclerosis
19. Females who are pregnant, nursing or planning a pregnancy during the study 
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
20. Patient has a post void residual volume above 200 mL f for patients who micturate or have a 
mixed catheterization/spontaneous micturition pattern.
21.
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
22. Patient is currently participating in or has previously participated in another therapeutic study 
within 30 days prior to the start of the Screening phase
23. 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 200 mL
5.3.
Re-treatment Criteria
Patient can request re-treatment at any time the scheduled post-treatment since week 12 after 
treatment. The following re-treatment criteria must be used for the qualification of patient. As well the 
patient can requests re-treatment via telephone. If the patient requests re-treatment via telephone, a 
qualification for re-treatment visit should be conducted within approximately 1-2 weeks of the patient 
request.
Qualification for re-treatment criteria:
1）Patient must have initiated request for re-treatment


2016N276451_06
CONFIDENTIAL
204948
- 29 -
2）Patient experienced ≥ 4 episodes of urinary incontinence, with no more than one  
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 is < 200 mL (for patients who micturate or have a mixed 
catheterization/spontaneous micturition pattern)
4）Body weight ≥40 kg
5）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）Patient is asymptomatic for UTI on day of treatment.
2）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)
3）Negative urine pregnancy test for women of childbearing potential. 
4）For patients without a UTI as determined from the urinalysis or urine culture using the 
sample collected at qualification for re-treatment visit and/or investigator opinion, has 
initiated prophylactic antibiotic medication 1 to 3 days prior to study treatment. For patients 
with a UTI as determined from the urinalysis or urine culture and/or investigator opinion, 
has initiated antibiotic medication at least 5 days prior to study treatment.
5）No occurrence of bladder stones since entry into the study
6）A minimum of 12 weeks (84 days) must have elapsed since the previous treatment
7）Period after 1st treatment did not exceed 36 weeks
8）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


2016N276451_06
CONFIDENTIAL
204948
- 30 -
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
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).


2016N276451_06
CONFIDENTIAL
204948
- 31 -
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.
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. 


2016N276451_06
CONFIDENTIAL
204948
- 32 -
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.

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.


2016N276451_06
CONFIDENTIAL
204948
- 33 -
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)
200 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  (1.0 mL evenly distributed 
into 30 sites, avoiding the trigone and bladder dome)
6.1.2.
Treatment Administration
6.1.2.1.
Antibiotics
For patients without a UTI as determined from the urinalysis or urine culture and/or investigator 
opinion (see section 7.4.6.2.2), prophylactic antibiotics are to be administered 1* to 3 days before 
treatment, on the day of treatment, and 1 to 3 days after treatment.  For patients with a UTI as 
determined from the urinalysis or urine culture and/or investigator opinion (see section 7.4.6.2.2), an
antibiotic to which the identified organism is sensitive is to be administered at least 5 days prior to 
study treatment and continued for at least 3 days following the procedure.
*: If prophylactic antibiotic therapy initiate one day before treatment, it 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, 
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).


2016N276451_06
CONFIDENTIAL
204948
- 34 -
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.

General anesthesia:

must be used for SCI subjects with neurological injury level C5 to C8, according to 
local site practice.

may be used per investigator discretion for subjects with MS or SCI with neurological 
injury level T1 and below, according to local site practice.
Note: the use of neuromuscular blocking agents is not permitted to all subjects
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 three 10 mL syringe pre-filled with 30 mL of study 
medication and one 1 mL syringe pre-filled with saline. The 30 mL of study drug will be administered 
as 30 injections each of 1.0 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 or 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 bladder wall visualization should be immediately 
drained.
Indwelling catheters may be used during the 24 hour post treatment period at the discretion of the 
investigator(or subinvestigator).
All patients must be observed for at least 30 minutes following the study treatment administration. 
Safety monitoring and assessments are to be done according to local site practice (e.g, monitoring of 
blood pressure, pulse rate and, for patients with the ability to spontaneously void, ensuring that patient 
has emptied the bladder before leaving the site).
Spinal cord injury patients with lesions above the T6 level are particularly at risk of developing 
autonomic dysreflexia, which presents with symptoms of increased blood pressure, relative 
bradycardia, headache, and skin flushing [Blackmer, 2003; Paralyzed Veterans of 


2016N276451_06
CONFIDENTIAL
204948
- 35 -
America/Consortium for Spinal Cord Medicine, 2001]. Should autonomic dysreflexia develop in a 
patient, the condition should be immediately handled according to local site practice. An occurrence 
of autonomic dysreflexia during study drug administration will be reported as an adverse event. 
Prior to leaving the study clinic, patients will be instructed to contact the study site if they experience 
any adverse events post-treatment.
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 200 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 NDO etiology (SCI with 
neurological injury level C5 to C8, SCI with neurological injury level T1 or below, or MS).
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 200 U 
will be injected to all subjects.
Other details will be provided in study reference manual (SRM).
6.2.1.
Re-registration of subject
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 in 
to the registration center when a re-screening procedure is started.
See SRM for procedures regarding failure / re-registration of subjects.


2016N276451_06
CONFIDENTIAL
204948
- 36 -
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.


2016N276451_06
CONFIDENTIAL
204948
- 37 -
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.


2016N276451_06
CONFIDENTIAL
204948
- 38 -
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
Patients who will not continue taking medications or therapies* for urinary incontinence due to NDO
should discontinue these medications or therapies* from at least 7 days before the start of the 
screening phase. Patients who will continue using the medications or therapies* for urinary 
incontinence due to NDO should maintain the same dose from at least 7 days before the start of the 
screening phase and throughout Treatment phase 1. Patients can only reduce or discontinue these 
medications or therapies throughout 2nd treatment phase. 
*：. Does not apply to electrostimulation/neuromodulation devices (implanted or external)
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

Intravesical pharmacologic agent for OAB symptom (capsaicin, resiniferatoxin or 
anticholinergic)

Use of electrical stimulation and neuromodulation devices (implanted and external) for the 
treatment of urinary incontinence due to NDO

Use of baclofen pump

Use of indwelling catheters (exception: indwelling catheters may be used during the 24 hour post 
treatment period at the discretion of the investigator).

Cholinesterase inhibitor for the treatment of urinary disturbance
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 have been 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])


2016N276451_06
CONFIDENTIAL
204948
- 39 -

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.

Aminoglycoside antibiotics

Curare-like agents (e.g., rocuronium)
Use of following medications is to be avoided at the same time as the study treatment.

Neuromuscular blocking agents
Initiation of the following non-drug therapy is to be avoided after screening period.

Temporary indwelling balloon catheter
Note: Patients entering the study using temporary balloon catheter may continue its use 
during the study. However, the patient must not use during the 3-day patient bladder diary 
collection period., Patients not already using temporary balloon catheter at screening, must 
not initiate this therapy after screening. 
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.


2016N276451_06
CONFIDENTIAL
204948
- 40 -
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
18a
(verification 
by tel.)
24
30 a
(verification 
by tel.)
36
42
(verification 
by tel.)
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
Xb
Inclusion / exclusion criteria
X
Xb
Neutralizing antibody
Xm
X
X
Efficacy
Urodynamic assessment
Xc
X
Check of bladder diary d
Xb
X
X
X
X
X
X
X
X
X
X
KHQ
Xb
X
X
X
X
X
X
TBS
X
X
X
X
X
X
X
Safety
Adverse eventse
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
Height, Weight
X
Xf
Xf
Vital signs
X
Xb
X
X
X
X
X
X
X
ECG
X
X
X
X
Clinical laboratory (hematology and blood 
chemistry)
X
X
X
X
HBsAg・HCVAb（for subjects who receive or plan 
to receive immunosuppressants）
X
Urinalysis (dipstick)
X
Xb
X
X
X
X
X
X
X
Urinalysis (clinical laboratory) / 
Urine culture / sensitivity g
X
Xb
X
X
X
X
X
X
X
PVR
Xc
X
X
X
X
X
X
X
Ultrasound (kidney / bladder)
X
X
X
X
Urine cytology
X
PSA (Only male)
X
Urinary pregnancy test (Only females of 
reproductive potential) h
X
Xb
X
X
X
X
X
X
X


2016N276451_06
CONFIDENTIAL
204948
- 41 -
EDSS (Only MS patients)
X
Investigational product
Treatment of antibiotic i
X
Treatment of investigational product
X
Confirmation of qualification for re-treatment criteria 
j, k
X
X
X
X
X
Concomitant meds / therapies
Xl
X
X
X
X
X
X
X
X
X
X
X
d = day (s)
(a) Patient can request re-treatment at any time via telephone since week 12 after 1st treatment. If the patient requests re-treatment via telephone, a qualification for re-treatment visit 
should be conducted within approximately 1-2 weeks of the patient request.
(b) Performed prior to treatment.
(c) May be performed during the screening period through Day 1 (prior to randomization) excluding diary data collection days
(d) 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 
during the screening phase). The volume voided is recorded by subjects for one 24-hour period during the 3 day diary collection period.
(e) Only serious adverse events assessed as related to study participation or a GSK product will be recorded from the time when a subject consents
(f) Measured only body weight
(g) Urine culture and sensitivity is performed by the central laboratory when dipstick results are positive for nitrites or leukocyte esterase.
(h) For patients with doubtful reaction in urinary pregnancy test, the investigator (or subinvestigator) may conduct serum pregnancy test.
(i) For patients without a UTI as determined from the urinalysis or urine culture and/or investigator opinion, prophylactic antibiotic are to be administered 1 to 3 days before study 
treatment, on the day of treatment, and 1 to 3 days after treatment. For patients with a UTI as determined from the urinalysis or urine culture and/or investigator opinion, an antibiotic to 
which the identified organism is sensitive is to be administered at least 5 days prior to study treatment and continued for at least 3 days following the procedure. 
(j) 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”.
(k) Patients who are not re-treated will remain in Treatment phase 1 and continue to visit at the scheduled study visit.
(l) Patients who are using the medications or therapies urinary incontinence due to NDO should maintain the same dose from at least 7 days before the start of the screening phase
throughout Treatment phase 1.
(m) Samples may be colleced during the screening period through Day 1 (prior to randomization)


2016N276451_06
CONFIDENTIAL
204948
- 42 -
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-
treatm
ent
Re-treatment (2nd)
Withdra
wal
2
6
12
18a
(verifi
cation 
by tel.) 
b
24a
30a(ve
rificati
on by 
tel.)  
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(ve
rificati
on by 
tel.) 
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 diary c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
KHQ
X
X
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
Xd
Xd
Xd
Xd
Xd
Vital signs
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
ECG
Xf
X
X
Xf
X
X
X
Clinical laboratory 
(hematology and blood 
chemistry)
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
Urinalysis (clinical 
laboratory) / Urine culture / 
sensitivity g
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
PVR
X
X
X
X
X
X
X
X
X
X
X
X
Ultrasound (kidney/bladder)
Xf
X
X
Xf
X
X
X
Urinary pregnancy test (Only 
females of reproductive 
potential) h
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X


2016N276451_06
CONFIDENTIAL
204948
- 43 -
EDSS (Only MS patients)
X
Investigational product
Treatment of antibiotici
X
X
Confirmation of day of 
re-treatment criteriaj
X
X
Treatment of 
investigational productk
X
X
Confirmation of 
qualification for 
re-treatment criteria j,l
Xj, k
Xj ,k
Xj, k
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) Patient can request 2nd re-treatment at any time via telephone since week 12 after re-treatment. If the patient requests re-treatment via telephone, a qualification for re-treatment visit 
should be conducted within approximately 1-2 weeks of the patient request.
(c) 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.
(d) Measured only body weight
(e) Performed prior to treatment
(f) These examination can be completed at the Qualification for re-treatment visit or at any time within 21 days prior to re-treatment
(g) Urine culture and sensitivity is performed by the central laboratory when dipstick results are positive for nitrites or leukocyte esterase
(h) For patients with doubtful reaction in urinary pregnancy test, the investigator (or subinvestigator) may conduct serum pregnancy test.
(i) For patients without a UTI as determined from the urinalysis or urine culture and/or investigator opinion, prophylactic antibiotic are to be administered 1 to 3 days before study 
treatment, on the day of treatment, and 1 to 3 days after treatment. For patients with a UTI as determined from the urinalysis or urine culture and/or investigator opinion, an antibiotic to 
which the identified organism is sensitive is to be administered at least 5 days prior to study treatment and continued for at least 3 days following the procedure. 
(j) Patients who are not retreated will continue to visit at the scheduled study visit.
(k) 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
(l) If qualification for re-treatment criteria was met, the patient will undergo the exams specified in the column marked “If qualification for re-treatment criteria was met”


2016N276451_06
CONFIDENTIAL
204948
- 44 -
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)

Medical history of NDO and etiology

History of NDO medication/reason for NDO 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)
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 at
each clinic visit. The subjects bring the bladder diary of telephone visit at next clinical 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


2016N276451_06
CONFIDENTIAL
204948
- 45 -

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 voidb will be determined by the sponsor 
from the total urine volume measured by the subjects divided by the number of voids (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. Diary collection days should not 
include days in which urodynamics are performed.
Patients must not use temporary indwelling balloon catheter during the 3-day patient bladder diary 
collection period.
a: used for evaluation of primary endpoint (Change from baseline in the daily average number of 
urinary incontinence episodes a at week 6 after the first treatment)
7.3.1.2.
Urodynamic test
Urodynamic testing will be standardized across all study sites and will be conducted according to 
International Continence Society (ICS) standard guidelines (Homma et al, 2002). Patient eligibility, 
with regard to the presence of detrusor overactivity (inclusion criteria # 3) is determined by the 
investigator from the urodynamics procedure completed at screening or randomization/day 1 (prior to 
treatment). The principal investigator, subinvestigator, or trained technician will perform urodynamic 
procedures. Data were interpreted by the principal investigator or a sub-investigator for CRF 
completion. Refer to SRM for the standardized urodynamic procedure.
The following urodynamic parameters are to be measured:

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the first involuntary detrusor contraction (IDC)（
PmaxIDC）

Volume at first IDC (VPmaxIDC)

Maximum detrusor pressure during the storage phase (PdetMax)
7.3.1.3.
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 NDO with urinary incontinence will be assessed using patient-
completed questionnaires as specified below. Questionnaires should be administered in accordance 
with the study scheduleand 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.


2016N276451_06
CONFIDENTIAL
204948
- 46 -
7.3.1.3.1.
King’s Health Questionnaire (KHQ)
Impact of urinary incontinence on QOL will be assessed using KHQ in accordance with the study 
schedule.
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.
7.3.1.3.2.
Treatment Benefit Scale (TBS)
Treatment benefit of GSK1358820 will be assessed with TBS in accordance with the study schedule.
TBS was developed as questionnaire for a patient-based treatment benefit assessment for urinary 
incontinence, and its appropriateness was verified in OAB patients [Colman, 2008]. Since NDO is the 
disorder associated with urinary incontinence as is the case with OAB, TBS is considered to be able to 
assess treatment benefit in NDO patients. It is recommended that subjective evaluation of treatment 
benefit by subjects is used in a clinical study of medical product for the treatment of urinary 
incontinence in EU [EMEA, 2002].
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.
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.


2016N276451_06
CONFIDENTIAL
204948
- 47 -
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. 
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. 


2016N276451_06
CONFIDENTIAL
204948
- 48 -
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 electrocardiograms which are evaluated same day. Refer to Section 5.5.2 for QTc 
withdrawal criteria and additional QTc readings that may be necessary.


2016N276451_06
CONFIDENTIAL
204948
- 49 -
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3must 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.
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 


2016N276451_06
CONFIDENTIAL
204948
- 50 -
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 are positive for nitrites or 
leukocyte esterase and are suggestive of a UTI, 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.
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, 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
For non-catheterizing patients, 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.
For catheterizing patients, the investigator will take into account patient symptoms, presence of 
significant leukocyturia, urine culture results, need for antibiotic treatment, etc. A urinary tract 
infection will be recorded as an adverse event if in the opinion of the investigator, it is symptomatic 
and requires antibiotic treatment. 
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.


2016N276451_06
CONFIDENTIAL
204948
- 51 -
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 will only be measured in non-catheterizing patients, or those with “mixed” patterns (ie, they do 
both CIC and spontaneous voiding). PVR urine volume will be assessed by ultrasound, bladder scan
or catheterization 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. 
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) in patients who were not catheterizing at the 
initiation of the 1st treatment phase 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 


2016N276451_06
CONFIDENTIAL
204948
- 52 -
symptoms (such as voiding difficulties or bladder fullness in patients who have sensation), 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.
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
c.
If the patient does not have bladder sensation and therefore cannot report symptoms, then 
initiation of CIC is per the investigators discretion.
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 


2016N276451_06
CONFIDENTIAL
204948
- 53 -
sponsor if an indwelling catheter is necessary (exception: indwelling catheters may be used during the 
24 hour post treatment period at the discretion of the investigator).
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 in patients who were not catheterizing at baseline 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.
*: If the patient does not have bladder sensation and therefore cannot report symptoms, then initiation 
of CIC is per the investigators discretion.
The following will occur when initiating CIC, in patients who were not catheterizing at baseline:
1）CIC should be performed using sterile, single-use catheters (exception: indwelling catheters 
may be used during the 24 hour post treatment period at the discretion of the investigator)
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 
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.


2016N276451_06
CONFIDENTIAL
204948
- 54 -
Note:  If despite reaching the above criteria, the patient wishes to continue on CIC for reasons of 
convenience, this will be reported on the case report form.
Definition of AE urinary retention
For patients who are not catheterizing at baseline:
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.
*: If the patient does not have bladder sensation and therefore cannot report symptoms, then initiation 
of CIC is per the investigators discretion.
For patients with a “mixed” CIC pattern at baseline:
An adverse event of urinary retention should be recorded if the patient progresses to a “CIC 
exclusive” pattern (ie, no longer able to spontaneously void).
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.
7.4.9.
EDSS
EDSS will be performed only at the screening visit for the purposes of defining the patient’s baseline 
score for inclusion criteria # 2.
7.4.10.
Definition of AE MS exacerbation 
Patients may experience an MS exacerbation during study participation. An MS exacerbation for this 
protocol will be defined as the appearance of a new symptom(s) or worsening of an old symptom(s) 
consistent with a clinical demyelinating event. The symptom(s) must be:


2016N276451_06
CONFIDENTIAL
204948
- 55 -
1.
separated by at least 30 days from the onset of a preceding MS exacerbation
2.
present for at least 24 hours
3.
occurs in the absence of fever or infection
4.
consistent with optic neuritis, myelitis, cerebellar, brainstem, and/or focal cerebral dysfunction. 
Definite focal sensory symptoms will also suffice.
5.
fatigue, bowel, or bladder symptoms alone will not qualify as an exacerbation
Once determined to fulfill the protocol definition, the MS exacerbation will be reported as an adverse 
event on the adverse event eCRF. Symptoms reported but determined not to meet the protocol 
definition of an MS exacerbation (eg, occurred in the presence of an infection, not consistent with a 
clinical demyelinating event, etc.) will not be recorded on the adverse events eCRF as an MS 
exacerbation; however, the symptoms will be reported individually on the adverse events eCRF.
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
This study is not designed to evaluate formal statistical hypotheses.


2016N276451_06
CONFIDENTIAL
204948
- 56 -
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
30 subjects (15 subjects for each treatment group) will be randomized in this study to evaluate the 
efficacy and safety of GSK1358820.
There is no formal calculation of sample size or power for this study. The sample size was determined 
based on the feasibility concerns in Japanese subjects with NDO.
The mean difference in the change from baseline in the daily average number of urinary incontinence 
episodes at week 6 after first treatment between GSK1358820 and placebo was -1.5 episodes/day and 
the standard deviations in GSK1358820 and placebo are 3.10 and 2.56 episodes/day in the integrated 
data of studies 191622-515/191622-516. It is assumed that the mean difference and common standard 
deviation between GSK1358820 and placebo are -1.5 and 3.0 episodes/day from these studies results. 
In the case of 15 subjects for each treatment group, the power at the two-sided significance level of 
5% to detect the treatment difference between GSK1358820 and placebo is 26%. The probability that 
the point estimate of the change from baseline in the daily average urinary incontinence episodes in 
GSK1358820 has a greater magnitude than in placebo is approximately 92%.
9.2.2.
Sample Size Sensitivity
The sample size sensitivity is not evaluated for this study because the sample size was determined 
based on the feasibility rather than the statistical considerations.
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.


2016N276451_06
CONFIDENTIAL
204948
- 57 -
9.3.2.
Interim Analysis
When all the subjects complete treatment phase 1 (or week 24 of treatment phase 1, except for the 
premature withdrawls) 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 6 after the first treatment.
This will be analyzed using a mixed model for repeated measures (MMRM). This model will include 
the treatment group, visit, patient etiology and treatment-by-visit interaction as fixed factors and 
baseline values as a covariate. 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.  
Least-squares mean and its two-sided 95% confidence intervals will be estimated. The dataset 
including only data until week 12 after the first treatment will be used for MMRM.
If the number of subjects for a given etiology group is too few to analyze, then the patient etiology 
will be excluded from the model.
9.4.2.
Secondary Analyses
Efficacy
The following endpoints until week 12 after the first treatment will be analyzed using MMRM. This 
model will include the treatment group, visit, patient etiology and treatment-by-visit interaction as 
fixed factors and baseline values and baseline-by-visit interaction as a covariate. 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, patient etiology as fixed 
factors, and baseline values as a covariate. Least-squares mean and its two-sided 95% confidence 
intervals will be estimated.

Change from baseline and percent change from baseline:

Daily average number of urinary incontinence episodes (except for change from 
baseline at week 6 after the first treatment)

Average volume voided per void

Daily average number of voids
The following endpoints will be analyzed using ANCOVA model at each visit. This model will 
include the treatment group, patient etiology as fixed factors, and baseline values as a covariate. Least-
squares mean and its two-sided 95% confidence intervals will be estimated.

Change from baseline

Urodynamic assessment

Maximum cystometric capacity (MCC)


2016N276451_06
CONFIDENTIAL
204948
- 58 -

Maximum detrusor pressure during the first involuntary detrusor contraction 
(IDC)（PmaxIDC）

Volume at first IDC (VPmaxIDC)

Maximum detrusor pressure during the storage phase (PdetMax)

King's Health Questionnaire (KHQ) domain score
The following endpoints will be summarized by visit. Odds ratio and its two-sided 95% confidence 
intervals will be estimated.

Proportion of subjects attaining 100%, ≥75% and ≥50% reduction from baseline in the daily 
average of urinary 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 qualification for 2nd treatment from the day of 1st treatment

Time to the subject’s first request for 2nd treatment from the day of 1st treatment 
(regardless of fulfilment of the re-treatment criteria)
The time to event will be graphically displayed as Kaplan-Meier curves. Time to request/qualification 
for 2nd and 3rd treatment will not be analyzed.
No formal statistical tests will be done, therefore no adjustment for multiplicity will be made for 
secondary endpoints.
If the number of subjects for a given etiology group is too few to analyze, then the patient etiology 
will be excluded from the models.
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 (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, injection procedure related), AEs leading to 
discontinuation, AEs by intensity, and SAEs also will be provided.
PVR urine volume will be summarized by visit and etiology. The proportion of patients who will have 
a change from baseline in PVR category (urine volume of < 100 mL, ≥ 100 to < 200 mL, ≥ 200 to < 
350 mL, and ≥ 350 mL) will be summarized by visit and etiology.
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.


2016N276451_06
CONFIDENTIAL
204948
- 59 -
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:

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


2016N276451_06
CONFIDENTIAL
204948
- 60 -
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.  

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 


2016N276451_06
CONFIDENTIAL
204948
- 61 -
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, 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.
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.
Blackmer J. Rehabilitation medicine: 1. Autonomic dysreflexia. CMAJ 2003;169:931-935.
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


2016N276451_06
CONFIDENTIAL
204948
- 62 -
Committee for Preparation of the Clinical Guideline for voiding impairment in spinal cord injury, the 
Japanese Continence Society / Japan Medical Society of Spinal Cord Leision. Clinical Guideline for
voiding impairment in spinal cord injury. RichHill Medical Inc. Tokyo. 2011.
Committee for Proprietary Medicinal Products, EMEA. Note for guidance on the clinical investigation 
of medicinal products for the treatment of urinary incontinence. 2002.
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.
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, 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.
Igawa Y. Botulinum toxin injection into bladder wall in neurogenic detrusor overactivity. Voiding 
Disorders Digest. 2012; 20: 217-23.
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
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.
Paralyzed Veterans of America / Consortium for Spinal Cord Medicine. Acute management of 
autonomic dysreflexia: individuals with spinal cord injury presenting to health-care facilities. 
Washington: Paralyzed Veterans of America; 2001.
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.
Sekido N. Medical treatment for neurogenic detrusor overactivity due to spinal cord disorder. Voiding 
Disorders Digest. 2011;19:233-40.
Yokoyama M. Botulinum toxin therapy in urology. Prog Med. 2008;28:1151-5.


2016N276451_06
CONFIDENTIAL
204948
- 63 -
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
EDSS
Expanded Disability Status Scale
EMEA
The European Agency for Evaluation of Medicinal Products
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
IDC
Involuntary Detrusor Contractions
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
KHQ
King’s Health Questionnaire
LDH
Lactate Dehydrogenase
MCC
Maximum Cystometric Capacity
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeated Measures


2016N276451_06
CONFIDENTIAL
204948
- 64 -
MRI
magnetic resonance imaging
NDO
Neurogenic Detrusor Overactivity
OAB
Overactive Bladder
PdetMax
Maximum detrusor pressure during storage phase
PmaxIDC
Maximum detrusor pressure during the first IDC
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
VpmaxIDC
Volume at first IDC
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
BOTOX®
SAS®
InForm™


2016N276451_06
CONFIDENTIAL
204948
- 65 -
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 


2016N276451_06
CONFIDENTIAL
204948
- 66 -
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 


2016N276451_06
CONFIDENTIAL
204948
- 67 -
monitor liver chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.


2016N276451_06
CONFIDENTIAL
204948
- 68 -
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.


2016N276451_06
CONFIDENTIAL
204948
- 69 -
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


2016N276451_06
CONFIDENTIAL
204948
- 70 -

ALT 3xULN and INR** > 1.5.
* 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.


2016N276451_06
CONFIDENTIAL
204948
- 71 -
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.


2016N276451_06
CONFIDENTIAL
204948
- 72 -

The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

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.


2016N276451_06
CONFIDENTIAL
204948
- 73 -
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.


2016N273767_06
CONFIDENTIAL
204948
- 74 -
12.5.
Appendix 5: Management guideline of PVR (in subjects who were not catheterizing at baseline)
PVR <200 mL
PVR 200 mL, <350 mL
PVR 350 mL
Usual study 
visit
No symptoms needing CICa
or patient has associated symptoma but not requiring CIC 
by investigator (or sub-investigator)b
Symptoms requiring
CICa by investigator 
(or sub-investigator)b
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 CICa
by investigator 
(or sub-
investigator)b
No symptoms needing CICa
or patient has associated symptoma
but not requiring CIC 
by investigator (or sub-investigator)b
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 CICa
by investigator 
(or sub-
investigator)b
No symptoms 
needing CICa or 
patient has 
associated 
symptoma but not 
requiring CIC 
by investigator (or 
sub-investigator)b
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 symptomsa
- 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 a
requiring CIC
Follow-up visit 1 week after
discontinuation of CIC
a: such as voiding difficulties or sensation of bladder fullness in 
patients who have sensation
b: if the patient does not have bladder sensation, initiation of 
CIC is per the investigators discretion.


2016N276451_06
CONFIDENTIAL
204948
- 75 -
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 December, 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


2016N276451_06
CONFIDENTIAL
204948
- 76 -
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


2016N276451_06
CONFIDENTIAL
204948
- 77 -
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


2016N276451_06
CONFIDENTIAL
204948
- 78 -
12.7.
Appendix 7：Protocol Changes
12.7.1.
Changes from Original (Effective Date: 28-Apr-2016) to Amendment 01
Corresponding 
part (described 
part before the 
changes)
Before
After
Reason for the 
changes
5.1.Inclusion 
Criteria, # 8
(Page 23)
8. 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]
8. 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.
5.1.Inclusion 
Criteria, # 8
(Page 24)
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.


2016N276451_06
CONFIDENTIAL
204948
- 79 -
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: 13-May-2016) to Amendment 
02
Corresponding part 
(described part 
before the changes)
Before
After
Reason for the 
changes
5.2. Exclusion 
Criteria, #13
(Page 26)
Patient with a negative urinalysis or 
urine culture result has not initiated 
antibiotic medication 1 to 3 days
prior to the initiation of Treatment 
phase 1 (Week 0). Patient with a 
positive urine culture result has not 
initiated antibiotic medication at 
least 5 days prior to the initiation of 
Treatment phase 1 (Week 0)
Patient without a UTI as 
determined from the urinalysis or 
urine culture and/or investigator 
opinion, has not initiated 
prophylactic antibiotic medication 1
to 3 days prior to the initiation of 
Treatment phase 1 (Week 0).
Patient with a UTI as determined 
from the urinalysis or urine culture 
and/or investigator opinion, has not 
initiated antibiotic medication at 
least 5 days prior to the initiation of 
Treatment phase 1 (Week 0)
Change the 
sentence for 
clarification of 
the requirement 
to administrate 
the antibiotic 
medication
6.1.2.1. Antibiotics
(Page 32)
For patients with negative result for 
UTI in urinalysis or urine culture,
prophylactic antibiotics are to be 
administered 1* to 3 days before 
treatment, on the day of treatment, 
and 1 to 3 days after treatment.  
For patients with a positive urine 
culture result indicating a UTI, an
antibiotic to which the identified 
organism is sensitive is to be 
administered at least 5 days prior to 
study treatment and continued for 
at least 3 days following the 
procedure.
For patients withouta UTI as 
determined from the urinalysis or 
urine culture and/or investigator 
opinion (see section 7.4.6.2.2),
prophylactic antibiotics are to be 
administered 1* to 3 days before 
treatment, on the day of treatment, 
and 1 to 3 days after treatment.  
For patients with a UTI as 
determined from the urinalysis or 
urine culture and/or investigator 
opinion (see section 7.4.6.2.2), an
antibiotic to which the identified 
organism is sensitive is to be 
administered at least 5 days prior to 
study treatment and continued for at 
least 3 days following the 
procedure.
Change the 
sentence for 
clarification of 
the requirement 
to administrate 
the antibiotic 
medication
7.1. Time and 
Events Table, Table 
1 footnote (g)
(Page 40)
Table 2 footnote (g)
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 dipstick results are positive 
for nitrites or leukocyte esterase
Change the 
sentence in 
consideration of 
operability in 
central 


2016N276451_06
CONFIDENTIAL
204948
- 80 -
Corresponding part 
(described part 
before the changes)
Before
After
Reason for the 
changes
(Page 42)
laboratory
7.1. Time and 
Events Table, Table 
1 footnote (i)
(Page 40)
Table 2 footnote (i)
(Page 42)
For patients with a negative
urinalysis or urine culture result, an 
antibiotic medication must be
initiated 1 to 3 days prior to study 
treatment on the day of treatment, 
and 1 to 3 days after treatment. For 
patients with a positive urine 
culture result indicating a UTI, an
antibiotic to which the identified 
organism is sensitive is to be 
administered at least 5 days prior to 
study treatment and continued for 
at least 3 days.
For patients without a UTI as 
determined from the urinalysis or 
urine culture and/or investigator 
opinion, prophylactic antibiotic are 
to be administered 1 to 3 days 
before study treatment, on the day 
of treatment, and 1 to 3 days after 
treatment. For patients with a UTI 
as determined from the urinalysis or
urine culture and/or investigator 
opinion, an antibiotic to which the 
identified organism is sensitive is to 
be administered at least 5 days prior 
to study treatment and continued 
for at least 3 days following the 
procedure.
Change the 
sentence for 
clarification of 
the requirement 
to administrate 
the antibiotic 
medication
7.4.6.2.1.Urinalysis 
using a urine 
reagent strip
(Page 49)
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 are 
positive for nitrites or leukocyte 
esterase and are suggestive of a 
UTI, 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
7.4.6.2.2.Urinalysis, 
Culture and 
Sensitivity
(Page 49)
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 49)
•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
For non-catheterizing patients, 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.
For catheterizing patients, the 
investigator will take into account 
patient symptoms, presence of 
Change the 
sentences in 
consideration of 
test result values 
in central 
laboratory
Change the 
sentences for 
clarification of 
the definition in 
urinary tract 
infection


2016N276451_06
CONFIDENTIAL
204948
- 81 -
Corresponding part 
(described part 
before the changes)
Before
After
Reason for the 
changes
significant leukocyturia, urine 
culture results, need for antibiotic 
treatment, etc. A urinary tract 
infection will be recorded as an 
adverse event if in the opinion of 
the investigator, it is symptomatic 
and requires antibiotic treatment.
7.4.7.Post-void 
residual (PVR) 
urine volume
(Page 53)
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)
*: such as voiding difficulties or 
sensation of bladder fullness
a: such as voiding difficulties or 
sensation of bladder fullness in 
patients who have sensation
b: if the patient does not have 
bladder sensation, initiation of
CIC is per the investigators 
direction
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
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. 
12.7.3.
Changes from Amendment 02 (Effective Date: 24-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.
4.6.1.Risk 
Assessment, Use of 
the cystoscopy
It is possible that the cystoscopy 
required for the administration of 
the BOTOX injections could result 
It is possible that the cystoscopy 
required for the administration of 
the BOTOX injections could result 
Change the 
sentence based 
on the revise of 
PPD


2016N276451_06
CONFIDENTIAL
204948
- 82 -
Corresponding part 
(described part after
the changes)
Before
After
Reason for the 
changes
(Page 21)
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)
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 6.2 Warnings and 
Precautions)
the reference
document.
5.2.Exclusion 
Criteria, #8
(Page 26)
Patient has been treated with any 
intravesical pharmacologic agent 
(e.g., capsaicin, resiniferatoxin) for 
urinary incontinence due to NDO
within 12 months prior to initiation 
of Treatment phase 1 (Week 0)
Patient has been treated with any 
intravesical pharmacologic agent
for urinary incontinence due to 
NDO during following period:
・Capsaicin or resiniferatoxin: 
within 12 months prior to initiation 
of Treatment phase 1 (Week 0)
・Anticholinergic within 4 weeks 
prior to start of screening
Change the 
sentence due to 
add the criteria 
for the 
intravesical 
pharmacological 
agent 
(anticholinergic).
5.3.Re-treatment 
Criteria, Day of re-
treatment criteria #4
(Page 28)
For patients with a negative 
urinalysis or urine culture result 
using the sample collected at 
qualification for re-treatment visit, 
an antibiotic medication has been 
initiated 1 to 3 days prior to study 
treatment. For patients with a
positive urine culture result 
indicating a UTI, an antibiotic to 
which the identified organism is 
sensitive is to be administered at 
least 5 days prior to study treatment
For patients without a UTI as
determined from the urinalysis or 
urine culture using the sample 
collected at qualification for re-
treatment visit and/or investigator 
opinion, has initiated prophylactic
antibiotic medication 1 to 3 days 
prior to study treatment. For 
patients with a UTI as determined 
from the urinalysis or urine culture 
and/or investigator opinion, has 
initiated antibiotic medication at 
least 5 days prior to study 
treatment.
Change the 
sentence for 
clarification of 
the criteria 
regarding the 
duration of
antibiotic 
administration 
required before 
re-treatment
6.9.2.Prohibited 
Medications and 
Non-Drug 
Therapies
(Page 37)
・Intravesical pharmacologic agent 
for OAB symptom (e.g.: capsaicin 
or , resiniferatoxin)
・Intravesical pharmacologic agent 
for OAB symptom (capsaicin, 
resiniferatoxin or anticholinergic)
Change the 
sentence for the 
clarification 
regarding 
intravesical 
pharmacological 
agent.
7.4.7.Post-void 
residual (PVR) 
urine volume, 
Initiation of CIC
(Page 52)
・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.
・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.
*: If the patient does not have 
bladder sensation and therefore 
cannot report symptoms, then 
initiation of CIC is per the 
investigators discretion.
Change the 
sentence for 
clarification of 
the requirement 
to initiate CIC
7.4.7.Post-void 
residual (PVR) 
urine volume, 
Definition of AE 
urinary retention
(Page 53)
・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 
・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 
Change the 
sentence for the 
clarification of 
the definition of 
urinary retention 
as an adverse 


2016N276451_06
CONFIDENTIAL
204948
- 83 -
Corresponding part 
(described part after
the changes)
Before
After
Reason for the 
changes
require CIC.
require CIC.
*: If the patient does not have 
bladder sensation and therefore 
cannot report symptoms, then 
initiation of CIC is per the 
investigators discretion.
event.
12.7.4.
Changes from Amendment 03 (Effective Date: 07-Sep-2016) to Amendment 
04
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 4)
Bell Medical Solutions, Inc.
BI Medical Solutions, Inc.
The name of the 
company was 
changed
Treatment Arms 
and Duration (Page 
12)
4.2. Treatment 
Arms and Duration
(Page 17)
At the randomization, patients will 
be stratified according to NDO 
etiology (spinal cord injury [SCI] 
or multiple sclerosis[MS])
At the randomization, patients will 
be stratified according to NDO 
etiology (spinal cord injury [SCI] 
with neurological injury level C5 to 
C8, SCI with neurological injury 
level T1 or below, or multiple 
sclerosis[MS])
Newly set the 
stratification 
factor since SCI 
patient with 
neurological 
injury level C5 
to C8 is added 
as the new 
candidate for this 
study.
4.4.Design 
Justification, 
Treatment phase
(Page 18)
To maintain the balance of patient 
background between the treatment 
groups, stratified randomization, 
according to NDO etiology (SCI or 
MS), will be used.
To maintain the balance of patient 
background between the treatment 
groups, stratified randomization, 
according to NDO etiology (SCI 
with neurological injury level C5 to 
C8, SCI with neurological injury 
level T1 or below, or MS), will be 
used.
Newly set the 
stratification 
factor since SCI 
patient with 
neurological 
injury level C5 
to C8 is added as 
the new 
candidate for this 
study.
5.1.Inclusion 
Criteria, Inclusion 
criteria 2
(Page 23)
•Spinal cord injury patients must 
have a stable neurological injury 
level at T1 or below (cervical 
injuries are excluded) occurring ≥ 6 
months prior to screening.
•Spinal cord injury patients must 
have a stable neurological injury 
level at C5 or below occurring ≥ 6 
months prior to screening.
SCI patient with 
neurological 
injury level C5 
to C8 is added as 
the new 
candidate for this 
study.
5.1.Inclusion 
Criteria, Inclusion 
criteria 6
(Page 24)
Patient currently uses or is willing 
to use clean intermittent 
catheterization (CIC) to empty the 
bladder (indwelling catheter is not 
permitted). Patients currently on 
CIC should be willing to maintain a 
CIC schedule of at least 3 times per 
Patient currently uses clean
intermittent catheterization (CIC) 
and/or temporary indwelling 
balloon catheter, or is willing to use 
CIC to empty the bladder 
(continuous indwelling catheter is 
not permitted). Patients currently on 
Patient currently 
uses temporary 
indwelling 
balloon catheter 
may be included 
in this study.
PPD


2016N276451_06
CONFIDENTIAL
204948
- 84 -
Corresponding part 
(described part after 
the changes)
Before
After
Reason for the 
changes
day throughout the study. Caregiver 
may perform CIC.
CIC should be willing to maintain a 
CIC schedule of at least 3 times per 
day throughout the study. Caregiver 
may perform CIC. Patients must 
not use temporary indwelling 
balloon catheter during the 3-day 
patient bladder diary collection 
period.
5.2. Exclusion 
Criteria, Exclusion 
criteria 7
(Page 27)
－
Patient has aspiration pneumonia, 
aspiration pneumonitis or acute 
respiratory failure within 12 months 
prior to Screening.
To exclude the 
high risk patient 
in terms of 
patient’s safety 
since SCI patient 
with 
neurological 
injury level C5 
to C8 is added as 
the new 
candidate for this 
study.
5.2. Exclusion 
Criteria, Exclusion 
criteria 8
(Page 27)
－
Patient currently requires or may 
require use of supplemental oxygen 
therapy and/or ventilatory support.
To exclude the 
high risk patient 
in terms of 
patient’s safety 
since SCI patient 
with 
neurological 
injury level C5 
to C8 is added as 
the new 
candidate for this 
study.
6.1.2.2. Use of 
Anesthesia
(Page 34)
•General anesthesia may be used 
according to local site practice 
Note: the use of neuromuscular 
blocking agents is not permitted.
•General anesthesia:
•must be used for SCI subjects 
with neurological injury level C5 to 
C8 according to local site practice.
•may be used per investigator 
decision for subjects with MS or
SCI with neurological injury level 
T1 and below, according to local 
site practice.
Note: the use of neuromuscular 
blocking agents is not permitted to 
all subjects
Since SCI patient 
with 
neurological 
injury level C5 
to C8 are at 
increased risk of 
autonomic 
dysreflexia, 
general 
anesthesia during 
injection 
procedure must 
be used for the 
patient..
6.2.Treatment 
Assignment
(Page 35)
At the time of subject assignment, 
patients will be stratified according 
to NDO etiology (SCI or MS).
At the time of subject assignment, 
patients will be stratified according 
to NDO etiology (SCI with 
neurological injury level C5 to C8, 
SCI with neurological injury level 
T1 or below, or MS).
Newly set the 
stratification 
factor since SCI 
patient with 
neurological 
injury level C5 
to C8 is added as 
the new 
candidate for this 
study.
6.9.2. Prohibited 
Medications and 
Non-Drug 
Therapies
－
Cholinesterase inhibitor for the 
treatment of urinary disturbance
Newly set as 
prohibited 
medication 


2016N276451_06
CONFIDENTIAL
204948
- 85 -
Corresponding part 
(described part after 
the changes)
Before
After
Reason for the 
changes
(Page 38)
6.9.2. Prohibited 
Medications and 
Non-Drug 
Therapies
(Page 39)
－
Initiation of the following non-drug 
therapy is to be avoided after 
screening period. In addition, 
patient must not use the following 
non-drug therapy during the 3-day 
patient bladder diary collection 
period.
•Temporary indwelling balloon 
catheter
Note: Patients entering the study 
using temporary balloon catheter 
may continue its use during the 
study. However patients not already 
using temporary balloon catheter at 
screening, must not initiate this 
therapy after screening.
Patient currently 
uses temporary 
indwelling 
balloon catheter 
is to be included 
in this study, 
however should 
not initiate after 
screening period, 
and/or should not 
use during the 
diary collection 
period.
7.1. Time and 
Events Table, 
footnote (m) (Page 
40, 41)
－
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
7.3.1.1. Bladder 
diary
(Page 45)
－
Patients must not use temporary 
indwelling balloon catheter during 
the 3-day patient bladder diary 
collection period.
Patient currently 
uses temporary 
indwelling 
balloon catheter 
is to be included 
in this study, 
however should 
not use during 
the diary 
collection period.
12.7.5.
Changes from Amendment 04 (Effective Date: 14-Apr-2017) to Amendment 
05
Corresponding part 
(described part after 
the changes)
Before
After
Reason for the 
changes
12.6.1.3. Study 
Period
(Page 75)
July, 2016 to August, 2018
July, 2016 to October, 2018
To enroll target 
number of 
subjects


2016N276451_06
CONFIDENTIAL
204948
- 86 -
12.7.6.
Changes from Amendment 05 (Effective Date: 20-Jul-2017) to Amendment 06
Corresponding 
part (described 
part after the 
changes)
Before
After
Reason for the 
changes
Medical 
Monitor/SAE 
Contact 
Information
(Page 4)
Role: Medical Monitor
Name: 
 MD, Ph.D
Phone Number: 
Fax Number: 
Site Address: Glaxo Smith Kline 
K.K. 6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Role: Medical Monitor
Name: 
 MD, Ph.D
Phone Number: 
Fax Number: 
Site Address: Glaxo Smith Kline 
K.K. 8-1, Akasaka 1-chome, Minato-
ku, Tokyo 107-0052 JAPAN
Due to transfer of 
sponsor’s 
headquarter
Medical 
Monitor/SAE 
Contact 
Information
(Page 4)
Role: SAE contact information
Name: GSK1358820 Section, 
Clinical Operation Department
Phone Number: 
Fax Number: 
Site Address: Glaxo Smith Kline 
K.K. 6-15, Sendagaya 4-chome, 
Shibuya-ku, Tokyo 151-8566 
JAPAN
Role: SAE contact information
Name: GSK1358820 Section, 
Clinical Operation Department
Phone Number: 
Fax Number: 
Site Address: Glaxo Smith Kline 
K.K. 8-1, Akasaka 1-chome, Minato-
ku, Tokyo 107-0052 JAPAN
Due to transfer of 
sponsor’s 
headquarter
Emergency 
Contact 
Information
(Page 4)
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
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
Due to transfer of 
sponsor’s 
headquarter
Sponsor Legal 
Registered 
Address
(Page 4)
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
GlaxoSmithKline K.K（GSK）
8-1, Akasaka 1-chome, Minato-ku, 
Tokyo 107-0052 JAPAN
Study Director: 
 
The head of Neurosciences TA 
Office, Medicines Development
Due to transfer of 
sponsor’s 
headquarter
12.6.1.3. Study 
Period
(Page 75)
July, 2016 to October, 2018
July, 2016 to December, 2018
To enroll target 
number of 
subjects
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204948
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 204948
A phase III study to evaluate the efficacy and safety of 
GSK1358820 (botulinum toxin type A) in patients with 
urinary incontinence due to neurogenic detrusor overactivity
Compound Number 
:
GSK1358820
Effective Date 
:
30-JUL-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204948.

This RAP is intended to describe the efficacy and safety analyses required for the 
study. 

This RAP will be provided to the study team members to convey the content of the 
interim and final Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval 
Method
25-JUL-2018
Statistician, Biostatistics Group 2, Biomedical 
Data Sciences, Japan
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
2018N378022_00
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
204948
2
RAP Team Approvals:
Approver
Date
Approval 
Method
25-JUL-2018
e-mail
Manager, Statistical Programming & Reporting 
Group, Biomedical Data Sciences, Japan
25-JUL-2018
e-mail
Japan Project Leader, Future Pipelines 
Discovery Office, Medicines Development, 
Japan
25-JUL-2018
e-mail
Clinical Investigation Leader, Future Pipelines 
Discovery Office, Medicines Development, 
Japan
25-JUL-2018
e-mail
Data Quality Leader, Data Practice Group 1, 
Biomedical Data Sciences, Japan
25-JUL-2018
e-mail
Operations and Science Leader, Clinical 
Operations, Japan
25-JUL-2018
e-mail
Medical Writer, Medical Writing Office, 
Medicines Development, Japan
26-JUL-2018
e-mail
Clinical Safety Scientist, PV Information 
Management Service Dept., Japan
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
27-JUL-2018
e-mail
Manager, Biostatistics Group 2, Biomedical 
Data Sciences, Japan
30-JUL-2018
e-mail
Head, Biomedical Data Sciences, Japan
2018N378022_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
204948
3
2018N378022_00


CONFIDENTIAL
204948
4
TABLE OF CONTENTS
PAGE
RAP AUTHOR(S):...........................................................................................................1
RAP TEAM APPROVALS: ..............................................................................................2
CLINICAL STATISTICS AND CLINICAL PROGRAMMING LINE APPROVALS:.............2
PAGE..............................................................................................................................4
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
5.1.
Study Treatment & Sub-group Display Descriptors.....................................15
5.2.
Baseline Definitions ....................................................................................15
5.3.
Multicentre Studies .....................................................................................16
5.4.
Examination of Covariates, Other Strata and Subgroups............................16
5.4.1.
Covariates and Other Strata ........................................................16
5.4.2.
Examination of Subgroups...........................................................16
5.5.
Multiple Comparisons and Multiplicity .........................................................16
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................16
6.
STUDY POPULATION ANALYSES .......................................................................18
6.1.
Overview of Planned Study Population Analyses........................................18
6.1.1.
Subject Disposition and Populations............................................18
6.1.2.
Protocol Deviation........................................................................18
6.1.3.
Demographic and Baseline Characteristics..................................18
6.1.4.
Prior and Concomitant Medications .............................................19
6.1.5.
Exposure and Treatment Compliance..........................................20
7.
EFFICACY ANALYSES..........................................................................................21
7.1.
Primary Efficacy Analyses ..........................................................................21
7.1.1.
Endpoint / Variables.....................................................................21
7.1.2.
Summary Measure ......................................................................21
7.1.3.
Population of Interest...................................................................21
2018N378022_00


CONFIDENTIAL
204948
5
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
7.1.5.
Statistical Analyses / Methods .....................................................21
7.2.
Secondary Efficacy Analyses......................................................................23
7.2.1.
Endpoint / Variables.....................................................................23
7.2.2.
Summary Measure ......................................................................23
7.2.3.
Population of Interest...................................................................23
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................23
7.2.5.
Statistical Analyses / Methods .....................................................24
8.
SAFETY ANALYSES .............................................................................................27
8.1.
Adverse Events Analyses ...........................................................................28
8.2.
Adverse Events of Special Interest Analyses..............................................29
8.3.
Clinical Laboratory Analyses.......................................................................30
8.4.
Other Safety Analyses ................................................................................31
8.5.
Study Specific Safety Analyses...................................................................31
8.5.1.
Post Void Residual (PVR) Urine Volume......................................31
8.5.2.
Clean Intermittent Catheterization (CIC) ......................................32
8.5.3.
Ultrasound ...................................................................................32
8.5.4.
General Anesthesia .....................................................................32
8.6.
Patient Profile Listings ................................................................................33
9.
OTHER ANALYSIS ................................................................................................34
10. REFERENCES.......................................................................................................35
11. APPENDICES........................................................................................................36
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................36
11.1.1.
Exclusions from Per Protocol Population .....................................36
11.2.
Appendix 2: Schedule of Activities ..............................................................37
11.2.1.
Protocol Defined Schedule of Events...........................................37
11.3.
Appendix 3: Assessment Windows .............................................................41
11.3.1.
Definitions of Assessment Windows for Efficacy Analyses...........41
11.3.2.
Definitions of Assessment Windows for Safety Analyses 
(only Week 48 visit and Withdraw visit)........................................42
11.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................44
11.4.1.
Study Phases ..............................................................................44
11.4.2.
Treatment Emergent Flag for Adverse Events .............................46
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................47
11.5.1.
Reporting Process .......................................................................47
11.5.2.
Reporting Standards....................................................................47
11.6.
Appendix 6: Derived and Transformed Data ...............................................49
11.6.1.
General........................................................................................49
11.6.2.
Study Population..........................................................................49
11.6.3.
Efficacy........................................................................................51
11.6.4.
Safety ..........................................................................................57
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................60
11.7.1.
Premature Withdrawals................................................................60
11.7.2.
Handling of Missing Data.............................................................60
11.7.3.
Handling of Missing Data for Statistical Analysis..........................61
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................62
2018N378022_00


CONFIDENTIAL
204948
6
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................63
11.9.1.
Abbreviations...............................................................................63
11.9.2.
Trademarks .................................................................................64
11.10. Appendix 10: List of Data Displays..............................................................65
11.10.1. Data Display Numbering..............................................................65
11.10.2. Mock Example Shell Referencing ................................................65
11.10.3. Deliverables.................................................................................65
11.10.4. Convention for titles of Tables, Figures and Listings....................65
11.10.5. Study Population Tables..............................................................67
11.10.6. Efficacy Tables ............................................................................69
11.10.7. Efficacy Figures ...........................................................................75
11.10.8. Safety Tables...............................................................................77
11.10.9. Safety Figures .............................................................................86
11.10.10.ICH Listings .................................................................................87
11.10.11.Non-ICH Listings..........................................................................90
11.10.12.Patient Profile Listings .................................................................91
11.11. Appendix 11: Example Mock Shells for Data Displays ................................92
11.12. Appendix 12: How to identify the records for the interim analysis................93
2018N378022_00


CONFIDENTIAL
204948
7
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Protocol Revision Chronology:
Original 
2016N276451_00
28-Apr-2016
Original
Amendment 
Number 01
2016N276451_01
13-May-2016

Delete the contraceptive methods which can not be 
used in Japan.
Amendment 
Number 02
2016N276451_02
24-Jun-2016
Clarify the requirement for antibiotic administration 
which is needed before study treatment
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
Amendment 
Number 03
2016N276451_03
07-Sep-2016
Change the part of exclusion criteria for the use of 
intravesical pharmacological agent
Clarify the day of re-treatment criteria regarding the 
duration of antibiotic administration
Clarify the intravesical pharmacological agent as a 
prohibited medication
Clarify the initiation of clean intermittent 
catheterization and definition of urinary retention as 
an adverse event
Amendment 
Number 04
2016N276451_04
14-Apr-2017
Change the inclusion criteria, and add the 
exclusion criteria and the stratification factor since 
spinal cord injury patient with neurological injury 
level C5 to C8 is added as the new candidate for 
this study.
Change the use of general anesthesia partially 
since spinal cord injury patient with neurological 
injury level C5 to C8 is added as the new candidate 
for this study.
Change the inclusion criteria since patient currently 
uses temporary indwelling balloon catheter is to be 
2018N378022_00


CONFIDENTIAL
204948
8
included in this study.
Add the cholinesterase inhibitor for the treatment of 
urinary disturbance as the prohibited medication
Change the schedule of sample collection for 
neutralizing antibody partially
Amendment 
Number 05
2016N276451_05
20-Jul-2017
Extend the study period
Amendment 
Number 06
2016N276451_06
16-Nov-2017
Change the medical monitor/sponsor information 
page
Extend the study period
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
To use MMRM and ANCOVA for 
percent change from baseline in

Daily average number of urinary 
incontinence

Average volume voided per void

Daily average number of voids
To provide only summary 
statistics, not statistical 
analyses.
Upon blind review for 
endpoints of percent change 
from baseline, it was 
considered that normality 
assumptions are violated for 
percent change from baseline 
in "Daily average number of 
urinary incontinence". 
Therefore, it is not 
appropriate to apply 
MMRM/ANCOVA for these 
endpoints and only summary 
statistics will be provided. To 
be consist with this change, 
only summary statistics of 
percent change from baseline 
in "Average volume voided 
per void" and "Daily average 
number of voids" will be 
provided without any 
statistical analyses.
2018N378022_00


CONFIDENTIAL
204948
9
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objective
Primary Endpoint

To evaluate the efficacy of a 
single dose treatment of 
GSK1358820 200 U

Change from baseline in the daily average number 
of urinary incontinence episodes at week 6 after the 
first treatment.
Secondary Objectives
Secondary Endpoint

To evaluate the efficacy of a 
single dose treatment of 
GSK1358820 200 U compared 
with placebo

To evaluate the efficacy of 
repeated dose treatment of 
GSK1358820 200 U

Changes from baseline at week 6 after the first 
treatment in the following endpoints by urodynamic 
assessment

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the 
first involuntary detrusor contraction
(IDC) (PmaxIDC)

Volume at first IDC (VPmaxIDC)

Maximum detrusor pressure during the 
storage phase (PdetMax)

Changes from baseline and percentage change 
from baseline in the following endpoints

Daily average number of urinary 
incontinence episodes

Daily average number of voids

Average volume voided per void

Proportion of patients attaining 100%, ≥75% and 
≥50% reduction from baseline in the daily average 
of urinary 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 score

Proportion of patients with positive 
response on the Treatment Benefit Scale 
(TBS)

To evaluate the safety of a single 
dose treatment of GSK1358820 
200 U compared with placebo

To evaluate the safety of a 
repeated dose treatment of 
GSK1358820 200 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 
2018N378022_00


CONFIDENTIAL
204948
10
Objectives
Endpoints
(CIC) for urinary retention / elevated 
PVR [Only patients who are able to 
spontaneously void (excluding mixed 
catheterization) at baseline]

Kidney and bladder ultrasound

Pregnancy test

Twelve-lead electrocardiogram (ECG)
Other Objectives
Other Endpoints

To evaluate the existence of 
toxin-neutralizing antibody after 
the treatment of GSK1358820 
200U

Neutralizing antibody measurement
Note: “Daily average” means “Daily frequency calculated by 3-day dairy”. More detail 
for calculation methods will be in section 11.6.3.
2018N378022_00


CONFIDENTIAL
204948
11
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
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
Dosing

Subjects meeting the eligibility criteria will be randomly assigned by the 
registration center to one of the 2 treatment arms (either 200 U 
GSK1358820 or placebo) in a ratio of 1:1. Subsequently, in Treatment 
phase 1, subjects will receive single treatment with the allocated study drug 
(30 injections each of 1.0 mL) which will be injected into the detrusor muscle 
of bladder.

Subjects who meet the criteria for re-treatment between 12 to 36 weeks 
after 1st treatment will enter to Treatment phase 2 to receive re-treatment. 
Subjects are permitted to receive re-treatment until up to 36 weeks after 1st 
treatment and at most 2 times
Treatment 
Assignment

Number of subjects (randomized subjects): 30 (15 per group)

GSK RandAll NG will be used to generate the randomization schedule.

The randomization will be stratified by NDO etiology (SCI with neurological 
injury level C5 to C8, SCI with neurological injury level T1 or below, or MS).
Interim 
Analysis

Interim analysis is planned in this study as described in 3.1.
2.4.
Statistical Hypotheses / Statistical Analyses
This study is not designed to evaluate formal statistical hypotheses.
2018N378022_00


CONFIDENTIAL
204948
12
3.
PLANNED ANALYSES
3.1.
Interim Analyses
The interim planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed treatment phase 1 (or week 24 of treatment phase 1, 
except for the premature withdraw) as defined in the protocol.
2.
If the subject completes treatment phase 1 and receives 2nd treatment, this subject 
should have completed the visit corresponding to 24 weeks after 1st treatment.

The subject who completed Week 12 visit and was re-treated at a visit before Week 
18 in treatment phase 1 should complete the Week 12 visit in treatment phase 2.

The subject who completed Week 18 visit and was re-treated at a visit before Week 
24 in treatment phase 1 should complete the Week 6 visit in treatment phase 2.
3.
All required database cleaning activities have been completed and interim database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
4.
All criteria for unblinding the randomization codes have been met. 
5.
Randomization codes have been distributed according to RandAll NG procedures.
The interim analyses will be performed for regulatory submission. However subject level 
data will not be disclosed to people who work at the sites including investigators.
In interim analyses, the following analyses will be done with datasets which will include 
data until 24 weeks after 1st treatment.

Study population

Efficacy and safety analyses for treatment cycle (TC) 1 (except for time to event 
analyses)

Safety analyses for Overall period (i.e., the analyses for population “SP1”, which 
include subjects who had at least one GSK1358820 treatment)
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final DBR and 
DBF has been declared by Data Management.
2018N378022_00


CONFIDENTIAL
204948
13
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprise all screened subjects

Study Population
Enrolled

All participants who passed screening and entered 
the study. Included are: only Randomized 
Participants

Note screening failures (who never passed 
screening even if rescreened) are excluded from 
the Enrolled population as they did not enter the 
study.

Study Population
Full Analysis Set
1 (FAS1)

Comprise all randomized subjects who have at 
least 1 post-baseline efficacy assessment.

This population will be based on the treatment 
to which the subject was randomized (this will 
be applied to FAS2 and FAS3).

Any subject who receives a treatment 
randomization number will be considered to 
have been randomized.

Study Population

Efficacy for the TC 1 
(double blind phase)
Full Analysis Set 
2 (FAS2)

Comprise all randomized subjects who have at 
least 1 post-2nd treatment efficacy 
assessment after 2nd treatment.

Efficacy for the TC 2
Full Analysis Set 
3 (FAS3)

Comprise all randomized subjects who have at 
least 1 post-3rd treatment efficacy assessment 
after 3rd treatment.

Efficacy for the TC 3
Safety for double 
blind phase
(SPDB)

Comprise all subjects who receive at least one 
dose of study treatment.

This population will be based on the treatment 
the subject actually received (this will be 
applied to all safety population).

Safety for the TC 1 
(double blind phase)
Safety 1 (SP1)

Comprise all subjects who receive at least one 
dose of GSK1358820

Safety for at least 
one dose of 
GSK1358820
treatment
Safety 2 (SP2)

Comprise all subjects who receive at least two 
doses of GSK1358820

Safety for two doses 
of GSK1358820
treatment
Safety 3 (SP3)

Comprise all subjects who receive three doses 
of GSK1358820.

Safety for three 
doses of 
GSK1358820
2018N378022_00


CONFIDENTIAL
204948
14
Population
Definition / Criteria
Analyses Evaluated
treatment
NOTES : 

Please refer to Appendix 10: List of Data Displays: List of Data Displays which details the population to be used for 
each display being generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [25JUL2018, version 1.4].
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
summary will be based on data as recorded on the inclusion/exclusion page of the eCRF.
2018N378022_00


CONFIDENTIAL
204948
15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
In TC1, the treatment group description will be used as above table.
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
GSK1358820 200U vs Placebo
In re-treatment, all subjects who met re-treatment criteria will be administered 
GSK1358820 200U, therefore, but the treatment group description as below table will be 
used except for TC1. 
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. For urinary diary data, the baseline value will be the latest pre-dose 3-day diary 
which has at least one valid diary day. If time is not collected, Day 1 assessments are 
assumed to be taken prior to first dose and used as baseline. This baseline means “study 
baseline”. “Study baseline” will be used for all analyses using baseline data (e.g., change 
from baseline).
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
Treatment Group Descriptions for TC1
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF
A
GSK1358820 200U
GSK1358820 200U
2
B
Placebo
Placebo
1
Treatment Group Descriptions except for TC1
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF
A
GSK1358820 200U
GSK1358820 200U /
GSK1358820 200U
2
B
Placebo
Placebo / GSK1358820 200U
1
2018N378022_00


CONFIDENTIAL
204948
16
5.3.
Multicentre Studies
In this multicentre local study, randomization will be presented by investigative site.
In primary efficacy analysis, centres will not be included in statistical model. Treatment-
by-centre interaction will not be evaluated.
5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered.
Category
Item
Details
Strata
NDO etiology (SCI with 
neurological injury level 
C5 to C8, SCI with 
neurological injury level 
T1 or below, or MS)
This is the randomization strata factor.
This factor will NOT be included in all statistical model, because 
the numbers of subjects of SCI with neurological injury level 
C5 to C8 and MS are small.
Descriptive summaries results will also not be provided by each 
category.
Covariate
Nothing
Considering small number of subjects in this study, subgroup 
analysis will not be meaningful.

5.4.2.
Examination of Subgroups
Examination of subgroup will not be done in this study. Considering small subjects in 
this study, subgroup analysis will not be meaningful.
5.5.
Multiple Comparisons and Multiplicity
This study is not designed to evaluate formal statistical hypotheses. Therefore, the 
multiplicity will not be adjusted for any endpoints.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
2018N378022_00


CONFIDENTIAL
204948
17
Section
Component
11.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.5
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
2018N378022_00


CONFIDENTIAL
204948
18
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “FAS1” population, unless otherwise 
specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 10: List of Data Displays.
6.1.1.
Subject Disposition and Populations
For FAS1 population, the number and percentage of subjects who completed the study as 
well as withdraw early from study will be summarized in each treatment group, along 
with the reasons for early withdrawal. In addition, the number and percentage of subjects 
of screening status (enrolled or failed) and the reason for screen failure will be 
summarized.
Using Screened population, the number and percentage of subjects in each treatment 
group and non-randomized subjects will be summarized by status (entered, completed or 
withdrawn) at each epoch (screening phase, double blind phase and open label phase).
The number and percentage of subjects at each centre and country will be summarized 
(this study includes only Japan as country, but country will be displayed) in each 
treatment group and total.
Using Screened population, the number of subjects in each population (Screened, passed 
screening phase (Enrolled), entered each phase (FAS1, FAS2, FAS3, SPDB, SP1, SP2, 
SP3)) will be summarized total and by treatment group (not including the screened 
population). 
The subjects excluded from any FAS population or SP population will be only listed, not 
summarized.
6.1.2.
Protocol Deviation
The number and percentage of subjects with important protocol deviation will be 
summarized.
6.1.3.
Demographic and Baseline Characteristics
Each of the following types of data will be summarized in each treatment group and total:

Demographic data (age, sex, ethnicity, weight, height, body mass index 
(BMI), race and racial combinations)
2018N378022_00


CONFIDENTIAL
204948
19

Baseline disease characteristics 
Items of diary data

Daily average episodes of urinary incontinence

Daily average episodes of voids

Average volume voided per void
PVR volume and number and percentage of subjects with its category (no 
measurement of PVR, < 100 mL, >= 100 mL to < 200 mL, >= 200 mL to 
< 350 mL or >= 350mL)
Duration of NDO history
Number and percentage of subjects with NDO etiology (SCI with 
neurological injury level C5 to C8, SCI with neurological injury level T1 
or below, or MS)
(For subject with SCI only): Number and percentage of subjects with 
ASIA (American Spinal Injury Association) impairment scale (A: 
complete, B: sensory incomplete, C: motor incomplete, D: motor 
incompletes or E: normal)
Number and percentage of subjects of void pattern (CIC only, Mixed
(catheterization and spontaneous void), Spontaneous void only, Mixed 
(Intermittent balloon catheter and spontaneous void), CIC and 
Intermittent balloon catheter or Mixed (CIC, Intermittent balloon catheter 
and spontaneous void))
Urodynamics

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the first involuntary detrusor 
contraction (IDC) (PmaxIDC)

Volume at first involuntary detrusor contraction (VPmaxIDC)

Maximum detrusor pressure during the storage phase (PdetMax)

Age ranges (for EudraCT requirement)
6.1.4.
Prior and Concomitant Medications
All medication used in this study will be coded according to drug name as defined in the 
GSK Drug Dictionary. The relationship between the ATC level 1 and ingredient will be 
summarized for the all concomitant medication and the prior or concomitant NDO
medication.
The number and percentage of subjects who used prior NDO medication (anticholinergic 
drug, beta-3 agonist or both anticholinergic drug and beta-3 agonist) will be summarized 
by treatment group. In addition, the number and percentage of subjects with use of NDO 
medication (anticholinergic drug and/or beta-3 agonist, or No use) at baseline will be 
2018N378022_00


CONFIDENTIAL
204948
20
summarized by treatment group. Identification of anticholinergic drug and beta-3 agonist 
is written in section 11.6.2,
The primary reason the prior medication NOT considered to adequately manage the 
symptom by NDO medication will be summarized. The reasons should be ‘Lack of 
efficacy’ or ‘Adverse Event’. 
The listing will be provided for Current/Past medical conditions. The conditions will not 
be coded any dictionary, and will be presented as verbatim text.
6.1.5.
Exposure and Treatment Compliance
In this study, subjects who met the eligibility criteria will receive either GSK1358820 
200 U or placebo at week 0. After 12 weeks or later, subjects who met the criteria for re-
treatment may receive re-treatment of GSK1358820 200U and at most 2 times (i.e., one 
subject may receive the treatment at most 3 times). It is noted that a minimum of 12 
weeks need to be elapsed since previous study treatment. Considering this study drug 
characteristics, treatment compliance will not be calculated. Instead, cumulative duration 
of follow-up in Overall period (by using SP1) and duration of follow-up by treatment 
cycle (TC1 by using SPDB, GTC1, GTC2 and GTC3 by using SP1) and number of study 
treatment injection will be presented (by using SPDB). Duration of follow-up will be 
calculated as described in 11.6.2
The number and percentage of subjects will be summarized in accordance with following 
category. For (cumulative) duration of follow-up, summary statistics will also be 
provided.
Item
Category
(Cumulative) duration of follow-up
< 2 weeks
>= 2 weeks
>= 6 weeks
>= 12 weeks
>= 18 weeks
>= 24 weeks
>= 30 weeks
>= 36 weeks
>= 42 weeks
>= 48 weeks
In addition, summary statistics will be calculated.
Number of study treatment injection
1
2
3
2018N378022_00


CONFIDENTIAL
204948
21
7.
EFFICACY ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint is change from baseline in the daily average number of urinary 
incontinence episodes at week 6 after the first treatment.
Note: “Daily average” means “Daily frequency calculated by 3-day dairy”. More detail 
for calculation methods will be in section 11.6.3
7.1.2.
Summary Measure
Mean treatment difference at week 6 after the first treatment
7.1.3.
Population of Interest 
The primary efficacy analyses will be based on the FAS1 population.
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Following strategy will be planed for intercurrent events. Note that these strategies will 
be applied for the data until 12 weeks after first administration.
Intercurrent Events
Strategy
Treatment discontinuation / Study 
withdrawal
Considering the characteristics of study treatment, treatment 
discontinuation is not defined in this study.
In primary analysis, the missing data after study withdrawal will 
not be imputed and treated as missing. This means it is 
assumed that missing mechanism is missing-at-random for 
primary endpoint. This study is not designed to confirm formal 
statistical hypothesis, so sensitivity analysis will not be done.
Use of protocol inhibited medication
Not planned any specific handling for use of protocol inhibited 
medication.
Use of rescue medication
Rescue medication is not defined in this study.
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
2018N378022_00


CONFIDENTIAL
204948
22
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and
listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Change from baseline in the daily average number of urinary incontinence episodes at week 
6 after the first treatment
o
“Daily average” means “Daily frequency calculated by 3-day dairy”. More detail 
for calculation methods will be in section 11.6.3
Model Specification

The endpoint will be analyzed using a mixed model for repeated measures (MMRM).

Terms fitted in the MMRM model will include:

Fixed, categorical effects: treatment, visit, treatment-by-visit interaction

Fixed, continuous effects: baseline daily average number of urinary incontinence 
episodes, baseline-by-visit interaction

Since the numbers of subjects of both SCI with neurological injury level C5 to C8 and MS are 
small, NDO etiology will not be included in MMRM, as described in study protocol.

An unstructured variance structure will be used to model the within-subject errors, shared 
across treatments.

The Kenward-Roger option in SAS PROC MIXED will be used to estimate denominator 
degrees of freedom and standard errors.
Model Checking & Diagnostics

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ 
on the REPEATED line.
o
In the event that this model fails to converge, alternative correlation structures 
may be considered such as CSH or CS. 

Akaike's Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
Model Results Presentation

Adjusted means (least square means: LS means) and corresponding standard errors (SEs)
of means will be presented for each treatment by visit, together with estimated treatment 
differences (GSK1358820 – Placebo), the corresponding 95% confidence intervals. The 
primary treatment comparison will be the contrast between treatments at week 6 after the 
first treatment.

Plots of LS means and SEs from the model will be generated for each treatment by visit.
Data included in Model

The dataset including only data until week 12 after the first treatment will be used.
2018N378022_00


CONFIDENTIAL
204948
23
7.2.
Secondary Efficacy Analyses
Secondary endpoints include ones for both double blind phase and open label phase. For 
endpoint in open label phase, only summary statistics and no statistical analyses will be 
provided because treatment comparison is not of interest for open label phase.
7.2.1.
Endpoint / Variables

Changes from baseline at week 6 after the first treatment in the following 
endpoints by urodynamic assessment
o
Maximum cystometric capacity (MCC)
o
Maximum detrusor pressure during the first involuntary detrusor
contraction (IDC)（PmaxIDC）
o
Volume at first IDC (VPmaxIDC)
o
Maximum detrusor pressure during the storage phase (PdetMax)

Changes from baseline and percentage change from baseline in the following 
endpoints
o
Daily average number of urinary incontinence episodes
o
Daily average number of voids
o
Average volume voided per void

Proportion of patients attaining 100%, ≥75% and ≥50% reduction from baseline in 
the daily average of urinary incontinence episodes

Duration of treatment effect after 1st treatment
o
Time to qualification for retreatment
o
Time to request for retreatment

Health outcome
o Changes from baseline in King's Health Questionnaire (KHQ) domain score
o Proportion of patients with positive response on the Treatment Benefit Scale 
(TBS)
7.2.2.
Summary Measure
Mean treatment difference or odds ratio by visit, or hazard ratio for double blind period.
No treatment comparison for open label period.
7.2.3.
Population of Interest 
The secondary efficacy analyses will be based on the FAS1, FAS2 or FAS3 population, 
unless otherwise specified. Population will depend on TCs.
7.2.4.
Strategy for Intercurrent (Post-Randomization) Events
For binary data, DO=NR rule will be applied to missing data until 12 weeks after 1st
treatment. For time to event data, missing data will be treated as censor. All missing data 
for other secondary endpoints not mentioned above are treated as missing, will not be 
imputed, unless otherwise specified.
2018N378022_00


CONFIDENTIAL
204948
24
7.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
Note that statistical methodology will be applied to only TC1. Summary statistics will be 
provided for TC2 and TC3.
7.2.5.1.
Statistical Methodology Specification
Secondary Statistical Analyses for change from baseline  until week12 after first treatment
Endpoint(s)

Change from baseline

Daily average number of urinary incontinence

Average volume voided per void

Daily average number of voids
Model Specification

The endpoints will be analyzed using a mixed model for repeated measures (MMRM).

Terms fitted in the MMRM model will include:

Fixed, categorical effects: treatment, visit, treatment-by-visit interaction

Fixed, continuous effects: baseline value, baseline-by-visit interaction

Since the numbers of subjects of both SCI with neurological injury level C5 to C8 and MS are 
small, NDO etiology will not be included in MMRM, as described in study protocol.

An unstructured variance structure will be used to model the within-subject errors, shared 
across treatments.

The Kenward-Roger option in SAS PROC MIXED will be used to estimate denominator 
degrees of freedom and standard errors.
Model Checking & Diagnostics

Refer to 7.1.5.
Model Results Presentation

Adjusted means (LS means) and corresponding SEs of means will be presented for each 
treatment by visit, together with estimated treatment differences (GSK1358820 – Placebo), the 
corresponding 95% confidence intervals.
Data included in Model

The dataset including only data until week 12 after the first treatment will be used.
Secondary Statistical Analyses for change from baseline after week12 after first treatment
Endpoint(s)

Change from baseline

Daily average number of urinary incontinence

Average volume voided per void
2018N378022_00


CONFIDENTIAL
204948
25
Secondary Statistical Analyses for change from baseline after week12 after first treatment

Daily average number of voids
Model Specification

The endpoints will be analyzed using an analysis of covariance (ANCOVA) model.

Terms fitted in the ANCOVA model will include:

Fixed, categorical effects: treatment

Fixed, continuous effects: baseline value

Since the numbers of subjects of both SCI with neurological injury level C5 to C8 and MS are 
small, NDO etiology will not be included in MMRM, as described in study protocol.

The Kenward-Roger option in SAS PROC MIXED will be used to estimate denominator 
degrees of freedom and standard errors.
Model Results Presentation

Adjusted means (LS means) and corresponding SEs of means will be presented for each 
treatment by visit, together with estimated treatment differences (GSK1358820 – Placebo), the 
corresponding 95% confidence intervals.
Secondary Statistical Analyses for change from baseline after first treatment
Endpoint(s)

Change from baseline at week 6 after the first treatment

Maximum cystometric capacity (MCC)

Maximum detrusor pressure during the first involuntary detrusor contraction (IDC) (PmaxIDC)

Volume at the first involuntary detrusor contraction (VPmaxIDC)

Maximum detrusor pressure during the storage phase (PdetMax)

KHQ domain score (role limitations, social limitations)
Model Specification

Same as “Secondary Statistical Analyses for change from baseline after week12 after first 
treatment”.
Model Results Presentation

Same as “Secondary Statistical Analyses for change from baseline after week12 after first 
treatment”.
Secondary Statistical Analyses for Binary data
Endpoint(s)

Proportion of subjects attaining 100%, ≥75% and ≥50% reduction from baseline in the daily 
average of urinary incontinence episodes

Proportion of subjects with positive response on the TBS
Results Presentation

The number and percent of subjects who met each endpoint will be summarized by treatment 
and visit.

The odds ratio and its 95% confidence interval will also be presented.
Missing Data

Missing data until week 12 after first treatment will be treated as non-responder or no positive 
response. Missing data after week 12 after first treatment will be treated as missing.
2018N378022_00


CONFIDENTIAL
204948
26
Secondary Statistical Analyses for Binary data

This rule will be called as “DO=NR” rule. DO=NR means dropout equals to non-responder.
Secondary Statistical Analyses for Time to Event data
Endpoint(s)

Time to the subject’s first request for 2nd treatment from the day of 1st treatment 

Time to the subject’s first qualification for 2nd treatment from the day of 1st treatment
Model Specification

The above endpoints will be displayed as Kaplan-Meier curves.
Model Results Presentation

Only summary statistic will be calculated. No statistical model will be applied.
Definition of Event in these endpoints
Time to the subject’s first request for 2nd treatment from the day of 1st treatment

Event is considered to occur at “Date of subject status” in eCRF when the following items 
meet for the first time.
o
Answer to question “Did patient initiate request for retreatment?” in eCRF = “Yes”
o
Regardless of answer to question “Did patient qualify for retreatment?” in eCRF
Time to the subject’s first qualification for 2nd treatment from the day of 1st treatment

Event is considered to occur at “Date of subject status” in eCRF when the following items 
meet for the first time.
o
Answer to question “Did patient initiate request for retreatment?” in eCRF = “Yes”
o
Answer to question “Did patient qualify for retreatment?” in eCRF = “Yes”
(Time to the subject’s first request for 2nd treatment from the day of 1st treatment)
= (the earliest date when “Yes” response to the eCRF question “Did patient initiate request for 
retreatment?”) – the day of first treatment + 1
(Time to the subject’s first qualification for 2nd treatment from the day of 1st treatment)
= (the earliest date when “Yes” response to the eCRF question “Did patient qualify for 
retreatment?”) – the day of first treatment + 1
Censoring

If the subject withdraws the study prematurely before receiving 2nd treatment, this subject will 
be regarded as censored at the date of study withdraw.

If the subject completes the study without request for the 2nd treatment, the subject will be 
regarded as censored at the date of study complete.
For urodynamic measurement, there might be the subjects in whom an IDC was 
confirmed as not occurring during urodynamics. Since the absence of IDC shows a 
positive treatment effect, the number of subjects in whom an IDC was confirmed as not 
occurring will be summarized at week 6. Statistical analysis will not be provided for the 
number of subjects in whom an IDC was confirmed as not occurring. Urodynamics data 
convention is in section 11.6.3.
2018N378022_00


CONFIDENTIAL
204948
27
8.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population, unless otherwise specified.
In detail, each Safety population will be used for each study phase as below table. In 
principle, summaries for TC1 will be only by treatment group, and summaries for GTC1, 
GTC2, GTC3 and Overall will be by treatment group and its total.
For AEs:
Study phase
Population
Summary Group
TC1
SPDB
By treatment group
GTC1
SP1
By treatment group and total
GTC2
SP2
By treatment group and total
GTC3
SP3
By treatment group and total
Overall
SP1
By treatment group and total
NOTES:

The definition of population is described in Analysis Populations.
For other than AEs:
Study phase
Population
Summary Group
TC1
SPDB
By treatment group
GTC1, GTC2, GTC3
SP1
By treatment group and total
NOTES:

The definition of population is described in Analysis Populations.
Safety data from unscheduled visit will not be included in safety analysis (but included in 
listing), and the safety data at last visit will be treated as Study Exit in safety analyses 
(but treated as Withdrawal in listing).
Visit displayed in safety analyses will be summarized below table for study phases and 
endpoints. SPDB (for TC1) and SP1 (for GTC1, GTC2 and GTC3) will be used for these 
summaries. Separate displays will be provided for TC1 and for GTCs (GTC1, GTC2 and 
GTC3).
Endpoints
Study phase
Study visit displayed in safety analyses table
Vital Sign
TC1
Baseline, Week 2, Week 6, Week 12, Week 24, Week 
36, Study exit
GTC1
Study baseline, Qualification for GTC1[1], Week 0 [1], 
Week 2, Week 6, Week 12, Week 24, Week 36, Study 
exit
GTC2
Qualification for GTC2, Week 0, Week 2, Week 6, 
Week 12, Week 24, Study exit
GTC3
Qualification for GTC3, Week 0, Week 2, Week 6, 
Week 12, Study exit
Clinical laboratory 
(chemistry and 
hematology), ECG
TC1
Baseline, Week 12, Study exit
GTC1
Study baseline, Qualification for GTC1 [1], Week 12, 
Study exit
2018N378022_00


CONFIDENTIAL
204948
28
Endpoints
Study phase
Study visit displayed in safety analyses table
GTC2
Qualification for GTC2, Week 12, Study exit
GTC3
Qualification for GTC3, Week 12, Study exit
Body Weight
TC1
Baseline, Study exit
GTC1
Study baseline, Qualification for GTC1 [1], Study exit
GTC2
Qualification for GTC2, Study exit
GTC3
Qualification for GTC3, Study exit
PVR
TC1
Baseline, Week 2, Week 6, Week 12, Week 24, Week 
36, Study exit
GTC1
Study baseline, Qualification for GTC1 [1], Week 2, 
Week 6, Week 12, Week 24, Week 36, Study exit
GTC2
Qualification for GTC2, Week 2, Week 6, Week 12, 
Week 24, Study exit
GTC3
Qualification for GTC3, Week 2, Week 6, Week 12, 
Study exit
NOTES:

Baseline means study baseline defined as 5.2.

Study baseline will be used for the derivation of change from baseline

Urinalysis results will be displayed by using worst case results post-baseline relative to baseline for 
protein and occult blood urinalysis only in accordance with IDSL standards rationale, not by visit

Study exit includes withdrawal.

[1]: only for subjects with Placebo at TC 1
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
All AEs will be classified using the standard GSK Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary, and grouped by SOC and PT, unless otherwise stated. 
The investigator will evaluate all AEs with respect to seriousness, severity, and causality.
AEs analyses will be by treatment group (and total for GTC1, GTC2, GTC3 and Overall)
and study phases (i.e., TC1, TC1 <= 84 days, GTC1, GTC2, GTC3 and Overall, see 
section 11.4). Note that Overall includes all AEs after GSK1358820 treatment. 
The number and percentage of subjects experiencing an AE and the total number of AEs 
(the number of subjects with any AEs) will be summarized for each of the following AE 
categories by treatment group (and total for GTC1, GTC2, GTC3 and Overall):

All AEs (by SOC and PT; by SOC and PT and maximum severity)

Serious AEs (by SOC and PT)

Treatment related AEs (by SOC and PT; by SOC and PT and maximum severity)
2018N378022_00


CONFIDENTIAL
204948
29

Study drug related AEs (by SOC and PT; by SOC and PT and maximum severity)

Injection related AEs (by SOC and PT; by SOC and PT and maximum severity)

Serious treatment related AEs (by PT, for PLS)

Non-serious treatment related AEs (by PT, for PLS)
The tabular summary for each category of AE listed above will include the number of 
subjects who reported at least one event, and percentage of subjects who reported at least 
one AE (incidence) by treatment group (and total for GTC1, GTC2, GTC3 and Overall)
for each SOC (where applicable), each PT, and overall. By default, adverse events will be 
sorted by MedDRA SOCs, in descending order from the SOC with the highest total 
incidence (i.e., summed across all treatment groups) for any adverse event within the 
class, to the SOC with the lowest total incidence. If the total incidence for any two or 
more adverse events is equal, the events will be presented in alphabetical order. Only 
SOCs with observed AE PTs will be presented. Repeat sort order for MedDRA PTs 
within each SOC.
Common AEs will not be summarized, except for the analysis of requirement by FDAAA 
and EudraCT. Because the number of subjects is small (target is N=30, so expected 
number of subjects is about 15/treatment group), if only 1 subject had a given AE, 
percentage of subjects who had that AE is over 5%. Therefore, summary of common AE 
is meaningless in this study. As for requirement by FDAAA and EudraCT, the number 
and percentage of subjects and the number of events will be summarized for common (>= 
5%) non-serious AEs by SOC and PT in TC1, GTC1, GTC2 and GTC3.
Any subgroup analysis for AEs will not be produced.
As for AEs by SOC and PT and severity, the number and percentage of subjects will be 
summarized as mild, moderate and severe on the maximum severity observed within each 
PT for a given subject.
Listing will be produced for each of the following AE categories:

All AEs

Serious AEs

AEs resulting in withdrawal from study
8.2.
Adverse Events of Special Interest Analyses
The definition of AEs of special interest and their MedDRA preferred term is described 
as 11.6.4. The number and percentage of subjects experiencing an AE of special interest 
and the total number of AEs of special interest will be summarized. Listing will also be 
produced.
2018N378022_00


CONFIDENTIAL
204948
30
8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays.
Clinical laboratory analyses will be by treatment group (and total for GTC1, GTC2, 
GTC3) and study phases (i.e., TC1, GTC1, GTC2 and GTC3, see section 11.4. Note that 
TC1 <= 84 days and Overall will not be included for these analyses).
Raw value and change from baseline for laboratory data will be summarized by treatment 
group (and total for GTC1, GTC2 and GTC3) for each visit.
Shifts from baseline relative to the normal range will be also summarized by treatment 
group (and total for GTC1, GTC2 and GTC3) for each visit.
Worst case urinalysis results relative to baseline for protein (category: NEG, TRA, 1+, 2+, 
3+, 4+) and occult blood (category: NEG, TRA, 1+, 2+, 3+) urinalysis only will be 
summarized by treatment group (and total for GTC1, GTC2 and GTC3) for each study 
phases (TC1 and GTC1, GTC2 and GTC3). The categories for worst case are: No 
Change/Decreased, Any Increase, Increase to TRA, Increase to 1+, Increase to 2+, 
Increase to 3+, Increase to 4+. The categorization is determined by comparing the 
baseline category to the worst case post-baseline category.  The determination of the 
worst case post-baseline takes into account both planned and unscheduled assessments.  
The percentages are based on the number of subjects in the treatment group with data for 
the test post-baseline. Subjects with missing baseline value are to be assumed to have 
normal/within range baseline value.
For Chemistry and Hematology data, the scatter plots between baseline and 
Week12/Withdrawal will be prepared by treatment group for TC1.
In order to provide detailed information regarding liver monitoring/stopping events which 
are classified as adverse events in case that these events occurred, following summary 
and listings (IDSL number to use) will be provided. 

Summary of Hepatobiliary Laboratory Abnormalities(LIVER10)

Listing of Medical Conditions for Subjects with Liver Stopping Events (MH2)

Listing of Substance Use for Subjects with Liver Stopping Events (SU2)

Listing of Liver Monitoring/Stopping Event Reporting(LIVER5)

Listing of Liver Stopping Event Information for RUCAM Score(LIVER6)

Listing of Liver Biopsy Details(LIVER7)

Listing of Liver Imaging Details(LIVER8)
2018N378022_00


CONFIDENTIAL
204948
31

Listing of Subjects Meeting Hepatobiliary Laboratory Criteria Post-
Baseline(LIVER13)
8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
ECG findings (Normal, Abnormal - not clinically significant, Abnormal – clinically 
significant) will be summarized by treatment group (and total for GTC1, GTC2 and 
GTC3) for each visit.
Raw value and change from baseline for vital sign data will be summarized by treatment 
group (and total for GTC1, GTC2 and GTC3) for each visit.
Any other safety endpoint will not be described in this RAP.
8.5.
Study Specific Safety Analyses
Since urinary events are of interest for this study, some study specific safety analyses will 
be analysed for following item.
These analyses will be done by treatment group in only TC1, and using Safety population 
(SPDB).
8.5.1.
Post Void Residual (PVR) Urine Volume
PVR will only be measured in non-catheterizing subjects, or those with “mixed” patterns 
(ie, they do both CIC and spontaneous voiding). Therefore, analyses for PVR will include 
only subjects with Mixed (catheterization and spontaneous void), Spontaneous void only, 
Mixed (Intermittent balloon catheter and spontaneous void) or Mixed (CIC, Intermittent 
balloon catheter and spontaneous void)
Summary statistics and listing will be provided for PVR urine volume and its change 
from baseline.
Listing of PVR data will be produced. This listing will include the following items.

Site ID, Subject ID, Treatment group, Visit, Date, Study day, PVR value, Change 
from baseline in PVR, Flag at initiating CIC
Flag at initiating CIC will be marked ONLY for subjects with “Spontaneous void only”
or “Intermittent balloon catheter and spontaneous void” as void pattern. This flag will set 
to PVR data at the time of initiation of CIC (with the reason for urinary retention or 
elevated PVR) or 2 weeks prior to CIC if not available at the time of initiation.
2018N378022_00


CONFIDENTIAL
204948
32
Note that use of CIC includes use of indwelling catheter, if exists. The reason to use CIC 
are urinary retention, elevated PVR or other. Only data of use of CIC with the reason for 
urinary retention or elevated PVR will be used for any analyses.
8.5.2.
Clean Intermittent Catheterization (CIC)
No summary table will be prepared for CIC related endpoints. In this study, CIC related 
endpoints for subjects with “Spontaneous void only” or “Intermittent balloon catheter and 
spontaneous void” as void pattern are of interest, but the number of subjects with 
“Spontaneous void only” or “Intermittent balloon catheter and spontaneous void” as void 
pattern are small (less than 5 in total). Therefore, only listing will be produced for CIC 
related endpoints.
Duration of using CIC in each CIC use will be listed. Duration of using CIC will be 
calculated for the CIC with the reason for urinary retention or elevated PVR not include 
CIC with reason for “other”. Duration of using CIC is calculated cumulatively as
(Duration of using CIC) = (Date of A) – (“start date of CIC”) + 1

(For CIC not using at date of study complete or withdrawal) Date of A= “stop date 
of CIC”

(For CIC using at date of study complete or withdrawal) Date of A= (later of “stop 
date of CIC” or “date of study complete or withdrawal”)
Time to onset of first CIC will be calculated as:
(Time to onset of first CIC) = (The date of using CIC first in TC1) – (the date of first 
treatment) + 1
Listing of CIC data will be produced. This listing will include the following items.

Site ID, Subject ID, Treatment group, Start date of CIC / End date of CIC, Duration 
of CIC, Time to onset of first CIC in TC1, Reason for catheterization (urinary 
retention, elevated PVR or other), Additional reason for other
8.5.3.
Ultrasound
The listing of kidney and bladder ultrasound data will be prepared.
Listing will display the date of morphology, Yes / No for “Was the subject detected 
kidney stone?” and Yes / No for “Was the subject detected bladder stone?” at least.
8.5.4.
General Anesthesia
The listing of using general anesthesia will be prepared.
2018N378022_00


CONFIDENTIAL
204948
33
8.6.
Patient Profile Listings
Listing for patient profiles will be produced if one of the events is reported below.
CV EVENTS (ARRHYTHMIAS, CONGESTIVE HEART FAILURE, 
CEREBROVASCULAR EVENTS STROKE AND TRANSIENT ISCHEMIC ATTACK, 
DEEP VEIN THROMBOSIS (DVT) /PULMONARY EMBOLISM (PE), 
MYOCARDIAL INFARCTION, PERIPHERAL ARTERIAL THROMBOEMBOLISM, 
PULMONARY HYPERTENSION, REVASCULARISATION, VALVULOPATHY) and
DEATH
2018N378022_00


CONFIDENTIAL
204948
34
9.
OTHER ANALYSIS
Any analyses of neutralizing antibody measurement will not be described in this RAP.
2018N378022_00


CONFIDENTIAL
204948
35
10.
REFERENCES

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.

GlaxoSmithKline Document Number 2016N276451_06: Study Protocol of 204948, 
A phase III study to evaluate the efficacy and safety of GSK1358820 (botulinum 
toxin type A) in patients with urinary incontinence due to neurogenic detrusor 
overactivity
2018N378022_00


CONFIDENTIAL
204948
36
11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from Per Protocol Population
Per protocol population is not defined in this study.
2018N378022_00


CONFIDENTIAL
204948
37
11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Table 2    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
18a
(verification 
by tel.)
24
30 a
(verification 
by tel.)
36
42
(verification 
by tel.)
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
Xb
Inclusion / exclusion criteria
X
Xb
Neutralizing antibody
Xm
X
X
Efficacy
Urodynamic assessment
Xc
X
Check of bladder diary d
Xb
X
X
X
X
X
X
X
X
X
X
KHQ
Xb
X
X
X
X
X
X
TBS
X
X
X
X
X
X
X
Safety
Adverse eventse
X
X
X
X
X
X
X
X
X
X
X
Physical exam
X
X
X
Height, Weight
X
Xf
Xf
Vital signs
X
Xb
X
X
X
X
X
X
X
ECG
X
X
X
X
Clinical laboratory (hematology and blood 
chemistry)
X
X
X
X
HBsAg・HCVAb（for subjects who receive or plan 
to receive immunosuppressants）
X
Urinalysis (dipstick)
X
Xb
X
X
X
X
X
X
X
Urinalysis (clinical laboratory) / 
Urine culture / sensitivity g
X
Xb
X
X
X
X
X
X
X
PVR
Xc
X
X
X
X
X
X
X
2018N378022_00


CONFIDENTIAL
204948
38
Ultrasound (kidney / bladder)
X
X
X
X
Urine cytology
X
PSA (Only male)
X
Urinary pregnancy test (Only females of 
reproductive potential) h
X
Xb
X
X
X
X
X
X
X
EDSS (Only MS patients)
X
Investigational product
Treatment of antibiotic i
X
Treatment of investigational product
X
Confirmation of qualification for re-treatment criteria 
j, k
X
X
X
X
X
Concomitant meds / therapies
Xl
X
X
X
X
X
X
X
X
X
X
X
d = day (s)
(a) Patient can request re-treatment at any time via telephone since week 12 after 1st treatment. If the patient requests re-treatment via telephone, a qualification for re-treatment visit 
should be conducted within approximately 1-2 weeks of the patient request.
(b) Performed prior to treatment.
(c) May be performed during the screening period through Day 1 (prior to randomization) excluding diary data collection days
(d) 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 
during the screening phase). The volume voided is recorded by subjects for one 24-hour period during the 3 day diary collection period.
(e) Only serious adverse events assessed as related to study participation or a GSK product will be recorded from the time when a subject consents
(f) Measured only body weight
(g) Urine culture and sensitivity is performed by the central laboratory when dipstick results  are positive for nitrites or leukocyte esterase.
(h) For patients with doubtful reaction in urinary pregnancy test, the investigator (or subinvestigator) may conduct serum pregnancy test.
(i) For patients without a UTI as determined from the urinalysis or urine culture and/or investigator opinion, prophylactic antibiotic are to be administered 1 to 3 days before study 
treatment, on the day of treatment, and 1 to 3 days after treatment. For patients with a UTI as determined from the urinalysis or urine culture and/or investigator opinion, an antibiotic to 
which the identified organism is sensitive is to be administered at least 5 days prior to study treatment and continued for at least 3 days following the procedure. 
(j) 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”.
(k) Patients who are not re-treated will remain in Treatment phase 1 and continue to visit at the scheduled study visit.
(l) Patients who are using the medications or therapies urinary incontinence due to NDO should maintain the same dose from at least 7 days before the start of the screening phase
throughout Treatment phase 1.
(m) Samples may be collected during the screening period through Day 1 (prior to randomization)
2018N378022_00


CONFIDENTIAL
204948
39
Table 3    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-
treatm
ent
Re-treatment (2nd)
Withdra
wal
2
6
12
18a
(verifi
cation 
by tel.) 
b
24a
30a(ve
rificati
on by 
tel.)  
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(ve
rificati
on by 
tel.) 
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 diary c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
KHQ
X
X
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
Xd
Xd
Xd
Xd
Xd
Vital signs
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
ECG
Xf
X
X
Xf
X
X
X
Clinical laboratory 
(hematology and blood 
chemistry)
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
Urinalysis (clinical 
laboratory) / Urine culture / 
sensitivity g
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
PVR
X
X
X
X
X
X
X
X
X
X
X
X
Ultrasound (kidney/bladder)
Xf
X
X
Xf
X
X
X
Urinary pregnancy test (Only 
females of reproductive 
potential) h
X
Xe
X
X
X
X
X
X
Xe
X
X
X
X
X
2018N378022_00


CONFIDENTIAL
204948
40
EDSS (Only MS patients)
X
Investigational product
Treatment of antibiotici
X
X
Confirmation of day of 
re-treatment criteriaj
X
X
Treatment of 
investigational productk
X
X
Confirmation of 
qualification for 
re-treatment criteria j,l
Xj, k
Xj ,k
Xj, k
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) Patient can request 2nd re-treatment at any time via telephone since week 12 after re-treatment. If the patient requests re-treatment via telephone, a qualification for re-treatment visit 
should be conducted within approximately 1-2 weeks of the patient request.
(c) 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.
(d) Measured only body weight
(e) Performed prior to treatment
(f) These examination can be completed at the Qualification for re-treatment visit or at any time within 21 days prior to re-treatment
(g) Urine culture and sensitivity is performed by the central laboratory when dipstick results are positive for nitrites or leukocyte esterase
(h) For patients with doubtful reaction in urinary pregnancy test, the investigator (or subinvestigator) may conduct serum pregnancy test.
(i) For patients without a UTI as determined from the urinalysis or urine culture and/or investigator opinion, prophylactic antibiotic are to be administered 1 to 3 days before study 
treatment, on the day of treatment, and 1 to 3 days after treatment. For patients with a UTI as determined from the urinalysis or urine culture and/or investigator opinion, an antibiotic to 
which the identified organism is sensitive is to be administered at least 5 days prior to study treatment and continued for at least 3 days following the procedure. 
(j) Patients who are not retreated will continue to visit at the scheduled study visit.
(k) Re-treatment must be occurred 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
(l) If qualification for re-treatment criteria was met, the patient will undergo the exams specified in the column marked “If qualification for re-treatment criteria was met”
2018N378022_00


CONFIDENTIAL
204948
41
11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Assessment Windows for Efficacy Analyses
Analysis Set 
/ Domain
Parameter     
(if applicable)
Target Number 
of Days from 
Day 1 in each TC
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
e.g. “Safety”, 
“Efficacy” or 
list specific 
domains if 
required
e.g. “All” or list 
specific 
parameters (i.e. 
tests) if 
required
The target or 
most desired 
relative day or 
relative time 
value for a given 
visit. e.g. “Day 7”
e.g. “Day 1”
e.g. “Day 10”
e.g. VISIT 1
Efficacy
Study Baseline
Day 1 [1]
Study Baseline
Efficacy
Day 15
Day 2
Day 29
TC1 Week 2
Efficacy
Day 43
Day 30
Day 64
TC1 Week 6
Efficacy
Day 85
Day 65
Day106
TC1 Week 12
Efficacy
Day 127
Day 107
Day 148
TC1 Week 18
Efficacy
Day 169
Day149
Day190
TC1 Week 24
Efficacy
Day 211
Day191
Day 232
TC1 Week 30
Efficacy
Day 253
Day 233
Day 274
TC1 Week 36
Efficacy
Day 295
Day 275
Day 316
TC1 Week 42
Efficacy
Day 337
Day 317
Day 358
TC1 Week 48
Efficacy
Day 1
Latest pre-dose 
assessment before 2nd
treatment [2]
TC2 Week 0
Efficacy
Day 15
Day 2
Day 29
TC2 Week 2
Efficacy
Day 43
Day 30
Day 64
TC2 Week 6
Efficacy
Day 85
Day 65
Day106
TC2 Week 12
Efficacy
Day 127
Day 107
Day 148
TC2 Week 18
Efficacy
Day 169
Day149
Day190
TC2 Week 24
Efficacy
Day 211
Day191
Day 232
TC2 Week 30
Efficacy
Day 253
Day 233
Day 274
TC2 Week 36
Efficacy
Day 1
Latest pre-dose 
assessment before 3rd
treatment [2]
TC3 Week 0
Efficacy
Day 15
Day 2
Day 29
TC3 Week 2
Efficacy
Day 43
Day 30
Day 64
TC3 Week 6
Efficacy
Day 85
Day 65
Day106
TC3 Week 12
Efficacy
Day 127
Day 107
Day 148
TC3 Week 18
Efficacy
Day 169
Day149
Day190
TC3 Week 24
NOTES :

[1] prior to treatment. If the date of assessment of efficacy endpoint is the same as the date of 
treatment, this can be regarded as prior to treatment according to study protocol.
2018N378022_00


CONFIDENTIAL
204948
42
Analysis Set 
/ Domain
Parameter     
(if applicable)
Target Number 
of Days from 
Day 1 in each TC
Analysis Window
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint

[2] typically to use data of qualification for re-treatment

Day 1 is the treatment date in each TC
11.3.2.
Definitions of Assessment Windows for Safety Analyses (only 
Week 48 visit and Withdraw visit)
Table below shows the assessment window which applied to safety data at week 48 visit 
and withdrawal visit. Safety data at week 48 visit or withdrawal visit will be used as data 
of the visit within an assessment window, only if safety data for the planed scheduled 
visit is missing.
This assessment window will not be applied to any safety data at other visits. This means 
safety data except for week 48 visit and withdrawal visit will be only used as visit 
collected in eCRF.
Note that as described in section section 8, safety data at last visit (typically, this is week 
48 visit or withdrawal visit) will be also treated as study exit.
Rationale: For example, if a given subject receive 2nd treatment at week 36 after 1st
treatment and complete study (i.e., complete week 48 visit), data for week 48 visit will be 
entered in “Week 48” page in eCRF, not in “Week 12 from 2nd treatment” page. In this 
case, data for week 12 from 2nd treatment seems to be missing in eCRF, but this is not 
true. This is the case for other situations. In order to summarize safety data at week 48 
visit or withdrawal visit appropriately in a given TC or GTCs, this assessment window is 
needed.
Analysis Set 
/ Domain
Parameter     
(if applicable)
Target Number 
of Days from 
Day 1 in each 
TC/GTC
Analysis Window
Analysis 
Timepoint in 
appropriate 
study phase 
(TC1 or GTCs)
Beginning 
Timepoint
Ending 
Timepoint
e.g. “Safety”, 
“Efficacy” or 
list specific 
domains if 
required
e.g. “All” or list 
specific 
parameters (i.e. 
tests) if 
required
The target or 
most desired 
relative day or 
relative time 
value for a given 
visit. e.g. “Day 7”
e.g. “Day 1”
e.g. “Day 10”
e.g. VISIT 1
Safety
Day 15
Day 12
Day 18
Week 2
Safety
Day 43
Day 36
Day 50
Week 6
Safety
Day 85
Day 78
Day 92
Week 12
Safety
Day 127
Day 120
Day 134
Week 18
Safety
Day 169
Day 162
Day 176
Week 24
Safety
Day 211
Day 204
Day 218
Week 30
Safety
Day 253
Day 246
Day 260
Week 36
Safety
Day 295
Day 288
Day 302
Week 42
2018N378022_00


CONFIDENTIAL
204948
43
Analysis Set 
/ Domain
Parameter     
(if applicable)
Target Number 
of Days from 
Day 1 in each 
TC/GTC
Analysis Window
Analysis 
Timepoint in 
appropriate 
study phase 
(TC1 or GTCs)
Beginning 
Timepoint
Ending 
Timepoint
Safety
Day 337
Day 330
Day 343
Week 48
NOTES :

Day 1 is the treatment date in each TC/GTC
2018N378022_00


CONFIDENTIAL
204948
44
11.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
11.4.1.
Study Phases
Assessments and events will be classified according to time of occurrence relative to the 
start date of the study treatment and/or study withdraw date.
11.4.1.1.
Study Phases for Efficacy Data
Treatment State
Definition
Pre-Treatment 
Date ≤1st treatment Date
Treatment Cycle 1
(TC1)
1st treatment Date < Date 
(if the subject completes /withdraws without 2nd treatment) ≤ Study 
Exit/Withdraw Date 
or 
(if the subject take 2nd treatment) ≤2nd treatment Date
Treatment Cycle 2
(TC2)
2nd treatment Date < Date
(if the subject completes / withdraws without 3rd treatment) ≤ Study
Exit/Withdraw Date 
or
(if the subject take 3rd treatment) ≤3rd treatment Date
Treatment Cycle 3
(TC3)
3rd treatment Date < Date ≤ Study Exit/Withdraw Date
NOTES: 

If the date of assessment of efficacy endpoint is the same as the date of 1st treatment, this can be regarded 
as prior to treatment according to study protocol.
11.4.1.2.
Study Phases for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date
Onset Time Since 
1st Dose (Days)
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Treatment Cycle 
1 (TC1) ≤84 
days from 1st 
treatment
1st treatment Date ≤ AE Start Date ≤1st treatment Date +83
Treatment Cycle 
1 (TC1)
1st treatment Date ≤ AE Start Date
(if the subject completes / withdraws without 2nd treatment) ≤ Study Exit/Withdraw 
Date 
or 
(if the subject take 2nd treatment) < 2nd treatment Date
2018N378022_00


CONFIDENTIAL
204948
45
Treatment State
Definition
GSK1358820 
Treatment Cycle 
1 (GTC1)
For subjects who received GSK1358820 as 1st treatment:
1st treatment Date ≤ AE Start Date
(if the subject completes / withdraws without 2nd treatment) ≤ Study Exit/Withdraw 
Date 
or 
(if the subject take 2nd treatment) < 2nd treatment Date
For subjects who received placebo as 1st treatment:
2nd treatment Date /Time ≤ AE Start Date / Time
(if the subject completes / withdraws without 3rd treatment) ≤ Study Exit/Withdraw 
Date 
or
(if the subject take 3rd treatment) < 3rd treatment Date
GSK1358820 
Treatment Cycle 
2 (GTC2)
For subjects who received GSK1358820 as 1st treatment:
2nd treatment Date /Time ≤ AE Start Date / Time
(if the subject completes / withdraws without 3rd treatment) ≤ Study Exit/Withdraw 
Date 
or
(if the subject take 3rd treatment) < 3rd treatment Date
For subjects who received placebo as 1st treatment:
3rd treatment Date / Time ≤ AE Start Date / Time ≤ Study Exit/Withdraw Date 
GSK1358820 
Treatment Cycle 
3 (GTC3)
For subjects who received GSK1358820 as 1st treatment:
3rd treatment Date / Time ≤ AE Start Date / Time ≤ Study Exit/Withdraw Date
For subjects who received placebo as 1st treatment:
Not applicable because 3rd treatment of GSK1358820 is not allowed for subjects who 
received placebo as 1st treatment
Overall
For subjects who received GSK1358820 as 1st treatment
1st treatment Date ≤ AE Start Date ≤ Study Exit/Withdraw Date
For subjects who received placebo as 1st treatment
2nd treatment Date ≤ AE Start Date ≤ Study Exit/Withdraw Date
NOTES: 

If the study withdraw date is missing then the AE will be considered to be On-Treatment.
11.4.1.3.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before the first treatment date
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.

The definition of “prior” for prior NDO medication is different from above definition, in accordance with study 
protocol.
2018N378022_00


CONFIDENTIAL
204948
46
11.4.2.
Treatment Emergent Flag for Adverse Events
Treatment emergent flag for AEs is not defined in this study.
2018N378022_00


CONFIDENTIAL
204948
47
11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Compound
[for interim analyses]: arenv/arprod/gsk1358820/mid204948/primary
[for final analyses]: arenv/arprod/gsk1358820/mid204948/final
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset standards. .
Generation of RTF Files

RTF files will not be generated.
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
2018N378022_00


CONFIDENTIAL
204948
48
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
N, mean, standard deviation (or standard error), median, minimum, maximum.
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
2018N378022_00


CONFIDENTIAL
204948
49
11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window (as per Section 11.3.1) the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the value for the 
earlier date will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. 
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
11.6.2.
Study Population
Duration of Follow-Up instead of Extent of Exposure

Number of days of follow-up after study drug administration will be calculated based on the 
formula by Overall and TCs:  
Duration of Follow-Up in Days = Date X – (Date Y) + 1
For subjects who received GSK1358820 as first treatment
Overall / TC for 
calculation
Subject status
X
Y
Overall
All subjects
Study Exit / 
Withdraw Date
1st treatment date
TC1
Study Exit or
Withdraw in TC1
Study Exit / 
Withdraw Date [1]
1st treatment date
TC1
Receive next 
treatment
Date prior to 2nd 
treatment [1]
1st treatment date
GTC1
The same days as TC1
GTC2
Study Exit or
Withdraw in TC2
Study Exit / 
Withdraw Date
2nd treatment date
GTC2
Receive next 
treatment
Date prior to 3rd 
treatment
2nd treatment date
GTC3
All subjects in 
GTC3
Study Exit /
Withdraw Date
3rd treatment date
For subjects who received Placebo as first treatment
2018N378022_00


CONFIDENTIAL
204948
50
Duration of Follow-Up instead of Extent of Exposure
Overall / TC for 
calculation
Subject status
X
Y
Overall
All subjects
Study Exit / 
Withdraw Date
2nd treatment date 
(1st treatment date 
of GSK1358820)
TC1
Study Exit or
Withdraw in TC1
Study Exit / 
Withdraw Date [1]
1st treatment date
TC1
Receive next 
treatment
Date prior to 2nd 
treatment [1]
1st treatment date
GTC1
Study Exit or
Withdraw in GTC1
Study Exit / 
Withdraw Date
2nd treatment date 
(1st treatment date 
of GSK1358820)
GTC1
Receive next 
treatment
Date prior to 3rd 
treatment
2nd treatment date 
(1st treatment date 
of GSK1358820)
GTC2
All subjects in 
GTC2
Study Exit / 
Withdraw Date
3rd treatment date 
(2nd treatment date 
of GSK1358820)
GTC3
Not applicable, because GSK1358820 treatment is allowed only 
two times for subjects who received Placebo as first treatment 
in this study.

[1] In interim analysis, use the following date:

Date of withdraw date for subjects who do not receive 2nd treatment and withdraw 
before week 24 after 1st treatment

Date of the Week 24 visit in treatment phase 1 for subjects who do not receive 2nd
treatment and do not withdraw

Date prior to 2nd treatment for subjects who receive 2nd treatment at the Week 12 / 
18 visit in treatment phase 1.
Duration of NDO history

Duration of NDO history is defined as the duration (years) from the date of diagnosis to the date 
of screening visit. 
Identification of anticholinergic drug and beta-3 agonist
2018N378022_00


CONFIDENTIAL
204948
51

Since information of anticholinergic drug and beta-3 agonist was collected as ‘prior NDO
medication’ , it is needed to identify which codes will be regarded as anticholinergic drug and 
beta-3 agonist. Following code will be in SI dataset
Drug
Term Name
Code
Anticholinergics
FESOTERODINE
54026501
FESOTERODINE 
FUMARATE
54026502
IMIDAFENACIN
53735601
OXYBUTYNIN
00538901
OXYBUTYNIN 
HYDROCHLORIDE
00538902
PROPIVERINE
01241601
PROPIVERINE 
HYDROCHLORIDE
01241602
SOLIFENACIN
53085701
SOLIFENACIN SUCCINATE
53085702
TOLTERODINE
01350201
TOLTERODINE TARTRATE
01350202
TOLTERODINE FUMARATE
01350203
beta-3 adrenergic receptor 
agonist
MIRABEGRON
54321501
.
11.6.3.
Efficacy
Diary Data Convention
General Convention

For baseline and post-treatment visits, analyses will be based on the diary data collected during 
a 3-day interval for each visit. Each 3-day interval consists of 3 consecutive 24-hour periods, 
with the first period starting from the time of the first urinary episode on the first of the 3 days.

A valid diary day is defined as any of the three 24-hour periods with 2 or more any type of 
urinary episodes. Data collected from a 24-hour period with less than 2 urinary episodes (i.e., 
an invalid diary day) will be set to missing in this day.

For baseline and post-treatment visits, the 3-day diary will be determined based on the following 
algorithm:

Apply assessment windows defined in Section 11.3.1, which are based on days 
from the date of study treatment.

Determine the time of the first urinary episode that is within the assessment window 
(in the example below, 7:30am on Apr3). Count forwards for 3 consecutive days (in 
the example below, APR3 is considered as 7:30am on Apr3 to 7:29am on APR4, 
APR4 is considered as 7:30am on Apr4 to 7:29am on APR5 and APR5 is 
2018N378022_00


CONFIDENTIAL
204948
52
Diary Data Convention
considered as 7:30am on Apr5 to 7:29am on APR6 for diary data handling). As for 
volume voided, the time of the first collection of volume voided should be 
determined independently of the time of the first urinary episode. Note: the last 24-
hour period should end within the window, i.e., prior or on the last day specified in 
the window definition; otherwise, the 24-hour data will not be used for the 
corresponding window. For baseline diary data, the urinary episodes that occurred 
on injection day but before the injection time will be counted for baseline diary data.

Using the example below, the first 24-hour time period starts from 7:30am on Apr 3 
and ends at 7:29am on Apr 4. The second 24-hour time period starts from 7:30am 
on Apr4 and ends at 7:29am on Apr 5. Note that this 24-hour is considered an as 
invalid diary day since it has only one episode during the 24 hours. The third or the 
last 24-hour time period starts from 7:30am on Apr 5 and ends at 7:29am on Apr6.

At least one valid 24-hour diary day within the window is required for the visit. 
Otherwise, the 3-day diary data will be missing for the visit.
Apr 3
Apr4
Apr 5
Apr 6
7:30am
6:15am
10:30am
11:23am
2:30pm
9:20am
5:30pm
4:23pm
For diary data with a diary date but missing the urinary time, the diary time will be set to mid-day at 
12:00pm.
Example for date of diary data handling

Here, the example of handling of diary data of 3 consecutive days and its relation to 
assessment window is described for the case of TC1 week 12.

As shown in 11.3.1, the target data of TC1 week 12 is day 85 and the assessment window of 
TC1 week 12 is from day 65 to day 106. The time of the first urinary episode should be within 
day 65 to day106 for diary data of TC1 week 12. In addition, only the data until day106 is 
available for TC1 week12.

All examples below are assumed that valid diaries were taken for 3 consecutive days.

In example 1, the first day is not from day 65 to day 106. Therefore, all the diary data for this 
visit are NOT available for TC1 week12.

In example 2 and 3, all diary data are available because diary date for data handling are from 
day 65 to day 106.

In example 4 and 5, a part of diary date for data handling is out the range (day 65-106). Diary of 
these days are regarded as invalid diary.
Example
The time of the first 
After 3 consecutive 
Diary date for 
Available data for 
2018N378022_00


CONFIDENTIAL
204948
53
Diary Data Convention
number
urinary episode
24-hour period (3 
consecutive days)
data handling
diary data of TC1 
week 12
1
Day 64 9:00am
Day 67 8:59am
Day 64, 65, 66
No data available
2
Day 65 9:00am
Day 68 8:59am
Day 65, 66, 67
All data available
3
Day 104 9:00am
Day 107 8:59am
Day 104, 105, 
106
All data available
4
Day 105 9:00am
Day 108 8:59am
Day 105, 106, 
107
Day 105 and 106 
are available
5
Day 106 9:00am
Day 109 8:59am
Day 106, 107, 
108
Only day 106 is 
available
Derivation of diary endpoints

Following endpoint will be derived as “A” divided by “B”. “A” and “B” are defined below for 
each endpoint. Derivation should be done by visit. These derivations will be done by using 
only diary data in valid diary days.
For valid diary day, if no episodes are recorded, “A” on that day will be treated as zero.
Endpoint
A
B
Daily average number of 
urinary incontinence 
episodes
Number of “Yes“ response to 
the diary question of “Did you 
have accidental urinary 
leakage?”
Number of valid diary days in 
the visit
Daily average number of 
voids
Number of 
“Yes“ response to the diary 
question of “Did you urinate 
into the toilet?”
Or
“Yes“ response to the diary 
question of “Did you use a 
catheter to urinate?”
Average volume voided per 
void
The total volume collected in 
24-hour period
Number of the urinary 
volume records which are not 
missing
For the endpoint of Proportion of patients attaining 100%, ≥75% and ≥50% reduction from 
baseline in the daily average of urinary incontinence episodes, if change from baseline in 
the daily average of urinary incontinence episodes 
o
is -100%, then this subject will attain 100%, ≥75% and ≥50%
o
falls the range (-100 <, <=-75%), then this subject will attain ≥75% and ≥50% 
o
falls the range (--75 <, <=-50%), then this subject will attain ≥50% 
is larger than -50%, then this subject will not attain any category
Handling of partial missing data in diary (except for urinary time)

If the response to the diary question of “Record volume collected OR indicate “not collected” for 
2018N378022_00


CONFIDENTIAL
204948
54
Diary Data Convention
each episode” is missing, then this response will be treated as missing, not zero of volume.

As for other response, the missing response will be treated as missing. In other words, this is 
the same meaning to be treated as “No” to the response to the diary question.
Handling of missing urinary time

For diary data with a diary date but missing the urinary time, the diary time will be set to mid-day 
at 12:00 pm at that day.
Handling of partial missing day in diary

Partial missing day is defined as any missing diary day or invalid diary day in 3-day period.

If there are 1 or 2 partial missing days in 3- day bladder diary, these days will be treated as 
missing and no imputation will be done for partial missing day.

Therefore, endpoints in 3- day bladder diary will be calculated by using 1 or 2 valid diary data, if 
there is any partial missing day in the visit.
Definition of Incomplete 3-day diary

Incomplete 3-day diary is defined as the diary which does not have 3 valid diary days.
KHQ Convention
Derivation of KHQ domains
Following table shows the derivation of KHQ domains [Committee for Preparation of the Clinical 
Guideline for Overactive Bladder, the Japanese Continence Society, 2015]. 
Only role limitations and social limitations will be analysed by ANCOVA model. Other domains will 
be only summarized.
Domain
ITEMS
Question in 
eCRF
scale
Derivation
General Health 
Perception
1 (1 item)
1= Very Good
2= Good
3= Fair
4= Poor
5= Very Poor
Domain Score =
(score of left item -1 ) / 4 
* 100
Incontinence 
Impact
2 (1item)
1= Not at all
2= A little
3= Moderately
4= A lot
Domain Score =
(score of left item -1 ) / 3 
* 100
Role Limitations
3a and 3b (2 
items)
1= Not at all
2=Slightly
3=Moderately
4= A lot
Domain Score =
(summed scores of left 
items -2 ) / 6 * 100
Physical 
Limitations
4a and 4b (2 
items)
1= Not at all
2=Slightly
3=Moderately
4=A lot
Domain Score =
(summed scores of left 
items -2 ) / 6 * 100
Social 
Limitations
4c, 4d, 5c (3 
items)
0= N/A
1= Not at all
Domain Score =
(summed scores of left 
2018N378022_00


CONFIDENTIAL
204948
55
KHQ Convention
Derivation of KHQ domains
2=Slightly
3=Moderately
4=A lot
items -3 ) / 9 * 100
If score of 5c = 0 then 
Domain Score =
(summed scores of left 
items -2 ) / 6 * 100
Personal 
Relationships
5a and 5b (2 
items)
0= N/A
1= Not at all
2=Slightly
3=Moderately
4=A lot
Domain Score =
(summed scores of left 
items -2 ) / 6 * 100
If summed scores of left 
items = 1 then 
Domain Score =
(summed scores of left 
items -1 ) / 3 * 100
If summed scores of left 
items = 0 then 
Domain Score will be 
treated as missing
Emotions
6a, 6b and 6c (3 
items)
1= Not at all
2=Slightly
3=Moderately
4=Very Much
Domain Score =
(summed scores of left 
items -3 ) / 9 * 100
Sleep/Energy
7a and 7b (2 
items)
1= Never
2=Sometimes
3=Often
4=All the time
Domain Score =
(summed scores of left 
items -2 ) / 6 * 100
Severity/Coping 
Measures
8a, 8b, 8c, 8d 
and 8e (5 items)
1= Never
2=Sometimes
3=Often
4=All the time
Domain Score =
(summed scores of left 
items -5 ) / 15 * 100
Handling of partial missing data

If missing data exists in KHQ data in the visit, the corresponded item or domain will be treated 
as missing.
2018N378022_00


CONFIDENTIAL
204948
56
TBS
Answers and positive response of TBS
TBS (treatment benefit scale) consists of 4 answers to 1 questions “Please complete the following 
question by considering your current condition (urinary problems, urinary incontinence) compared 
to your condition before you received any study treatment in this trial”. Subjects will select their 
answer to this question considering their condition. Available answers are below and will be coded 
1 to 4 in order to use statistical analysis.

1 - Greatly improved

2 - Improved

3 - Not changed

4 - Worsened
The answers of 1 – Greatly improved or 2 – Improved will be regarded as positive response.
Other answers including missing data will be regarded as NO positive response.
Urodynamics
Urodynamics Data Convention for No IDC occurred
To take into account that there will be subjects post-treatment in whom an involuntary detrusor 
contraction was confirmed as not occurring during urodynamics, the data will be analysed below.

Maximum detrusor pressure during the first IDC (PmaxIDC)
A value will not be imputed for subjects with no IDC since MDP during first IDC cannot be 
evaluated.

Volume at first IDC (VPmaxIDC)
A value will be imputed by MCC for subjects with no IDC.
2018N378022_00


CONFIDENTIAL
204948
57
11.6.4.
Safety
Adverse Events
AE’S OF Special Interest
Adverse events of special interest are classified as follows, and how they will be identified are 
tabulated below:

Urinary tract infections

Urinary retention

Residual urine volume

Possible Distant Spread of Toxin

Hypersensitivity

Potential risk of pyelonephritis
AEs of Special Interest
Preferred Term
Urinary tract infections
Urinary tract infection; 
Urinary tract infection bacterial; 
Urinary tract infection pseudomonal;
Urinary retention
Urinary retention
Residual urine volume increased
Residual urine volume increased
Hypersensitivity
Drug eruption;
Dermatitis allergic;
Angioedema;
Stevens-Johnson syndrome;
Toxic epidermal necrolysis;
Drug hypersensitivity;
Hypersensitivity; 
Anaphylactic reaction; 
Anaphylactic shock; 
Anaphylactoid reaction; 
Anaphylactoid shock;
Potential risk of pyelonephritis
Bacterial pyelonephritis;
Pyelonephritis;
Pyelonephritis acute;
As for Possible Distant Spread of Toxin, following SOC and PT terms will be used.
System Organ Class
Preferred Term
Cardiac Disorders
Bradycardia
Eye Disorders
Accommodation disorder
Diplopia
Extraocular muscles paresis
Eyelid function disorder
2018N378022_00


CONFIDENTIAL
204948
58
Eyelid ptosis
Pupillary reflex impaired
Vision blurred
Gastroinstestinal Disorders
Constipation
Dry mouth
Dysphagia
Ileus paralytic
Infections and Infestations
Botulism
Musculoskeletal and Connective Tissue 
Disorders
Muscular weakness
Nervous System Disorders
Bulbar palsy
Cranial nerve palsies multiple
Cranial nerve paralysis
Dysarthria
Facial paralysis
Facial paresis
Hyporeflexia
Hypotonia
Paralysis
Paresis cranial nerve
Peripheral paralysis
Peripheral nerve palsy
Speech disorder
Vocal cord paralysis
Vocal cord paresis
Renal and Urinary Disorders
Urinary retention [1]
Reproductive System and Breast Disorders
Pelvic floor muscle weakness
Respiratory, Thoracic and Mediastinal Disorders
Aspiration
Diaphragmatic paralysis
Dysphonia
Dyspnoea
Pneumonia aspiration
Respiratory arrest
Respiratory depression
Respiratory failure
[1]; Note that since GSK1351880 is injected into the urinary bladder for the treatment of OAB, and 
urinary retention is considered an expected localized effect, the PT “urinary retention” will not be 
considered a Possible Distant Spread of Toxin event for this study.
Treatment 
Relationship
Definition
Treatment-related
Yes, If relationship in study drug-related and/or injection procedure-related is ‘Yes’ 
according to below definitions.
Study Drug-
related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
Injection 
procedure-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
NOTES: 
2018N378022_00


CONFIDENTIAL
204948
59
Treatment 
Relationship
Definition

If the study withdraw date is missing then the AE will be considered to be On-Treatment.
2018N378022_00


CONFIDENTIAL
204948
60
11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as “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”.

Withdrawn subjects were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF does not allow for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. For example, 
this is the case for AEs status of ‘ongoing’ or AEs in interim analyses.
Concomitant 
Medications/
Medical 
History/NDO 
history

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
2018N378022_00


CONFIDENTIAL
204948
61
11.7.3.
Handling of Missing Data for Statistical Analysis
For MMRM, missing data will not be imputed. Other handling rules for efficacy endpoints are 
described in section of statistical analyses/methods.
The cases of partial missing data in the urinary diary (i.e., missing data in part of diary data to be 
needed for assessment of the endpoint) are mentioned in 11.6.3.
2018N378022_00


CONFIDENTIAL
204948
62
11.8.
Appendix 8: Values of Potential Clinical Importance
Potential clinical importance will not be applied to this study.
2018N378022_00


CONFIDENTIAL
204948
63
11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
ASIA
American Spinal Injury Association
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EDSS
Expanded Disability Status Scale
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
GTC
GSK1358820 Treatment Cycle
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
MS
Multiple Sclerosis
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SCI
Spinal Cord Injury
SDSP
Study Data Standardization Plan
2018N378022_00


CONFIDENTIAL
204948
64
Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TC
Treatment Cycle
TFL
Tables, Figures & Listings 
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NA
[SAS]
2018N378022_00


CONFIDENTIAL
204948
65
11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
For interim analyses:
Section
Tables
Figures
Study Population
1.1 to 1.19
N/A
Efficacy
2.1 to 2.59
2.1 to 2.2
Safety
3.1 to 3.101
3.1 to 3.2
Section
Listings
ICH Listings
1 to 30
Other Listings
31 to 38
For final analyses: these numbering are added “10” to the numbering for interim analyses
Section
Tables
Figures
Study Population
11.1 to 11.19
N/A
Efficacy
12.1 to 12.61
12.3 to 12.4
Safety
13.9 to 13.101
N/A
Section
Listings
ICH Listings
2 to 30
Other Listings
31 to 38
11.10.2.
Mock Example Shell Referencing

Example mock shells will be prepared as a separate document.
11.10.3.
Deliverables
This is not applied to this study.
11.10.4.
Convention for titles of Tables, Figures and Listings
For interim analyses, the wording “(Interim)” should be postfixed to the following Title.
For final analyses, the wording “(Final)” should be postfixed to the following Title.
For example, the title of table 1.1 (this numbering is for interim analyses, as described in 
11.10.1) should be prepared as Summary of Subject Disposition (Interim), and the title of table 
2018N378022_00


CONFIDENTIAL
204948
66
11.1 (this numbering is for final analyses, as described in 11.10.1) should be prepared as 
Summary of Subject Disposition (Final).
2018N378022_00


CONFIDENTIAL
204948
67
11.10.5.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Subject Disposition
1.1.
FAS1
ES1
Summary of Subject Disposition
ICH E3, GSK CTR, FDAAA, 
EudraCT
Y
Y
1.2.
Screened
ES4
Summary of Participant Disposition at Each Study 
Epoch
ICH E3
Y
Y
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen 
Failure
Journal Requirements
Y
1.4.
FAS1
NS1
Summary of Number of Subjects by Site ID
EudraCT
Y
Protocol Deviation
1.5.
FAS1
DV1
Summary of Important Protocol Deviations
ICH E3
Y
Y
Population Analysed
1.6.
Screened
SP1
Summary of Study Populations
IDSL
Y
Y
Demographic and Baseline Characteristics
1.7.
FAS1
DM1
Summary of Demographic Characteristics
ICH E3, GSK CTR, FDAAA, 
EudraCT
Y
1.8.
FAS1
DM1
Summary of Baseline Disease Characteristics
Y
1.9.
FAS1
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
Y
1.10.
Enrolled
DM11
Summary of Age Ranges 
FDAAA, EudraCT
Y
Prior and Concomitant Medications
1.11.
FAS1
CM1
Summary of Concomitant Medications
ICH E3
Y
Y
2018N378022_00


CONFIDENTIAL
204948
68
Study Population Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
1.12.
FAS1
CM1
Summary of Prior or Concomitant NDO Medications
Y
1.13.
FAS1
Non-
Standard
Summary of Number of Subjects with Prior NDO 
Medication
Y
1.14.
FAS1
Non-
Standard
Summary of Number of Subjects with Concomitant NDO 
Medication at Baseline
Y
1.15.
FAS1
Non-
Standard
Summary of Primary Reason the prior NDO Medication 
NOT Considered to Adequately Manage the Symptom
Y
Exposure and Treatment Compliance
1.16.
SP1
Non-
Standard
POP_T1
Summary of Cumulative Duration of Follow-up in Overall
ICH E3
Y
Y
1.17.
SPDB
Non-
Standard
POP_T1
Summary of Duration of Follow-up in Double Blind 
Phase
ICH E3
Y
Y
1.18.
SP1
Non-
Standard
POP_T1
Summary of Duration of Follow-up in GTC1, GTC2 and 
GTC3
ICH E3
Y
1.19.
SPDB
Non-
Standard
POP_T2
Summary of Number of Study Treatment Injection
Y
Y
2018N378022_00


CONFIDENTIAL
204948
69
11.10.6.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Daily Average Number of Urinary Incontinence Episodes
2.1.
FAS1
PSY1
Summary of Daily Average Number of Urinary 
Incontinence Episodes (FAS1): TC1 
Y
Y
2.2.
FAS1
PSY2
Summary of Change from Baseline in Daily Average 
Number of Urinary Incontinence Episodes (FAS1): TC1
Y
Y
2.3.
FAS1
PSY2
Summary of Percent Change from Baseline in Daily 
Average Number of Urinary Incontinence Episodes 
(FAS1): TC1
Y
Y
2.4.
FAS1
PSY4
Summary of MMRM analysis for Change from Baseline in 
Daily Average Number of Urinary Incontinence Episodes 
(FAS1)
Y
2.5.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in Daily 
Average Number of Urinary Incontinence Episodes 
(FAS1)
Y
Y
2.6.
FAS2
PSY1
Summary of Daily Average Number of Urinary 
Incontinence Episodes (FAS2): TC2
Y
2.7.
FAS2
PSY2
Summary of Change from Baseline in Daily Average 
Number of Urinary Incontinence Episodes (FAS2): TC2
Y
2.8.
FAS2
PSY2
Summary of Percent Change from Baseline in Daily 
Average Number of Urinary Incontinence Episodes 
(FAS2): TC2
Y
2018N378022_00


CONFIDENTIAL
204948
70
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.9.
FAS3
PSY1
Summary of Daily Average Number of Urinary 
Incontinence Episodes (FAS3): TC3
Y
2.10.
FAS3
PSY2
Summary of Change from Baseline in Daily Average
Number of Urinary Incontinence Episodes (FAS3): TC3
Y
2.11.
FAS3
PSY2
Summary of Percent Change from Baseline in Daily 
Average Number of Urinary Incontinence Episodes 
(FAS3): TC3
Y
Average Volume Voided per Void
2.12.
FAS1
PSY1
Summary of Average Volume Voided Per Void (FAS1): 
TC1
Y
Y
2.13.
FAS1
PSY2
Summary of Change from Baseline in Average Volume 
Voided Per Void (FAS1): TC1
Y
Y
2.14.
FAS1
PSY2
Summary of Percent Change from Baseline in Average 
Volume Voided Per Void (FAS1): TC1
Y
Y
2.15.
FAS1
PSY4
Summary of MMRM analysis for Change from Baseline in 
Average Volume Voided Per Void (FAS1)
Y
2.16.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in 
Average Volume Voided Per Void (FAS1)
Y
Y
2.17.
FAS2
PSY1
Summary of Average Volume Voided Per Void (FAS2): 
TC2
Y
2.18.
FAS2
PSY2
Summary of Change from Baseline in Average Volume 
Voided Per Void (FAS2): TC2
Y
2.19.
FAS2
PSY2
Summary of Percent Change from Baseline in Average 
Volume Voided Per Void (FAS2): TC2
Y
2018N378022_00


CONFIDENTIAL
204948
71
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.20.
FAS3
PSY1
Summary of Average Volume Voided Per Void (FAS3): 
TC3
Y
2.21.
FAS3
PSY2
Summary of Change from Baseline in Average Volume 
Voided Per Void (FAS3): TC3
Y
2.22.
FAS3
PSY2
Summary of Percent Change from Baseline in Average 
Volume Voided Per Void (FAS3): TC3
Y
Daily Average Number of Voids
2.23.
FAS1
PSY1
Summary of Daily Average Number of Voids (FAS1): TC1
Y
Y
2.24.
FAS1
PSY2
Summary of Change from Baseline in Daily Average 
Number of Voids (FAS1): TC1
Y
Y
2.25.
FAS1
PSY2
Summary of Percent Change from Baseline in Daily
Average Number of Voids (FAS1): TC1
Y
Y
2.26.
FAS1
PSY4
Summary of MMRM analysis for Change from Baseline in 
Daily Average Number of Voids (FAS1)
Y
2.27.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in Daily 
Average Number of Voids (FAS1)
Y
Y
2.28.
FAS2
PSY1
Summary of Daily Average Number of Voids (FAS2): TC2
Y
2.29.
FAS2
PSY2
Summary of Change from Baseline in Daily Average 
Number of Voids (FAS2): TC2
Y
2.30.
FAS2
PSY2
Summary of Percent Change from Baseline in Daily
Average Number of Voids (FAS2): TC2
Y
2.31.
FAS3
PSY1
Summary of Daily Average Number of Voids (FAS3): TC3
Y
2.32.
FAS3
PSY2
Summary of Change from Baseline in Daily Average 
Number of Voids (FAS3): TC3
Y
2018N378022_00


CONFIDENTIAL
204948
72
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.33.
FAS3
PSY2
Summary of Percent Change from Baseline in Daily
Average Number of Voids (FAS3): TC3
Y
Maximum Cystometric Capacity
2.34.
FAS1
PSY1
Summary of Maximum Cystometric Capacity (FAS1)
Y
2.35.
FAS1
PSY2
Summary of Change from Baseline in Maximum 
Cystometric Capacity (FAS1)
Y
2.36.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in 
Maximum Cystometric Capacity (FAS1)
Y
Maximum Detrusor Pressure during the first Involuntary Detrusor Contraction
2.37.
FAS1
PSY1
Summary of Maximum Detrusor Pressure during the 
first Involuntary Detrusor Contraction (FAS1)
Y
2.38.
FAS1
PSY2
Summary of Change from Baseline in Maximum 
Detrusor Pressure during the first Involuntary 
Detrusor Contraction (FAS1)
Y
2.39.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in 
Maximum Detrusor Pressure during the first 
Involuntary Detrusor Contraction (FAS1)
Y
Volume at first Involuntary Detrusor Contraction
2.40.
FAS1
PSY1
Summary of Volume at first Involuntary Detrusor
Contraction (FAS1)
Y
2.41.
FAS1
PSY2
Summary of Change from Baseline in Volume at first 
Involuntary Detrusor Contraction (FAS1)
Y
2018N378022_00


CONFIDENTIAL
204948
73
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.42.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in 
Volume at first Involuntary Detrusor Contraction
(FAS1)
Y
Maximum Detrusor Pressure during the Storage Phase
2.43.
FAS1
PSY1
Summary of Maximum Detrusor pressure during the 
Storage Phase (FAS1)
Y
2.44.
FAS1
PSY2
Summary of Change from Baseline in Maximum 
Detrusor pressure during the Storage Phase (FAS1)
Y
2.45.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in 
Maximum Detrusor pressure during the Storage 
Phase (FAS1)
Y
Urodynamics (Involuntary Detrusor Contraction)
2.46.
FAS1
PSY5
Number of Subjects without an IDC (FAS1)
Y
KHQ Domain Score 
2.47.
FAS1
PSY1
Summary of KHQ Domain Score (FAS1): TC1
Y
Y
2.48.
FAS1
PSY2
Summary of Change from Baseline in KHQ Domain 
Score (FAS1): TC1
Y
Y
2.49.
FAS1
PSY3
Summary of ANCOVA for Change from Baseline in KHQ 
Domain Score – Role Limitations and Social Limitations
(FAS1)
ANCOVA will be done for only Role 
Limitations and Social Limitations
Y
Y
2.50.
FAS2
PSY1
Summary of KHQ Domain Score (FAS2): TC2
Y
2.51.
FAS2
PSY2
Summary of Change from Baseline in KHQ Domain 
Score (FAS2): TC2
Y
2018N378022_00


CONFIDENTIAL
204948
74
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.52.
FAS3
PSY1
Summary of KHQ Domain Score (FAS3): TC3
Y
2.53.
FAS3
PSY2
Summary of Change from Baseline in KHQ Domain 
Score (FAS3): TC3
Y
Proportion of Subjects attaining 100%, ≥75% and ≥50% Reduction from Baseline in the Daily Average of Urinary Incontinence Episodes
2.54.
FAS1
PSY5
Number and Percentage of Subjects Attaining 100%, 
≥75% and ≥50% Reduction from Baseline in the Daily 
Average of Urinary Incontinence Episodes (FAS1): TC1
Y
Y
2.55.
FAS2
PSY5
Number and Percentage of Subjects Attaining 100%, 
≥75% and ≥50% Reduction from Baseline in the Daily 
Average of Urinary Incontinence Episodes (FAS2): TC2
Y
2.56.
FAS3
PSY5
Number and Percentage of Subjects Attaining 100%, 
≥75% and ≥50% Reduction from Baseline in the Daily 
Average of Urinary Incontinence Episodes (FAS3): TC3
Y
Proportion of Subjects with Positive Response on the TBS
2.57.
FAS1
PSY5
Number and Percentage of Subjects with positive 
response on the TBS (FAS1): TC1
Y
Y
2.58.
FAS2
PSY5
Number and Percentage of Subjects with positive 
response on the TBS (FAS2): TC2
Y
2.59.
FAS3
PSY5
Number and Percentage of Subjects with positive 
response on the TBS (FAS3): TC3
Y
Time to the Subject’s First Request for 2nd Treatment from the Day of 1st treatment
2.60.
FAS1
TTE3
Time to the subject’s first request for 2nd treatment from 
the day of 1st treatment (FAS1)
Y
Time to the Subject’s First Qualification for 2nd Treatment from the Day of 1st treatment
2018N378022_00


CONFIDENTIAL
204948
75
Efficacy: Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
2.61.
FAS1
TTE3
Time to the subject’s first qualification for 2nd treatment 
from the day of 1st treatment (FAS1)
Y
11.10.7.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Daily Average Number of Urinary Incontinence Episodes
2.1.
FAS1
Study specific
Plot of Adjusted Mean with SEs for Change from in Daily 
Average Number of Urinary Incontinence Episodes 
Based on MMRM Analysis
Y
Average Volume Voided per Void
2.2.
FAS1
Study specific
Plot of Adjusted Mean with SEs for Change from in 
Average volume voided per void Based on MMRM 
Analysis
Y
Time to the Subject’s First Request for 2nd Treatment from the Day of 1st treatment
2.3.
FAS1
Study specific
Kaplan-Meier Curve for Time to the subject’s first request 
for 2nd treatment from the day of 1st treatment (FAS1)
Y
Time to the Subject’s First Qualification for 2nd Treatment from the Day of 1st treatment
2.4.
FAS1
Study specific
Kaplan-Meier Curve for Time to the subject’s first 
qualification for 2nd treatment from the day of 1st 
treatment (FAS1)
Y
2018N378022_00


CONFIDENTIAL
204948
76
2018N378022_00


CONFIDENTIAL
204948
77
11.10.8.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Adverse Events (AEs)
3.1.
SPDB
AE1
Summary of All Adverse Events TC1 <= 84 days from the 
first treatment
ICH E3
Y
3.2.
SPDB
AE1
Summary of All Treatment-Related Adverse Events TC1 
<= 84 days from the first treatment
GSK CTR
Y
3.3.
SPDB
AE1
Summary of All Study Drug-Related Adverse Events TC1 
<= 84 days from the first treatment
GSK CTR
Y
3.4.
SPDB
AE1
Summary of All Injection Procedure-Related Adverse 
Events TC1 <= 84 days from the first treatment
GSK CTR
Y
3.5.
SPDB
AE5A
Summary of All Adverse Events by maximum severity: 
TC1 <= 84 days from the first treatment
ICH E3
Y
3.6.
SPDB
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: TC1 <= 84 days from the first 
treatment
GSK CTR
Y
3.7.
SPDB
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: TC1 <= 84 days from the first 
treatment
GSK CTR
Y
3.8.
SPDB
AE5A
Summary of All Injection Procedure-Related Adverse 
Events by maximum severity: TC1 <= 84 days from the 
first treatment
GSK CTR
Y
3.9.
SPDB
AE1
Summary of All Adverse Events TC1
ICH E3
Y
Y
2018N378022_00


CONFIDENTIAL
204948
78
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.10.
SPDB
AE1
Summary of All Treatment-Related Adverse Events TC1
GSK CTR
Y
Y
3.11.
SPDB
AE1
Summary of All Study Drug-Related Adverse Events TC1
GSK CTR
Y
Y
3.12.
SPDB
AE1
Summary of All Injection Procedure-Related Adverse 
Events TC1
GSK CTR
Y
Y
3.13.
SPDB
AE5A
Summary of All Adverse Events by maximum severity:
TC1
ICH E3
Y
Y
3.14.
SPDB
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: TC1
GSK CTR
Y
Y
3.15.
SPDB
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: TC1
GSK CTR
Y
Y
3.16.
SPDB
AE5A
Summary of All Injection Procedure-Related Adverse 
Events by maximum severity: TC1
GSK CTR
Y
Y
3.17.
SPDB
AE15
Summary of Subjects and Number of Occurrences of 
Common Non-Serious Adverse Events TC1
FDAAA, EudraCT
Y
Y
3.18.
SP1
AE1
Summary of All Adverse Events: GTC1
ICH E3
Y
3.19.
SP1
AE1
Summary of All Treatment-Related Adverse Events: 
GTC1
GSK CTR
Y
3.20.
SP1
AE1
Summary of All Study Drug-Related Adverse Events: 
GTC1
GSK CTR
Y
3.21.
SP1
AE1
Summary of All Injection Procedure-Related Adverse 
Events: GTC1
GSK CTR
Y
3.22.
SP1
AE5A
Summary of All Adverse Events by maximum severity: 
GTC1
ICH E3
Y
2018N378022_00


CONFIDENTIAL
204948
79
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.23.
SP1
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: GTC1
GSK CTR
Y
3.24.
SP1
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: GTC1
GSK CTR
Y
3.25.
SP1
AE5A
Summary of All Injection Procedure-Related Adverse 
Events by maximum severity: GTC1
GSK CTR
Y
3.26.
SP1
AE15
Summary of Subjects and Number of Occurrences of 
Common Non-Serious Adverse Events: GTC1
FDAAA, EudraCT
Y
3.27.
SP2
AE1
Summary of All Adverse Events GTC2
ICH E3
Y
3.28.
SP2
AE1
Summary of All Treatment-Related Adverse Events 
GTC2
GSK CTR
Y
3.29.
SP2
AE1
Summary of All Study Drug-Related Adverse Events 
GTC2
GSK CTR
Y
3.30.
SP2
AE1
Summary of All Injection Procedure-Related Adverse 
Events GTC2
GSK CTR
Y
3.31.
SP2
AE5A
Summary of All Adverse Events by maximum severity: 
GTC2
ICH E3
Y
3.32.
SP2
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: GTC2
GSK CTR
Y
3.33.
SP2
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: GTC2
GSK CTR
Y
3.34.
SP2
AE5A
Summary of All Injection Procedure-Related Adverse 
Events by maximum severity: GTC2
GSK CTR
Y
2018N378022_00


CONFIDENTIAL
204948
80
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.35.
SP2
AE15
Summary of Subjects and Number of Occurrences of 
Common Non-Serious Adverse Events GTC2
FDAAA, EudraCT
Y
3.36.
SP3
AE1
Summary of All Adverse Events GTC3
ICH E3
Y
3.37.
SP3
AE1
Summary of All Treatment-Related Adverse Events 
GTC3
GSK CTR
Y
3.38.
SP3
AE1
Summary of All Study Drug-Related Adverse Events 
GTC3
GSK CTR
Y
3.39.
SP3
AE1
Summary of All Injection Procedure-Related Adverse 
Events GTC3
GSK CTR
Y
3.40.
SP3
AE5A
Summary of All Adverse Events by maximum severity:
GTC3
ICH E3
Y
3.41.
SP3
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: GTC3
GSK CTR
Y
3.42.
SP3
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: GTC3
GSK CTR
Y
3.43.
SP3
AE5A
Summary of All Injection Procedure-Related Adverse 
Events maximum by severity: GTC3
GSK CTR
Y
3.44.
SP3
AE15
Summary of Subjects and Number of Occurrences of 
Common Non-Serious Adverse Events GTC3
FDAAA, EudraCT
Y
3.45.
SP1
AE1
Summary of All Adverse Events Overall Period
ICH E3
Y
Y
3.46.
SP1
AE1
Summary of All Treatment-Related Adverse Events 
Overall Period
GSK CTR
Y
Y
3.47.
SP1
AE1
Summary of All Study Drug-Related Adverse Events 
Overall Period
GSK CTR
Y
Y
2018N378022_00


CONFIDENTIAL
204948
81
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.48.
SP1
AE1
Summary of All Injection Procedure-Related Adverse 
Events Overall Period
GSK CTR
Y
Y
3.49.
SP1
AE5A
Summary of All Adverse Events by maximum severity:
Overall Period
ICH E3
Y
Y
3.50.
SP1
AE5A
Summary of All Treatment-Related Adverse Events by 
maximum severity: Overall Period
GSK CTR
Y
Y
3.51.
SP1
AE5A
Summary of All Study Drug-Related Adverse Events by 
maximum severity: Overall Period
GSK CTR
Y
Y
3.52.
SP1
AE5A
Summary of All Injection Procedure-Related Adverse 
Events by maximum severity: Overall Period
GSK CTR
Y
Y
Serious and Other Significant Adverse Events
3.53.
SPDB
AE1  
Summary of Serious Adverse Events TC1 <= 84 days 
from the first treatment
IDSL / GSK CTR
Y
3.54.
SPDB
AE1  
Summary of Special Interest Adverse Events TC1 <= 84 
days from the first treatment
Y
3.55.
SPDB
AE1  
Summary of Serious Adverse Events TC1
IDSL / GSK CTR
Y
Y
3.56.
SPDB
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences) TC1
FDAAA, EudraCT
Y
Y
3.57.
SPDB
AE1  
Summary of Special Interest Adverse Events TC1
Y
Y
3.58.
SP1
AE1  
Summary of Serious Adverse Events: GTC1
IDSL / GSK CTR
Y
3.59.
SP1
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences): GTC1
FDAAA, EudraCT
Y
2018N378022_00


CONFIDENTIAL
204948
82
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.60.
SP1
AE1  
Summary of Special Interest Adverse Events: GTC1
Y
3.61.
SP2
AE1  
Summary of Serious Adverse Events: GTC2
IDSL / GSK CTR
Y
3.62.
SP2
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences): GTC2
FDAAA, EudraCT
Y
3.63.
SP2
AE1  
Summary of Special Interest Adverse Events: GTC2
Y
3.64.
SP3
AE1  
Summary of Serious Adverse Events: GTC3
IDSL / GSK CTR
Y
3.65.
SP3
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences): GTC3
FDAAA, EudraCT
Y
3.66.
SP3
AE1  
Summary of Special Interest Adverse Events: GTC3
Y
3.67.
SP1
AE1  
Summary of Serious Adverse Events: Overall Period
IDSL / GSK CTR
Y
Y
3.68.
SP1
AE1  
Summary of Special Interest Adverse Events: Overall 
Period
Y
Y
AEs for PLS
3.69.
SPDB
AE3
Summary of Serious Treatment Related Adverse 
Events by Overall Frequency: TC1
PLS
Y
3.70.
SP1
AE3
Summary of Serious Treatment Related Adverse 
Events by Overall Frequency: GTC1
PLS
Y
3.71.
SP2
AE3
Summary of Serious Treatment Related Adverse 
Events by Overall Frequency: GTC2
PLS
Y
3.72.
SP3
AE3
Summary of Serious Treatment Related Adverse 
Events by Overall Frequency: GTC3
PLS
Y
2018N378022_00


CONFIDENTIAL
204948
83
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.73.
SP1
AE3
Summary of Serious Treatment Related Adverse 
Events by Overall Frequency: Overall Period
PLS
Y
3.74.
SPDB
AE3
Summary of Non-Serious Treatment Related Adverse 
Events by Overall Frequency: TC1
PLS
Y
3.75.
SP1
AE3
Summary of Non-Serious Treatment Related Adverse 
Events by Overall Frequency: GTC1
PLS
Y
3.76.
SP2
AE3
Summary of Non-Serious Treatment Related Adverse 
Events by Overall Frequency: GTC2
PLS
Y
3.77.
SP3
AE3
Summary of Non-Serious Treatment Related Adverse 
Events by Overall Frequency: GTC3
PLS
Y
3.78.
SP1
AE3
Summary of Non-Serious Treatment Related Adverse 
Events by Overall Frequency: Overall Period
PLS
Y
Laboratory: Chemistry 
3.79.
SPDB
LB1
Summary of Chemistry Data: TC1
Y
Y
3.80.
SP1
LB1
Summary of Chemistry Data: GTCs
Y
3.81.
SPDB
LB1
Summary of Chemistry Changes from Baseline: TC1 
ICH E3
Y
Y
3.82.
SP1
LB1
Summary of Chemistry Changes from Baseline: GTCs
ICH E3
Y
3.83.
SPDB
LB3
Summary of Shift from Baseline with Relative to Normal 
Range in Chemistry Results: TC1
ICH E3
Y
Y
3.84.
SP1
LB3
Summary of Shift from Baseline with Relative to Normal 
Range in Chemistry Results: GTCs
ICH E3
Y
Laboratory: Hematology
3.85.
SPDB
LB1
Summary of Hematology Data: TC1
Y
Y
2018N378022_00


CONFIDENTIAL
204948
84
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.86.
SP1
LB1
Summary of Hematology Data: GTCs
Y
3.87.
SPDB
LB1
Summary of Hematology Changes from Baseline: TC1
ICH E3.
Y
Y
3.88.
SP1
LB1
Summary of Hematology Changes from Baseline: GTCs
ICH E3.
Y
3.89.
SPDB
LB3
Summary of Shift from Baseline with Relative to Normal 
Range in Hematology: TC1
ICH E3
Y
Y
3.90.
SP1
LB3
Summary of Shift from Baseline with Relative to Normal 
Range in Hematology: GTCs
ICH E3
Y
Laboratory: Urinalysis
3.91.
SPDB
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline: 
TC1
ICH E3
Y
Y
3.92.
SP1
UR1
Summary of Worst Case Urinalysis Results (Discrete or 
Character Values) Post-Baseline Relative to Baseline: 
GTCs
ICH E3
Y
Laboratory: Hepatobiliary (Liver)
3.93.
SP1
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
Y
Y
ECG
3.94.
SPDB
EG1
Summary of ECG Findings: TC1 
IDSL
Y
Y
3.95.
SP1
EG1
Summary of ECG Findings: GTCs
IDSL
Y
Vital Signs
3.96.
SPDB
VS1
Summary of Vital Signs Data by Visit: TC1
Y
Y
3.97.
SP1
VS1
Summary of Vital Signs Data by Visit: GTCs
Y
2018N378022_00


CONFIDENTIAL
204948
85
Safety : Tables
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
3.98.
SPDB
VS1
Summary of Change from Baseline in Vital Signs by Visit: 
TC1
ICH E3
Y
Y
3.99.
SP1
VS1
Summary of Change from Baseline in Vital Signs by Visit: 
GTCs
ICH E3
Y
Post Void Residual (PVR) urine volume
3.100.
SPDB
Study specific
Summary of PVR urine volume:TC1
Y
Y
3.101.
SPDB
Study specific
Summary of Change from Baseline in PVR urine 
volume:TC1
Y
Y
2018N378022_00


CONFIDENTIAL
204948
86
11.10.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Report at 
Interim
Report at 
Final
Laboratory
3.1.
SPDB
Scatter Plot of Week12/Withdrawal vs. Baseline for
Chemistry
IDSL
Y
3.2.
SPDB
Scatter Plot of Week12/Withdrawal vs. Baseline for 
Hematology
IDSL
Y
2018N378022_00


CONFIDENTIAL
204948
87
11.10.10. ICH Listings
ICH : Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
Y
2.
FAS1
ES2
Listing of Reasons for Study Withdrawal
ICH E3
Y
Y
3.
FAS1
BL1
Listing of Subjects for Whom the Treatment Blind was 
Broken
ICH E3
Y
Y
4.
FAS1
TA1
Listing of Planned and Actual Treatments
IDSL
Y
Protocol Deviations
5.
FAS1
DV2
Listing of Important Protocol Deviations
ICH E3
Y
Y
6.
FAS1
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
ICH E3
Y
Y
Populations Analysed
7.
Enrolled
SP3
Listing of Subjects Excluded from Any Population
ICH E3
Y
Y
Demographic and Baseline Characteristics
8.
FAS1
DM2
Listing of Demographic Characteristics
ICH E3
Y
9.
FAS1
DM2
Listing of Baseline Disease Characteristics
Y
10.
FAS1
DM9
Listing of Race
ICH E3
Y
Current and Past Medical Conditions, Prior and Concomitant Medications
11.
FAS1
MH2
Listing of Medical Conditions 
Y
Y
12.
FAS1
CM3
Listing of Concomitant Medications
IDSL
Y
Y
2018N378022_00


CONFIDENTIAL
204948
88
ICH : Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
13.
FAS1
CM3
Listing of Prior or Concomitant
NDO Medications
IDSL
Y
Exposure and Treatment Compliance
14.
FAS1
EX3
Listing of Exposure Data
ICH E3
Y
Y
Adverse Events
15.
SPDB
AE8 
Listing of All Adverse Events
ICH E3
Y
Y
16.
SPDB
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
Y
Y
17.
SPDB
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
IDSL
Y
Y
Serious and Other Significant Adverse Events
18.
SPDB
AE8
Listing of Fatal Serious Adverse Events
ICH E3
Y
Y
19.
SPDB
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
Y
Y
20.
SPDB
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event
ICH E3
.
Y
Y
21.
SPDB
AE8
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study Treatment
ICH E3
Y
Y
22.
SPDB
AE8
Listing of Special Interest Adverse Events
ICH E3
Y
Y
Hepatobiliary (Liver)
23.
SPDB
MH2
Listing of Medical Conditions for Subjects with Liver 
Stopping Events
IDSL
Y
Y
24.
SPDB
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
IDSL
Y
Y
25.
SPDB
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
IDSL
Y
Y
2018N378022_00


CONFIDENTIAL
204948
89
ICH : Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
26.
SPDB
LIVER6
Listing of Liver Stopping Event Information for 
RUCAM Score
IDSL
Y
Y
27.
SPDB
LIVER7
Listing of Liver Biopsy Details
IDSL
Y
Y
28.
SPDB
LIVER8
Listing of Liver Imaging Details
IDSL
Y
Y
29.
SPDB
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline
IDSL
Y
Y
All Laboratory
30.
SPDB
LB5
Listing of All Laboratory Data for Subjects with Any Value 
Outside Normal Range
ICH E3
Y
Y
2018N378022_00


CONFIDENTIAL
204948
90
11.10.11. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Interim
Report at 
Final
Urinary Diary Data
31.
FAS1
Study 
Specific
Listing of Urinary Diary Data
Y
Y
32.
FAS1
Study 
Specific
Listing of Derived Urinary Diary Data
Y
Y
Urodynamics Data
33.
FAS1
Study 
Specific
Listing of Urodynamics Data
Y
KHQ Data
34.
FAS1
Study 
Specific
Listing of KHQ Data
Y
Y
Study Specific Safety Data
35.
SPDB
Study 
Specific
Listing of PVR Data
Y
Y
36.
SPDB
Study 
Specific
Listing of CIC Data
Y
Y
37.
SPDB
Study 
Specific
Listing of Ultrasound
Y
Y
38.
SPDB
Study 
Specific
Listing of General Anesthesia
Y
Y
2018N378022_00


CONFIDENTIAL
204948
91
11.10.12. Patient Profile Listings
Patient Profiles: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Report at
Final
CV Events
39.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias
If an event occurs
40.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure
If an event occurs
41.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events Stroke and Transient Ischemic 
Attack
If an event occurs
42.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Deep Vein Thrombosis / Pulmonary Embolism
If an event occurs
43.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction / Unstable Angina
If an event occurs
44.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thromboembolism
If an event occurs
45.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension
If an event occurs
46.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation
If an event occurs
47.
SPDB
IDSL 
standard
Listing of Investigator Reported Cardiovascular Events: 
Valvulopathy
If an event occurs
48.
SPDB
IDSL 
standard
Listing of Investigator Reported Events: Deaths
If an event occurs
2018N378022_00


CONFIDENTIAL
204948
92
11.11.
Appendix 11: Example Mock Shells for Data Displays
Example mock shells will be provided as other document.
2018N378022_00


CONFIDENTIAL
204948
93
11.12.
Appendix 12: How to identify the records for the interim analysis
This document defines the details how to apply the records to the interim analysis of BOTOX NDO 204948 from the released 
dataset(SIDATA), which includes the records won’t be used for. Basically, described in the RAP, the records until 24weeks from the first 
treatment of each subject will be adopted for the analysis, however there are some data needed to be handled with particular handling rule. 
This document is provided to give a detailed description of these special handling rules as well as to suggest the physical structure of the 
analysis datasets from the aspect of data cutting. 
Released data will be judged by record whether it should be included in the interim analysis or not, by comparing with the reference 
visit or date (Data cut visit or Data cut date) corresponding to 24 weeks of each subject. However, the Liver event and Cardiovascular
event data will be decided for their adoption, by their specific rules described in chapter (2) and (3), instead of judgement by record. 
(1) How to derive the reference visit or date (Data Cut Visit or Data Cut Date) corresponding to 24 weeks of each subject and the 
basic approach of judgement
Most of the records in SIDATA except for the records of Liver event or Cardiovascular event can be decided their adoption by 
comparing with the Data cut visit or Data cut date of each subject defined in below. Application of data cut type, i.e. visit or date, is 
determined by dataset considering its attribution. If the data is linked to particular visit in SIDATA, then it will be compared with Data cut 
visit by Visit number and will be adopted when it is smaller or equal to the reference. Data cut date will be used for the comparison with 
the relevant date of the logs data (i.e., AEs, conmeds, CIC etc.). The data up to or on Data cut date will be adopted.
   The practical approach for each SIDATA will be described in chapter (4). Data cut visit(CUTVISIT), Data cut visit number
(CUTVISN) and Data cut date(CUTDT) will be stored in ARDATA.MSTONE with Withdrawal until 24W (WDR24WFL), so that they 
can be used for the judgement in the process of ARDATA creation. 
2018N378022_00


CONFIDENTIAL
204948
94
Condition 1
Withdrawn until 
24W?
Condition 2
Last regular visit *1 of Treatment Cycle 1
In SIDATA.VISIT
Data cut visit
(Data cut visit number 
in 204947)
Data cut date
Subject without 
withdrawal until 
24W 
DSCONT of 
24w eq Y
In 
DMDATA.DS
POST TX1 WEEK24 or later
POST TX1 WEEK24(170/300)
Visit date of the Data cut 
visit in 
SIDATA.VISIT, which will 
be imputed with “The date of 
first injection + 24 x 7” in the 
case of missing.
POST TX1 WEEK18
treatment until 24w*2: Twice
POST TX2 WEEK6(1020/1020)
treatment until 24w: Once
POST TX1 WEEK24(170/300)
POST TX1 WEEK12
treatment until 24w: Twice
POST TX2 WEEK12(1030/1100)
treatment until 24w: Once
POST TX1 WEEK24(170/300)
Others besides
POST TX1 WEEK24(170/300)
Subject withdrew until 24W 
Last visit of the subject in 
SIDATA.VISIT
Visit date of the Data cut 
visit in SIDATA.VISIT
*1 : Regular visits are the visits named with “TX1”, except the ones for the assessment of re-treatment or qualification, i.e. the visits 
named with “–add” in 204947.
*2 : Treatment until 24w doesn’t include the treatment just on 24w.
(2) How to make judgement of Liver Event data（with Visit number 8000s）
2018N378022_00


CONFIDENTIAL
204948
95
All of the liver event data (with Visit number 8000s) of the subject, to whom a liver event happens until 24W, will be adopted for the 
interim analysis. Whether the liver event happens until 24W or not will be judged by comparing the first detected date of liver event 
(LERSTDT in SIDATA.LEREPORT) and Data cut date of the subject, and if it starts before or equal to the reference date then the subject 
will be regarded with Liver event. This information will be stored in ARDATA.MSTONE as a variable of “Liver Event flag within w24 
after 1st trt (LE24WFL)”.
(3) How to make judgement of Cardiovascular Event data（with Visit number 3000s）
None of the Cardiovascular Event data (with Visit number 3000s) will be used for the interim analysis. The patient profiles of CV 
events will be generated only at the end of the study, as defined in the display standard.
(4) The individual approach for the judgement of the adoption for the interim analysis
Following table shows the conditions to adopt the records for the interim analysis, which can be settled by dataset. The outcome of the 
judgement will be stored in a flag named as “Flag for interim analysis(ANLINTFL)” in each ARDATA. The records not used for the 
interim analysis will be included in ARDATA but will be excluded from the analysis by using “Flag for interim analysis”.
2018N378022_00


CONFIDENTIAL
204948
96
SIDATA
ARDAT
A
English 
Description
Visit num <3000
or
logs data 
Visit num 8000s
(liver event data)
Visit num 3000s
(Cardiovascular 
event data)
Note
demo
demo
Demography
all
-
-
No data cut 
required
exposure
exposure
Exposure
VISITNUM<=CUTVI
SN
-
-
ds
ds
Subject 
disposition
Adopt all records, 
except for the subject 
logs data (VISITNUM 
eq 0) of the subject 
who continued after 
24w 
MSTONE.WDR24WF
L eq N). 
-
-
Both of Visit 
data and logs 
data are involved
dv1
dv1
Protocol 
Deviations
DVSTDT <=CUTDT
-
-
conmeds
conmeds
Concomitant 
medications
the records meet with 
any of following 
conditions will be 
adopted.
1) Compare the start 
date with the data cut 
date and adopt the 
-
excluded 
CV data can be 
identified with 
CONMEDS
CMTYPCD eq 
31
2018N378022_00


CONFIDENTIAL
204948
97
SIDATA
ARDAT
A
English 
Description
Visit num <3000
Visit num 8000s
Visit num 3000s
Note
smaller or equal to 
(CMSTDT<=CUTDT)
. CMSTDT needs to be 
imputed as in RAP 
definition.  2) the 
records with 
'CMPRIOR eq Y' will 
be adopted.  
For OAB
3) the records of prior 
medicine for OAB 
(CMTYPCD eq 25) 
will be adopted. 
For NDO
3) the records of prior 
medicine for NDO 
(CMTYPCD eq 224) 
will be adopted. 
cmanal
Concomitant 
medications 
analysis dataset
-
-
--
Carry flags from 
conmeds
blind
blind
Status of 
Treatment Blind
all
-
-
No data cut 
required
elig
elig
Eligibility 
(inclusion/exclusi
all
-
-
No data cut 
required
2018N378022_00


CONFIDENTIAL
204948
98
SIDATA
ARDAT
A
English 
Description
Visit num <3000
Visit num 8000s
Visit num 3000s
Note
on)
medhist
medhist
Medical History
all
If the subject’s 
LE24WFL eq Y
excluded
race
race
Collected race 
(check all that 
apply)
all
-
-
No data cut 
required
face
face
Findings About 
Clinical Event 
VISITNUM<=CUTVI
SN
-
-
khqking2
khqking
2
Kings Health 
Questionnaire 
King-2
VISITNUM<=CUTVI
SN
-
-
oabss
oabss
Overactive 
Bladder Symptom 
Score
VISITNUM<=CUTVI
SN
-
-
Only for OAB
tbsm
tbsm
Treatment Benefit 
Scale - Modified
VISITNUM<=CUTVI
SN
-
-
ae
ae
Adverse Event
AESTDT  <=CUTDT
-
-
lab
lab
Laboratory Data 
VISITNUM<=CUTVI
SN
excluded
Liver Events 
visit numbers 
8000s are not 
used in LAB in 
the current 
standard.
<LE related records>
If the subject’s 
LE24WFL eq Y and 
2018N378022_00


CONFIDENTIAL
204948
99
SIDATA
ARDAT
A
English 
Description
Visit num <3000
Visit num 8000s
Visit num 3000s
Note
LAB.VISITDT is 
between LERSTDT and 
LERENDT of 
sidata.lereport
ecg
ecg
ECG
VISITNUM<=CUTVI
SN
-
excluded
vitals
vitals
Vital Signs Data
VISITNUM<=CUTVI
SN
-
excluded
mo
mo
Morphology
VISITNUM<=CUTVI
SN
-
surgery
surgery
Surgical 
procedures
SPDT<=CUTDT
-
excluded
lereport
lereport
Liver event 
reporting 
-
If the subject’s 
LE24WFL eq Y
-
subuse
subuse
Substance Use
all
If the subject’s 
LE24WFL eq Y
-
rucam
rucam
Liver Events 
RUCAM Scoring
-
If the subject’s 
LE24WFL eq Y
-
lbiopsy
lbiopsy
Liver Biopsy 
-
If the subject’s 
LE24WFL eq Y
-
limaging
limagin
g
Liver Imaging
-
If the subject’s 
LE24WFL eq Y
-
2018N378022_00


CONFIDENTIAL
204948
100
SIDATA
ARDAT
A
English 
Description
Visit num <3000
Visit num 8000s
Visit num 3000s
Note
bacteria
bacteria
Bacteriology
VISITNUM<=CUTVI
SN
-
-
ce
ce
Clinical Events
-
-
excluded
cvdxtest
cvdxtest
Cardiovascula
r Events 
Diagnostic 
Tests
-
-
excluded
dth
dth
Death event
DDDT<=CUTDT
-
-
evidence
evidenc
e
Physical 
Evidence
-
-
excluded
facv
facv
Findings 
About 
Cardiovascula
r Events
-
-
excluded
fadth
fadth
Findings 
About Death
all
-
Famh
Famh
Findings about 
medical 
history
all
204948 only
Cc
CC
all
204948 only
EDSS
EDSS
all
204948 only
2018N378022_00


CONFIDENTIAL
204948
101
SIDATA
ARDAT
A
English 
Description
Visit num <3000
Visit num 8000s
Visit num 3000s
Note
famhist
famhist
Family History
all
-
hru
hru
Healthcare 
Resource 
Utilisation
-
-
excluded
nyhascr
nyhascr
NYHA Score
-
-
excluded
risk
risk
Risks Factors
-
-
excluded
ss
ss
Subject 
Status
VISITNUM<=CUTVI
SN
-
(5) Special Notes
-
If the date of the record of logs data is missing then it will be excluded from the analysis. 
-
In the comparison of visit number. If the data of Unscheduled Visit exists in the same visit number of Data cut visit, it will be adopted 
as far as its visit number is smaller than the Data cut visit number precisely. i.e. if Data cut visit number = 1020, data with 1020.1 will 
be excluded from the analysis. 
2018N378022_00