Clinical trial NCT02058368
Conditions: Prostatic Hyperplasia
Keywords: Benign Prostatic Hyperplasia Quality of Life
Sponsor: GlaxoSmithKline
Start date: 2014-02-10; Completion date: 2017-03-03
Enrollment: 607 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicentre, randomised, double-blind, parallel group study in Asian subjects. The aim of the study is to investigate whether combination therapy with dutasteride and tamsulosin is more effective than tamsulosin monotherapy for the improvement of symptoms and health outcomes in an at risk population of benign prostatic hyperplasia (BPH) clinical progression including older men (\>=50 years), with moderate-severe symptoms of BPH, enlarged prostates (\>=30 cubicentimeter \[cc\]) and prostate specific antigen (PSA) \>= 1.5 nanograms per milliliter (ng/mL). Each subject who met the eligibility criteria at screening will enter a four-week single-blind, placebo run-in period following which each subject will be randomised into a 2 year double-blind treatment phase. The total study duration for each subject will be up to 110 weeks.

Detailed description:

Arms: arm 1: Run-in phase: All subjects qualifying for the study will entered into a placebo run-in phase will receive one soft gelatin placebo capsule (swallowed whole and not chewed) and one oral disintegrating placebo tablet once daily (OD) (dissolved on the tongue then swallowed not chewed), following the first meal each day for four weeks. Randomized treatment phase: Subjects will be instructed to take 1 dutasteride 0.5 milligram (mg) capsule (swallowed whole and not chewed) and one tamsulosin 0.2mg tablet OD (dissolved on the tongue then swallowed not chewed) following the first meal each day for 104 weeks. arm 2: Run-in phase: All subjects qualifying for the study will entered into a placebo run-in phase will receive one soft gelatine placebo capsule (swallowed whole and not chewed) and one oral disintegrating placebo tablet OD (dissolved on the tongue then swallowed not chewed), following the first meal each day for four weeks. Randomized treatment phase: Subjects will be instructed to take 1 placebo dutasteride 0.5mg capsule (swallowed whole and not chewed) and one tamsulosin 0.2mg tablet OD (dissolved on the tongue then swallowed not chewed) following the first meal each day for 104 weeks.
Interventions: intervention 1: Dutasteride 0.5mg capsules intervention 2: Dutasteride placebo capsules intervention 3: Tamsulosin 0.2mg tablets intervention 4: Disintegrating placebo tamsulosin tablet
Intervention descriptions: intervention 1: Dutasteride 0.5mg capsules will be supplied as plain, oblong, opaque, dull yellow soft gelatin capsules. intervention 2: Dutasteride placebo will be supplied as plain, oblong, opaque, dull yellow soft gelatin capsules. intervention 3: Commercially available tamsulosin 0.2mg tablets will be supplied. intervention 4: Disintegrating placebo tamsulosin tablet will be supplied for the run-in period.

Protocol documents:
Prot_000.pdf: 
RM2010/00134/05
CONFIDENTIAL
The GlaxoSmithKline group of companies
ARI114265
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomized, double-blind, parallel group study to compare the 
efficacy and safety of combination treatment with dutasteride 
(0.5mg) and tamsulosin (0.2mg) with tamsulosin (0.2mg) 
monotherapy, administered once daily for 2 years, on the 
improvement of symptoms and health outcomes in men with 
moderate to severe benign prostatic hyperplasia
Compound Number:
GI198745
Effective Date:
08-JUL-2014
Protocol Amendment Number:  4
Subject: Infection, Quality of Life
Author:
 
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology:
RM2010/00134/00
2010-SEP-30
Original
RM2010/00134/01
2012-FEB-23
Amendment No.: 01
!
Change in the storage conditions 
for study drug, Section 5.3
!
Addition of text on serum PSA 
measure at one additional visit, 
Section 7.3.4.2 
!
Addition of text on sexually 
related AE follow up, Section 6.3
!
Addition of text on three 
supplementary efficacy measures, 
Section 7.2.1.2, Section 7.2.2.4, 
Section 7.4.2.2 and Section 9.3.6.1
!
Correction of text on vital sign 
measures to include measures at 
Visit 3 and Visit 5, Section 7.3.3
!
Correction of the treatment 
assignment language, Section 5.4.
!
Clarification on study treatment 
discontinuation and study 
discontinuation, Section 4.2.1, 
Section 6.3, Section 7.4.4 and  
Section 7.2.2.5
!
Clarification of data collected for 
partner pregnancies, 
Section 7.4.3.1 and  
Section 7.4.3.2.
!
Clarification on the collection  of 
Questionnaires in Appendix 2, 
Section 7.5.3.1
!
Correction to T &E table,  
Section 7
!
Clarification of language on 
protocol waivers, Section 3 
!
Clarification of language in PGx  
Section 2.3, Section 7.6 and 
Appendix 1 
!
Administrative change to correct 
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spelling errors and re-wording to 
provide clarification and 
consistency
!
Removal of details which will be
documented in the Study 
Procedures Manual.
!
Addition of text on an optional 
SMS reminder service 
Section 7.2.3
!
Addition of text to allow 
unscheduled visits when medically 
necessary Section 7
RM2010/00134/02
2013-SEP-25
Amendment No.: 02
!
Addition of a PPK substudy for 
subjects of Chinese origin, living 
in China (only) Section 2.4, 
Section 7.7, Section 9.3.10 and 
Appendix 7.
!
Addition of suicidality 
assessments, at pre-screening 
(V1a), and at 6, 12 and 24 months 
on treatment. Section 7.3.1, 
Section 7.3.9, Section 7.4.6, and 
Section 9.3.7.2.1.
!
Addition of information on QTc 
events, liver events and partner 
pregnancy. Section 7.4.3, 
Section 7.4.4 and Section 7.4.5.
!
Clarification on the information 
collected at baseline and at the 
pre-screening (V1a) and screening 
(V1b) visits. Protocol Summary.
!
Update to Sponsor Signatory, 
Medical Monitoring Contact 
Information and List of Authors. 
Sponsor Information Page. 
!
Clarification that the study will be 
posted to clinical trial registries 
Section 10.1.
!
Clarification of condom use for 
study subjects with female 
partners of childbearing potential. 
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Section 4.1.2 and Section 7.4.5.
!
Clarification on the use of PDE-5 
inhibitors. Section 4.1.3 and 
Section 6.2.
!
Update to T & E table to show 
new assessments for suicidality 
(all subjects) and PPK (Chinese 
subjects only). Section 7
!
Additional information on 
definition of SAEs for 
cardiovascular events and death. 
Section 7.4.2 
!
Clarification on the wording for 
BPH related quality of life
!
The details of the uroflow meter 
will be included in the study 
procedures manual.
!
Administrative changes to correct 
spelling errors and re-wording to 
provide clarification and 
consistency
RM2010/00134/03
2013-NOV-12
Amendment No.: 03
!
Removed the exclusion criteria for 
subjects previously treated with 
PDE-5 inhibitors in Section 4.1.3.
!
Other minor typographical 
changes.
RM2010/00134/04
2014-JUL-03
Amendment No.: 4 
!
Correction of SAE fax number 
and e-mail address
!
Insertion of details of secondary 
medical monitor
!
Allowance 
of 
automated 
prostate volume calculator for 
TRUS measurements
!
Restriction of selective beta 3 -
adrenoreceptor
agonist 
for 
over-active bladder syndrome 
(e.g. mirabegron)
!
Restriction 
of 
ginseng 
for 
treatment of BPH or sexual 
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dysfunction
!
To correct that the C-SSRS 
questionnaire 
will 
be 
administered by  a trained rater
!
To correct that a Hepatitis RNA 
test will be used to confirm a 
Hepatitis C antibody positive 
result rather than a Hepatitis 
RIBA immunoblot assay
!
Insertion of text for sentinel 
adverse event monitoring
!
Administrative 
changes 
to 
provide consistency
!
Removal of transition zone 
volume measurement
!
Revision of text concerning 
provision of rhythm strip for 
ECG monitoring
RM2010/00134/05
2014-JUL-08
Amendment No.: 4 (Republished)
!
Compound number 
confirmation
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number ARI114265 
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 clinical 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 Signature
Date
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................13
PROTOCOL SUMMARY...............................................................................................15
1.
INTRODUCTION....................................................................................................18
1.1.
Background ................................................................................................18
1.2.
Study Rationale ..........................................................................................20
2.
OBJECTIVE(S) ......................................................................................................20
2.1.
Primary Objective .......................................................................................20
2.2.
Secondary Objective(s)...............................................................................21
2.2.1.
Efficacy........................................................................................21
2.2.2.
Safety ..........................................................................................21
2.2.3.
Health Outcomes.........................................................................21
2.3.
Exploratory Pharmacogenetics (PGx) Research Objective .........................21
2.4.
Exploratory Population Pharmacokinetics (PPK) Research 
Objective.....................................................................................................21
3.
STUDY DESIGN ....................................................................................................22
3.1.
Discussion of Design ..................................................................................23
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................23
4.1.
Subject Selection Criteria............................................................................23
4.1.1.
Number of Subjects .....................................................................23
4.1.2.
Inclusion Criteria..........................................................................24
4.1.3.
Exclusion Criteria.........................................................................24
4.1.4.
Other Eligibility Criteria Considerations........................................26
4.1.4.1.
Precautions ................................................................27
4.2.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................27
4.2.1.
Permanent Discontinuation from Study Treatment.......................27
4.2.2.
Subject Completion......................................................................28
5.
STUDY TREATMENTS..........................................................................................28
5.1.
Investigational Product................................................................................28
5.1.1.
Dosage and Administration..........................................................28
5.2.
Packaging and Labeling..............................................................................29
5.3.
Handling and Storage of Study Treatment ..................................................29
5.4.
Treatment Assignment................................................................................30
5.5.
Blinding.......................................................................................................30
5.6.
Product Accountability ................................................................................31
5.7.
Treatment Compliance................................................................................31
5.8.
Dose Modifications .....................................................................................31
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................31
6.1.
Permitted Medications and Non-Drug Therapies.........................................31
6.2.
Prohibited Medications and Non-Drug Therapies........................................31
6.2.1.
Non-Drug Therapies ....................................................................32
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6.3.
Treatment after Discontinuation of Study treatment or 
Discontinuation of Study .............................................................................32
6.4.
Treatment of Study Medication Overdose...................................................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
7.1.
Critical Baseline Assessments....................................................................38
7.2.
Efficacy.......................................................................................................38
7.2.1.
Primary Endpoint .........................................................................38
7.2.1.1.
Secondary Endpoints .................................................38
7.2.1.2.
Other Efficacy Measures ............................................39
7.2.1.3.
Health Outcome Measures Endpoints ........................39
7.2.2.
Efficacy Assessment....................................................................39
7.2.2.1.
International Prostate Symptom Score (IPSS)............39
7.2.2.2.
Prostate Volume.........................................................39
7.2.2.3.
Urinary Flow Measurement.........................................40
7.2.2.4.
Definition of Other Efficacy Measures.........................41
7.2.2.5.
End of Study Treatment Assessments........................42
7.2.3.
Short Messaging Service Reminder System................................42
7.3.
Safety .........................................................................................................43
7.3.1.
Endpoints.....................................................................................43
7.3.2.
Medical History, Concomitant Medications, ECG, Physical 
Examination.................................................................................43
7.3.3.
Physician’s assessments and vital signs......................................44
7.3.4.
Clinical Laboratory Assessments .................................................44
7.3.4.1.
Haematology and Clinical Chemistry..........................45
7.3.4.2.
Prostate Specific Antigen (PSA) .................................46
7.3.5.
Post Void Residual Volume .........................................................46
7.3.6.
Acute Urinary Retention...............................................................47
7.3.7.
Surgical and Minimally-Invasive/Non-surgical Interventions 
for BPH........................................................................................47
7.3.8.
For-Cause Biopsy for Diagnosis of Prostate Cancer ....................47
7.3.9.
Suicidality ....................................................................................48
7.3.10.
Collection of Other Efficacy Measures .........................................48
7.4.
Adverse Events...........................................................................................48
7.4.1.
Definition of an AE.......................................................................48
7.4.2.
Definition of a SAE.......................................................................49
7.4.2.1.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................51
7.4.2.2.
Cardiovascular Events................................................51
7.4.2.3.
Death Events..............................................................51
7.4.2.4.
Sentinel Events ..........................................................52
7.4.2.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................52
7.4.3.
QTc Events..................................................................................53
7.4.4.
Liver Events.................................................................................53
7.4.5.
Partner Pregnancy.......................................................................53
7.4.5.1.
Time period for collecting partner pregnancy 
information .................................................................53
7.4.5.2.
Action to be taken if partner pregnancy occurs...........53
7.4.6.
Suicidality Monitoring...................................................................54
7.4.7.
Time Period and Frequency of Detecting AEs and SAEs.............54
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7.4.8.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................55
7.4.9.
Regulatory reporting requirements for SAEs................................55
7.5.
Health Outcomes........................................................................................56
7.5.1.
BPH-related Quality of Life ..........................................................56
7.5.2.
Questionnaire administration .......................................................57
7.5.3.
Recording of data ........................................................................57
7.5.3.1.
Collection and storage of subject 
questionnaires............................................................57
7.5.4.
Medical resource utilisation..........................................................57
7.6.
Pharmacogenetics......................................................................................58
7.7.
Population Pharmacokinetics (Chinese Subjects Only)...............................58
8.
DATA MANAGEMENT ...........................................................................................58
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................60
9.1.
Hypotheses.................................................................................................60
9.2.
Study Design Considerations......................................................................60
9.2.1.
Sample Size Assumptions ...........................................................60
9.2.2.
Sample Size Sensitivity................................................................60
9.2.3.
Sample Size Re-estimation..........................................................60
9.3.
Data Analysis Considerations .....................................................................61
9.3.1.
Analysis Populations....................................................................61
9.3.2.
Per Protocol Populations .............................................................61
9.3.3.
PPK Population............................................................................61
9.3.4.
Analysis Data Sets.......................................................................61
9.3.5.
Treatment Comparisons ..............................................................62
9.3.5.1.
Primary Comparison of Interest ..................................62
9.3.5.2.
Other Comparisons of Interest....................................62
9.3.6.
Interim Analysis ...........................................................................63
9.3.7.
Key Elements of Analysis Plan ....................................................63
9.3.7.1.
Efficacy Analyses .......................................................63
9.3.7.2.
Safety Analyses..........................................................65
9.3.7.2.1.
Other Safety Measures...........................66
9.3.7.3.
Health Outcomes Analyses ........................................68
9.3.8.
Medical Resource Utilisation........................................................68
9.3.9.
Pharmacogenetic Analyses .........................................................68
9.3.10.
Population Pharmacokinetic Analyses .........................................69
10. STUDY CONDUCT CONSIDERATIONS ...............................................................69
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............69
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................69
10.3.
Quality Control (Study Monitoring) ..............................................................69
10.4.
Quality Assurance.......................................................................................70
10.5.
Study and Site Closure ...............................................................................70
10.6.
Records Retention......................................................................................70
10.7.
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ...................................................................71
11. REFERENCES.......................................................................................................72
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12. APPENDICES........................................................................................................73
12.1.
Appendix 1: PGx.........................................................................................73
12.2.
Appendix 2: Study Assessment Schedule In Order of Performance............78
12.3.
Appendix 3: Country Specific Requirements...............................................84
12.4.
Appendix 4: Prostatic Surgical and Minimally-invasive/Non surgical 
Interventions for BPH..................................................................................85
12.5.
Appendix 5: IPSS Questionnaire.................................................................86
12.6.
Appendix 6: Health Outcomes / QoL Questionnaires ..................................88
12.7.
Appendix 7: Population Pharmacokinetic Substudy (Chinese 
Subjects Only) ............................................................................................90
12.8.
Appendix 8: Protocol Amendment Changes................................................92
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LIST OF ABBREVIATIONS
5 ARI
5 Alpha-Reductase Inhibitor
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUR
Acute Urinary Retention
BHS
BPH-related Health Status
BII
BPH Impact Index
BPH
Benign Prostatic Hyperplasia
CIB
Clinical Investigator Brochure
CNS
Central Nervous System
CS
Clinically significant
C-SSRS
Columbia Suicide Severity Rating Scale
DHT
Dihydrotestosterone
DRE
Digital Rectal Examination
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCSP
Global Clinical Safety Pharmacovigilance
GSK
GlaxoSmithKline
HBsAG
Hepatitis B Antigen
HGPIN
High grade prostatic intraepithelial neoplasia
HIFU
High Intensity Focused Ultrasound
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International Nationalized Ratio
IPSS
International Prostate Symptom Score
IRB
Institutional Review Board
ITT
Intent-to-treat
IVRS
Interactive Voice Response System
LOCF
Last observation carried forward
LUTS
Lower urinary tract symptoms
MSDS
Material Safety Data Sheet
NCS
Not clinically significant
ODT
Oral Disintegrating tablet
PAS-SFI
Problem Assessment Scale Sexual Function Inventory
PDE-5
Phosphodiesterase-5
PGx
Pharmacogenetic
PPK
Population pharmacokinetics
PPSM
Patient Perception of Study Medication
PSA
Prostate Specific Antigen
PSRAE
Possible Suicidality Related Adverse Event form
Qmax
Maximum (peak) urinary flow rate
RAMOS
Registration and medication ordering system
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RAP
Reporting and Analysis Plan
RBC
Red Blood Cell
RTP
Research Triangle Park
SAE
Serious Adverse Event
SCA
Standard clarification agreement
SD
Standard deviation
SPM
Study Procedure manual
TRUS
Transrectal ultrasound
TUMT
Transurethral Microwave Thermotherapy
TUNA
Transurethral Needle Ablation
TURP
Transurethral resection of the prostate
USA
United States of America
UTI
Urinary Tract Infection
WBC
White Blood Cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
AVODART
Flomax
Harnal D
Propecia
Proscar
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PROTOCOL SUMMARY
Rationale
GlaxoSmithKline plans to develop a Fixed Dose Combination (FDC) containing 0.5mg 
of dutasteride and 0.2mg of tamsulosin hydrochloride (hereafter referred to as 
tamsulosin) for the treatment of  moderate to severe lower urinary track symptoms 
associated with Benign Prostatic Hypertrophy (BPH) in Asian men.
GSK conducted a 4 year study; Combination of Dutasteride and Tamsulosin (CombAT) 
in which dutasteride 0.5mg and tamsulosin 0.4mg were co-administered once daily for 
4years, and compared to dutasteride 0.5mg  and tamsulosin 0.4mg, administered as 
monotherapies. The study demonstrated that the co-administration of dutasteride and 
tamsulosin provided superior symptom improvement compared to each of the 
monotherapies alone. This symptom improvement was seen after 2 and 4 years of 
treatment. The 2 year pre-planned analysis of the CombAT data supported the approval 
of co-administration in the USA and Europe in 2008. The 2 year symptom data also 
supported the approval of an NDA and MAA for a single combination capsule in the 
USA and Europe in 2010.
To support the development of an FDC in the Asia Pacific region, GSK will conduct a 
study similar to CombAT using dutasteride 0.5mg co-administered with the approved and 
widely used 0.2mg dose of tamsulosin. The reason tamsulosin 0.2mg is the proposed dose 
for this study is the data from the tamsulosin PK studies  showed that in Japanese subjects 
taking tamsulosin 0.4mg, the Cmax was higher compared with Caucasian subjects taking 
the same dose. The lower dose of tamsulosin is preferred in Asia, considering a key 
complication associated with the higher dose, postural hypotension. 
The Japanese phase III dutasteride study (ARI105326) was a clinical study that allowed 
subjects to take tamsulosin 0.2mg for 52 weeks. In this study, subjects who were taking 
tamsulosin 0.2mg prior to the study start were instructed to continue taking tamsulosin 
0.2mg concomitantly with dutasteride throughout the trial. The data from this subgroup 
and the dutasteride monotherapy group demonstrated superior symptom improvement 
compared to placebo and tamsulosin monotherapy. These results suggest that there is 
symptom improvement with the co-administration of tamsulosin at a lower dose. 
The study will be conducted solely in Asian men from the Asia Pacific region. 
Objective(s)
The primary objective of the study is to assess the efficacy of combination treatment with 
dutasteride 0.5mg and tamsulosin 0.2mg once daily in providing superior symptomatic 
improvement in subjects with BPH compared with once daily tamsulosin 0.2mg 
monotherapy after 2 years of treatment.
The secondary objective is to assess efficacy and safety of combination treatment with 
dutasteride 0.5mg and tamsulosin 0.2mg including the clinical outcomes of AUR or 
BPH-related prostatic surgery compared with tamsulosin 0.2mg monotherapy after 2 
years of treatment.
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Study Design
This is a multicentre, randomized, double-blind, parallel group study. The aim of the 
study is to investigate whether combination therapy with dutasteride and tamsulosin is 
more effective than tamsulosin monotherapy for the improvement of symptoms and 
health outcomes in a population at increased risk of BPH clinical progression including 
older men (≥50yrs), with moderate-severe symptoms of BPH, enlarged prostates (≥30cc) 
and PSA≥1.5ng/mL.
Eligible subjects will receive placebo tamsulosin and placebo dutasteride for four weeks. 
Following the four-week, single-blind, placebo, run-in period, each subject will be 
randomized to one of the following two treatment groups, according to a pre-determined 
randomisation schedule (1:1 ratio) for the double-blind phase of the study:
!
Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily
!
Dutasteride placebo once daily + tamsulosin 0.2mg once daily
Subjects will self-administer the study medication once daily for up to 104 weeks 
(2 years). Subjects will return to the clinic at 13 week intervals post-randomisation during 
the 2 year treatment period (i.e. at 13, 26, 39, 52, 65, 78, 91, and 104 weeks).
Approximately 586 men with symptomatic BPH will be randomized.
Study Assessments
The primary efficacy endpoint of this study is change in IPSS from baseline at Year 2. 
The secondary efficacy endpoints of this study are:
!
Percent change in prostate volume from baseline
!
Proportion of subjects with IPSS improvement.
!
Change in Qmax from baseline and proportion of subjects with Qmax improvement 
from baseline.
!
Time to event / proportion of subjects with AUR or BPH related prostatic surgery.
!
Health Outcome Measures:
!
Change from baseline in BPH-related Health Status (Q8 of IPSS),
!
Change from baseline in BPH Impact Index (BII), and 
!
Change from baseline in Problem Assessment Scale of the Sexual Function 
Inventory (PAS-SFI). 
The planned assessments for all study participants include prostate volume by TRUS at 
screening (V1b) and annually thereafter for up to 2 years. Additionally, IPSS, 
BPH-related health status Q8 of IPSS, BPH Impact Index (BII) will be administered at 
pre-screening (V1a), baseline and every 13 weeks thereafter. The PAS-SFI will be 
administered at screening (V1b), baseline and annually thereafter. Peak urinary flow 
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(Qmax), and post void residual volume (PVR) will be measured at pre-screening (V1a), 
screening (V1b, if necessary), baseline and every 26 weeks thereafter. A physical 
examination with a qualitative breast examination, will be conducted at screening (V1b) 
and every 26 weeks thereafter. Measures of the total PSA will be conducted at 
pre-screening (V1a), 6 months, 52 weeks and every 52 weeks thereafter.
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1.
INTRODUCTION
1.1.
Background
Benign prostatic hyperplasia (BPH) is a chronic and progressive disease. It is the most 
common benign neoplasm in the aging male population, with pathological changes found 
in 88% of men in their ninth decade and symptoms reported in nearly 50% of men aged 
≥50 years in the general population [Napalkov, 1995]. The known proximal cause of 
BPH is age-related prostate growth that is stimulated primarily by the presence of 
dihydrotestosterone (DHT). DHT is formed when testosterone is reduced through the 
activity of the 5α-reductase enzymes type 1 and type 2, although type 2 is considered 
primarily responsible for this conversion in benign prostate tissue. Prostatic growth may 
lead to urethral obstruction that causes lower urinary tract symptoms (LUTS) such as 
weak or intermittent flow, urgency, frequency, nocturia and incontinence, which interfere 
with normal activities. The potentially progressive nature of the disease has been 
associated with an increased risk of acute urinary retention (AUR) and the need for 
surgery [Oelke, 2011].
The aim of BPH therapy is to improve symptoms and quality of life of patients, and to 
prevent or reduce the risk of BPH-related complications such as urinary retention or 
upper urinary tract dilatation [AUA, 2010; Oelke, 2011]. Commonly used and 
recommended treatment options include pharmacotherapeutic agents such as alpha 
blockers and 5α-reductase inhibitors (5ARIs), and surgical intervention in appropriate 
cases. With the more frequent use of pharmacotherapeutic agents, the rate of surgery for 
BPH has declined in recent years [Napalkov, 1995; Roehrborn, 2002]. However, a single 
pharmacotherapeutic agent may not be completely effective for patients with moderate-
to-severe symptoms or patients at increased risk of disease progression. The combination 
of two compounds with different and complementary mechanisms of action provides 
additional benefits in disease management compared to either monotherapy alone. In 
November 2003, GSK initiated a multinational study over a 4-year treatment period 
(CombAT, ARI40005) to evaluate the efficacy and safety of co-administration of the two 
drugs (dutasteride 0.5 mg/ tamsulosin 0.4mg versus dutasteride 0.5mg and tamsulosin 
0.4mg monotherapy).
Study ARI40005 considered the results from previous studies that explored the benefits 
of the combination of a single type 2 5ARI, finasteride, with different alpha blockers in 
BPH symptoms and outcomes in an average BPH population. The inclusion criteria for 
ARI40005 were designed to select men at increased risk for BPH progression, and 
included a requirement for baseline PV ∀30 mL, serum PSA levels ∀1.5 ng/mL, and an 
International Prostate Symptom Score [IPSS] ∀12 points. Efficacy measures included the 
combined endpoint of time to acute urinary retention (AUR) or BPH-related surgery after 
4 years of treatment and symptom improvement after 2 and 4 years of treatment. Results 
of a planned Year 2 analysis demonstrated the efficacy and safety of co-administration,
[Roehrborn, 2008]. Results of the planned Year 4 analyses for CombAT were published 
[Roehrborn, 2010]. The study demonstrated that in men with moderate to severe lower 
urinary tract symptoms (LUTS) and prostate enlargement (30 cc or greater), combination 
therapy with dutasteride (0.5mg) and tamsulosin (0.4mg) once daily provided a 
significantly greater degree of symptomatic benefit than either tamsulosin (0.4mg) or 
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dutasteride (0.5mg) monotherapy at the end of 2 and 4 years of treatment. In addition, at 
4 years, dutasteride and tamsulosin in combination significantly reduced the risk of AUR 
and BPH related surgery compared to tamsulosin monotherapy. The data from the 4 year 
treatment study supports the long term use of dutasteride 0.5mg and tamsulosin 0.4mg 
co-administered in men with moderate to severe lower urinary track symptoms due to 
BPH and prostate enlargement. 
In the overall CombAT population [4844 subjects], the observed safety and tolerability 
profile of combination therapy was generally consistent with the known safety profiles 
for the individual monotherapies. There was an observed imbalance in cardiac failure 
events [14 subjects (0.9%) in the combination group, 4 subjects (0.2 %) in the dutasteride 
group, and 10 subjects (0.6%) in the tamsulosin monotherapy group]. There was a higher 
incidence of ejaculation disorders [172 subjects (10.7 %) in the combination group 
compared to the individual monotherapies, 40 subjects (2.5%) in the dutasteride 
monotherapy group and 59 subjects (3.7%) in the tamsulosin monotherapy group]. No 
cardiac failure events were reported in the Asian subpopulation (a total of 325 subjects or 
7% of the total population enrolled in the study). 
The Japanese phase III study (ARI105326) suggests the benefits of co-administration of 
dutasteride in patients already receiving tamsulosin [Tsukamoto, 2009]. For this study, it 
was decided to include patients who had started tamsulosin before the start of the study 
and still had moderate to severe symptoms and an enlarged prostate. Stratified 
randomization of these patients and patients without any concurrent BPH medication was 
carried out to compare dutasteride and placebo.
Changes from baseline in the IPSS, peak urinary flow rate, and prostate volume were 
compared between the dutasteride group and the placebo group at Week 52. The 
dutasteride group, with regard to the whole group as well as to the subgroup receiving 
tamsulosin at baseline, showed superior improvement as compared to the placebo group. 
In the tamsulosin treated subgroup, the treatment difference in mean change from 
baseline in IPSS, which was the primary endpoint, was -1.7 between  the dutasteride 
group (add-on to tamsulosin) and placebo group (tamsulosin monotherapy). This was 
comparable to the treatment difference of -1.6 between the whole dutasteride group and
the placebo group, which suggests symptom improvement through the combination 
therapy to patients who have moderate or severe symptoms and an enlarged prostate with 
tamsulosin therapy.
In study ARI105326, the incidence of adverse events in the dutasteride group with and 
without the use of tamsulosin were comparable. The incidence of adverse events 
considered to be drug related was slightly higher in the dutasteride group without 
tamsulosin, however, no clear difference due to tamsulosin was confirmed with regard to 
each individual adverse event.
Approval of the co-administration therapy for the treatment of BPH was obtained in 
Europe and USA in 2008. In another study (ARI109882), bioequivalence between a 
newly developed fixed-dose combination (dutasteride 0.5mg / tamsulosin hydrochloride 
0.4mg) and the co-administration therapy was demonstrated, and the fixed dose 
combination product was approved in Europe in March 2010 and in the US June 2010.
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Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the study treatments is provided in the approved label and in the 
clinical investigator brochure (CIB).
1.2.
Study Rationale
GlaxoSmithKline plans to develop a Fixed Dose Combination (FDC) containing 0.5mg 
of dutasteride and 0.2mg of  tamsulosin for the treatment of moderate to severe lower 
urinary track symptoms associated with Benign Prostatic Hypertrophy (BPH) in Asian 
men.
GSK conducted a 4 year study; Combination of Dutasteride and Tamsulosin (CombAT) 
in which dutasteride 0.5mg and tamsulosin 0.4mg were co-administered once daily for 
4 years, and compared to dutasteride 0.5mg and tamsulosin 0.4mg  monotherapy. This 
study demonstrated that the co-administration of dutasteride and tamsulosin provided 
superior symptom improvement compared to the monotherapies alone. This was seen 
after 2 and 4 years of treatment. The 2 year preplanned data CombAT supported the 
approval of co-administration in the USA and Europe in 2008. The 2 year symptom data 
also supported the approval of the NDA and MAA for a single combination product in 
the USA and Europe in 2010.
To support the development of an FDC in the Asia Pacific region, GSK will conduct a 
study similar to CombAT using dutasteride 0.5mg co-administered with the approved and 
widely used the 0.2mg dose of tamsulosin. Tamsulosin PK data showed that in Japanese 
subjects taking tamsulosin 0.4mg, the Cmax was higher compared to Caucasian subjects 
taking the same dose. The lower dose of tamsulosin is preferred in Asia, considering a 
key complication associated with the higher dose; postural hypotension. 
The Japanese phase III dutasteride study (ARI105326) was a clinical study that  allowed 
subjects  to take tamsulosin 0.2mg for 52 weeks. In this study subjects who were taking 
tamsulosin 0.2mg prior to the study start were instructed to continue taking tamsulosin 
0.2mg concomitantly with dutasteride throughout the trial. The data from this subgroup 
and the dutasteride monotherapy group demonstrated superior symptom improvement 
compared to placebo and tamsulosin monotherapy. These results suggest that there is 
symptom improvement with the co-administration of tamsulosin at a lower dose.
The study will be conducted solely in Asian men from the Asia Pacific region. 
2.
OBJECTIVE(S)
2.1.
Primary Objective
The primary objective of the study is to assess the efficacy of combination treatment with 
dutasteride 0.5mg and tamsulosin 0.2mg once daily in providing superior symptomatic 
improvement in subjects with BPH compared with once daily tamsulosin 0.2mg 
monotherapy after 2 years of treatment.
The primary efficacy endpoint is presented in Section 7.2.1 of this protocol.
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2.2.
Secondary Objective(s)
2.2.1.
Efficacy
The secondary efficacy objective is:
To assess efficacy of combination treatment with dutasteride 0.5mg and tamsulosin 
0.2mg on the clinical outcomes of AUR or BPH-related prostatic surgery compared with 
tamsulosin 0.2mg monotherapy after 2 years of treatment.
The secondary efficacy endpoints are presented in Section 7.2.1.1 of this protocol.
2.2.2.
Safety
The safety objective is to assess the safety and tolerability of co-administered dutasteride 
0.5 mg once daily and tamsulosin 0.2 mg once daily compared to tamsulosin 
monotherapy 0.2 mg once daily.
The safety endpoints are presented in Section 7.3.1 of this protocol.
2.2.3.
Health Outcomes
The health outcome objective is:
!
To assess the effects of combination treatment with dutasteride 0.5mg and 
tamsulosin 0.2mg and tamsulosin 0.2mg monotherapy on health outcome measures 
(BII, Q8 of IPSS, PAS-SFI).
The health outcomes endpoints are presented in Section 7.2.1.3 of this protocol.
2.3.
Exploratory Pharmacogenetics (PGx) Research Objective
The exploratory PGx objectives for this study are to investigate the relationships between 
genetic variants in DNA from patient blood and any unexplained or unexpected response 
to treatment (as monitored by safety, tolerability, and efficacy parameters) that may have 
an underlying genetic mechanism.
2.4.
Exploratory Population Pharmacokinetics (PPK) Research 
Objective
To characterize the PPK of dutasteride when given in combination with tamsulosin to 
Chinese men with BPH.
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3.
STUDY DESIGN
This is a multicentre, randomized, double-blind, parallel group study.The aim of the 
study is to investigate whether combination therapy with dutasteride and tamsulosin is 
more effective than tamsulosin monotherapy for improvement of symptoms and health 
outcomes in a population of men at risk of BPH clinical progression including older men 
(≥50yrs), with moderate-severe symptoms of BPH, enlarged prostates (≥30cc) and 
PSA≥1.5ng/mL.
Subjects who provide informed consent will be screened for inclusion into the study and 
eligible subjects will receive placebo tamsulosin and placebo dutasteride for four weeks. 
Following the four-week single-blind, placebo run-in period, each subject will be 
randomized to one of the following two treatment groups, according to a pre-determined 
randomisation schedule (1:1 ratio) for the double-blind phase of the study:
!
Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily
!
Dutasteride placebo once daily + tamsulosin 0.2mg once daily
Subjects will self-administer the study medication once daily for up to 104 weeks 
(2 years). Subjects will return to the clinic at 13 week intervals post-randomisation during 
the 2 year treatment period (i.e. at 13, 26, 39, 52, 65, 78, 91, and 104 weeks), for the 
assessments listed in the Time and Events Schedule, Section 7.
The total study duration for each subject will be up to 110 weeks, involving 11 scheduled 
visits. Due to the circadian changes in urinary flow measurements in BPH subjects, study 
visits for an individual subject should be conducted consistently in either the morning or 
afternoon hours to assess all urinary flow measurements.
Every effort will be made to ensure that all randomized subjects complete study 
assessments. The investigator and site staff are reminded that the subject should make 
every effort to adhere to all scheduled protocol visits/procedures and their associated 
windows. In circumstances where this is not possible, e.g. subject is on holiday and is 
late/early or even misses a study visit, this should be documented in the subject notes 
with reasons. The investigator should make every effort to ensure the subject always has 
sufficient study medication between study visits. If visit windows associated with each 
visit are utilized, the next visit should be scheduled in line with the randomisation 
baseline visit (Visit 2).
Every effort will be made to ensure that all randomized subjects complete study 
assessments refer to Appendix 2.
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.
The term ‘study treatment’ is used throughout the protocol to generally describe the 
combination of products or individual products under evaluation in this protocol. When 
referring to specific compounds, the compound names will be used.
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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety. 
3.1.
Discussion of Design
The study design has been well established. The design is based on previous BPH 
dutasteride monotherapy trials and the co-administration BPH trials. The trial includes a 
4 week placebo run-in period to reduce subjective “placebo responses” in subsequent 
results reported after randomization with active treatment.
There is no placebo control group in this trial, since the clinical benefits from active 
treatments used in this trial have been previously demonstrated. Dutasteride 0.5mg and 
tamsulosin 0.2mg are both approved for treatment of BPH treatments either as 
monotherapies or in mutual co- administration. 
The dose of tamsulosin 0.2mg is the approved and widely used dose in the Asia Pacific 
region. Tamsulosin PK data showed that in Japanese subjects taking tamsulosin 0.4mg, 
the  Cmax was higher compared to Caucasian subjects taking the same dose. The lower 
dose of tamsulosin is preferred in Asia, considering a key complication associated with 
the higher dose; postural hypotension.
The pharmacokinetics of dutasteride and tamsulosin in Western subjects is 
well-understood (CIB). In contrast, pharmacokinetic data for these two drugs in Chinese 
subjects are limited. Following a request to provide this information from the Regulatory 
Authority in China, subjects of Chinese origin living in China will participate in a PPK 
sub-study in this study,which aims to characterize the PK of dutasteride when dosed in 
combination with tamsulosin to Chinese men with BPH.
The benefits of tamsulosin 0.2mg co-administered with dutasteride 0.5mg has been 
previously demonstrated in a Japanese phase III study where subjects were allowed to 
take tamsulosin 0.2mg concomitantly with dutasteride. 
4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
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 or rights. Therefore, adherence to the criteria as specified in the protocol is 
essential. 
4.1.1.
Number of Subjects
Approximately 586 men with symptomatic BPH will be randomized into the treatment
phase. It is expected that approximately 1000 patients will need to be screened to allow 
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for a screening failure rate of approximately 40%. The overall enrolment target number 
may be adjusted depending on the actual experience of enrolment and retention of 
participants, to ensure that the overall evaluable subject number target is met. See 
Section 9.2.1 for sample size assumptions.
4.1.2.
Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1.
males, aged ≥50 years
2.
clinical diagnosis of BPH by medical history and physical examination, including a 
digital rectal examination (DRE)
3.
International Prostate Symptom Score (IPSS) ≥12 points at Screening
4.
prostate volume ≥30cc (by transrectal ultrasonography; TRUS)
5.
total serum Prostate Specific Antigen (PSA) ≥1.5ng/mL and ≤ 10 ng/mL at 
Screening
6.
maximum urinary flow rate (Qmax) >5mL/sec and ≤15mL/sec and minimum voided 
volume of≥125mL at Screening 
7.
Asparate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2x upper 
limit of normal (ULN); alkaline phosphatase and bilirubin # 1.5xULN (isolated 
bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%)
8.
Fluent and literate in local language with the ability to comprehend and record 
information on the IPSS, BHS, BII, and PAS- SFI questionnaires
9.
Men with a female partner of childbearing potential must agree to use a condom up 
to 6 months after the last dose (applies only to countries where the local product 
monograph for dutasteride mandates condom use for men with a female partner of 
childbearing potential) 
4.1.3.
Exclusion Criteria
Subjects meeting the following criteria must not be enrolled in the study:
Medical Condition Exclusions:
1.
History or evidence of prostate cancer (e.g. positive biopsy or ultrasound, 
suspicious DRE). Patients with suspicious ultrasound or DRE who have had a 
negative biopsy within the preceding 6 months and stable PSA are eligible 
for the study.
Note: If total serum PSA is >4ng/mL and unless PSA value has been stable
for at least the past 2 years, the investigator should make every appropriate 
effort to exclude the possibility of prostate cancer, including consideration of 
prostate biopsy.
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2.
Previous prostatic surgery (including TURP, laser, HIFU (transrectal high 
intensity focused ultrasounds), thermotherapy, TUNA, (transurethral needle 
ablation), balloon dilatation, and stent replacement) or other invasive 
procedures to treat BPH.
3.
History of  flexible/rigid cystoscopy or other instrumentation of the urethra 
within 7 days prior to the Screening Visit. Catheterisation (<10F) is 
acceptable with no time restriction.
4.
History of AUR within 3 months prior to Screening Visit.
5.
Post-void residual volume >250mL (suprapubic ultrasound) at Screening.
6.
Any conditions other than BPH, which may in the judgment of the 
investigator, result in urinary symptoms or changes in flow rate (e.g. 
neurogenic bladder, bladder neck contracture, urethral stricture, bladder 
malignancy, acute or chronic prostatitis, or acute or chronic urinary tract 
infections).
7.
Unstable liver disease (chronic stable hepatitis B and C are acceptable if 
subject meets entry criteria).
8.
History of renal insufficiency, or serum creatinine >1.5 times the upper limit 
of normal at Screening.
9.
Any unstable, serious co-existing medical condition(s) including, but not 
limited to: 
a.
Myocardial infarction, coronary bypass surgery, unstable angina, cardiac 
arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident 
within 6 months prior to Screening visit; uncontrolled diabetes or peptic ulcer 
disease which is uncontrolled by medical management.
b.
Postural hypotension, dizziness, vertigo or any other signs and symptoms of 
orthostasis, which in the opinion of the investigator could be exacerbated by 
tamsulosin and result in putting the subject at risk of injury.
c.
Any serious and/or unstable pre-existing medical, psychiatric disorder, or other 
conditions that could interfere with subject’s safety*, obtaining informed consent or 
compliance to study procedures in the opinion of the investigator or GSK medical 
monitor.
d.
History of breast cancer or clinical breast examination finding suggestive of 
malignancy.
e.
History of malignancy within the past five years, except for basal cell carcinoma of 
the skin. Subjects with a priori malignancy who have had no evidence of disease for 
at least the past 5 years are eligible.
*Investigator may consult with GSK Medical Monitor if condition could interfere 
with subject’s safety
10. Current or Previous Use of the following medications:
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a.
Use of any 5-alpha-reductase inhibitor (e.g. Proscar, Propecia), 
any drugs with antiandrogenic properties (e.g. spironolactone, 
flutamide, bicalutamide, cimetidine, ketoconazole, progestational 
agents), or other drugs noted for gynaecomastia effects, or that 
could affect prostate volume, within  the 6 months  preceding the 
historical TRUS or Screening Visit and throughout the study 
(other than as study medication). Previous use of AVODART™ 
should not be within 6 months of the baseline or historical TRUS.
b.
Anabolic steroids (subject must discontinue for 6 months prior to 
study entry to be eligible) and agree not to take them for the 
duration of the study.
c.
Phytotherapy for BPH within 2 weeks of Screening Visit and/or 
predicted to need phytotherapy during the study.
d.
Use of any alpha-adrenoreceptor blockers within 2 weeks of 
Screening Visit (i.e. indoramin, prazosin, terazosin, tamsulosin, 
alfuzosin, doxazosin, silodosin) and/or predicted to need any 
alpha blockers other than the study prescribed tamsulosin.
e.
Use of any alpha-adrenoreceptor agonists (e.g. pseudoephedrine, 
phenylephedrine, ephedrine) or anticholinergics (e.g. 
oxybutynin,tolterodine, darifenacin, solifenacin,propantheline) or 
cholinergics (e.g. bethanecol chloride) within 48 hours prior to all 
uroflowmetry assessments.
f.
Use of selective beta 3-adrenoceptor agonist (mirabegron) within 
2 weeks prior to all uroflowmetry assessments.
11. Hypersensitivity to any alpha-/beta- adrenoreceptor blocker or 
5-alpha-reductase inhibitor, or other chemically-related drugs.
12. Participation in any investigational or marketed drug trial within 30 days (or 
5 half-lives of drug, whichever is the longer) preceding the Screening Visit 
and/or plans to participate in such a trial during the course of this study.
4.1.4.
Other Eligibility Criteria Considerations
In order to assess any potential impact on subject eligibility with regard to safety, the 
Investigator must refer to the relevant document(s) for detailed information regarding 
warnings, precautions, contraindications, adverse events, drug interactions, and other 
significant data pertaining to the study drug(s) being used in this study. These documents 
include, but may not be limited to, the following: the dutasteride Clinical Investigator's 
Brochure (CIB) or equivalent document provided by GlaxoSmithKline (GSK), the 
dutasteride (AVODART) local product monograph, where available, the approved 
product label(s) for tamsulosin (Harnal D, Flomax) and dutasteride (AVODART), if 
applicable. Study Procedures Manuals will outline information contained in the local 
product monographs that must be relayed to patients (e.g. use of a condom to avoids 
exposure of his partner when taking the study drugs), as applicable to a specific country.
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4.1.4.1.
Precautions
Investigator must refer to the relevant document(s) for detailed information regarding 
precautions as mentioned above. Local product monograph should be checked carefully 
to adhere to local labelling guidelines. 
4.2.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
4.2.1.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until completion of 2 years of study. In addition, 
study treatment may be permanently discontinued for any of the following reasons:
!
deviation(s) from the protocol
!
adverse event
!
request of the subject 
!
subject who has BPH-related prostatic surgery or any minimally-invasive/non-
surgical intervention for treatment of BPH symptoms at any time during the 
study period 
!
investigator’s discretion
!
subject is lost to follow-up
!
study is closed or terminated.
A subject, who experiences an AUR, does not need to be withdrawn from the study 
treatment. Any subject who has BPH-related prostatic surgery or any minimally-
invasive/non-surgical intervention for treatment of BPH symptoms at any time during the 
study period must be withdrawn from the study treatment.
The primary reason for permanent discontinuation of study treatment must be 
documented in the subject’s medical records and eCRF. 
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated or replaced. 
All subjects who prematurely discontinue from study treatment may not necessarily be 
withdrawn from the study as further study procedures or follow-up may be performed 
(Section 6.3).
Subjects with sexual function related adverse events (contact GSK Medical Monitor if in 
doubt) leading to study withdrawal, will be followed up for up to 6 months after the last 
dose of study drug. The sexual function Targeted Follow-Up Questionnaire to be used for 
these subjects follow-up can be found in the Study Procedures Manual.
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4.2.2.
Subject Completion
A subject will be considered to have completed the study if he completes the 4-week 
placebo run-in and the 104 week study treatment period.
5.
STUDY TREATMENTS
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. 
5.1.
Investigational Product
Dutasteride 0.5mg capsules along with commercially sourced tamsulosin 0.2mg tablets 
and placebo will be provided to sites by GSK.
The dutasteride 0.5mg and placebo, manufactured for GSK by Catalent Pharma Solutions 
in Beinheim, France will be supplied as plain, oblong, opaque, dull yellow soft gelatin 
capsules. 
Commercially available tamsulosin 0.2mg tablets will be supplied by GSK.
An oral disintegrating placebo tamsulosin tablet will be supplied by GSK for the run-in 
period.
5.1.1.
Dosage and Administration
Two treatment groups will be studied in parallel. 
Run-in phase (single-blind):
Each subject qualifying for the study according to the inclusion/exclusion criteria will be 
entered into a placebo run-in phase and will be dispensed single-blind medication at the 
second screening visit, Visit 1b (this is to permit return of PSA/ haematology/ 
biochemistry results before dispensing placebo medication). Subjects will receive a 1-
month supply of study medication. All subjects will be instructed to take one soft gelatin 
placebo capsule (swallowed whole and not chewed) and one oral disintegrating placebo 
tablet (dissolved on the tongue then swallowed not chewed), following the first meal each 
day for four weeks. They will then be randomized to a double-blind treatment phase for a 
further 104 weeks.
Randomized treatment phase (double-blind):
Subjects will be randomized in a 1:1 ratio to receive either: 
Dutasteride 0.5mg + tamsulosin 0.2mg once daily for 104 weeks, OR 
Dutasteride placebo +tamsulosin 0.2mg once daily for 104 weeks,X
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At randomisation, Visit 2, subjects will receive a 3-month supply of study medication. 
Study subjects will be instructed to take 1 dutasteride capsule (swallowed whole and not 
chewed) and one tamsulosin tablet (dissolved on the tongue then swallowed not chewed) 
following the first meal each day for 104 weeks.
Study medication will be resupplied at 13 week intervals during scheduled clinic visits 
(Visits 3-9).
The investigator or designee should not make any adjustments to the dosage or frequency 
of study medication.
Subjects will be reminded to return all medication to the study centre during scheduled 
clinic visits. Study staff at the centre will conduct counts of all returned study medication 
to ensure compliance. At the end of the study, all bottles (used and unused) must be 
returned to the sponsor or destroyed (and destruction documented) according to local 
site/local operating company procedures.
5.2.
Packaging and Labeling
Dutasteride study medication for both phases of the study will be provided in high 
density, polyethylene bottles with plastic child-resistant closures. Dutasteride 0.5mg and 
its matching placebo will be packaged to be indistinguishable irrespective of treatment. 
Commercially available tamsulosin 0.2mg will be provided by GSK. 
The tamsulosin tablet placebos will be packaged in blister packs. 
5.3.
Handling and Storage of Study Treatment
Investigational product must be dispensed or administered according to procedures 
described herein. Only subjects enrolled in the study may receive investigational product, 
in accordance with all applicable regulatory requirements. Only authorized site staff may 
supply or administer investigational product. All investigational products must be stored 
in a secure area with access limited to the investigator and authorized site staff and under 
physical conditions that are consistent with investigational product-specific requirements.
Dutasteride is absorbed through the skin; therefore, women who are pregnant or may be 
pregnant should not handle dutasteride because of the possibility of absorption and the 
potential risk of a male foetal abnormality. If contact is made with leaking capsules, the 
contact area should be washed immediately with soap and water.
The dutasteride capsules should be stored at temperatures up to 25°C (77°F). The 
commercial tamsulosin and placebo should be stored as per the instructions on the label.
Relevant label details will be provided in the study SPM.  
All study drug shipped to the investigator will be accompanied by a packing slip which 
will detail the contents of the shipment. The investigator or designee must sign and date 
the form where indicated confirming receipt of the investigational product shipment as 
listed. The form should be retained for the investigator’s records.
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A Material Safety Data Sheet (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request.
Final disposition (e.g. destroyed at the site, returned to GSK or a third party contractor) of 
unused study medication will be specified in the Study Procedure Manual.
5.4.
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the GSK 
interactive voice response system (IVRS), by the investigator or authorized site staff.  
Subjects will be randomized by investigative site using a randomization schedule 
generated by the GSK Biostatistical Department, which will assign subjects in a 1:1 ratio 
to either dutasteride 0.5mg +  tamsulosin 0.2mg  or placebo + tamsulosin 0.2mg. Once a 
randomization number has been assigned it must not be re-assigned even in cases of 
errors.
5.5.
Blinding
Once study treatment is initiated, all subjects will receive tamsulosin 0.2mg as open-
labeled medication.
The investigator or treating physician may unblind a subject’s treatment assignment 
(dutasteride or placebo) only in the case of an emergency, when knowledge of the study 
treatment is essential for the appropriate clinical management or welfare of the subject. 
Whenever possible, the investigator must first discuss options with the GSK Medical 
Monitor or through the appropriate GSK study personnel before unblinding the subject’s 
treatment assignment. If this is impractical, the investigator must notify GSK as soon as 
possible, 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 recorded in the eCRF.
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 clinical investigators in 
accordance with local regulations and/or GSK policy.
Unblinding will be conducted through RAMOS. Additional details are provided in the 
SPM.
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5.6.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of GSK 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable. Product accountability records must be maintained throughout the course of 
the study. Refer to the SPM for further detailed instructions on product accountability.
5.7.
Treatment Compliance
Compliance with study treatment will be assessed through querying the subject during the 
site visits and documented in the source documents and eCRF. 
A record of the number of capsules and tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates will be recorded in the eCRF. 
5.8.
Dose Modifications
Dose modification will not be conducted in this study.
If a subject’s treatment has been interrupted for more than 30 days. The Investigator must 
contact the GSK Medical Monitor to review the subject’s condition in order to resume the 
study treatment.
6.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
6.1.
Permitted Medications and Non-Drug Therapies
All concomitant medications taken during the study will be recorded in the eCRF with 
indication, dose information, and dates of administration.
Although discouraged, use of dietary supplements (e.g. selenium, Vitamin E) are 
permitted during the study.
6.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications will be prohibited during the study:
a.
Not permitted at any time:
!
Finasteride (Proscar, Propecia)
!
Any other investigational or marketed 5∃-reductase inhibitors (other than 
study medication)
!
Any alpha-adrenoreceptor blockers (other than study medication)
!
BPH-related phytotherapy
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!
Concurrent  use of anabolic steroids
!
Drugs with antiandrogenic properties (e.g. spironolactone, flutamide, 
bicalutamide, cimetidine, ketoconazole, progestational agents) or other drugs 
that are noted for gynaecomastia effects or could affect prostate volume.  
!
Any PDE-5 inhibitor (e.g. sildenafil, vardenafil, tadalafil)
!
Ginseng  utilised for the treatment of BPH or sexual dysfunction
b.
Not permitted within 48 hours prior to each IPSS or peak flow assessment:
!
Any alpha-adrenoreceptor agonist (e.g. pseudoephedrine, phenylephedrine, 
ephedrine)
!
Anticholinergics (e.g. oxybutynin, propantheline, danifenacin, solifenacin, 
tolterodine)
!
Cholinergics (e.g. bethanecol chloride)
c.
Not permitted within 2 weeks prior to each IPSS or peak flow assessment:
!
Selective beta 3-adrenoceptor agonist (mirabegron)
Questions regarding permitted and prohibited concomitant medications and non drug 
therapies should be directed to the GSK Medical Monitor for clarification.
6.2.1.
Non-Drug Therapies
Any occurrence of BPH-related prostatic surgical intervention and/or any minimally-
invasive/non-surgical procedures for treatment of BPH performed during the conduct of 
the study will be recorded in the eCRF.  
Surgical interventions for BPH include but are not limited to adenomectomy, balloon 
dilatation, prostatotomy, prostatectomy and transurethral resection of the prostate 
(TURP) or laser surgery. Non-surgical or minimally-invasive procedures for BPH include 
but are not limited to transrectal high intensity focused ultrasound (HIFU), transurethral 
needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT).
6.3.
Treatment after Discontinuation of Study treatment or 
Discontinuation of Study
Post study treatment will not be provided as part of the protocol. Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) therapy at 
the discretion of the treating physician. The investigator is responsible for ensuring that 
consideration has been given to the post-study care of the patient’s medical condition 
whether or not GSK is providing specific post-study treatment.
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If a subject discontinues study treatment permanently after Visit 2 (post-randomisation) 
for any reason, other than lost to follow-up, the investigator should make every effort to 
complete the following activities listed below: (Note: the subject has the right to refuse 
any further contact for study-related follow-up information).
!
End of Study Treatment Assessments as outlined in Section 7.2.2.5.
!
Biannual follow-up for clinical events via telephone contact every 6 months 
relative to baseline visit (Visit 2) until the 2 year anniversary of randomisation.
Any occurrence of death, AUR, BPH-related prostatic surgery or minimally-
invasive/non-surgical intervention for BPH, prostate cancer /biopsy reported 
after premature withdrawal of study treatment, and outcomes of sexually related 
adverse events reported during the treatment period, should be fully documented 
in the eCRF and source documents. The purpose of the collection of these data is 
to more fully document study endpoints and related events. 
No additional study activities other than those that are stated above are planned after a 
subject’s permanent discontinuation from study treatment
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
The primary reason for permanent discontinuation of study must be documented in the 
subject’s medical records and eCRF.
Subjects who are withdrawn from the study after randomisation will not be replaced.
In the event that a subject is prematurely discontinued from the study treatment or 
withdraw from the study at any time due to an AE (as defined in Section 7.4.1, 
“Definition of an AE”) or SAE (as defined in Section 7.4.2, “Definition of an SAE”), the 
procedures described in Section 7.4.7 (“AEs and SAEs”) must be followed.
6.4.
Treatment of Study Medication Overdose
In volunteer studies, single doses of dutasteride up to 40mg/day (80 times the therapeutic 
dose) for 7 days have been administered without significant safety concerns. In clinical 
studies doses of 5mg daily have been administered to patients for 6 months with no 
additional adverse effects to those seen at therapeutic doses of 0.5mg.
There is no specific antidote for 5ARI overdose. In cases of suspected overdose, subjects 
should be managed with appropriate supportive therapy as determined by the 
investigator.
In case of acute hypotension occurring after overdose with tamsulosin hydrochloride, 
cardiovascular support should be given. Restoration of blood pressure and normalization 
of heart rate may be accomplished by lying the patient down. If this is inadequate, 
administration of volume expanders and if necessary vasopressors should then be used 
and renal function should be monitored and supported as needed. Laboratory data 
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indicate that tamsulosin hydrochloride is 94% to 99% protein bound; therefore, dialysis is 
unlikely to be of benefit in removing tamsulosin from the body.
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.
Refer to the Time and Events Table for the timing of all assessments (Table 1). Details on 
efficacy and safety assessments are presented in Section 7.2 and Section 7.3 respectively. 
Further details of study procedures and assessments can be found in the study procedures 
manual (SPM).
For health outcome measures refer to Section 7.5, for PGx samples refer to Appendix 1
Unscheduled visits/assessment may be performed by the investigator as medically 
necessary. 
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
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Table 1
Time and Events Table
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline +
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
ICF
X
Incl/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X
%
X
Physical Examinationa
X
X
X
Xh
X
Vital signsb
X
X
X
X
X
X
%
X
Haematology/clinical 
chemistry
X
X
X
HBsAG and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
Xh
X
AEs d
X 
X 
X
X
X
X
%
X
Suicidality (C-SSRS)
X
X
X
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X
%
X
Prostate Volume (TRUS)
X
X
X
Peak Urine Flow (Qmax)
X
X***
X
X
X
Xh
X
AUR or BPH-related Surgery
X
X
X
X
%
X
X
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline +
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
Pharmacokineticsj
Serum PK samplesj
X
X
X
Health Outcomes:
BPH Health Status Q 8 IPSS 
(BHS)
X
X
X
X
X
X
%
X
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X
%
X
BPH Impact Index (BII) 
X
X
X
X
X
X
%
X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X
%
X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X
%
Compliance check/Collection
X
X
X
X
X
%
X
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Table 1
Time and Events Table
** This second screening visit is mandatory before dispensing placebo run-in medication. This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
%  ongoing assessment
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RNA test should be reflexively performed to confirm the result)
h.
Only performed at Visit 8 (Month 18)
i.
Performed for End of Study Treatment Assessments as well when a subject discontinues the study treatment (see Section 6.3 and Section 7.2.2.5)
j.
Serum PK samples are only applicable to subjects of Chinese origin living in China (see Appendix 7 for more details)
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7.1.
Critical Baseline Assessments
Demographic characteristics will be collected during screening. Subject’s year of birth,
race, height (in centimeters), and weight (in kilograms) will be recorded in the eCRF. In 
addition the following assessments will be completed at screening:
!
Cardiovascular medical history/risk factors including history of angina pectoris, 
myocardial infarction, stroke, diabetes, hypertension, and hyperlipidemia
!
Smoking history 
!
Premature Cardiovascular disease in first degree relatives. 
!
Medical history, a complete physical examination (including DRE and breast 
examination)
!
A 12-lead ECG, vital signs; clinical laboratory including hematology, clinical 
chemistry; total PSA; prostate volume*; post void residual volume (PVR); peak 
urinary flow (Qmax) and health outcomes questionnaires: IPSS, BHS, BII and 
PAS SFI and C-SSRS questionnaire
*All subjects will undergo a TRUS at Screening (Visit 1b) for determination of prostate 
volume, unless this has been performed within the previous 6 months. However, if a 
previous TRUS is to be used, the prostate volume must have been calculated using the 
formula in Section 7.2.2.2 or the raw data for dimensions must be available to use in the 
ellipsoidal formula.
7.2.
Efficacy
7.2.1.
Primary Endpoint
!
The primary efficacy endpoint of this study is change in IPSS from baseline at 
Year 2 (see Section 7.2.2.1 for details of the IPSS).
7.2.1.1.
Secondary Endpoints
The secondary efficacy endpoints of this study are:
!
Percent change in prostate volume from baseline
!
Proportion of subjects with IPSS improvement of ≥2 points and ≥3 points from 
baseline and, separately, ≥25% improvement from baseline
!
Change in Qmax from baseline
!
Proportion of subjects with Qmax improvement of ≥3mL/sec and, separately, ≥30% 
improvement from baseline
!
Time to event/ proportion of subjects with AUR or BPH related prostatic surgery 
!
Time to event/proportion of subjects with AUR
!
Time to event/proportion of subjects undergoing BPH related prostatic surgery
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7.2.1.2.
Other Efficacy Measures
The following are potential BPH disease related events not captured as primary or 
secondary endpoints. They will be collected in this study for possible comparison to 
historical BPH studies and to insure consistency of disease-related adverse event 
definition (see Section 7.4.2.5). 
!
Urinary tract infection/urosepsis
!
Urinary incontinence (overflow/urge)
!
Renal insufficiency
7.2.1.3.
Health Outcome Measures Endpoints
Change in BPH-related Health Status (Q8 of IPSS) from Baseline
Change in BPH Impact Index (BII) from Baseline
Change in Problem Assessment Scale of the Sexual Function Inventory (PAS-SFI), from 
Baseline
Resource Use related to AUR and BPH-related surgical events.
7.2.2.
Efficacy Assessment
See the Time and Events Table (Section 7) for the schedule of efficacy assessments. 
Assessments must be performed on a calendar schedule. For post baseline assessments, a 
window of [&14 days] is permitted to allow for flexible scheduling.
7.2.2.1.
International Prostate Symptom Score (IPSS)
The IPSS is a 7 item instrument (essentially the same as the American Urological 
Association Symptom Index, AUA-SI) designed to quantify urinary symptoms but with 
an additional, independent eighth question on quality of life (See Appendix 5). The IPSS 
will be administered at Pre-screening (Visit 1a), at Baseline (Visit 2) and at every 13 
week clinic visit thereafter during the study treatment period. At Pre-screening (Visit 1a), 
subjects with IPSS ∋12 points (based on the first 7 questions) should be excluded from 
the study. Also, subjects must be instructed to abstain from using any alpha adrenergic 
agonist, cholinergic or anticholinergic agents including anti-histamines or decongestants 
within 48 hours prior to conducting each IPSS. In addition subjects must also abstain 
from taking selective beta 3-adrenoceptor agonist (mirabegron) for over-active bladder 
syndrome  two weeks prior to each IPSS. If the subject did not adhere to these 
guidelines, study procedures should not be performed and the visit should be rescheduled. 
For details of the IPSS assessment see Section 7.5.1.
7.2.2.2.
Prostate Volume
Prostate volume measurements will be conducted at screening Visit 1b and annually 
post-randomisation at Visits 6, and 10, during the two year treatment period. The 
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anteroposterior, cephalocaudal, and transverse diameters of the prostate will be obtained 
by TRUS to calculate the prostate volume using the following formula:
(/ 6 (anteroposterior width X cephalocaudal width X transverse width).
Prostate volume calculated by pre-programmed equipment will be accepted if the 
anteroposterior, cephalocaudal and transverse are also outputted and recorded in the 
eCRF. If the prostate volume calculated by pre-programmed equipment is utilised for a 
subject, then the same equipment and hence calculator, must be used for the duration of 
the subject’s participation in the study.
For each individual subject, all TRUS procedures should be performed by the same 
technique and, if possible, the same individual and, ideally, that individual will not be 
responsible for soliciting adverse events or assessing relatedness of adverse events to 
study medication. At Visit 1b, if the prostate volume is ∋30cc the patient should not be 
randomized to the double blind phase.
The diagrams below show how the maximum dimension of each section will be 
determined. The transverse (T) dimension and the anteroposterior (AP) dimension are to 
be measured in the transverse plane. Scanning in the sagittal (longitudinal) plane would 
allow for the cephalocaudal (L) measurement of the prostate length from the apex to the 
bladder neck.
Transverse Scan
Sagittal Scan
[TZ=transition zone; PZ=peripheral zone; CZ=central zone; SV=seminal vesicle; AFS=anterior fibromuscular stroma]
7.2.2.3.
Urinary Flow Measurement
Measurements of urinary flow will be conducted using a Uroflow Meter (details will be 
provided in the study procedures manual) at Screening Visit 1a/b, Baseline (Visit 2) and 
every scheduled 26 week clinic visit post-randomisation thereafter during the treatment 
period.
The following assessments will be collected:
!
peak (maximum) flow (Qmax) at a voided volume ∀125 ml at all visits 
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!
voided volume (ml)
During screening, the patient should undergo a urine flow assessment at the same 
visit, i.e. at Pre-screening (Visit 1a), if possible. If a subject is unable to perform the 
urine flow at the first screening visit (Visit 1a), then the subject can retry at Visit 1b, prior 
to starting the placebo run-in period. The subject will only be eligible to be enrolled in 
the study if Qmax is >5mL/sec and #15mL/sec and the voided volume is ∀125mL for one 
assessment. If the voided volume is less than 125mL at any assessment, the subject 
should be instructed to drink more water until his bladder is full when the test can be 
repeated. During the study, if the repeat voided volume is less than 125ml the first voided 
volume will be recorded in the eCRF. 
All uroflow traces should incorporate subject identifiers, date and time of assessment and 
should be signed and dated by the investigator and retained with the subjects study 
records. During continuous use, the correct functioning of the uroflow meter will be 
checked once a week (especially if moved) and appropriate actions taken to ensure good 
maintenance of the machine.
Due to the circadian changes in urinary flow measurements in BPH subjects, study visits 
for an individual subject should be conducted consistently in either the morning or 
afternoon hours to assess all urinary flow measurements. Subjects should be instructed to 
drink at least 2 glasses of water 2-3 hours prior to their clinic visit and to keep drinking 
every 15 minutes filling the bladder. Also, subjects must be instructed to abstain from 
using any alpha adrenergic agonist, cholinergic or anticholinergic agents including anti-
histamines or decongestants within 48 hours prior to conducting this test. In addition 
subjects must also abstain from taking selective beta 3-adrenoceptor agonist (mirabegron)
for over-active bladder syndrome for two weeks prior to this test. If the subject did not 
adhere to these guidelines, study procedures should not be performed and the visits 
should be rescheduled.
When conducting uroflow measurements, the funnel should be kept at the subject’s knee 
level and the printout away from the subject’s view. Subjects should be blinded from all 
uroflow measurement data throughout the study.
7.2.2.4.
Definition of Other Efficacy Measures
Other efficacy measures are noted in Section 7.2.1.2. The following provides clinical 
definition for these measures.
Renal insufficiency is defined as >=50% sustained rise in baseline serum creatinine and 
>=1.5mg/dL; BPH-relatedness will be assessed by the investigator.
Urinary tract infection (UTI) is defined as symptomatic infection of 105 cfu/mL during 
the study; recurrent UTI is defined as two or more UTI episodes during the study. BPH-
relatedness will be assessed by the investigator. 
Incontinence (overflow or urge) is defined as socially or hygienically unacceptable
involuntary leakage of urine). BPH-relatedness will be assessed by the investigator.
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7.2.2.5.
End of Study Treatment Assessments
During the study period that is between the scheduled visits, if a subject discontinues 
study treatment permanently after Visit 2 (post-randomisation) for any reason, other than 
lost to follow-up, the investigator should make every effort to schedule a visit by the 
subject to the study site and complete the following assessment: 
!
Concomitant medications
!
Adverse events
!
Physical exam including vital signs, DRE and qualitative breast examination
!
Obtain blood samples for hematology, clinical chemistry and PSA determinations
!
Administer health outcome questionnaires (IPSS, BHS,BII and PAS-SFI)
!
Administration of C-SSRS questionnaire
!
Record any episodes of AUR, and, BPH-related prostatic surgery or minimally-
invasive/non-surgical interventions
!
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
!
Retrieve any unused double-blind study medication, assess compliance and record 
date of last dose of study medication
!
Discuss the biannual follow-up phone call schedule
!
Complete subject eCRF
If the decision for a subject’s study treatment discontinuation is made during a regularly 
scheduled visit, the procedure that are stated above should be completed, in addition to 
any scheduled procedure that is not listed above.
7.2.3.
Short Messaging Service Reminder System
To help with the retention of the subjects and planning of their scheduled follow up 
throughout the study, subjects will be sent text messages via their mobile telephone, or 
email reminders, regarding their scheduled appointments. Sites will gain consent from the 
subject in the ICF before enrolling their mobile phone number or e-mail address into the 
secure short messaging service (SMS) reminder system. The system will then transmit 
text messages or e-mails to the subject in the local language regarding their next 
appointment.
!
Subject participation in the SMS reminder system is voluntary and refusal to 
participate will not indicate withdrawal from the clinical study. Refusal to participate 
will involve no penalty or loss of benefits to which the subject would otherwise be 
entitled. The SMS reminder system may not be available for all study sites or 
countries. Even if available, study sites or countries may choose not to participate in 
the SMS reminder system. All text message/e-mail content will be reviewed and 
approved by the IRB/IEC prior to use.
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7.3.
Safety
7.3.1.
Endpoints
!
Change in total serum PSA from baseline
!
Vital signs
!
Post-void residual volume
!
Clinical laboratory measurements (including haematology, chemistry) 
!
Adverse events (including AUR or BPH-related surgery and Prostate Cancer and 
prostate biopsy)
!
Physical examination: digital rectal examination (DRE) and qualitative  breast 
examination
!
An assessment of suicidality
See Section 7.4 for a complete description of adverse event assessments. 
7.3.2.
Medical History, Concomitant Medications, ECG, Physical 
Examination
A medical history will be obtained at Pre-screening Visit 1a with particular attention 
paid to the following:
!
Approximate time (date) LUTS first noted by patient; time since diagnosis of BPH; 
previous usage of alpha-1-adrenoreceptor antagonists and/or phytotherapy.
!
A thorough review of body systems, both past or current conditions including 
conditions of interest, smoking history, alcohol, and an assessment of sexual 
activity/sexual dysfunction;
!
Family history of premature cardiovascular disease
!
Pharmacotherapy, chronic use of any medication (prescribed and over the counter, 
including dietary supplements);
!
History of allergies or idiosyncratic reactions to drugs;
!
Family history of prostate cancer
!
Family history of male/female breast cancer
Concomitant medications will be assessed at every clinic visit. Use of dietary 
supplements (i.e. selenium, Vitamin E) during the study is discouraged but not 
prohibited. All concomitant medications and use of dietary supplements will be recorded 
in the eCRF. Additional details related to concomitant medications are addressed in 
Section 6 of this protocol.
A good quality 12-lead ECG recording will be obtained for each subject at Screening 
Visit 1b. The subject should rest supine for 5 minutes before the 12-lead ECG is 
recorded. Additionally a rhythm strip will be obtained to assess for presence of 
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arrhythmias. The ECG must be calibrated, labelled and initialled by the person 
performing the recording. The ECG tracing must be signed and dated by the examining 
physician to indicate review and any clinically important abnormalities reported on the
appropriate page of the eCRF. A copy of the ECG tracing will remain with the subject’s 
medical notes at the site.
A complete physical examination will be conducted at Screening Visit 1b and will 
include measurements of height, weight, blood pressure, digital rectal exam, and a 
qualitative breast exam (nipple tenderness and/or palpable breast tissue).
Weight will be measured on a standard calibrated scale. Subjects should be dressed in 
light indoor clothing without shoes. Weight will be documented in kilograms to the 
nearest tenth of a kilogram using the following conversion factor:
Pounds x 0.4536 = kg
For height measurements, subjects should be measured without shoes. Height will be 
documented to the nearest tenth of a centimeter using the following formula:
Inches x 2.54 = centimeters
The physical exam will be performed by a licensed physician. Full details of the physical 
examination will be recorded in the source documents at the site.
7.3.3.
Physician’s assessments and vital signs
At each clinic visit prior to dispensing study drug, a physician will assess the subject’s 
continued eligibility and safety.
Vital signs (blood pressure followed by pulse) will be assessed at Screening Visit 1b, 
Baseline Visit 2 and at each scheduled 13 week clinic visit thereafter. The subject must 
be sitting quietly for at least 5 minutes before measurements are taken. No other 
procedures will be performed during this 5 minute stabilisation period. Pulse rate will be 
measured for 30 seconds.
In addition, a physical examination will be conducted at Visit 4 (26 weeks post-
randomisation) and at 26 week intervals thereafter during the treatment period, and will 
include a digital rectal exam and a qualitative breast examination (nipple tenderness 
and/or palpable breast tissue).
The physical exam will be performed by a licensed physician. Full details of the physical 
examination will be recorded in the source documents at the site.
7.3.4.
Clinical Laboratory Assessments
Blood samples for all laboratory assessments throughout the study will be collected prior 
to undergoing any clinical procedures. In order to determine each subject’s eligibility to 
participate in the study, the results of the screening clinical laboratory tests must be 
assessed by the principal investigator or designee prior to study drug administration. Any 
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subject having a laboratory result that falls outside the specifications noted in the 
inclusion or exclusion criteria will be excluded from the study.
Out-of-threshold range values indicated on the clinical laboratory test reports must be 
assessed as “not clinically significant” (NCS), “clinically significant” (CS), or “repeat” 
(to indicate a repeat test will be performed). If any laboratory values are deemed 
clinically significant, the subject must return to the clinic for re-evaluation. All clinically 
significant changes from baseline will be followed until resolution or stabilization as 
determined by the principal investigator or designee. The results of all clinical laboratory 
tests must be assessed by the investigator in order to determine each subject's eligibility 
to continue in the study.
Haematology and clinical chemistry assessments will be performed at Pre-screening 
(Visit 1a) to establish eligibility for enrolment and annually post-randomisation at Visits 
6, 10. Additionally, a blood draw for HBsAG, and Hepatitis C Antibody should be 
performed at Visit 2 (baseline).
Laboratory Assessment
Visit Frequency
Hematology
Visits 1a,6, 10
Clinical Chemistry
Visits 1a, 6, 10
PSA
Visits 1a, 4, 6, 10
HBsAG and Hepatitis C Antibody 
Visit 2
7.3.4.1.
Haematology and Clinical Chemistry
Haematological and biochemical analyses will be conducted by a central laboratory 
designated by GlaxoSmithKline. The following tests will be performed:
Haematology
Clinical Chemistry (Serum)
Total WBC Count
Platelet Count
Glucose
Haemoglobin
Sodium
RBC
Potassium
Total protein
PSA (Serum)
Total PSA
Total bilirubin
BUN or urea
Albumin
HBsAG and Hepatitis C Antibody
ALT (SGPT)
AST (SGOT)
Alkaline Phosphatase
Creatinine
All clinical laboratory analyses will be conducted at a Central Laboratory selected by 
GSK. Laboratory data will be electronically transferred from the contract Central 
Laboratory to GSK or their designee. A printout of results will be transmitted via 
facsimile to the investigator or designee and must be retained in each subject's study file. 
In addition to the facsimile results, the investigator will be notified of alert values (out-of-
threshold range values or exclusions) by telephone.
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7.3.4.2.
Prostate Specific Antigen (PSA)
Total serum PSA concentrations will be assessed at Pre-screening Visit 1a and post-
randomisation at Visit 4, (Month 6), and annually at Visits 6 and 10. For total PSA, the 
actual value will be reported at Pre-screening; an adjusted value will be reported for all 
assessments after 6 months of treatment – see below.
A number of clinical situations (e.g. prostatitis, biopsy, prostatic abscess) can cause 
transient rises in PSA. Therefore, blood samples for evaluating PSA levels must be 
collected within the study-defined time windows and prior to performing any clinical 
procedures (i.e. TRUS and DRE). If a situation arises requiring interim intervention, PSA 
determinations must be postponed for a period of 1 month following any procedure 
performed on the prostate and for 3 months following initiation of treatment for acute 
bacterial prostatis.
Screening PSA results will be reported immediately to the investigators to determine 
eligibility of study subjects. All post-baseline PSA levels will subsequently be reported 
following blinding adjustment of the PSA result (where appropriate) as described below. 
In order to maintain investigator blinding to study treatment, an independent reviewer 
who is unblinded to the PSA results as well as the drug random code, will adjust PSA 
values for appropriate participants. After a subject completes six month of treatment, 
PSA results will be reported to the principal investigators using the following methods: 
(1) for subjects on tamsulosin monotherapy, the actual PSA value will be reported; (2) for 
subjects receiving combination therapy, the PSA value will be multiplied by two (x 2) to 
account for the known effect of 5ARI's on reducing PSA (data from Phase IIIa and 
CombAT studies of dutasteride in BPH patients demonstrated a decrease in serum PSA 
levels by approximately 50% after 6 months of treatment). In dutasteride-treated subjects 
receiving combination therapy, the doubled PSA value will be randomly stated as the 
doubled value or a value 0.1 units higher or lower, so that all doubled values expressed to 
one decimal place will not automatically be reported as an even number. 
Note:  Dutasteride reduces total serum PSA concentration by approximately 40% 
following 3 months of treatment and by approximately 50% following 6, 12, and 
24 months of treatment. PSA measurements should not be performed prior to 6 months of 
treatment because of the variable effect of dutasteride on serum PSA during this time. 
Although discouraged, if an additional PSA measurement outside the scheduled 
assessments is necessary, it should be assayed through the study central laboratory.
Central laboratory, study sites, and monitors will remain blinded to treatment 
assignments throughout the duration of the study.
7.3.5.
Post Void Residual Volume
Post void residual volume will be measured suprapubically by ultrasound (immediately 
following the urinary flow measurement) at Pre-screening Visit 1a/1b (if Qmax inclusion 
criteria not met at Visit 1A), at Baseline (Visit 2) and at 26 week clinic visits thereafter 
during the treatment period. Subjects with post void residual volumes >250mL as 
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measured at Screening (Visit 1a/1b) should be excluded from participating in the study. 
The time of bladder scan and the time of the preceding void will also be recorded.
7.3.6.
Acute Urinary Retention
A subject is considered to have acute urinary retention (AUR) when he is unable to 
urinate and requires bladder catheterisation.  
At Visit 2 (Baseline) and each scheduled 13 week clinic visit post-randomisation, the 
investigator will record in the designated section of the eCRF any incidence of AUR the 
subject experiences during his participation in the study.  
Any occurrence of AUR should not be captured as an adverse event unless considered by 
the investigator to be more severe than expected for the subject’s condition or unrelated 
to BPH. See Section 7.4.1 and Section 7.4.7 . If in the investigator’s opinion, the event 
meets the definition of serious as outlined in Section 7.4.2 then the event must be 
reported as an SAE (see also Section 7.4.7.).
7.3.7.
Surgical and Minimally-Invasive/Non-surgical Interventions for 
BPH
At Visit 2 (Baseline) and each scheduled 13 week clinic visit post-randomization, the 
investigator will record in the designated section of the eCRF any BPH-related prostatic 
surgery and/or any minimally-invasive/non-surgical procedures undergone by the subject 
during his participation in the study (see Appendix 4 for a glossary of prostatic surgical 
and minimally-invasive/non-surgical interventions.).
Any resected tissue from patients undergoing prostatic surgery during the study should be 
sent to the local pathology laboratory for routine histopathology analysis. Information 
including the date of surgery, reason for surgery and histology results (including high 
grade prostatic intraepithelial neoplasia (HGPIN) diagnosis and Gleason score, if prostate 
cancer diagnosis) will be collected and recorded in the eCRF, as applicable.
7.3.8.
For-Cause Biopsy for Diagnosis of Prostate Cancer
TRUS-guided for-cause biopsies may be conducted at any time during a subject's 
participation in the study if, in the judgement of the investigator, there is a clinically 
significant medical trigger, such as:
!
Adverse change in digital rectal exam
!
Clinically significant increase in serum PSA
!
Nodular areas suspicious detected on TRUS
Tissue from all for-cause biopsy cores will be sent to the local pathology laboratory for 
histopathology analysis.
For all subjects undergoing for-cause biopsy during the study, information including the 
date of biopsy, reason for biopsy, biopsy results, number of cores obtained, high grade 
prostatic intraepithelial neoplasia (HGPIN) diagnosis, and surgery outcome will be 
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collected and recorded in the eCRF, as applicable. In addition, for those subjects with a 
positive biopsy, information about prostate cancer, including date of diagnosis, Gleason 
score (classic scoring or modified scoring system) at biopsy and/or surgery, percentage of 
core involved (semi-quantification of volume of prostate cancer), cancer positive cores 
(reported as number of positive cores over total number of cores) will be collected and 
recorded in the eCRF.
7.3.9.
Suicidality
Dutasteride is considered to be an active compound in human central nervous system 
(CNS) that may affect mood or behavior via effects on the CNS (directly or indirectly). A 
GSK review of published literature and clinical trial data for dutasteride has shown that 
dutasteride is not associated with an increased risk of suicidal thinking or behavior when 
given to this patient population.
There has been some concern that some CNS-active drugs may be associated with an 
increased risk of suicidal thinking or behavior when given to some subjects with certain 
conditions. Although these drugs and other similar drugs of the same class have not been 
associated with an increased risk of suicidal thinking or behavior when given to this 
patient population, GSK considers it important to monitor for such events before or 
during clinical studies with compounds such as this.  
Subjects in Study ARI114265 will be assessed for suicidality and unusual changes in 
behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). To protect 
subjects in the study, scores from C-SSRS tests will be reviewed in real time by the 
investigator and appropriate advice given to participants. Consideration should be given 
to discontinuing study treatments in subjects who experience signs of suicidal ideation or 
behavior. Refer to Section 7.4.6 for more information.
7.3.10.
Collection of Other Efficacy Measures
At Visit 2 (Baseline)  each scheduled 13 week clinic visit, the investigator will record in 
the designated section of the eCRF defined incidences of urinary tract infection/urosepsis, 
urinary incontinence, and renal insufficiency the subject experiences during his 
participation in the study.
7.4.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.4.1 and 
Section 7.4.2.
7.4.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
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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. For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE 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 grade 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 is not to be 
reported as an AE or SAE. However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:
!
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be 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.
!
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.
7.4.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
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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-subject setting. Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfils 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, or
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.
Medical or scientific judgement 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.
All events of possible drug-induced liver injury with hyperbilirubinaemia, defined as 
ALT ∀3xULN and bilirubin ∀2xULN (>35% direct) (or ALT ∀3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants.)
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin ∀2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.  
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Other events that must be reported as Serious AEs in this study, regardless of 
satisfying criteria a-g, are:
h.
Male Breast Cancer
i.
Spontaneous Abortion in female partner of male subject (see Partner Pregnancy, 
Section 7.4.5)
7.4.2.1.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (hematology, or clinical chemistry) 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 are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs
7.4.2.2.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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
!
Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.4.2.3.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
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7.4.2.4.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:
!
Acquired Long QT Syndrome
!
Agranulocytosis/Severe Neutropenia 
!
Anaphylaxis & Anaphylactoid Reactions 
!
Hepatotoxicity
!
Acute Renal Failure
!
Seizure
!
Stevens Johnson syndrome/Toxic epidermal necrosis
7.4.2.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
A disease-related event is an event generally associated with the disease under study and 
is not typically associated with the use of the investigational product. In this study, 
disease-related events will be captured as part of efficacy assessments and hence will be 
reported as AEs or SAEs only under the following circumstances:
!
If a disease-related event is considered by the investigator to be more severe 
than expected for the subject’s condition, but does not meet the definition of 
serious as outlined in Section 7.4.2, the event should be reported as an AE.
!
If a disease-related event is considered by the investigator to be more severe 
than expected for the subject’s condition and meets the definition of serious as 
outlined in Section 7.4.2, the event must be reported as an SAE.  
!
If a disease-related event is life-threatening or fatal, regardless of the 
investigator’s assessment of severity expected for the subject’s condition, the 
event must be reported as an SAE.  
Disease-related events for this study are listed below.  
!
BPH symptoms (incomplete emptying, frequency, intermittency, urgency, weak 
stream, straining, nocturia)
!
Changes in Qmax 
!
Changes in subject’s response to questions asked in the IPSS and humanistic 
assessments.
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!
Acute urinary retention
!
Urinary tract infection/urosepsis
!
Urinary incontinence (overflow/urge)
!
BPH-related Renal insufficiency
7.4.3.
QTc Events
If QTc events occur the investigator should promptly contact the medical monitor to 
receive advice on measures to be taken. 
7.4.4.
Liver Events
If serious liver events occur the investigator should follow the standard serious event 
reporting process described in the protocol. For non-serious liver events that are clinically 
significant, the investigator will contact the medical monitor to receive advice on 
measures to be taken.
7.4.5.
Partner Pregnancy
As with other 5-alpha reductase inhibitors, dutasteride inhibits the conversion of 
testosterone to dihydrotestosterone and may, if administered to a woman carrying a male 
fetus, inhibit the development of the external genitalia of the fetus (see CIB). Small 
amounts of dutasteride have been recovered from the semen in subjects receiving 
dutasteride 0.5 mg per day. Based on studies in animals, it is unlikely that a male fetus 
will be adversely affected if his mother is exposed to the semen of a patient being treated 
with dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy). 
Even though it is unlikely that a male fetus will be adversely affected if his mother is 
exposed to the semen of a partner being treated with dutasteride, some countries 
recommend the use of condoms in the local dutasteride labels. For these countries it is 
recommended that the patient avoids exposure of his partner to semen by use of a 
condom for 6 months after drug discontinuation.
7.4.5.1.
Time period for collecting partner pregnancy information
Pregnancy information should be collected on any female partner of a male study subject 
who is pregnant or becomes pregnant while the subject is participating in the study. All 
pregnancies in female partners of male subjects will be collected after the start of dosing 
until 6 months after the subject’s last dose of study drug.
7.4.5.2.
Action to be taken if partner pregnancy occurs
The investigator or designee should make every effort to collect pregnancy information 
on any female partner who is pregnant or becomes pregnant by a male subject during his 
participation in this study. The investigator, or his/her designee, should record pregnancy 
information on the appropriate form and submit this to GSK within 2 weeks of learning 
that a study subject's partner is pregnant, having first obtained the necessary written 
informed consent from the female partner directly. The subject's female partner should be 
followed to determine the outcome of the pregnancy. Information on the status of the 
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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 premature termination of the 
pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or a SAE. A spontaneous abortion will always be reported as a SAE.  
Any SAE occurring as a result of a post-study pregnancy (6-months after last dose) and
considered reasonably related to the investigational product by the investigator will be 
reported to GSK. While the investigator is not obligated to actively seek this information 
in former study participants, he/she may learn of an SAE through spontaneous reporting.
See the Clinical Investigator Brochure and AVODART approved product label (if 
applicable) for additional details about dutasteride's potential effects on the male fetus.
7.4.6.
Suicidality Monitoring
Assessment of suicidality will be performed using the C-SSRS which will be 
administered at baseline, during the course of study, and at the end of the study. Training 
to investigators and sites on suicidality assessment will be integral to the study 
implementation. Any AEs which, in the investigator's opinion, are possibly 
suicidality-related, will be recorded in the Possible Suicidality Related Adverse Event 
form (PSRAE); a supplemental CRF form designed to collect detailed information on the 
circumstances of reported AEs related to suicidality.
The ‘baseline/screening’ version of C-SSRS will be used at the pre-screening visit (V1a). 
The ‘since last visit’ version of C-SSRS will be used at Visits 4, 6 and 10 (6, 12 and 
24 months post randomization respectively).
A trained rater will administer the C-SSRS questionnaires according to the schedule 
detailed in Table 1. The C-SSRS questionnaire will be completed during the clinical visit 
separately from the medical history and the standard adverse event questions.
7.4.7.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the start of the placebo run-in phase until the end of the two 
year study period.
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., investigational product, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a GSK 
concomitant medication, will be recorded from the time a subject consents to participate 
in the study up to the end of the two year study period. All SAEs will be reported to GSK
within 24 hours, as indicated in Section 7.4.8. 
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After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up. Investigators are not required to actively seek information on adverse events 
occurring after the follow-up contact, but may report any adverse event that they believe 
may be related to investigational product regardless of when the event occurs.
7.4.8.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, partner pregnancies, and liver function abnormalities and any other events meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines the event meets the protocol 
definition for that event.
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Partner Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
ALT∀3xULN and 
bilirubin ∀2xULN 
(>35% direct)
(or ALT∀3xULN and 
INR>1.5, if INR 
measured) 2
24 hours1 
SAE data 
collection tool.
24 hours
Updated SAE data 
collection tool. 
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM. Procedures for post-study AEs/SAEs are provided in the SPM. 
7.4.9.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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.
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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.
7.5.
Health Outcomes
7.5.1.
BPH-related Quality of Life
The effect of study treatment on BPH-related quality of life will be assessed using three 
self-administered questionnaires: the BPH-related health status (question 8 of IPSS); the 
BPH Impact Index (BII) and Problem Assessment Scale of the Sexual Function Index 
(PAS SFI). Each questionnaire is briefly described below and will measure impact of 
BPH symptoms, health-related quality of life and sexual function.
a.
International Prostate Symptom Score (IPSS) [Badia, 1997; Barry, 1992]
The IPSS is a 7 item instrument (essentially the same as the American Urological 
Association Symptom Index, AUA-SI) designed to quantify urinary symptoms but with 
an additional, independent eighth question BPH on quality of life (see Appendix 5). The
IPSS will be administered at Pre-screening (Visit 1a), at Baseline (Visit 2) after 
completion of the placebo run-in period and at every 13 week clinic visit thereafter 
during the study treatment period. At Pre-screening (Visit 1a), subjects with IPSS ∋12 
points (based on the first 7 questions) should be excluded from the study
b.
BPH Impact Index (BII) [Barry, 1995]
The BII is a 4 item instrument which assesses the overall impact of BPH on a patient’s 
general sense of well being and measures aspects of physical discomfort, worry and 
bother, all of which can be affected by BPH and its symptoms (See Appendix 6).
The BII will be administered at Pre-screening (Visit 1a), at Baseline (Visit 2) after 
completion of the placebo run-in period and at every 13 week clinic visit thereafter 
during the study treatment period.
c.
Problem Assessment Scale of the Sexual Function Inventory (PAS-SFI) 
[O’Leary, 1995]
Because BPH and subsequent medical treatments may potentially affect sexual 
functioning, a brief Sexual Function Index will be included in this trial to capture 
information about various aspects of patients’ sexual functioning [O’Leary, 1995] 
(See Appendix 6). The PAS-SFI will be administered at screening (visit 1b, during 
(Baseline) Visit 2 after completion of the placebo run-in, then annually thereafter 
following randomization.
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7.5.2.
Questionnaire administration
The subject will complete self-administered questionnaires according to the schedule 
detailed on the Time and Events Table.
The investigator will ask the study subject to complete a questionnaire during the clinical 
visit separately from the medical history and the standard adverse event questions.
Questionnaires should be completed in a quiet place (preferably the same place each 
time, if possible), and at as consistent a time during the study visit as possible. To avoid 
biasing responses, subjects should not be told the results of diagnostic tests prior to 
completing the questionnaire. Regardless of when the questionnaire is completed, the 
subject should be given adequate time to complete all items. No stated or implied time 
limit for completing the questionnaire items will be given.
The subject should be asked to complete the questionnaires as completely and as 
accurately as possible. If the subject requests help or clarification of any question, he 
should be asked to read the instructions again and to give the best answer possible to 
each question. Subjects should be encouraged to report their own experiences and 
opinions. The investigator will not provide the subject with an answer to any question 
nor interpret any portion of the question.
7.5.3.
Recording of data
The use of black ink is required for subject completed questionnaires. If any changes are 
necessary, subjects must be instructed to make any changes by drawing a line through the 
undesired response, initialling the change, and then recording the desired response. Once 
a subject returns the questionnaire, no change will be allowed. 
7.5.3.1.
Collection and storage of subject questionnaires
Upon completion of the questionnaires, the investigator will retrieve the questionnaires 
from the subject, and check that the header section (Subject Number, Visit Date, etc) is 
completed. The investigator (or qualified designated member of their staff) will use the 
subject completed questionnaires to enter the recorded data into the appropriate section 
of the eCRF. The original version of the completed questionnaires will stay with the
subject’s source documents. A completed questionnaire should not be given back to the 
subject once it has been returned to the source documents
7.5.4.
Medical resource utilisation
At Visit 2 (Baseline) and each scheduled 13 week clinic visit post-randomisation, the 
investigator will record details of any health care utilisation associated with an episode of 
acute urinary retention, BPH-related prostatic surgery and/or other minimally-invasive 
prostatic procedures for treatment of BPH. The following information will be collected in 
the eCRF as follows:
!
Incidence of hospital admissions for AUR and/or surgical interventions; number and 
type of procedures carried out
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!
Length of hospital stay (in days, hours) associated with incidence of AUR and/or 
surgical interventions, and associated ward type
7.6.
Pharmacogenetics
An important objective of the clinical study is PGx research. Participation in PGx is 
optional but all subjects who are eligible for the clinical study will be given the 
opportunity to participate. Subjects may decline participation without effect on their 
medical care or care during the clinical study. A separate consent signature is required for 
PGx research.
Patients who provide consent will have a blood sample taken for analysis at Visit 2. The
presence/absence of genetic variations in patient genes in DNA from blood will be 
analysed to determine their relationship with response (safety, tolerability, and efficacy) 
to treatment with either the combination of dutasteride and tamsulosin or tamsulosin 
alone.
Information regarding pharmacogenetic research is included in Appendix 1. The IEC/IRB 
and, where required, the applicable regulatory agency must approve the PGx assessments 
before these can be conducted at the site. The approval(s) must be in writing and will 
clearly specify approval of the PGx assessments (i.e., approval of Appendix 1). In some 
cases, approval of the PGx assessments can occur after approval is obtained for the rest of 
the study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted.
7.7.
Population Pharmacokinetics (Chinese Subjects Only)
A population pharmacokinetics (PPK) substudy will be performed only in subjects of 
Chinese origin, living in China, and participation in this substudy will be mandatory for 
these subjects. This substudy will estimate the PK parameters of dutasteride when dosed 
orally in combination (dutasteride 0.5 mg once daily and tamsulosin 0.2 mg once daily) 
in Chinese men with BPH. See Appendix 7 for more details on the PPK substudy.
Serum PK samples will be collected as indicated in Table 1. The actual date and time of 
each blood sample collection will be recorded, as well as the timing of the last dose of 
combination taken before the PK sample. Details of blood sample collection (including 
volume to be collected), processing, storage, and shipping procedures are provided in the 
SPM.
8.
DATA MANAGEMENT
For this study, data will be collected using defined electronic case report forms (eCRFs), 
transmitted electronically to GSK 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 
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errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using MedDRA and an internal validated medication dictionary, GSK 
Drug. Laboratory data (i.e., hematology and clinical chemistry) will be stored in a 
database maintained by the central laboratory and transferred to GSK at agreed times.
An appropriate medical dictionary that covers all approved drugs in the region must be 
referenced.
eCRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
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9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
The primary endpoint is change from baseline IPSS. Let the following represent the mean 
change from baseline IPSS for each treatment group:
Hdut+tam: combination (0.5mg dutasteride and 0.2mg tamsulosin) treatment group
Htam:  
0.2mg tamsulosin treatment group
Then the primary null and alternative hypotheses to be tested at Year 2 are as follows:
Description
Null Hypothesis
Alternative Hypothesis
Combination versus 0.2mg tamsulosin
Hdut+tam = Htam
Hdut+tam ≠ Htam
Two-sided tests of the null hypothesis will be conducted at the 0.05 level of significance 
to show superiority of the combination treatment group compared to 0.2mg tamsulosin at 
2 years of treatment.
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
The sample size was calculated based on estimates of IPSS change from baseline using 
information obtained from the CombAT study. Sample size estimates were computed in 
terms of a continuous response variable assuming a normal distribution, IPSS change 
from baseline mean difference between treatment groups of 1.8, a standard deviation of 6, 
and considering 90% power. With these assumptions, the required minimum sample size 
is 234 subjects per arm. Therefore, since a 20% treatment phase discontinuation rate is 
assumed, then randomization of 293 subjects per treatment arm (586 total) is required for 
90% power.
9.2.2.
Sample Size Sensitivity
Following is a chart showing scenarios of treatment differences of IPSS change from 
baseline after 2 years using assumptions above and the corresponding power estimates.
Scenario
IPSS change from baseline:  difference in 
Combination and 0.2mg Tamsulosin
Power
Alternative #1
1.6
82%
Planned
1.8
90%
Alternative #2
2.0
95%
9.2.3.
Sample Size Re-estimation
Sample size-re-estimation is not planned.
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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent-to-Treat (ITT) population will comprise all randomized subjects regardless of 
whether or not treatment was administered. This population will be based on the 
treatment to which the subject was randomized and will be the primary population for the 
analysis of efficacy and safety data. Any subject who receives a treatment randomisation 
number will be considered to have been randomized.
9.3.2.
Per Protocol Populations
The Per Protocol (PP) population will comprise all ITT subjects and who comply closely 
with the protocol. Major protocol deviations that would exclude subjects from the PP 
population will be defined and documented in the Reporting and Analysis Plan (RAP) 
prior to unblinding. The PP population will not be analysed if this population comprises 
more than 80% of the ITT population.
9.3.3.
PPK Population
The PPK population wil comprise all ITT subjects of Chinese origin, recuited in China, 
randomized to receive the combination (0.5mg dutasteride and 0.2mg tamsulosin) who 
have available PPK samples.  
9.3.4.
Analysis Data Sets
Endpoints measured at specific visits and analysed in terms of visit numbers include:  
IPSS, Qmax, prostate volume, PSA, post void residual volume, suicidality and health 
outcomes. Analysis of the data collected in terms of visit numbers will be performed 
using two different approaches to account for missing data.
1. LOCF (Last Observation Carried Forward) analysis: This involves bringing 
(carrying) forward the last non-missing post-baseline assessment for subjects with 
missing visit data and/or for subjects who discontinued from the study.
2. At Visit analysis: Missing values at post-baseline assessments are not replaced and 
are regarded as missing.
The LOCF approach will be considered primary. If the LOCF and At Visit results are not 
consistent with regard to the statistical analyses and conclusions, then further data 
analyses will be undertaken. 
Endpoints measured in terms of event calendar days and analyzed in terms of survival 
methodology include AUR and BPH-related surgical intervention. These analyses will 
use the observed-cases approach in which actual date of event is used; missing values 
post-baseline are not replaced and are regarded as missing.
Analysis datasets will be created with a structure to reflect the above noted approaches 
for each endpoint.
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9.3.5.
Treatment Comparisons
9.3.5.1.
Primary Comparison of Interest
The primary comparison of interest at year 2 (Month 24 visit) is the combination therapy 
versus 0.2mg tamsulosin in terms of change from baseline IPSS. The primary population 
of interest will be the ITT population and the primary comparison will be made using 
LOCF data.
If the Month 24 IPSS change from baseline two-sided p-value is #0.05 and the treatment 
difference supports combination superiority, then conclude that combination is superior 
to 0.2mg tamsulosin.
If the IPSS primary efficacy endpoint is statistically significant and treatment difference 
supports combination superiority at Month 24, as defined above, then statistical testing 
and interpretation of earlier visit timepoints  (Month 21, Month 18, Month 15, Month 12, 
Month 9, Month 6, Month 3 – in this order) will occur in a step-down manner [producing 
a closed test procedure] at the 0.05 level of significance. Multiplicity control for 
secondary endpoints will be defined in the RAP.
9.3.5.2.
Other Comparisons of Interest
Secondary endpoint treatment comparisons of interest are included in this section
Secondary Efficacy Endpoints:
!
Prostate volume % change from baseline
!
IPSS improvement of ∀2 points and ∀3 points and, separately, ∀25% improvement 
from baseline
!
Qmax change from baseline
!
Proportion of subjects  with Qmax improvement of ∀3ml/sec and, separately, ∀30% 
improvement from baseline
!
Time to event/ proportion of subjects with AUR or  BPH related prostatic surgery 
!
Time to event/proportion of subjects with AUR
!
Time to event/proportion of subjects  undergoing BPH related prostatic surgery
Health Outcomes Endpoints:
!
BPH Impact Index (BII) change from baseline
!
BPH-related Health Status (Q8 of IPSS) change from baseline
!
Problem Assessment Scale of the Sexual Function Inventory (PAS- SFI) change 
from baseline
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9.3.6.
Interim Analysis
No interim efficacy analyses are planned for this study.
9.3.7.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report. 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. Investigative centers will be pooled a priori into clusters based 
on geographic location; these clusters may be used in analyses to adjust for site effects. 
Clusters will be defined once all investigative sites have been identified and 
randomisation has been completed.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
Analyses will be performed as appropriate using the LOCF along with the At Visit 
approach or the observed-cases approach and which will be assigned in subsequent 
sections. Missing individual responses for the IPSS questionnaire will be imputed when 
at least four of the seven questions are answered (non-missing). Missing individual 
responses for the BII questionnaire will be imputed when at least two of the four 
questions are answered (non-missing). For the imputation, the average of the non-missing 
responses will be calculated and rounded to the nearest integer. This average score will 
be imputed for the original missing response(s). If at least 20% of the subjects have at 
least one imputed score for either IPSS or BII then that questionnaire’s statistical 
analyses will be repeated based on non-imputed scores.
For purposes of data analyses, the baseline value of a particular type of assessment for a 
given subject will be defined as the last assessment prior to the start of randomized 
treatment. Change from baseline for each subject will be computed as post-baseline value 
minus baseline value. Endpoints will be log-transformed where this will improve the 
assumptions underlying the analyses. Endpoints with log-transformations performed 
within the analysis model include prostate volume.
Demographic and baseline characteristics will be summarized.
9.3.7.1.
Efficacy Analyses
Primary Analysis
The primary efficacy parameter after two years of study treatment is change from 
baseline IPSS. Symptom improvement is measured using the IPSS and evaluated using 
change from baseline.
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Total IPSS, change from baseline IPSS, and percentage change from baseline IPSS will 
be summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment. Change in baseline IPSS will be compared at each 
scheduled post-baseline assessment for combination therapy versus 0.2mg tamsulosin 
using a general linear model with effects for treatment, cluster, and baseline IPSS at 
alpha=0.05.
Missing individual responses for the IPSS questionnaire will be imputed as defined in 
Section 9.3.7.
Secondary Analyses
The year 2 secondary efficacy endpoints include: Qmax; prostate volume; IPSS 
improvement of ∀2 points, ∀3 points and, separately, ∀25% improvement from baseline; 
and Qmax improvement of ∀3ml/sec and, separately, ∀30% improvement from baseline. 
Time to AUR or BPH-related surgical intervention is also a secondary efficacy endpoint.
The following describes the year 2 secondary efficacy endpoints and associated analyses. 
All treatment comparisons referenced are in terms of the combination therapy versus 
0.2 mg tamsulosin.
!
Prostate volume, change from baseline prostate volume, and percentage change from 
baseline prostate volume will be summarized by treatment group using both the 
LOCF and At Visit approaches at each scheduled post-baseline assessment. 
Percentage change from baseline prostate volume will be compared at each 
scheduled post-baseline assessment using the following general linear model:
log(post-baseline prostate volume/baseline prostate volume) = 
log(baseline prostate volume) + treatment + cluster 
!
Symptom improvement is measured using the IPSS and also evaluated using a 
categorical change from baseline improvement of  ∀2 points and ∀3 points and, 
separately, ∀25% improvement from baseline. Treatment comparisons will utilise a 
Mantel-Haenszel test controlling for cluster at alpha=0.05.
!
Maximum urinary flow (Qmax), change from baseline Qmax, and percentage change 
from baseline Qmax will be summarized by treatment group using both the LOCF 
and At Visit approaches at each scheduled post-baseline assessment. Change from 
baseline Qmax will be compared at each scheduled post-baseline assessment using a 
general linear model with effects for treatment, cluster, and baseline Qmax.
!
Qmax improvement of ∀3mL/sec and, separately, ∀30% improvement from baseline 
will be computed by treatment group. Treatment comparisons will utilise a Mantel-
Haenszel test controlling for cluster at alpha=0.05.
!
Time to first AUR or BPH-related surgical intervention will be defined as the 
number of days from date of first dose of randomized study drug to date of the first 
event (earliest occurring of either AUR or BPH-related surgery) for each subject. 
Censoring will occur at the earliest of the following dates as applicable: the date of 
prostatectomy, the date of last contact for AUR and surgical intervention assessment, 
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and the date of death. As an additional summary the number of subjects having the 
first AUR or BPH-related surgery event on or after first dose of study drug will be 
tabulated by treatment and by annual time period along with the number of subjects 
at risk during each of these time periods. Treatments will be compared in terms of 
time to first AUR or BPH-related surgery for the ITT population using a log rank test 
at the 0.05 level of significance.
Summary of Other Efficacy Measures
Urinary tract infection/urosepsis, urinary incontinence, and renal insufficiency are 
captured as potential BPH disease related events; reference Section 7.2.1.2. Frequencies 
of each event will be presented by treatment group; no formal treatment comparisons are 
planned.
9.3.7.2.
Safety Analyses
The Intent-to-Treat population will be used for the analysis of safety data. Complete 
details of the safety analyses will be provided in the RAP.
Extent of Exposure
Study drug exposure in days will be calculated for each subject as treatment stop date 
minus treatment start date plus one and will be summarized by treatment group. Study 
drug compliance between visits and cumulative study drug compliance will be calculated 
by dividing the number of study drug capsules used by the total number of study drug 
capsules prescribed and multiplying the result by 100. Study drug compliance between 
visits and cumulative study drug compliance will be summarized by treatment group.
Adverse Events
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). The frequency of events, the frequency of subjects and the percentage of 
subjects reporting each adverse event will be summarized by treatment group for all AEs 
and separately for drug-related AEs. The proportion of subjects reporting at least one AE, 
at least one drug-related AE, at least one serious AE, and at least one AE leading to 
withdrawal will be computed for each treatment group. Comparisons of treatment groups 
for each of these sets of AEs will be performed using Fisher’s exact test.
Special interest adverse events will be defined in the RAP. 
The incidence of deaths and the primary cause of death will be summarized.
Clinical Laboratory Evaluations
For purposes of statistical analyses, the final value of the laboratory test prior to the start 
of the randomized treatment will be used as the baseline value. Only those laboratory 
tests with a numeric normal range and at least one post baseline value will be analysed 
statistically.
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A laboratory value that is on or within the normal range is considered normal. A 
laboratory value that is outside the testing laboratory’s normal range is considered an 
abnormal laboratory value. A laboratory value that is above the upper limit of the normal 
range is considered high abnormal. A laboratory value that is below the lower limit of the 
normal range is considered low abnormal.
To describe the laboratory values at baseline, the frequency of subjects with an abnormal 
laboratory value at baseline among subjects with a baseline laboratory value and a post 
baseline laboratory value will be computed by treatment group. Among subjects with a 
normal value at baseline, the frequency of abnormal values, high abnormal values, and 
low abnormal values at any post baseline laboratory will be computed by treatment 
group.  Among subjects with a normal or low abnormal value at baseline, the frequency 
of high abnormal values at any post baseline will be computed by treatment group. 
Among subjects with a normal or high abnormal value at baseline, the frequency of low 
abnormal values at any post baseline laboratory will be computed by treatment group.
The threshold laboratory values are defined in terms of a multiplicative factor of the 
testing laboratory’s normal range. A laboratory value that is above the upper limit factor 
multiplied by the upper limit of the normal range is considered a high threshold value. A 
laboratory value that is below the lower limit factor multiplied by the lower limit of the 
normal range is considered a low threshold value. 
To describe the laboratory values at baseline, the frequency of subjects with a threshold 
laboratory value at baseline among subjects with a baseline laboratory value and a post 
baseline laboratory value will be computed by treatment group. Among subjects whose 
baseline value was not classified as threshold, the frequency of subjects with threshold 
values at any post baseline laboratory will be computed by treatment group. Among 
subjects whose baseline value was not high threshold, the frequency of subjects with high 
threshold values at any post baseline laboratory will be computed by treatment group. 
Among subjects whose baseline value was not low threshold, the frequency of subjects 
with low threshold values at any post baseline laboratory will be computed by treatment 
group.
Differences in laboratory values between baseline and the final scheduled laboratory 
assessment will be calculated for each laboratory test and summarized by treatment 
group.
9.3.7.2.1.
Other Safety Measures
Serum PSA
Total PSA, change from baseline total PSA, and percentage change from baseline total 
PSA will be summarized by treatment group using both the LOCF and At Visit 
approaches at each scheduled post-baseline assessment.
Change from baseline total PSA will be compared at each scheduled post-baseline 
assessment using a general linear model with effects for treatment and baseline total PSA.
Statistical analysis of the change from baseline total PSA comparing the treatment groups 
will begin using data from the final scheduled assessment. Abnormalities at any 
assessment will be listed by treatment and subject.
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Post Void Residual Volume
Post void residual volume, change from baseline post void residual volume, and 
percentage change from baseline post void residual volume will be summarized using 
both LOCF and At Visit approaches at each scheduled post-baseline assessment. 
Treatment groups will be compared in terms of the change from baseline distribution at 
each post baseline visit using a nonparametric van Elteren test controlling for cluster.
Qualitative Breast Examination
The percentage of subjects with any abnormal change in the qualitative breast 
examination will be summarized. The incidence of abnormal changes in these evaluations 
will be compared between treatment using Fisher’s exact test.
Blood Pressure, Pulse and DRE
The percentage of subjects exceeding the threshold criteria for blood pressure and pulse 
at any post-baseline assessment will be summarized by treatment group. The percentage 
of subjects with any abnormal change in the DRE evaluations will be summarized. The 
incidence of abnormal changes in these evaluations will be compared across treatment 
groups using Fisher’s exact test.
Suicidality
To protect subjects in the study, scores from C-SSRS tests will be reviewed in real time 
by the investigator and appropriate advice given to participants.  
The C-SSRS scale has 10 outcomes, with binary (yes/no) responses. At the end of study, 
results will be assessed as follows: 
!
Suicidal ideation will be defined as a positive response at any time during treatment 
to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS.
!
Suicidal behavior will be defined as a positive response at any time  during treatment 
to any one of the five suicidal behaviour questions (Categories 6-10) on the C-SSRS.
!
Suicidal ideation or behavior will be defined as a positive response at any time 
during treatment to any one of the ten suicidal ideation and behaviour questions 
(Categories 1-10) on the C-SSRS.
The numbers of subjects with a positive response for suicidal ideation or suicidal 
behaviour will be reported at baseline and during study treatment at Visits 4, 6 and 10 
(6, 12 and 24 months post randomization respectively). Scores on treatment will be 
compared with baseline scores and, for Visits 6 and 10, with scores at last visit to 
determine the incidence of treatment-emergent suicidality. An increase in C-SSRS total 
score to 4 or 5 will be considered as serious treatment-emergent suicidality. Due to the 
low numbers of subjects expected to exhibit suicidal behaviours, formal statistical testing 
will not be performed.
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9.3.7.3.
Health Outcomes Analyses
BPH-related quality of life (QOL) will be assessed using BPH-related  Health Status, 
question 8 of IPSS (BHS),  BPH Impact Index (BII) and sexual function with the 
Problem Assessment Scale of the Sexual Function Inventory (PAS SFI).
BPH-related Health Status
The BPH-related Health Status (BHS) score is collected on the IPSS questionnaire (Q8 of
IPSS) and ranges from 0 to 6. Total BHS, change from baseline BHS, and percentage 
change from baseline BHS will be summarized by treatment group using both the LOCF 
and At Visit approaches at each scheduled post-baseline assessment. Change in baseline 
BHS will be compared at each scheduled post-baseline assessment using a general linear 
model with effects for treatment, cluster, and baseline BHS.
BPH Impact Index
The BPH Impact Index (BII) is the sum of four questions with a total score range of 0 to 
13. Individual questionnaire missing responses will be imputed, if applicable, as defined 
in Section 9.3.7. Total BII, change from baseline BII, and percentage change from 
baseline BII will be summarized by treatment group using both the LOCF and At Visit 
approaches at each scheduled post-baseline assessment. Change in baseline BII will be 
compared at each scheduled post-baseline assessment using a general linear model with 
effects for treatment, cluster, and baseline BII.
Problem Assessment Scale of the Sexual Function Inventory
The Problem Assessment Scale of the Sexual Function Inventory (PAS SFI) is the sum of 
three questions each ranging from 0 to 4. Total score, change from baseline score, and 
percentage change from baseline will be summarized by treatment group using both the
LOCF and At Visit approaches. Change in baseline score will be compared at each 
scheduled post-baseline assessment using a general linear model with effects for 
treatment, cluster, and baseline score.
9.3.8.
Medical Resource Utilisation
Summary statistics will be tabulated for the following:
!
Incidence of hospital admissions for AUR and/or BPH-related surgical interventions; 
number and type of procedures carried out
!
Length of hospital stay (in days, hours) associated with incidence of AUR and/or 
BPH-related surgical interventions and associated ward type
9.3.9.
Pharmacogenetic Analyses
Further details on PGx analyses will be addressed in Appendix 1 and the RAP.
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9.3.10.
Population Pharmacokinetic Analyses
Details on PPK analyses will be addressed in Appendix 7 and the RAP.
10.
STUDY CONDUCT 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 enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with applicable country-specific 
regulatory requirements. 
The study will be conducted in accordance with Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:
!
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
approval of study protocol and any subsequent amendments.
!
Subject informed consent.
!
Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study. The contents and process of obtaining consent will be in accordance with all 
applicable regulatory requirements.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted 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 include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:
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!
Data are authentic, accurate, and complete.
!
Safety and rights of subjects are being protected.
!
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
10.4.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site. Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study. In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
10.5.
Study and Site Closure
The end of study is defined as last subject, last visit.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance. If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable). When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action. Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
10.6.
Records Retention
Following closure of the study, the investigator or 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 easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
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investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register 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 results summary will be posted to the Clinical Study Register no later than 12 
months after the last subject’s last visit (LSLV) or sooner if required by legal agreement, 
local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed 
journal for publication within 18 months of LSLV. When manuscript publication in a 
peer-reviewed journal is not feasible, further study information will be posted to the GSK 
Clinical Study Register to supplement the results summary. 
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12.
APPENDICES
12.1.
Appendix 1: PGx
Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in different populations.  There is increasing evidence that an individual's genetic 
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx analysis include:
Drug
Disease
Gene
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002]
HLA-B*5701
Individuals with HLA-B*5701 variant may be 
at increased risk for experiencing
hypersensitivity to abacavir. Clinical assays
are available for HLA-B*5701 but none has
been validated. HLA-B*5701 screening would 
supplement but never replace abacavir clinical 
risk management strategies aimed at 
minimising rare but serious outcomes 
associated with abacavir hypersensitivity.
Warfarin
Cardiovascular
[Neergard, 2006;
Wilke, 2005]
CYP2C9
Serious Adverse Events (SAEs) experienced
by some patients on warfarin may be
explained by variations in the CYP2C9 gene
that influences the degree of anticoagulation
achieved.
Irinotecan
Cancer
[FDA News
Release, 2005]
UGT1A1
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation, might be 
too high for another patient without this 
variation, raising the risk of certain side-
effects. A genetic blood test (Invader UGT1A1
molecular assay) is available that can detect
variations in the gene.
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
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"Collection of whole blood samples, even when no a priori hypothesis has been 
identified, may enable PGx analysis to be conducted if at any time it appears that there is 
a potential unexpected or unexplained variation in handling or response to the 
combination treatment of dutasteride and tamsulosin or tamsulosin monotherapy.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a possible genetic relationship to handling or response to the 
combination treatment of dutasteride and tamsulosin or tamsulosin monotherapy.  If at 
any time it appears there is potential variability in response in this clinical study or in a 
series of clinical studies with the combination treatment of dutasteride and tamsulosin or 
tamsulosin monotherapy that may be attributable to genetic variations of subjects, the 
following objectives may be investigated: 
!
Relationship between genetic variants and safety and/or tolerability of study 
treatment
!
Relationship between genetic variants and efficacy of study treatment]
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives study treatment may take part in 
the PGx research.  Any subject who has received an allogeneic bone marrow transplant 
must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study.  Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
Study Assessments and Procedures
A whole blood sample (~6mL) will be collected for the PGx research using a tube 
containing EDTA. It is recommended that the blood sample be taken at Baseline (the first 
opportunity after a subject has been randomized and provided informed consent for PGx 
research), but may be taken at any time while the subject is participating in the clinical 
study.  For the purposes of this trial, the PGx sample will be collected at Visit 2 
(Baseline).  However if the investigators deems it appropriate, the PGx sample may be 
taken at a later visit.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff. Coded samples do not carry 
personal identifiers (such as name or social security number). The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample. 
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis. This analysis will involve the genotyping of several genetic markers to confirm 
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the integrity of individual samples. If inconsistencies are noted in the analysis, then those 
samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
dutasteride or tamsulosin treatment or studies on prostate-related disease has been 
completed and the study data reviewed. In some cases, the samples may not be studied. 
e.g., no questions are raised about how people respond to dutasteride or tamsulosin. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers) will use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form. 
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:
!
The sample is retained for PGx research.
!
Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records.  In either case, GSK will only keep study 
information collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator must complete the appropriate documentation to request sample destruction 
within the timeframe specified by GSK and maintain the documentation in the site study 
records.
Pharmacogenetics Analyses
1.
Specific sections of DNA may be selected from areas of the genome (e.g., candidate 
genes) known to encode the drug target, drug metabolizing enzymes, areas 
associated with mechanisms underlying response or adverse events, and those linked 
to study disease and, thus, linked to drug response. In addition, continuing research 
may identify other enzymes, transporters, proteins or receptors that may be involved 
in response to dutasteride and tamsulosin or tamsulosin monotherapy.  The genes 
that may code for these proteins may also be studied..
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Wilke RA, Musana AK, Weber WW. Cytochrome P450 gene-based drug prescribing, 
and factors impacting translation into routine clinical practice. Personalized Med 2005; 2: 
213–224.
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12.2.
Appendix 2: Study Assessment Schedule In Order of 
Performance
ALL SUBJECTS MUST SIGN AN INFORMED CONSENT PRIOR TO ANY STUDY 
MEASUREMENTS/PROCEDURES.  
Visit 1 (Pre-Screening Visit 1a and Screening Visit 1b)
During Screening (Visits 1a and 1b) the procedures listed below will be completed in the 
following sequential order when possible. It is important that the IPSS questionnaire be 
administered first.
Visit 1a (Pre-screening)
1. Obtain informed consent from subject
2. Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS], BHS Q8 BPH Impact Index [BII] 
3. Administer suicidality questionnaire [C-SSRS]
4. Complete medical history, Cardiovascular history and demographics
5. Review concomitant medications
6. Measure peak urinary flow
7. Measure post void residual volume
8. Review inclusion/exclusion criteria for patient eligibility
9. Call RAMOS to register subject and obtain unique registration number
10. Collect blood samples for clinical laboratory tests including PSA
11. Schedule next clinic visit to complete screening procedures
Visit 1b (Placebo run-in)
Visit 1b should be conducted a maximum of 14 days after V1a (allowing sufficient time 
for lab results from V1a to be returned to site). 
1.
Review pre-screening PSA/laboratory results
2.
Administer  Problem Assessment Scale of the Sexual Function Index (PAS-SFI)
3.
Perform physical examination, including digital rectal exam, qualitative breast 
examination, height, weight, and vital signs blood pressure and pulse after 5 mins 
sitting
4.
Obtain a 12-lead electrocardiogram (after 5 mins supine)
5.
Assess SAEs
6.
Measure peak urinary flow (if required)
7.
Measure post void residual volume (if required)
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8.
Measure prostate volume by transrectal ultrasound (TRUS) if suitable TRUS not 
available
9.
Review inclusion/exclusion criteria, including concomitant medications, and confirm 
patient eligibility
10. Call RAMOS 
11. Dispense placebo run-in medication and provide dosing instructions
12. Schedule next clinic visit
Visit 2 (Baseline/Randomisation)
Visit 2 should be conducted 28 days (& 4 days) after Visit 1b.  For each subject, all visits 
should be scheduled at a similar time of day: morning or afternoon.  During Visit 2 the 
procedures listed below will be completed in the following sequential order:
1.
Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS], BHS Q8,BPH Impact Index [BII], Problem Assessment Scale of the 
Sexual Function Index (PAS-SFI)
2.
Review concomitant medication and assess continuing eligibility
3.
Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization.  
4.
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
5.
Collect blood samples for PGx and HBsAG and Hepatitis C Antibody
6.
Measure vital signs: blood pressure and pulse after 5 mins sitting
7.
Assess AEs
8.
Measure peak urinary flow
9.
Measure post void residual volume
10. Call RAMOS to randomize subject
11. Collect unused placebo run-in medication and assess compliance
12. Dispense a 3-month supply (of blinded study medication and provide dosing 
instructions
13. Schedule next clinic visit
Visit 3 (3 months post-randomisation)
Visit 3 will be conducted 13 weeks (& 14 days) after Visit 2. For each subject, all visits 
should be scheduled at a similar time of day: morning or afternoon.  The following study 
procedures will be conducted:
1. Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS],  BHS Q8, BPH Impact Index [BII], 
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2. Review concomitant medication and assess continuing eligibility
3. Measure vital signs after 5 mins sitting
4. Chinese origin subjects, recuited in China only: Blood sample for PPK
5. Assess AEs
6. Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization.
7. Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
8. Collect unused study medication and assess compliance
9. Call RAMOS and Dispense a 3-month supply of study medication
10. Schedule next clinic visit
Visit 4 (6 months post-randomisation)
Visit 4 will be conducted 26 weeks (& 14 days) after Visit 2.  For each subject, all visits 
should be scheduled at a similar time of day:  morning or afternoon.  The following study 
procedures will be conducted:
1.
Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS], BHS Q8, BPH Impact Index [BII]
2.
Administer suicidality questionnaire [C-SSRS]
3.
Review concomitant medication and assess continuing eligibility
4.
Perform physical examination, including digital rectal exam, qualitative breast 
examination and vital signs  blood pressure and pulse after 5 mins sitting
5.
Collect blood sample for PSA
6.
Chinese origin subjects, recuited in China only: Blood sample for PPK
7.
Assess AEs
8.
Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization.
9.
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
10. Measure peak urinary flow
11. Measure post void residual volume
12. Collect unused study medication and assess compliance
13. Call RAMOS and Dispense a 3-month supply of blinded study medication
14. Schedule next clinic visit
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Visit 5 (9 months post-randomisation)
Visit 5 will be conducted 39 weeks (& 14 days) after Visit 2. For each subject, all visits 
should be scheduled at a similar time of day: morning or afternoon.  The following study 
procedures will be conducted:
1. Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS], BHS,Q8, BPH Impact Index [BII], 
2. Review concomitant medication and assess continuing eligibility
3. Measure vital signs after 5 mins sitting
4. Chinese origin subjects, recuited in China only: Blood sample for PPK
5. Assess AEs
6. Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization
7. Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
8. Collect unused study medication and assess compliance
9. Call RAMOS and Dispense a 3-month supply of study medication.
10. Schedule next clinic visit
Visit 6 (12 months post-randomisation)
Visit 6 will be conducted 52 weeks (& 14 days) after Visit 2.  For each subject, all visits 
should be scheduled at a similar time of day: morning or afternoon.  The following study 
procedures will be conducted:
1.
Administer patient self-assessment questionnaires: International Prostate Symptom 
Score [IPSS], BHS Q8, BPH Impact Index [BII], Problem Assessment Scale of the 
Sexual Function Index [PAS-SFI] 
2.
Administer suicidality questionnaire [C-SSRS]
3.
Collect blood samples for clinical laboratory tests including PSA
4.
Review concomitant medication and assess continuing eligibility
5.
Perform physical examination, including digital rectal exam, qualitative  breast 
examination and vital signs blood pressures and pulse after 5 mins sitting
6.
Assess AEs
7.
Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization
8.
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency.
9.
Measure peak urinary flow
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10. Measure post void residual volume
11. Measure prostate volume by transrectal ultrasound (TRUS)
12. Collect unused study medication and assess compliance
13. Call RAMOS and Dispense a 3-month supply of blinded study medication 
14. Schedule next clinic visit
Visits 7, 8, 9, (15, 18, and 21 months post-randomisation)
Visits 7 to 9 in Year 2 will be conducted at successive 13 week intervals (& 14 days) 
thereafter. For each subject, all visits should be scheduled at a similar time of day: 
morning or afternoon.  The study procedures at Visits 7, 8, and 9 will be the same as 
those performed at Visit 5 except the following:
!
Physical Examination is scheduled to be performed at Month 18 (Visit 8).
!
Post-void residual volume (PVR) and Peak Urine Flow (Qmax) are scheduled to 
be performed at Month 18 (Visit 8)
Visit 10 (24 months post-randomisation)
Visit 10 will be conducted 104 weeks (& 14 days) after Visit 2. For each subject, all visits 
should be scheduled at a similar time of day: morning or afternoon.  The following study 
procedures will be conducted:
1.
Administer patient self-assessment questionnaires (International Prostate Symptom 
Score [IPSS], BHS Q8, BPH Impact Index [BII], Problem Assessment Scale of the 
Sexual Function Index (PAS-SFI)
2.
Adminster suicidality questionnaire [C-SSRS]
3.
Collect blood samples for clinical laboratory tests including PSA
4.
Review concomitant medication and assess continuing eligibility
5.
Perform physical examination, including digital rectal exam, qualitative breast 
examination and vital signs (after 5 mins sitting)
6.
Assess AEs
7.
Record any episodes of AUR or prostatic surgical and minimally-invasive/non-
surgical interventions along with associated resource utilization
8.
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency.
9.
Measure peak urinary flow
10. Measure post void residual volume
11. Measure prostate volume by transrectal ultrasound (TRUS)
12. Collect unused study medication and assess compliance
13. Call RAMOS to register the subject's end of treatment visit
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End of Study Treatment Assessment Visit
If a subject discontinues study treatment permanently after Visit 2 (post-randomisation) 
and between the scheduled visits, the investigator should make every effort to schedule a 
visit by the subject to the study site and complete the following assessments if possible: 
!
Concomitant medications
!
Adverse events
!
Physical exam including vital signs, DRE and qualitative breast examination
!
Obtain blood samples for hematology, clinical chemistry and PSA determinations
!
Administer health outcome questionnaires (IPSS,  BHS,BII and PAS-SFI)
!
Administer suicidality questionnaires [C-SSRS]
!
Record any episodes of AUR, and, BPH-related prostatic surgery or minimally-
invasive/non-surgical interventions
!
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
!
Retrieve any unused double-blind study medication, assess compliance and record 
date of last dose of study medication
!
Discuss the biannual follow-up phone call schedule
!
Complete subject eCRF
If the decision for a subject’s study treatment discontinuation is made dung a regularly 
scheduled visit, the procedures that are stated above should be completed, in addition to 
any scheduled procedure (e.g. Prostate Volume, Qmax) that is not listed above.
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12.3.
Appendix 3: Country Specific Requirements
There are no country specific requirements.
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12.4.
Appendix 4: Prostatic Surgical and Minimally-invasive/Non 
surgical Interventions for BPH
The following is a glossary of prostatic surgical and minimally-invasive/non-surgical 
interventions, including but not limited to:
Adenomectomy
Ballon dilatation
Electroresection
Thermotherapy (microwave or radiofrequency)
Laser resection
Prostatectomy (open, partial, retropubic with or without nerve sparing, suprapubic, 
transvesical, perineal, salvage, laparoscopic, laparoscopic assisted)
Prostatotomy
Transurethral resection of the prostate (TURP)
Transurethral drainage of prostatic abscess
Drainage of prostatic cysts
Radioactive seeding of the prostate (brachytherapy)
Prostatic urethral stenting
Incision of periuretheral stricture
Ethanol injections into the prostate
Transrectal high intensity focussed ultrasound (HIFU)
Transurethral needle ablation (TUNA)
Transurethral microwave thermotherapy (TUMT)
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12.5.
Appendix 5: IPSS Questionnaire
International Prostate Symptom Score (IPSS)
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12.6.
Appendix 6: Health Outcomes / QoL Questionnaires
BPH-Related Health Status, IPSS Q 8
BPH IMPACT INDEX (BII)
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A BRIEF SEXUAL FUNCTION INVENTORY
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12.7.
Appendix 7: Population Pharmacokinetic Substudy (Chinese 
Subjects Only)
Population PK (PPK) is the study of the sources and correlates of variability in drug 
concentrations among individuals who are the target patient population receiving 
clinically relevant doses of a drug of interest [Aarons, 1991]. Certain patient 
demographical, physiological, and therapeutic features, such as body weight, excretory 
and metabolic functions, and the presence of other therapies, may alter dose 
concentration relationships. PPK studies seek to identify the measurable physiologic 
factors that cause changes in the dose-concentration relationship and the extent of these 
changes so that, if such changes are associated with clinically significant shifts in the 
therapeutic index, dose can be appropriately modified.
The pharmacokinetics of dutasteride and tamsulosin in Western subjects is well-
understood (CIB). In contrast, pharmacokinetic data of these two drugs in Chinese 
subjects are limited. Following a request to provide this information from the Regulatory 
Authority in China, subjects of Chinese origin living in China will participate in a PPK 
sub-study in this study,which aims to characterize the PK of dutasteride when dosed in 
combination with tamsulosin to Chinese men with BPHSerum PK sampling
Serum PK samples will be obtained on Visits 3, 4, and 5 (Table 1). Subjects must 
contribute to PK sampling to be considered evaluable.  It is planned to use these data to 
develop population PK models in the target patient population and account for both inter-
individual and inter-occasion variability in dutasteride PK. These data will also be used to 
assess the influence of covariates (e.g., age, gender, weight) on the population PK 
parameters of dutasteride and their associated variability. 
Processing, storage and shipping procedures are provided in the SPM
Sample Analysis
Only samples from those subjects who received the combination (dutasteride 0.5 mg once 
daily and tamsulosin 0.2 mg once daily) will be analysed.  Serum analysis will be 
performed under the control of PTS-DMPK/Scinovo, GlaxoSmithKline, the details of 
which will be included in the SPM.  Concentrations of GI198745 (dutasteride) will be 
determined in serum samples using the currently approved bioanalytical methodology.  
Raw data will be archived at the bioanalytical site (detailed in the SPM).
Population Pharmacokinetic Analyses
Population pharmacokinetic models will be developed with the use of the nonlinear 
mixed effects modeling program (NONMEM) to characterize the pharmacokinetics of 
dutasteride following daily dosing in combination (dutasteride 0.5 mg once daily and 
tamsulosin 0.2 mg once daily). 
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Due to the sparseness of the PK samples, a Bayesian approach may be used. Namely, the 
two-compartment model with first-order absorption and parallel linear and non-linear 
elimination pathway published by [Gisleskog, 1999] may be used a priori. Data from the 
study will be used for generating a posterior model. The influence of covariates (e.g., age, 
gender, weight) on the population PK parameters of dutasteride and their associated 
variability may be evaluated. 
Analysis of the pharmacokinetics data is the responsibility of Clinical Pharmacology 
Modeling and Simulation (CPMS), GSK. Further details of pharmacokinetic analyses 
will be described in RAP; results of the analyses may be included in a report separate 
from the clinical study report.
References
Aarons L.  Population pharmacokinetics: theory and practice. Br J Clin Pharmacol. 1991 
Dec;32(6):669-70.
Gisleskog PO, Hermann D, Hammarlund-Udenaes M, Karlsson MO. The 
pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear 
and nonlinear elimination. Br J Clin Pharmacol. 1999 Jan;47(1):53-8.
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12.8.
Appendix 8: Protocol Amendment Changes
Protocol Amendment 1 main changes are listed below:
!
Change in the storage conditions for the study drug
!
Clarification on the collection of partner pregnancy information, 
!
Correction to the treatment assignment language 
!
Clarification on the collection of  the questionnaires and their sequence 
!
Deleted references to Pharmacokinetics 
!
Updates and clarifications to the PGx language 
!
Updates and clarifications to AE and SAE definition
!
Clarification on study treatment discontinuation and study discontinuation
!
Clarification of the language on protocol waivers 
!
Clarification on the wording regarding the number of subjects for enrolment
!
Removal of detailed information on the investigation product bottle fill counts and 
details on packaging and labeling as updated details will be in the Study Procedures 
Manual.
!
Correction to T & E table, spelling errors and re-wording to provide clarification
!
Addition of total serum PSA at visit 4 (6 months) as per the updated global data 
sheet
!
Addition of three supplementary efficacy measures, 
!
Addition of vital sign measures at Visit 3 and Visit 5 
!
The addition of the follow-up of sexually related AEs when a subject discontinues 
study treatment. 
!
Addition of a SMS text messaging system to aid retention and follow-up
!
Addition of text to allow unscheduled visits when medically necessary
This amendment includes re-wording and clarifications as listed:
Section: Title Page
Action: List of Authors updated
Rationale: New team members added/replaced
Original Text: Author(s):
 
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Updated Text: Author: 
 
 
Section:  Sponsor information
Action: Sponsor medical monitor contact name and details updated
Rationale:  An additional  medical monitor has been assigned to the study and contact 
details added
Original Text: Sponsor Medical Monitor Contact Information: 
 M.D.
Updated Text:
Primary:
 MD
2301 Renaissance Blvd, 
RN0410  King of Prussia, 
Pennsylvania PA 19406 . US
Office: 
 ; Cell:
 
Secondary:
 M.D.
2301 Renaissance Blvd, 
RN0410  King of Prussia, 
Pennsylvania PA 19406 . US
Office: 
 ; Cell:
  
Section: Protocol Summary
Action: Clarification changes listed are from baseline 
Rationale: Clarification that the health outcome measure will be the change from 
baseline in the BPH impact Index and Problem Assessment Scale of the Sexual Function 
Inventory
Original Text: 
!
Health Outcome Measures:
!
change from baseline in BPH-related Health Status (Q8 of IPSS),
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!
change in BPH Impact Index (BII), and 
!
change in Problem Assessment Scale of the Sexual Function Inventory (PAS-
SFI). 
Updated Text:
!
Health Outcome Measures:
!
Change from baseline in BPH-related Health Status (Q8 of IPSS),
!
Change from baseline in BPH Impact Index (BII), and 
!
Change from baseline in Problem Assessment Scale of the Sexual Function 
Inventory (PAS-SFI).
Section: Protocol Summary
Action:  Include PSA at Visit 4 (6 months)
Rationale: As per the updated Global Data Sheet
Original Text: Peak urinary flow (Qmax), and post void residual volume (PVR) will be 
measured at baseline and every 26 weeks thereafter, a physical examination with a 
qualitative breast examination at baseline and every 26 weeks thereafter, measures of the 
total PSA at baseline and every 52 weeks thereafter.
Updated Text: Peak urinary flow (Qmax), and post void residual volume (PVR) will be 
measured at baseline and every 26 weeks thereafter, a physical examination with a 
qualitative breast examination at baseline and every 26 weeks thereafter, measures of the 
total PSA at baseline, 6 months and every 52 weeks thereafter.
Section 1.1: Background
Action: References updated
Rationale: References have been updated to reflect the most up to date 
reference/guidance.
Original Text: The potentially progressive nature of the disease has been associated with 
an increased risk of acute urinary retention (AUR) and the need for surgery 
[McConnell, 1998]
The aim of BPH therapy is to improve symptoms and quality of life of patients, and to 
prevent or reduce the risk of BPH-related complications such as urinary retention or 
upper urinary tract dilatation [AUA Practice Guidelines Committee, 2003;
Madersbacher, 2004].
Updated Text: The potentially progressive nature of the disease has been associated with 
an increased risk of acute urinary retention (AUR) and the need for surgery 
[Oelke, 2011].
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The aim of BPH therapy is to improve symptoms and quality of life of patients, and to 
prevent or reduce the risk of BPH-related complications such as urinary retention or 
upper urinary tract dilatation [AUA, 2010 Practice Guidelines Committee; Oelke, 2011].
Section1.1: Background
Action: Additional Text added 
Rationale: To provide additional relevant information
Added Text: In addition, at 4 years, dutasteride and tamsulosin in combination 
significantly reduced the risk of AUR and BPH related surgery compared to tamsulosin 
monotherapy.
Section 1.1: Background
Action: Additional Text added 
Rationale: To provide clarity regarding the FDC approval
Original Text:In another study (ARI109882), bioequivalence between a newly 
developed fixed-dose combination (dutasteride 0.5mg / tamsulosin hydrochloride 0.4mg) 
and the co-administration therapy was demonstrated, and approved in Europe in March 
2010 and in the US June 2010.
Added Text: In another study (ARI109882), bioequivalence between a newly developed 
fixed-dose combination (dutasteride 0.5mg / tamsulosin hydrochloride 0.4mg) and the co-
administration therapy was demonstrated, and the fixed dose combination product was 
approved in Europe in March 2010 and in the US June 2010.
Section 1.1: Background
Action: Additional text added 
Rationale: To reference to the CIB/approved product label to provide risk:benefit 
information on investigational product.
Added Text:  Specific information regarding warnings, precautions, contraindications, 
AEs, and other pertinent information on the study treatments is provided in the approved 
label and in the clinical investigator brochure (CIB).
Section 2.3:  Exploratary Pharmacogenetics (PGx) Research Objective
Action: Text added
Rationale: As per new GSK template wording and deleted the reference to 
pharmacokinetics.
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Original Text:  The PGx objectives for this study are to investigate the relationships 
between genetic variants in DNA from patient blood and response to treatment (as 
monitored by safety, tolerability, pharmacokinetics, and efficacy parameters).
Updated Text:  The exploratory PGx objectives for this study are to investigate the 
relationships between genetic variants in DNA from patient blood and any unexplained or 
unexpected response to treatment (as monitored by safety, tolerability, and efficacy 
parameters) that may have an underlying genetic mechanism.
Section 3:  Study Design
Action: Text modified
Rationale: As per new GSK template wording
Original Text:  Protocol waivers or exemptions are not allowed. Therefore adherence to 
the study design requirements, including those specified in the Time and Events Table are 
essential
Amended Text:  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.
Section 4.1.1: Number of Subjects
Action:  Text corrected and updated 
Rationale: To correct the approximate number of subjects screened and clarify and 
correct previous wording. To include a statement re: adjustment of enrolment target if 
needed to ensure overall number of evaluable subjects.
Original Text: Approximately 586 men with symptomatic BPH will be randomized into 
a single blind placebo run-in phase followed by a 2-arm double-blind treatment phase.  It 
is expected that approximately 1050 patients will need to be screened to allow for up to 
40% screening failures and drop-outs during the placebo run in period.
Updated Text: Approximately 586 men with symptomatic BPH will be randomized into 
the treatment phase.  It is expected that approximately 1000 patients will need to be 
screened to allow for a screening failure rate of approximately 40%.  The overall 
enrolment target number may be adjusted depending on the actual experience of 
enrolment and retention of participants, to ensure that the overall evaluable subject 
number target is met.
Section 4.1.4: Other Eligibility Criteria Considerations
Action:  Text added
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Rationale: Information in local product monographs may impact consideration of a 
subject’s eligibility differently.  Additional wording added to guide investigators to locate 
relevant information readily and to ensure better compliance.
Original Text:  These documents include, but may not be limited to, the following: the 
dutasteride Clinical Investigator's Brochure (CIB) or equivalent document provided by 
GlaxoSmithKline (GSK), the dutasteride (AVODART) local product monograph, where 
available, the approved product label(s) for tamsulosin (Harnal D, Flomax) and 
dutasteride (AVODART), if applicable.  
Added Text: These documents include, but may not be limited to, the following: the 
dutasteride Clinical Investigator's Brochure (CIB) or equivalent document provided by 
GlaxoSmithKline (GSK), the dutasteride (AVODART) local product monograph, where 
available, the approved product label(s) for tamsulosin (Harnal D, Flomax) and 
dutasteride (AVODART), if applicable.  Study Procedures Manuals will outline 
information contained in the local product monographs that must be relayed to patients 
(e.g. use of a condom to avoids exposure of his partner when taking the study drugs), as 
applicable to a specific country.
Section 4.1.:Precautions
Action:  Paragraphs removed 
Rationale:  Study sites should exam all precautions that are stated in the product labels.  
Local countries to adhere to local labelling guidelines. Precautions in the ICF will be in 
accordance with local labelling.
Original Text: Women of childbearing potential, pregnant women, and lactating women 
should avoid exposure to study medication. Inhibitors of 5α-reductase block the 
conversion of testosterone to dihydrotestosterone; the latter plays an important role in the 
development of external genitalia in the male fetus. Consequently, male offspring of 
women exposed to therapeutic concentrations of a 5α-reductase inhibitor may be born 
with abnormal male genitalia.
The dose of dutasteride in a unit of blood donated by a dutasteride-treated subject 
receiving 0.5 mg daily has been calculated to be below the no effect dose for DHT 
suppression in humans and as a single dose is well below the exposure in a study in 
rhesus monkeys that produced no effect on male fetal masculinization (see CIB). 
However, to allow an extra margin of safety, men being treated with dutasteride should 
not donate blood while taking study medication and until at least 6 months following 
administration of the last dose. The purpose of this deferred period is to prevent 
administration of dutasteride to a pregnant female transfusion recipient.
Dutasteride has been reported to decrease sperm count and motility, and reduce semen 
volume in healthy volunteers (see CIB). The clinical significance of dutasteride's effect 
on sperm and semen characteristics for an individual man’s fertility is not known.
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Updated Text: Investigator must refer to the relevant document(s) for detailed 
information regarding precautions as mentioned above.  Local product monograph should 
be checked carefully to adhere to local labelling guidelines.
Section 4.2.1:  Permanent Discontinuation from study Treatment
Action: Text modified
Rationale: To provide clarification on discontinuation of study treatment vs 
discontinuation of study
Added Text: adverse event
Added Text (moved from Section 6.3): A subject, who experiences an AUR, does not 
need to be withdrawn from the study treatment.  Any subject who has BPH-related 
prostatic surgery or any minimally-invasive/non-surgical intervention for treatment of 
BPH symptoms at any time during the study period must be withdrawn from the study 
treatment.
Added Text:  All subjects who prematurely discontinue from study treatment may not 
necessarily be withdrawn from the study as further study procedures or follow-up may be 
performed (Section 6.3).
Deleted Text : Subjects who prematurely discontinue study treatment will be followed 
via telephone contact for clinical outcomes including AUR or BPH related prostatic 
surgery, through the remainder of the 2 year treatment period(see Section 6.3) 
Section 4.2.2:Subject Completion
Action: Deletion of repetitive text
Rationale: Deletion of repetitive text for clarification as the additional information is 
stated elsewhere in the protocol
Original Text: A subject will be considered to have completed the study if he completes 
the 4-weekplacebo run-in and the 104 week study treatment period. A subject will be 
considered tohave prematurely discontinued the study if the subject died, is lost to 
follow-up,withdraws consent, or if the study is closed/terminated.
Updated Text: A subject will be considered to have completed the study if he completes 
the 4-week placebo run-in and the 104 week study treatment period.
Section 5.1:  Investigational Product
Action: Clarification
Rationale: Clarify that the oral disintegrating placebo is for the tamsulosin placebo
Original Text: Oral disintegrating placebos will be supplied by GSK.
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Amended Text: An oral disintegrating placebo tamsulosin tablet will be supplied by 
GSK for the run-in period.
Section 5.1.1:  Dosage and Administration
Action: Removal of bottle fill counts and detailed subject dosing instructions 
Rationale: Updated details on the study drug will be in the Study Procedures Manual.
Original Text (Run-in phase (single-blind)):  Subjects will receive a 1-month supply of 
study medication (one bottle containing 35 capsules and one blister card containing 36 
tablets).  All subjects will be instructed to take one soft gelatin placebo capsule 
(swallowed whole and not chewed) and one oral disintegrating placebo tablet(dissolved 
on the tongue then swallowed not chewed) , approximately one-half hour following the 
first meal each day for four weeks. They will then be randomized to adouble-blind 
treatment phase for a further 104 weeks.
Amended Text (Run-in phase (single-blind)):  Subjects will receive a 1-month supply 
of study medication.  All subjects will be instructed to take one soft gelatin placebo 
capsule (swallowed whole and not chewed) and one oral disintegrating placebo tablet 
(dissolved on the tongue then swallowed not chewed), following the first meal each day 
for four weeks.  They will then be randomized to a double-blind treatment phase for a 
further 104 weeks.
Original Text (Randomized treatment phase (double-blind)):  one tamsulosin tablet 
(dissolved on the tongue then swallowed not chewed) approximately one-half hour 
following the first meal each day for 104 weeks
Amended Text (Randomized treatment phase (double-blind)):  one tamsulosin tablet 
(dissolved on the tongue then swallowed not chewed) following the first meal each day 
for 104 weeks.
Section 5.2: Packaging and Labeling
Action: Remove detailed text on packaging, fill counts and labelling
Rationale: Updated details on the study drug and the fill counts will be in the Study 
Procedures Manual
Original Text: Dutasteride study medication for both phases of the study will be 
provided in high density, polyethylene bottles with plastic child-resistant closures. For 
the Run-In Phase, dutasteride placebo will be packaged as 35 capsules per bottle.  For the 
Treatment Phase, dutasteride 0.5mg and its matching placebo will be packaged to be 
indistinguishable irrespective of treatment with 100 capsules per bottle, sufficient for 3 
months treatment . Each bottle will be labelled with a multi-language booklet label.  
Commercially available tamsulosin 0.2mg will be provided by GSK. Each pack will be 
labelled with a multi-language booklet label.
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Placebo ODT will be packaged in blister cards with 36 tablets per card. Each blister card 
will be labelled with a multi-language booklet label
Updated Text: Dutasteride study medication for both phases of the study will be 
provided in high density, polyethylene bottles with plastic child-resistant closures. 
Dutasteride 0.5mg and its matching placebo will be packaged to be indistinguishable 
irrespective of treatment. 
Commercially available tamsulosin 0.2mg will be provided by GSK. 
The tamsulosin tablet placebos will be packaged in blister packs. 
Section 5.3: Handling and Storage of Study Treatment
Action: Text updated
Rationale: Change in the storage conditions for study drug. Gelatin cross linking is 
temperature dependent. Reducing the storage temperature conditions will mitigate risk of  
shelf life failure. All new supplies will be labeled with the new storage conditions, “Store 
up to 25°C”.
Original Text: Prior to dispensing, all study medication will be kept safely locked and 
stored protectedfrom light and moisture. The dutasteride capsules should be stored at or 
below 30°C. The commercial tamsulosin can be stored at room temperature and the 
placebo ODT at room temperature (15-30°C).
Updated Text: The dutasteride capsules should be stored at temperatures up to 25°C 
(77°F).The commercial tamsulosin and placebo should be stored as per the instructions 
on the label.  Relevant label details will be provided in the study SPM.  
Section 5.4: Treatment Assignment
Action:  Treatment assignment clarified
Rationale: The subjects will be randomized by investigative sites, reference to central 
randomization removed,
Original Text: Subjects will be centrally randomized using a randomization schedule 
generated by the GSK Biostatistical Department
Updated Text: Subjects will be randomized by investigative site using a randomization 
schedule generated by the GSK Biostatistical Department
Section 6.2: Prohibited Medications and Non-Drug Therapies
Action: Text added
Rationale: Addition of the text on concomitant medications and non-drug therapies 
allow more consistent interpretation throughout the study sites. 
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Added Text: Questions regarding permitted and prohibited concomitant medications 
and non drug therapies should be directed to the GSK Medical Monitor for clarification.
Section 6.3: Treatment after Discontinuation of Study treatment or Discontinuation of 
Study
Action: Text modified
Rationale: To provide clarification on discontinuation of study treatment vs 
discontinuation of study
Original Text:  If a subject discontinues study participation after Visit 2
Amended Text: If a subject discontinues study treatment permanently after Visit 2.
Original Text:  End of Study Assessments as outlined in Section 7.2.2.5
Amended Text: End of Study Treatment Assessments as outlined in Section 7.2.2.5
Added Text: No additional study activities other than those that are stated above are 
planned after a subject’s permanent discontinuation from study treatment.
A subject is considered a ‘withdrawal’ from the study when no study procedure has 
occurred, no follow-up has been performed and no further information has been collected 
for this subject from the date of withdrawal/last contact.
The primary reason for permanent discontinuation of study must be documented in the 
subject’s medical records and eCRF.
Original Text: In the event that a subject is prematurely discontinued from the study at 
any time due to an AE
Amended Text: In the event that a subject is prematurely discontinued from the study 
treatment or withdraw from the study at any time due to an AE
Deleted Text (moved to Section 4.2): A subject, who experiences an AUR, does not 
need to be withdrawn from the study. Any subject who has BPH-related prostatic surgery 
or any minimally-invasive/non-surgical intervention for treatment of BPH symptoms at 
any time during the study period must be withdrawn from the study
Action: Text added
Rationale: The addition of text on the follow-up of sexually related AEs when a subject 
discontinues study treatment allow more fully document study related events. 
Original Text: after premature withdrawal of study treatment, should be fully 
documented in the eCRF and source documents.
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Updated Text: after premature withdrawal of study treatment, and outcomes of sexually 
related adverse events reported during the treatment period, should be fully documented 
in the eCRF and source documents.
Section 7: Study Assessements and Procedures 
Action: Text Aded
Rationale: The added text allows necessary visit/assessment to be performed when 
necessary.
Added Text: Unscheduled visits/assessment may be performed by the investigator as 
medically necessary
Action: Corrections to the Time and Events  table
Rationale:.  Additions and revisions to the T & E table to ensure consistency with 
protocol text [addition of PSA serum collection at visit 4, addition of vital signs at visits 3 
& 5, addition of AUR or BPH-related surgery at visits 2-10, addition of other efficacy 
measures (UTI/Incontinence/Renal Insufficiency at visits 2-10)].
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Original Text:
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b 
+ 28d ± 4 
days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 -
9
(Years 2, 
repeat as 
for V3-V5 
of Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of Placebo 
run-in
Start of 
Treatment 
Phase
Baseline
End of 
Treatment 
Phase
ICF
X
Incl/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X
%
X
Physical a Examination a
X
X
X
%
X
Vital signs b
X
X
X
X
%
X
Haematology/clinical chemistry
X
X
%
X
HBsAG and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
%
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
%
X
AEs d
X 
X 
X
X
X
X
%
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X
%
X
Prostate Volume (TRUS)
X
X
%
X
Peak Urine Flow (Qmax)
X
X ***
X
X
X
X
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b 
+ 28d ± 4 
days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 -
9
(Years 2, 
repeat as 
for V3-V5 
of Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of Placebo 
run-in
Start of 
Treatment 
Phase
Baseline
End of 
Treatment 
Phase
Health Outcome:
BPH Health Status Q 8 IPSS 
(BHS)
X
X
X
X
X
X
X
AUR or BPH related Surgery 
Medical Resource Utilisation
X
X
X
X
X
X
X
X
BPH Impact Index (BII) 
X
X
X
X
X
X
%
X
PAS-SFI
X
X
X
%
X
Register in RAMOS
X
Study Medication:
Call RAMOS/Dispense Meds/
X e
X f
X
X
X
X
%
Compliance check / Collection
X
X
X
X
X
%
X
** This second screening visit is mandatory before dispensing placebo run-in medication.  This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the same sample to 
confirm the result
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Updated Text:
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Rand i
ICF
X
Incl/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X
%
X
Physical a Examination a
X
X
X
X h
X
Vital signs b
X
X
X
X
X
X
%
X
Haematology/clinical 
chemistry
X
X
X
HBsAG and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
X h
X
AEs d
X 
X 
X
X
X
X
%
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X
%
X
Prostate Volume (TRUS)
X
X
X
Peak Urine Flow (Qmax)
X
X ***
X
X
X
X h
X
AUR or BPH-related Surgery
X
X
X
X
%
X
X
Health Outcomes:
BPH Health Status Q 8 IPSS 
X
X
X
X
X
X
%
X

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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Rand i
(BHS)
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X
%
X
BPH Impact Index (BII) 
X
X
X
X
X
X
%
X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X
%
X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X
%
Compliance check/Collection
X
X
X
X
X
%
X
** This second screening visit is mandatory before dispensing placebo run-in medication.  This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the same sample to 
confirm the result
h.
Only performed at Visit 8 (Month 18)
i.
Performed for assessment of Subject Completion as well when a subject discontinues the study (see Section 6.3 and Section 7.2.2.5)
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Section: 7.2.1.2 Other Efficacy Measures
Action: Addition of new section 
Rationale:  Additions to the list of potential disease related events to allow possible 
comparison to historical BPH studies and to insure consistency of disease-related adverse 
event definition .
Updated Text:.  The following are potential BPH disease related events not captured as 
primary or secondary endpoints.  They will be collected in this study for possible 
comparison to historical BPH studies and to insure consistency of disease-related adverse 
event definition (see Section 7.4.2.2). 
!
Urinary tract infection/urosepsis
!
Urinary incontinence (overflow/urge)
!
Renal insufficiency
Section 7.2.1.3: Health Outcome Measures Endpoints (previously Section 7.2.1.2)
Action: Clarification
Rationale: Clarification and correction of previous wording
Original Text: Change in Resources Use related to changes in safety events
Updated Text: Resource Use related to AUR and BPH-related surgical events.
Section 7.2.2.4: Definition of Other Efficacy Measures
Action: Added the section to define other efficacy measures. 
Rationale:  To provide clinical definitions for the measures as stated in Section 7.2.1.2.
Updated Text: Other efficacy measures are noted in Section 7.2.1.2.  The following 
provides clinical definition for these measures.
Renal insufficiency is defined as >=50% sustained rise in baseline serum creatinine and 
>=1.5mg/dL; BPH-relatedness will be assessed by the investigator.
Urinary tract infection (UTI) is defined as symptomatic infection of 105 cfu/mL during 
the study; recurrent UTI is defined as two or more UTI episodes during the study. BPH-
relatedness will be assessed by the investigator. 
Incontinence (overflow or urge) is defined as socially or hygienically unacceptable 
involuntary leakage of urine). BPH-relatedness will be assessed by the investigator.
Section 7.2.2.5: End of study treatment Assessment
Action: Text modified
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Rationale:  To be consistent with the added text on other efficacy measures defined in 
Section 7.2.1.2 and with the clarification made concerning discontinuation of study 
treatment vs study
Updated Text: Record any episodes of UTI/urosepsis, urinary incontinence (first episode 
or consistent worsening), and renal insufficiency.
Original Text: Assessment of Subject Completion
Amended Text: End of Study Treatment Assessment
Added Text: During the study period that is between the scheduled visits, if a subject 
discontinues study treatment permanently after Visit 2 (post-randomisation) for any 
reason, other than lost to follow-up, the investigator should make every effort to schedule 
a visit by the subject to the study site and complete the following assessment:
Deleted Text: The End of Study Assessments comprise an essential safety evaluation that 
should be completed prior to discharging any subject from the study 
Added Text: Discuss the biannual follow-up phone call schedule
Added Text:  If the decision for a subject’s study treatment discontinuation is made 
during a regularly scheduled visit, the procedure that are stated above should be 
completed, in addition to any scheduled procedure that is not listed above.
Section 7.2.3: Short Messaging Service Reminder System
Action: Additional Paragraph added
Rationale:  An SMS messaging reminder system will be used to help with subject 
retention and follow-up
Updated Text:Short Messaging Service Reminder System
To help with the retention of the subjects and planning of their scheduled follow up 
throughout the study, subjects will be sent text messages via their mobile telephone, or 
email reminders, regarding their scheduled appointments. Sites will gain consent from the 
subject in the ICF before enrolling their mobile phone number or e-mail address into the 
secure short messaging service (SMS) reminder system. The system will then transmit 
text messages or e-mails to the subject in the local language regarding their next 
appointment.
Subject participation in the SMS reminder system is voluntary and refusal to participate 
will not indicate withdrawal from the clinical study. Refusal to participate will involve no 
penalty or loss of benefits to which the subject would otherwise be entitled. The SMS 
reminder system may not be available for all study sites or countries. Even if available, 
study sites or countries may choose not to participate in the SMS reminder system. All 
text message/e-mail content will be reviewed and approved by the IRB/IEC prior to use.
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Section 7.3.1: Endpoints
Action: Text added
Rationale: Clarification that the change in PSA will be from baseline
Original Text: Change in total serum PSA
Updated Text: Change in total serum PSA from baseline
Section 7.3.3:  Physician’s Assessments and vital signs
Action: Correction of the text on vital sign to include Visit 3 and Visit 5 assessments
Rationale:  To better evaluate subjects’ health status at Visit 3 and Visit 5 and to allow 
possible comparison to the data of historical BPH studies. 
Original Text: Vital signs (blood pressure followed by pulse) will be assessed at Pre-
Screening Visit 1, Baseline Visit 2 and every 6 months thereafter.
Amended Text: Vital signs (blood pressure followed by pulse) will be assessed at Pre-
Screening Visit 1, Baseline Visit 2 and at each scheduled 13 week clinic visit thereafter.
Section 7.3.4: Clinical Laboratory Assessments
Action: PSA test added at Visit 4
Rationale:  As per the change in the Global Data Sheet
Original Text: 
Laboratory Assessment
Visit Frequency
Hematology
Visits 1a, 6, 10
Clinical Chemistry
Visits 1a, 6, 10
PSA
Visits 1a, 6, 10
HBsAG and Hepatitis C Antibody 
Visit 2
PGx
Visit 2
Updated Text:
Laboratory Assessment
Visit Frequency
Hematology
Visits 1a,6, 10
Clinical Chemistry
Visits 1a, 6, 10
PSA
Visits 1a, 4, 6, 10
HBsAG and Hepatitis C Antibody 
Visit 2
PGx
Visit 2
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Section: 7.3.4.2 Prostate Specific Antigen (PSA)
Action: PSA added at visit 4 and text amended
Rationale: As per the change in the Global Data Sheet and amended allow the 
implementation of the added measure in a consistent way.
Original Text: Total serum PSA concentrations will be assessed at Pre-screening Visit 
1a and annually post-randomisation at Visits 6 and 10.
Updated Text:  Total serum PSA concentrations will be assessed at Pre-screening Visit 
1a and post-randomisation at Visit 4, (Month 6), and annually at Visits 6 and 10.Total.
Original Text: All post-baseline PSA levels will subsequently be reported within 1 
weeks of blood draw following blinding adjustment of the PSA result (where appropriate) 
as described below.
In order to maintain investigator blinding to study treatment, an independent reviewer 
who is unblinded to the PSA results as well as the drug random code, will adjust PSA 
values for appropriate participants. After a subject completes one year of treatment, PSA 
results will be reported to the principal investigators using the following methods:
Updated Text:  All post-baseline PSA levels will subsequently be reported following 
blinding adjustment of the PSA result (where appropriate) as described below. 
In order to maintain investigator blinding to study treatment, an independent reviewer 
who is unblinded to the PSA results as well as the drug random code, will adjust PSA 
values for appropriate participants.  After a subject completes six month of treatment, 
PSA results will be reported to the principal investigators using the following methods:
Section 7.3.9: Collection of Other Efficacy Measures
Action: Text added
Rationale: To provide details on collection of other efficacy measures added in 
Section 7.2.1.2.
Updated Text: At Visit 2 (Baseline) each scheduled 13 week clinic visit, the investigator 
will record in the designated section of the eCRF defined incidences of urinary tract 
infection/urosepsis, urinary incontinence, and renal insufficiency the subject experiences 
during his participation in the study.
Section 7.4.1: Definition of an AE
Action: Additional text added
Rationale: Updated as per GSK updated template
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Updated Text: 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.
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) 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.
Section 7.4.2:  Definition of an SAE
Action:  Clarification”
Rationale:  To clarify that spontaneous abortion is referred to the female partner of a 
male subject
Original Text: Spontaneous Abortion (see Partner Pregnancy, Section 7.4.3)
Amended Text: Spontaneous Abortion in female partner of male subject (see Partner 
Pregnancy, Section 7.4.3)
Section 7.4.2.2:  Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Action: Additional Disease related event added
Rationale: Additions to the list of potential disease related events to allow possible 
comparison to historical BPH studies and to insure consistency of disease-related adverse 
event definition 
Added  Text:
!
Urinary tract infection/urosepsis
!
Urinary incontinence (overflow/urge)
!
Renal insufficiency
Section: 7.4.3.1. Time period for collecting partner pregnancy information
Action: Clarification of wording
Rationale: The timing of the collection of pregnancy information was clarified and 
updated to collect pregnancy information if the subject’s partner is pregnant or becomes 
pregnant according to GSK standard.
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Original Text: Pregnancy information should be collected on any female partner who 
becomes pregnant by a male subject participating in the study, providing the pregnancy 
occurred between the time of the subject's randomisation to the end of the two year 
treatment period.
Updated Text: Pregnancy information should be collected on any female partner of a 
male study subject who is pregnant or becomes pregnant while the subject is participating 
in the study.  All pregnancies in female partners of male subjects will be collected after 
the start of dosing until 37 weeks after the subject’s last dose of study drug. 
Section 7.4.2.5: Action to be taken if partner pregnancy occurs
Action: Clarification
Rationale: The action to be taken if partner pregnancy occurs was clarified to include 
subject’s partner that are pregnant or may become pregnant
Original text: The investigator, or his/her designee, should make every effort to collect 
pregnancy information on any female partner who becomes pregnant by a male subject 
during his participation in this study
Update text: The investigator or designee should make every effort to collect pregnancy 
information on any female partner who is pregnant or becomes pregnant by a male 
subject during his participation in this study
Section 7.4.2.6: Time Period and Frequency of Detecting AEs and SAEs
Action: Text modified
Rationale: To provide clarification on discontinuation of study treatment vs 
discontinuation of study
Original Text: AEs will be collected from the start of the placebo run-in phase until the 
end of the two year treatment period
Amended Text: AEs will be collected from the start of the placebo run-in phase until the 
end of the two year study period.  
Original Text: will be recorded from the time a subject consents to participate in the 
study up to the end of the two year treatment period.
Amended Text: will be recorded from the time a subject consents to participate in the 
study up to the end of the two year study period.
Section 7.5.3.1
Action:  Clarification
Rationale: Clarify that the questionnaire data will be entered by the site into the eCRF
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Original Text: Upon completion of the questionnaires, the investigator will retrieve the 
questionnaires from the subject, and check that the header section (Subject Number, Visit 
Date, etc) is completed.  A copy of the completed questionnaires will stay with the 
subject’s source documents. A completed questionnaire should not be given back to the 
subject once it has been returned to the source documents
Updated Text:Upon completion of the questionnaires, the investigator will retrieve the 
questionnaires from the subject, and check that the header section (Subject Number, Visit 
Date, etc) is completed.  The investigator (or qualified designated member of their staff) 
will use the subject completed questionnaires to enter the recorded data into the 
appropriate section of the eCRF.  A copy of the completed questionnaires will stay with 
the subject’s source documents. A completed questionnaire should not be given back to 
the subject once it has been returned to the source documents
Section 7.6: Pharmacogenetics
Action:  Removal of text
Rationale:  There are no PK samples being collected in this study, therefore text 
referencing PK samples was removed. 
Original Text: The presence/absence of genetic variations in patient genes in DNA from 
blood will be analyzed to determine their relationship with response (safety, tolerability, 
pharmacokinetics, and efficacy) to treatment with either the combination of dutasteride 
and tamsulosin or tamsulosin alone.
Updated Text: . The presence/absence of genetic variations in patient genes in DNA 
from blood will be analyzed to determine their relationship with response (safety, 
tolerability, and efficacy) to treatment with either the combination of dutasteride and 
tamsulosin or tamsulosin alone.
Section 9.3.6.1: Efficacy Analysis 
Action: Text added
Rationale: Description of summary of other efficacy measures in alignment with the text 
added in Section 7.2.1.2.
Updated Text: Summary of Other Efficacy Measures
Urinary tract infection/urosepsis, urinary incontinence, and renal insufficiency are 
captured as potential BPH disease related events; reference Section 7.2.1.2.  Frequencies 
of each event will be presented by treatment group; no formal treatment comparisons are 
planned.
Section 12.1:  Appendix 1 Pharmacogenetics
Action: Text updated 
Rationale: PGx language updated to reflect current GSK template.
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Original Text (Pharmacogenetics – Background): Collection of whole blood samples, 
even when no a priori hypothesis has been identified, may enable PGx analysis to be 
conducted if at any time it appears that there is a potential unexpected or unexplained 
variation in handling or response to
Amended Text (Pharmacogenetics – Background): Collection of whole blood 
samples, even when no a priori hypothesis has been identified, may enable PGx analysis 
to be conducted if at any time it appears that there is a potential unexpected or 
unexplained variation in handling or response to the combination treatment of dutasteride 
and tamsulosin or tamsulosin monotherapy.
Added Text (Pharmacogenetics – Study Assessments and Procedures): However if 
the investigators deems it appropriate, the PGX sample may be taken at a later visit.
Original Text (Pharmacogenetic Research Objectives):If at any time it appears there 
is potential variability in response in this clinical study or in a series of clinical studies 
with If at any time it appears there is potential variability in response in this clinical study 
or in a series of clinical studies with the combination treatment of dutasteride and 
tamsulosin or tamsulosin monotherapy that may be attributable to genetic variations of 
subjects, the following objectives may be investigated.
Amended Text (Pharmacogenetic Research Objectives): If at any time it appears there 
is potential variability in response in this clinical study or in a series of clinical studies 
with the combination treatment of dutasteride and tamsulosin or tamsulosin monotherapy 
that may be attributable to genetic variations of subjects, the following objectives may be
investigated. 
Original Text (Pharmacogenetics Analyses):. Genome-wide scans involving a large 
number of polymorphic markers (e.g., single nucleotide polymorphisms) located 
throughout the genome. This approach is often employed when potential genetic effects 
are not well understood. 
Replaced with the Text (Pharmacogenetics Analyses):. In addition, continuing 
research may identify other enzymes, transporters, proteins or receptors that may be 
involved in response to dutasteride and tamsulosin or tamsulosin monotherapy.  The 
genes that may code for these proteins may also be studied.
Section 12.2:  Appendix 2 Study Assessment Schedule in Order of Performance
Action: Text added or removed 
Rationale: Clarification on the collection of  the questionnaires and their sequence, 
removal of  reference to number of bottles dispensed as this is to be updated and 
confirmed in the study procedure manual,addtion of the PSA test at Visit 4, text addition 
and removal to ensure consistency with the text of the main body of the protocol & the 
T& E table
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Original Text (Visit 2 and Visit 6): Administer patient self-assessment questionnaires: 
International Prostate Symptom Score [IPSS], BHS Q8,BPH Impact Index [BII], Patient's 
Perception of Study Medication [PPSM] Questionnaire (Satisfaction)
Amended Text (Visit 2 and Visit 6):: Administer patient self-assessment questionnaires: 
International Prostate Symptom Score [IPSS], BHS Q8,BPH Impact Index [BII], Problem 
Assessment Scale of the Sexual Function Index (PAS-SFI)
Original Text (Visit 3- 5) :Administer patient self-assessment questionnaires: 
International Prostate Symptom Score [IPSS], BHS Q8, BPH Impact Index [BII], 
Problem Assessment Scale of the Sexual Function Index (PAS-SFI).
Amended Text (Visit 3- 5): Administer patient self-assessment questionnaires: 
International Prostate Symptom Score [IPSS], BHS Q8, BPH Impact Index [BII],
Original Text (Visit 2-9):: Dispense a 3-month supply (2 bottles) of blinded study 
medication and provide dosing instructions
Amended Text (Visit 2-9):: Dispense a 3-month supply of blinded study medication and 
provide dosing instructions.
Added Text (Visit 4): Collect blood sample for PSA
Deleted Text (Visit 1b): Assess resource utilisation for any AUR episode or BPH-related 
surgery
Original Text (Visit 2): Assess resource utilisation associated with any AUR episode or 
BPH-related surgery
Amended Text (Visit 2-10): Record any episodes of AUR or prostatic surgical and 
minimally-invasive/non-surgical interventions along with associated resource 
utilizationRecord any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
Original Text (Visit 7-9): Visits 7 to 9 in Year 2 will be conducted at successive 13 
week intervals (& 14 days) thereafter. For each subject, all visits should be scheduled at a 
similar time of day: morning or afternoon.  The study procedures at Visits 7, 8, and 9 will 
be the same as those performed at Visits 3, 4, and 5, respectively
Amended Text (Visit 7-9): Visits 7 to 9 in Year 2 will be conducted at successive 13 
week intervals (& 14 days) thereafter. For each subject, all visits should be scheduled at a 
similar time of day: morning or afternoon.  The study procedures at Visits 7, 8, and 9 will 
be the same as those performed at Visits 5 except the following:
!
Physical Examination is scheduled to be performed at Month 18 (Visit 8).
!
Post-void residual volume (PVR) and Peak Urine Flow (Qmax) are scheduled to 
be performed at Month 18 (Visit 8)
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Added Text:
End of Study Treatment Assessment Visit
If a subject discontinues study treatment permanently after Visit 2 (post-randomisation) 
and between the scheduled visits, the investigator should make every effort to schedule a 
visit by the subject to the study site and complete the following assessments if possible: 
!
Concomitant medications
!
Adverse events
!
Physical exam including vital signs, DRE and qualitative breast examination
!
Obtain blood samples for hematology, clinical chemistry and PSA determinations
!
Administer health outcome questionnaires (IPSS,  BHS,BII and PAS-SFI)Record 
any episodes of AUR, and, BPH-related prostatic surgery or minimally-invasive/non-
surgical interventions
!
Record any episodes of UTI/urosepsis, urinary incontinence (first episode or 
consistent worsening), and renal insufficiency
!
Retrieve any unused double-blind study medication, assess compliance and record 
date of last dose of study medication
!
Discuss the biannual follow-up phone call schedule
!
Complete subject eCRF
If the decision for a subject’s study treatment discontinuation is made dung a regularly 
scheduled visit, the procedures that are stated above should be completed, in addition to 
any scheduled procedure (e.g. Prostate Volume, Qmax) that is not listed above.
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Protocol Amendment 2 main changes are listed below:
!
Addition of a PPK substudy for subjects of Chinese origin, living in China (only) 
Section 2.4, Section 7.7, Section 9.3.9 and Appendix 7.
!
Addition of suicidality assessments, at pre-screening (V1a), and at 6, 12 and 24 
months on treatment. Section 7.3.1, Section 7.3.9, Section 7.4.6, and 
Section 9.3.6.2.1.
!
Addition of information on QTc events, liver events and partner pregnancy. 
Section 7.4.3, Section 7.4.4 and Section 7.4.5.
!
Clarification on the information collected at baseline and at the pre-screening (V1a) 
and screening (V1b) visits. Protocol Summary.
!
Update to Sponsor Signatory, Medical Monitoring Contact Information and List of 
Authors. Sponsor Information Page. 
!
Clarification that the study will be posted to clinical trial registries Section 10.1.
!
Clarification of condom use for study subjects with female partners of childbearing 
potential. Section 4.1.2 and Section 7.4.5.
!
Clarification on the use of PDE-5 inhibitors. Section 4.1.3 and Section 6.2.
!
Update to T & E table to show new assessments for suicidality (all subjects) and 
PPK (Chinese subjects only). Section 7
!
Additional information on definition of SAEs for cardiovascular events and death. 
Section 7.4.2 
!
Clarification on the wording for BPH related quality of life
!
Administrative changes to correct spelling errors and re-wording to provide 
clarification and consistency
This amendment includes re-wording and clarifications as listed:
Section: Title Page
Action: List of Authors updated
Rationale: New team members added/replaced
Original Text: Author(s):
 
 
Updated Text: Author(s): 
 
Section:  Sponsor signatory information
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Action: Sponsor signatory information updated
Rationale:  Reflects change in responsibilities for the study
Original Text:  
 BSc, MBChB, MRCP, PhD, SVP, 
Emerging Markets R & D
Updated Text:  
 MD, Director Clinical Development, Emerging Markets 
R&D
Section:  Sponsor Information Page.
Action: Sponsor medical monitor contact name and details updated.  There is now only 1 
primary contact for medical monitoring.
Rationale:  Medical monitor contact details have changed.
Original Text: Sponsor Medical Monitor Contact Information: 
Primary:
 MD, 2301 Renaissance Blvd, RN0410  King of Prussia, 
Pennsylvania PA 19406. US Office: 
 ; Cell:
 
Secondary:
 M.D., 2301 Renaissance Blvd, RN0410  King of Prussia, 
Pennsylvania PA 19406 . US. Office: 
 ; Cell:
  
Updated Text:
Primary: 
 MD, Alexander Drive, Research Triangle Park, North 
Carolina, United States. Cell: 
Section: Protocol Summary (Study Assessments).
Action: Clarification of the assessments performed at pre-screening, screening and 
baseline.
Rationale: Clarification of the text in the Protocol Summary to ensure consistency with 
the T & E table. 
Original Text:  The planned assessments for all study participants include prostate 
volume by TRUS at baseline and annually thereafter for up to 2 years. Additionally, 
IPSS, BPH-related health status Q8 of IPSS, BPH Impact Index (BII) will be 
administered at baseline and every 13 weeks thereafter. The PAS-SFI will be 
administered at screening (V1b), baseline and annually thereafter. Peak urinary flow 
(Qmax), and post void residual volume (PVR) will be measured at baseline and every 26 
weeks thereafter, a physical examination with a qualitative breast examination at baseline 
and every 26 weeks thereafter, measures of the total PSA at baseline, 6 months and every 
52 weeks thereafter.
Updated Text:  The planned assessments for all study participants include prostate 
volume by TRUS at screening (V1b) and annually thereafter for up to 2 years. 
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Additionally, IPSS, BPH-related health status Q8 of IPSS, BPH Impact Index (BII) will 
be administered at pre-screening (V1a), baseline and every 13 weeks thereafter. The 
PAS-SFI will be administered at screening (V1b), baseline and annually thereafter. Peak 
urinary flow (Qmax), and post void residual volume (PVR) will be measured at pre-
screening (V1a), screening (V1b, if necessary), baseline and every 26 weeks thereafter. A 
physical examination with a qualitative breast examination, will be conducted at 
screening (V1b) and every 26 weeks thereafter. Measures of the total PSA will be 
conducted at pre-screening (V1a), 6 months 52 weeks and every 52 weeks thereafter.
Section: 2.2.3  Health Outcomes. 
Action: Update link to section detailing the health outcomes endpoints. 
Rationale: Updated, as previous link was to another section.
Original Text: The health outcomes endpoints are presented in Section 7.2.1.2 of this 
protocol.
Updated Text:  The health outcomes endpoints are presented in Section 7.2.1.3 of this 
protocol.
Section:  New Section 2.4 Exploratory Population Pharmacokinetics (PPK) Research 
Objective.
Action:  New section added. 
Rationale:  To show PPK substudy as an exploratory objective.
Original Text: Not applicable.
Updated Text: Exploratory Population Pharmacokinetics (PPK) Research Objective.
To characterize the PPK of dutasteride when given in combination with tamsulosin to 
Chinese men with BPH.
Section:  Section 3.1  Discussion of Design. 
Action:  New paragraph added. 
Rationale:  To explain the rationale for the PPK substudy in the study design.
Original Text: Not applicable.
Updated Text: (additional text).
The pharmacokinetics of dutasteride and tamsulosin in Western subjects is well 
understood (CIB). In contrast, pharmacokinetic data for these two drugs in Chinese 
subjects are limited. Following a request to provide this information from the Regulatory 
Authority in China, subjects of Chinese origin living in China will participate in a PPK 
sub-study in this study,which aims to characterize the PK of dutasteride when dosed in 
combination with tamsulosin to Chinese men with BPH.
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Section: 4.1.2 Inclusion Criteria. 
Action: Additional inclusion criteria, applicable only to countries where the local product 
monograph for dutasteride mandates condom use for men with a female partner of 
childbearing potential to clarify the need for condom useage in men with female partners 
of childbearing potential.
Rationale: Some countries recommend the use of condoms in local dutasteride labels.  
The addition of this inclusion criteria makes study selection criteria consistent with these 
local labels.
Original Text: Not applicable.
Updated Text:  Added: 9.  Men with a female partner of childbearing potential must 
agree to use a condom up to 6 months after the last dose (applies only to countries where 
the local product monograph for dutasteride mandates condom use for men with a female 
partner of childbearing potential).
Section: 4.1.3 Exclusion Criteria. 
Action: Additional exclusion criteria, to clarify that use of PDE-5 inhibitors are 
prohibited in the study. 
Rationale: PDE-5 inhibitors are prohibited in the study.
Original Text: Not applicable.
Updated Text:  Added: 10 f. Phosphodiesterase-5 (PDE-5) inhibitors for Erectile 
Dysfunction.
Section: 4.2.1 Permanent Discontinuation from Study Treatment. 
Action: Additional text on actions to be taken for follow up of subjects discontinuing 
treatment because of a sexual function related AEs. 
Rationale: sexual function related AEs are of particular interest in the indiction of BPH 
and the protocol amendment aims to clarify that subjects discontinuing treatment because 
of a sexual function related AEs must be followed up. 
Original Text: Not applicable.
Updated Text:  Subjects with sexual function related adverse events (contact GSK 
Medical Monitor if in doubt) leading to study withdrawal will be followed up for up to 
6 months after the last dose of study drug. The sexual function Targeted Follow-Up 
Questionnaire to be used for these subjects follow-up can be found in the Study 
Procedures Manual.
Section: 6.2 Prohibited Medications and Non-Drug Therapies.
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Action: Deletion of PDE-5 inhibitors from the list of medications not permitted within 
6 hours of taking study medication and addition of PDE-5 inhibitors from the list of 
medications not permitted at any time.
Rationale: PDE-5 inhibitors are now a study exclusion critera.
Original Text: 
Use of the following medications will be prohibited during the study:
d.
Not permitted at any time:
!
Finasteride (Proscar, Propecia)
!
Any other investigational or marketed 5∃-reductase inhibitors (other than 
study medication)
!
Any alpha-adrenoreceptor blockers (other than study medication)
!
BPH-related phytotherapy
!
Concurrent  use of anabolic steroids
!
Drugs with antiandrogenic properties (e.g. spironolactone, flutamide, 
bicalutamide) or other drugs that are noted for gynaecomastia effects or could 
affect prostate volume.  
e.
Not permitted within 6 hours of taking study medication:
!
Any PDE-5 inhibitor (e.g. sildenafil, vardenafil, tadalafil)
Updated Text:  
Use of the following medications will be prohibited during the study:
a.
Not permitted at any time:
!
Finasteride (Proscar, Propecia)
!
Any other investigational or marketed 5∃-reductase inhibitors (other than 
study medication)
!
Any alpha-adrenoreceptor blockers (other than study medication)
!
BPH-related phytotherapy
!
Concurrent  use of anabolic steroids
!
Drugs with antiandrogenic properties (e.g. spironolactone, flutamide, 
bicalutamide) or other drugs that are noted for gynaecomastia effects or could 
affect prostate volume
!
Any PDE-5 inhibitor (e.g. sildenafil, vardenafil, tadalafil).  
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Section: 7 Table 1: Time and Events Table.
Action: Addition of assessments to reflect other amendments to the protocol. 
Rationale: To make the Time and Events Table consistent with the protocol.
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Original Text: Table 1
Time and Events Table
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
ICF
X
Incl/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X
%
X
Physical a Examination a
X
X
X
Xh
X
Vital signs b
X
X
X
X
X
X
%
X
Haematology/clinical 
chemistry
X
X
X
HBsAG and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
Xh
X
AEs d
X 
X 
X
X
X
X
%
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X
%
X
Prostate Volume (TRUS)
X
X
X
Peak Urine Flow (Qmax)
X
X ***
X
X
X
Xh
X
AUR or BPH-related Surgery
X
X
X
X
%
X
X
Health Outcomes:
BPH Health Status Q 8 IPSS 
X
X
X
X
X
X
%
X
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
(BHS)
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X
%
X
BPH Impact Index (BII) 
X
X
X
X
X
X
%
X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X
%
X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X
%
Compliance check/Collection
X
X
X
X
X
%
X
** This second screening visit is mandatory before dispensing placebo run-in medication.  This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the same sample to 
confirm the result
h.
Only performed at Visit 8 (Month 18)
i.
Performed for End of Study Treament Assessments as well when a subject discontinues the study treatment (see Section 6.3 and Section 7.2.2.5)
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Updated Text: Table 1
Time and Events Table
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline +
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
ICF
X
Incl/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X
%
X
Physical Examinationa
X
X
X
Xh
X
Vital signsb
X
X
X
X
X
X
%
X
Haematology/clinical 
chemistry
X
X
X
HBsAG and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
Xh
X
AEs d
X 
X 
X
X
X
X
%
X
Suicidality (C-SSRS)
X
X
X
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X
%
X
Prostate Volume (TRUS)
X
X
X
Peak Urine Flow (Qmax)
X
X***
X
X
X
Xh
X
AUR or BPH-related Surgery
X
X
X
X
%
X
X
Pharmacokineticsj
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline +
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomisation)
3 months post 
Randomisation
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
Serum PK samplesj
X
X
Xk
Health Outcomes:
BPH Health Status Q 8 IPSS 
(BHS)
X
X
X
X
X
X
%
X
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X
%
X
BPH Impact Index (BII) 
X
X
X
X
X
X
%
X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X
%
X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X
%
Compliance check/Collection
X
X
X
X
X
%
X
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Updated Text: Table 1
Time and Events Table
** This second screening visit is mandatory before dispensing placebo run-in medication. This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
%  ongoing assessment
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RIBA immunoblot assay should be reflexively performed on the same sample to 
confirm the result
h.
Only performed at Visit 8 (Month 18)
i.
Performed for End of Study Treament Assessments as well when a subject discontinues the study treatment (see Section 6.3 and Section 7.2.2.5)
j.
Serum PK samples are only applicable to subjects of Chinese origin living in China (see Appendix 7 for more details)
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Section: 7.1 Critical Baseline Assessments Table 1: Time and Events Table.
Action: Clarification of demographic information collected.
Rationale: Only the subject’s year of birth are collected.
Original Text:  Demographic characteristics will be collected during screening. 
Subject’s date of birth, race, height (in centimeters), and weight (in kilograms) will be 
recorded in the eCRF. In addition the following assessments will be completed at 
screening:
Updated Text:  Demographic characteristics will be collected during screening. 
Subject’s year of birth, race, height (in centimeters), and weight (in kilograms) will be 
recorded in the eCRF. In addition the following assessments will be completed at 
screening:
Section: 7.2.2.3 Urinary Flow Measurement
Action: The specific make and model of the Uroflow Meter have been removed and will 
be included in the study procedures manual.
Rationale: The exact make and model of the Uroflow meter may change during the 
course of the study, and will therefore be specified in the study procedures manual to 
avoid protocol deviations or protocol amendments.
Original Text: 
Measurements of urinary flow will be conducted using a Medtronic (formerly Dantec) 
Uroflow Meter (Urodyn 1000) or Duet)) with a Thompson filter at Screening Visit 
1a/b, Baseline (Visit 2) and every scheduled 26 week clinic visit post-randomisation 
thereafter during the treatment period.
Updated Text:
Measurements of urinary flow will be conducted using a Uroflow Meter (details will be 
provided in the study procedures manual) at Screening Visit 1a/b, Baseline (Visit 2) and 
every scheduled 26 week clinic visit post-randomisation thereafter during the treatment 
period.
Section: 7.3.1 Safety Endpoints.
Action: Addition of suicidality. 
Rationale: Assessment of suicidality included to comply with GSK internal guidance on 
suicidality assessment.
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Original Text:  
!
Change in total serum PSA from baseline
!
Vital signs
!
Post-void residual volume
!
Clinical laboratory measurements (including haematology, chemistry) 
!
Adverse events (including AUR or BPH-related surgery and Prostate Cancer and 
prostate biopsy)
!
Physical examination: digital rectal examination (DRE) and qualitative  breast 
examination
See Section 7.4 for a complete description of adverse event assessments. 
Updated Text:  Demographic
!
Change in total serum PSA from baseline
!
Vital signs
!
Post-void residual volume
!
Clinical laboratory measurements (including haematology, chemistry) 
!
Adverse events (including AUR or BPH-related surgery and Prostate Cancer and 
prostate biopsy)
!
Physical examination: digital rectal examination (DRE) and qualitative  breast 
examination
!
An assessment of suicidality
See Section 7.4 for a complete description of adverse event assessments. 
Section: 7.3.3  Physician’s assessments and vital signs.
Action: Clarification of timepoints for collection of vital signs information.
Rationale: The text has been made consistent with the Time and Events Table.
Original Text:  Vital signs (blood pressure followed by pulse) will be assessed at 
Pre-Screening Visit 1b, Baseline Visit 2 and at each scheduled 13 week clinic visit 
thereafter.  
Updated Text:  Vital signs (blood pressure followed by pulse) will be assessed at 
Screening Visit 1b, Baseline Visit 2 and at each scheduled 13 week clinic visit thereafter.  
Section: 7.3.4  Clinical Laboratory Assessments.
Action: The last row of the table in this section (PGx assessments) has been deleted.
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Rationale: PGx assessments are described in Section 7.6.
Original Text:
Laboratory Assessment
Visit Frequency
Hematology
Visits 1a,6, 10
Clinical Chemistry
Visits 1a, 6, 10
PSA
Visits 1a, 4, 6, 10
HBsAG and Hepatitis C Antibody 
Visit 2
PGx
Visit 2
Updated Text:  
Laboratory Assessment
Visit Frequency
Hematology
Visits 1a,6, 10
Clinical Chemistry
Visits 1a, 6, 10
PSA
Visits 1a, 4, 6, 10
HBsAG and Hepatitis C Antibody 
Visit 2
Section: 7.3.9  Suicidality.
Action: Addition of new section relating to suicidality.
Rationale: Assessment of suicidality included to comply with GSK internal guidance on 
suicidality assessment.
Original Text:  Not applicable.
Updated Text:  
Dutasteride is considered to be an active compound in human central nervous system 
(CNS) that may affect mood or behavior via effects on the CNS (directly or indirectly). A 
GSK review of published literature and clinical trial data for dutasteride has shown that 
dutasteride is not associated with an increased risk of suicidal thinking or behavior when 
given to this patient population.
There has been some concern that some CNS-active drugs may be associated with an 
increased risk of suicidal thinking or behavior when given to some subjects with certain 
conditions. Although these drugs and other similar drugs of the same class have not been 
associated with an increased risk of suicidal thinking or behavior when given to this 
patient population, GSK considers it important to monitor for such events before or 
during clinical studies with compounds such as this.  
Subjects in Study ARI114265 will be assessed for suicidality and unusual changes in 
behavior using the Columbia Suicide Severity Rating Scale (C-SSRS). To protect 
subjects in the study, scores from C-SSRS tests will be reviewed in real time by the 
investigator and appropriate advice given to participants. Consideration should be given 
to discontinuing study treatments in subjects who experience signs of suicidal ideation or 
behavior. Refer to Section 7.4.6 for more information.
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Section: 7.4.2 1 Definition of a SAE.
Action: Additional subsections created for cardiovascular events and death events.
Rationale: To provide additional information on how SAEs are defined.
Original Text:  Not applicable.
Updated Text: 
7.4.2.2 Cardiovascular Events
Investigators will be required to fill out event specific data collection tools 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
!
Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.4.2.3 Death Events
In addition, all deaths will require a specific death data collection tool to be completed.  
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
Section: 7.4.3  QTc Events.
Action: Addition of new section relating to QTc events.
Rationale: To comply with GSK internal guidance.
Original Text:  Not applicable.
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Updated Text:  If QTc events occur the investigator should promptly contact the medical 
monitor to receive advice on measures to be taken.
Section: 7.4.4  Liver Events.
Action: Addition of new section relating to liver events. 
Rationale: To comply with GSK internal guidance.
Original Text:  Not applicable.
Updated Text: If serious liver events occur the investigator should follow the standard 
serious event reporting process described in the protocol.  For non-serious liver events 
that are clinically significant, the investigator will contact the medical monitor to receive 
advice on measures to be taken.
Section: 7.4.5  Partner Pregnancy (previously Section 7.4.3).
Action: Additional information at the start of the section, to clarify the need for condom 
useage in men with female partners of childbearing potential.
Rationale: Some countries recommend the use of condoms in local dutasteride labels.  
Addition of this text makes Section 7.4.4 consistent with these local labels.
Original Text:  Not applicable.
Updated Text:  As with other 5-alpha reductase inhibitors, dutasteride inhibits the 
conversion of testosterone to dihydrotestosterone and may, if administered to a woman 
carrying a male fetus, inhibit the development of the external genitalia of the fetus (see 
CIB). Small amounts of dutasteride have been recovered from the semen in subjects 
receiving dutasteride 0.5 mg per day. Based on studies in animals, it is unlikely that a 
male fetus will be adversely affected if his mother is exposed to the semen of a patient 
being treated with dutasteride (the risk of which is greatest during the first 16 weeks of 
pregnancy). Even though it is unlikely that a male fetus will be adversely affected if his 
mother is exposed to the semen of a partner being treated with dutasteride, some 
countries recommend the use of condoms in the local dutasteride labels. For these 
countries it is recommended that the patient avoids exposure of his partner to semen by 
use of a condom for 6 months after drug discontinuation.
Section:  7.4.5.1.  Time period for collecting partner pregnancy information (previously 
Section 7.4.3.1).
Action: Information on the time period for collecting partner pregnancy information
changed from 37 weeks to 6 months.
Rationale: To be consistent with other sections of the protocol.
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Original Text:  Pregnancy information should be collected on any female partner of a 
male study subject who is pregnant or becomes pregnant while the subject is participating 
in the study. All pregnancies in female partners of male subjects will be collected after 
the start of dosing until 37 weeks after the subject’s last dose of study drug.
Updated Text:  Pregnancy information should be collected on any female partner of a 
male study subject who is pregnant or becomes pregnant while the subject is participating 
in the study. All pregnancies in female partners of male subjects will be collected after 
the start of dosing until 6 months after the subject’s last dose of study drug.
Section: 7.4.5.2 Action to be taken if partner pregnancy occurs (previously 
Section 7.4.3.2).
Action: Additional clarification of the time period for collecting partner pregnancy 
information.
Rationale: Clarification of timescales for reporting pregnancy-related SAEs.
Original Text:  Any SAE occurring as a result of a post-study pregnancy and considered 
reasonably related to the investigational product by the investigator will be reported to 
GSK.  While the investigator is not obligated to actively seek this information in former 
study participants, he/she may learn of an SAE through spontaneous reporting.
Updated Text:  Any SAE occurring as a result of a post-study pregnancy (6-months after 
last dose) and considered reasonably related to the investigational product by the 
investigator will be reported to GSK.  While the investigator is not obligated to actively 
seek this information in former study participants, he/she may learn of an SAE through 
spontaneous reporting.
Section: 7.4.6 New Section: Suicidality Monitoring.
Action: Clarification of the assessment methods for suicidality monitoring. 
Rationale: To comply with GSK internal guidance on suicidality assessment.
Original Text:  Not applicable.
Updated Text:  Assessment of suicidality will be performed using the C-SSRS which 
will be administered at baseline, during the course of study, and at the end of the study. 
Training to investigators and sites on suicidality assessment will be integral to the study 
implementation. Any AEs which, in the investigator's opinion, are possibly suicidality 
related, will be recorded in the Possible Suicidality Related Adverse Event form 
(PSRAE); a supplemental CRF form designed to collect detailed information on the 
circumstances of reported AEs related to suicidality.
The ‘baseline/screening’ version of C-SSRS will be used at the pre-screening visit (V1a). 
The ‘since last visit’ version of C-SSRS will be used at Visits 4, 6 and 10 (6, 12 and 24 
months post randomization respectively).
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The subject will complete the self-administered C-SSRS questionnaires according to the 
schedule detailed in Table 1. The investigator will ask the study subject to complete the 
C-SSRS questionnaire during the clinical visit separately from the medical history and 
the standard adverse event questions.
Section: 7.5.1 BPH-related Health Status assessments/Quality of Life.
Action: Clarification of the assessment methods for BPH-related quality of life. 
Rationale: To provide further clarifications on the assessment tools used.
Original text:  7.5.1 BPH-related Health Status assessments Quality of Life.
The effect of study treatment on BPH-related health status will be assessed using three 
self-administered questionnaires.  The International Prostate Symptom Score (IPSS) is a 
pivotal component of the primary endpoint and the BPH Impact Index (BII) and Problem 
Assessment Scale of the Sexual Function Index (PAS SFI) are secondary humanistic 
endpoints. Each questionnaire is briefly described below and will measure impact of BPH 
symptoms, health-related quality of life and sexual function.
a.
International Prostate Symptom Score (IPSS) [Badia, 1997; Barry, 1992]
The IPSS is a 7 item instrument (essentially the same as the American Urological 
Association Symptom Index, AUA-SI) designed to quantify urinary symptoms but with 
an additional, independent eighth question BPH Health Status, (BHS) on quality of life 
(See Appendix 3). The IPSS will be administered at Pre-screening (Visit 1a), at Baseline 
(Visit 2) after completion of the placebo run-in period and at every 13 week clinic visit 
thereafter during the study treatment period. At Pre-screening (Visit 1a), subjects with 
IPSS <12 points (based on the first 7 questions) should be excluded from the study.
Updated text:  7.5.1 BPH-related Health Status assessments Quality of Life
The effect of study treatment on BPH-related quality of life will be assessed using three 
self-administered questionnaires: the BPH-related health status (question 8 of IPSS); the 
BPH Impact Index (BII) and the Problem Assessment Scale of the Sexual Function Index 
(PAS SFI). Each questionnaire is briefly described below and will measure impact of 
BPH symptoms, health-related quality of life and sexual function.
a.
International Prostate Symptom Score (IPSS) [Badia, 1997; Barry, 1992]
The IPSS is a 7 item instrument (essentially the same as the American Urological 
Association Symptom Index, AUA-SI) designed to quantify urinary symptoms but with 
an additional, independent eighth question on quality of life (See Appendix 5). The IPSS 
will be administered at Pre-screening (Visit 1a), at Baseline (Visit 2) after completion of 
the placebo run-in period and at every 13 week clinic visit thereafter during the study 
treatment period. At Pre-screening (Visit 1a), subjects with IPSS <12 points (based on the 
first 7 questions) should be excluded from the study.
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Section: 7.6  Pharmacogenetics.
Action: Addition information on date for pharmacogenetics sample.
Rationale: Additional clarification of Visit at which sample for pharmacogenetics is 
taken.
Original Text:  Patients who provide consent will have a blood sample taken for 
analysis.  The presence/absence of genetic variations in patient genes in DNA from blood 
will be analysed to determine their relationship with response (safety, tolerability, and 
efficacy) to treatment with either the combination of dutasteride and tamsulosin or
tamsulosin alone.
Updated Text:  Patients who provide consent will have a blood sample taken for analysis 
at Visit 2.  The presence/absence of genetic variations in patient genes in DNA from 
blood will be analysed to determine their relationship with response (safety, tolerability, 
and efficacy) to treatment with either the combination of dutasteride and tamsulosin or 
tamsulosin alone.
Section: 7.7  New Section: Population PK (Chinese Subjects Only) and New Appendix: 
Appendix 7:  Population PK (Chinese Subjects Only).
Action: Addition of new assessements, applicable to men of Chinese origin, living in 
China, who are required to provide blood samples for PPK analysis. 
Rationale: To comply with a request from the Regulatory Authority in China.
Original Text:  Not applicable.
Updated Text:  (Section 7.7)  A population pharmacokinetics (PPK) substudy will be 
performed only in subjects of Chinese origin, living in China, and participation in this 
substudy will be mandatory for these subjects. This substudy will estimate the PK 
parameters of dutasteride when dosed orally in combination (dutasteride 0.5 mg once 
daily and tamsulosin 0.2 mg once daily) in Chinese men with BPH. See Appendix 7 for 
more details on the PPK substudy.
Serum PK samples will be collected as indicated in Table 1. The actual date and time of 
each blood sample collection will be recorded. Details of blood sample collection 
(including volume to be collected), processing, storage, and shipping procedures are 
provided in the SPM.
Section: 9.3.3  PPK Population. 
Action: Addition of new section for PPK.
Rationale: To describe the population to be used for the PPK analysis. 
Original Text:  Not applicable.
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Updated Text:  The PPK population wil comprise all ITT subjects of Chinese origin, 
recuited in China, randomized to receive the combination (0.5mg dutasteride and 0.2mg 
tamsulosin) who have available PPK samples.  
Section: 9.3.4  Analysis Data Sets. 
Action: Section re-numbered to account for addition of Section 9.3.3 regarding PPK 
population and information added on analysis of suicidality.
Rationale: Consistency with other sections of the protocol. 
Original Text:  Endpoints measured at specific visits and analysed in terms of visit 
numbers include:  IPSS, Qmax, prostate volume, PSA, post void residual volume, and 
health outcomes.  Analysis of the data collected in terms of visit numbers will be 
performed using two different approaches to account for missing data.
Updated Text:  Endpoints measured at specific visits and analysed in terms of visit 
numbers include:  IPSS, Qmax, prostate volume, PSA, post void residual volume, 
suicidality and health outcomes.  Analysis of the data collected in terms of visit numbers 
will be performed using two different approaches to account for missing data.
Section: 9.3.7.2.1  New Section: Suicidality.
Action: Addition of new section for suicidality.
Rationale: To describe the how c-SSRS scores will be analyzed. 
Original Text:  Not applicable.
Updated Text:  Suicidality
To protect subjects in the study, scores from C-SSRS tests will be reviewed in real time 
by the investigator and appropriate advice given to participants.  
The C-SSRS scale has 10 outcomes, with binary (yes/no) responses.  At the end of study, 
results will be assessed as follows: 
!
Suicidal ideation will be defined as a positive response at any time during treatment 
to any one of the five suicidal ideation questions (Categories 1-5) on the C-SSRS.
!
Suicidal behavior will be defined as a positive response at any time  during treatment 
to any one of the five suicidal behaviour questions (Categories 6-10) on the C-SSRS.
!
Suicidal ideation or behavior will be defined as a positive response at any time 
during treatment to any one of the ten suicidal ideation and behaviour questions 
(Categories 1-10) on the C-SSRS.
The numbers of subjects with a positive response for suicidal ideation or suicidal 
behaviour will be reported at baseline and during study treatment at Visits 4, 6 and 10 (6, 
12 and 24 months post randomization respectively).  Scores on treatment will be 
compared with baseline scores and, for Visits 6 and 10, with scores at last visit to 
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determine the incidence of treatment-emergent suicidality.  An increase in C-SSRS total 
score to 4 or 5 will be considered as serious treatment-emergent suicidality.  Due to the 
low numbers of subjects expected to exhibit suicidal behaviours, formal statistical testing 
will not be performed.
Section: 9.3.10  New Section: Population Pharmacokinetic Analyses.
Action: Addition of new section for PPK.
Rationale: To describe the how PPK data will be analyzed. 
Original Text:  Not applicable.
Updated Text:  Population Pharmacokinetic Analyses.
Details on PPK analyses will be addressed in Appendix 7 and the RAP
Section: 10.1 Posting of information.
Action: Changed specific reference to clintrials.gov to a more general reference to 
publicly available clinical trial registries.
Rationale: To cover the requirement to post study information on publicly-avaiable 
databases other than clintrials.gov 
Original Text:  Study information from this protocol will be posted on clinicaltrials.gov 
before enrolment of subjects begins.
Updated Text:  Study information from this protocol will be posted on publicly available 
clinical trial registers before enrolment of subjects begins.
Amendments to Study Appendices
Section: Appendix 1:  PGx.
Action: Volume of whole blood sample drawn for PGx research reduced from ~10 mL to 
~6 mL.
Rationale: The reduced volume is sufficient for the PGx analyses.
Section: Appendix 2:  Study Assessment Schedule In Order of Performance.
Action: Addition of relevant information for PPK and suicidality assessements.
Rationale: Consistency with the main text of the protocol.
Section: New Appendix: Appendix 7:  Population PK (Chinese Subjects Only).
Action: Addition of new assessements, applicable to men of Chinese origin, living in 
China, who are required to provide blood samples for PPK analysis.
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Rationale: To comply with a request from the Regulatory Authority in China.
Section: New Appendix :  Appendix 8 Protocol Changes (previously Appendix 7).
Action: Appendix for Protocol Changes re-numbered. 
Rationale: To accommodate new Appendix 7 for PPK monitoring.
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Protocol Amendment 3 Changes are listed below:
Rationale
To clarify that subjects who have received PDE-5 inhibitors in the past are eligible for 
enrolment into the study. Subjects must stop taking PDE-5 inhibitors as described in the 
prohibited medication Section 6.2.
Section 4.1.3. Exclusion Criteria
10.  Current or Previous Use of the following medications:
Text deleted
f.
Phosphodiesterase-5 (PDE-5) inhibitors for Erectile Dysfunction.
Appendix 7  Population Pharmacokinetic Substudy (Chinese Subjects Only)
Rationale
Amended to ensure consistency between Appendix 7 and Table 1 with respect to 
population PK sample collection.
Original text
Serum PK samples will be obtained on Visits 3, 5 and 5 (Table 1).
Revised text
Serum PK samples will be obtained on Visits 3, 4 and 5 (Table 1).
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Revised text:
f.
Use of selective beta 3-adrenoceptor agonist (mirabegron) within 2 weeks prior to all 
uroflowmetry assessments.
Section 6.2 Prohibited Medications and Non-Drug Therapies
Action: Insertion of restriction of ginseng for the treatment of BPH or sexual 
dysfunction.
Rationale : Ginseng is widely taken in the countries that are participating in the trial. 
Whist the use of ginseng is not advised, the use specifically for the treatment of BPH or 
sexual dysfunction is prohibited. 
Revised Text:
Addition of:
a.
Not permitted at any time:
!
Ginseng utilised for the treatment of BPH or sexual dysfunction
Section 6.2 Prohibited Medications and Non-Drug Therapies
Action: Correction of spelling of darifenacin
Rationale : To correct the spelling of darifenacin
Original text:
!
Anticholinergics (e.g. oxybutynin, propantheline, danifenacin, solifenacin, 
tolterodine)
Revised Text:
!
Anticholinergics (e.g. oxybutynin, propantheline, darifenacin, solifenacin, 
tolterodine)
Section 6.2 Prohibited Medications and Non-Drug Therapies
Action: Insertion of 14 day restriction of ß3 adrenergic receptor agonist for over-active 
bladder syndrome (e.g. Mirabegron) prior to each IPSS or peak flow assessment.
Rationale : As Mirabegron is used to treat overactive bladder and therefore improves the 
storage capacity of the bladder, a restriction on its use has been placed before each IPSS 
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or peak flow assessment. Fourteen days washout has been selected as Mirabegron has a 
half life of approximately 50 hours.
Revised Text:
b.
Not permitted within two weeks prior to each IPSS or peak flow assessment:
!
Selective beta 3-adrenoceptor agonist (mirabegron)
Section 7.1 Critical Baseline Assessments
Action: Insertion of C-SSRS in critical baseline assessment.
Rationale: The assessment is present on the Time and Events schedule but missing from 
the critical baseline assessments.
Original Text:
A 12-lead ECG, vital signs; clinical laboratory including hematology, clinical chemistry; 
total PSA; prostate volume*; post void residual volume (PVR); peak urinary flow 
(Qmax) and health outcomes questionnaires: IPSS, BHS, BII and PAS SFI.
Revised Text:
A 12-lead ECG, vital signs; clinical laboratory including hematology, clinical chemistry; 
total PSA; prostate volume*; post void residual volume (PVR); peak urinary flow 
(Qmax) and health outcomes questionnaires: IPSS, BHS, BII and PAS SFI and C-SSRS 
questionnaire.
Section 7.2.2.1 International Prostate Symptom Score (IPSS)
Action: To insert that if s subjects has taken the following medications prior to each 
IPSS, that the visit should be rescheduled.  a) alpha adrenergic agonist, cholinergic or 
anticholinergic agents including anti-histamines or decongestants within 48 hours or b) 
ß3 adrenergic receptor agonist for over-active bladder syndrome  within 14days 
Rationale: The above medications have an affect on urinary flow. The restriction of 48 
hours and 14 days respectively allows for a sufficient washout period before 
measurement of IPSS. 
Revised Text:
Also, subjects must be instructed to abstain from using any alpha adrenergic agonist, 
cholinergic or anticholinergic agents including anti-histamines or decongestants within 
48 hours prior to conducting each IPSS. In addition subjects must also abstain from 
taking selective beta 3-adrenoceptor agonist (mirabegron) for over-active bladder 
syndrome  two weeks prior to each IPSS. If the subject did not adhere to these guidelines, 
study procedures should not be performed and the visit should be rescheduled.
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Section: 7.2.2.2 Prostate Volume
Action: Insertion of text that use of a prostate volume calculator is acceptable.
Rationale: In assessing prostate volume, the standard clinical practice is that the prostate 
volume calculator inbuilt into the machine is utilised. Therefore for ease of use at the site, 
the prostate volume calculator will be allowed.
Original text:
Prostate volume calculated by pre-programmed equipment will not be accepted.
Revised text:
Prostate volume calculated by pre-programmed equipment will be accepted if the 
anteroposterior, cephalocaudal and transverse are also outputted and recorded in the 
eCRF. If the prostate volume calculated by pre-programmed equipment is utilised for a 
subject, then the same equipment and hence calculator, must be used for the duration of 
the subject’s participation in the study.
Section: 7.2.2.3 Urinary Flow Measurement
Action: To amend the text to allow less frequent calibration of the uroflow device.
Rationale: As the visits are every three months during the treatment phase, there may be 
long periods of inactivity for the uroflowmeter. Weekly calibration is therefore 
considered to frequent and site resource heavy when there is not constant use.
Original Text:
The correct functioning of the uroflow meter will be checked once a week (especially if 
moved) and appropriate actions taken to ensure good maintenance of the machine.
Revised text:
During constant use, the correct functioning of the uroflow meter should be checked 
once a week (especially if moved) and appropriate actions taken to ensure good 
maintenance of the machine.
Section: 7.2.2.3 Urinary Flow Measurement
Action: To add that subjects must abstain from selective beta 3-adrenoceptor agonist 
(mirabegron) for over-active bladder syndrome for two weeks prior to this test.
Rationale: A restriction for mirabegron has been added to the protocol.
Original text: 
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Also, subjects must be instructed to abstain from using any alpha adrenergic agonist, 
cholinergic or anticholinergic agents including anti-histamines or decongestants within 
48 hours prior to conducting this test. If the subject did not adhere to these guidelines, 
study procedures should not be performed and the visits should be rescheduled.
Revised text:
Also, subjects must be instructed to abstain from using any alpha adrenergic agonist, 
cholinergic or anticholinergic agents including anti-histamines or decongestants within 
48 hours prior to conducting this test. . In addition subjects must also abstain from taking 
selective beta 3-adrenoceptor agonist (mirabegron) for over-active bladder syndrome for 
two weeks prior to this test. If the subject did not adhere to these guidelines, study 
procedures should not be performed and the visits should be rescheduled.
Section 7.2.2.5 End of Study Treatment Assessments
Action: Insertion of C-SSRS in End of Treatment Study Assessments.
Rationale: The assessment is present on the time and events schedule but missing from 
the critical baseline assessments.
Revised text:.
!
Administration of C-SSRS questionnaire.
Section 7.3.2 Medical History, Concomitant Medications, ECG, Physical 
Examination
Action: Revision of text with regards generation of 30 second rhythm strip.
Rationale: To allow flexibility in duration of rhythm strip obtained.
Original Text: The subject should rest supine for 5 minutes before the 12-lead ECG is 
recorded. A 30-second rhythm strip will be obtained.
Revised text:. The subject should rest supine for 5 minutes before the 12-lead ECG is 
recorded. Additionally a rhythm strip will be obtained to assess for presence of 
arrhythmias.
Section: 7.4.2.4 Sentinel Events
Action: Insertion of standard text on GSK adverse events
Rationale: The current protocol is missing the standard GSK wording on sentinel events
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Revised text: 
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:
!
Acquired Long QT Syndrome
!
Agranulocytosis/Severe Neutropenia 
!
Anaphylaxis & Anaphylactoid Reactions 
!
Hepatotoxicity
!
Acute Renal Failure
!
Seizure
!
Stevens Johnson syndrome/Toxic epidermal necrosis
Section: 7.4.6 Suicidality Monitoring
Action: To correct that the C-SSRS will be completed by the subject.
Rationale: The C-SSRS needs to be administered by a trained rater rather than the 
subject.
Original text:
The subject will complete the self-administered C-SSRS questionnaires according to the 
schedule detailed in Table 1. The investigator will ask the study subject to complete the 
C-SSRS questionnaire during the clinical visit separately from the medical history and 
the standard adverse event questions.
Revised text:
A trained rater will administer the C-SSRS questionnaires according to the schedule 
detailed in Table 1. The C-SSRS questionnaire will be completed during the clinical visit 
separately from the medical history and the standard adverse event questions.
Section: 7.5.3.1 Collection and Storage 
Action: To correct that the original of the C-SSRS will be stored with the subject’s 
source notes rather than a copy.
Rationale: To allow the original to the source record in the subject’s notes.
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Original text:
The investigator (or qualified designated member of their staff) will use the subject 
completed questionnaires to enter the recorded data into the appropriate section of the 
eCRF.  A copy of the completed questionnaires will stay with the subject’s source notes. 
Revised text:
The investigator (or qualified designated member of their staff) will use the subject 
completed questionnaires to enter the recorded data into the appropriate section of the 
eCRF.  A copy of the completed questionnaires will stay with the subject’s source notes. 
Section: Appendix 2 
Action: Insertion of pre-screening Visit 1a and screening Visit 1b.
Rationale:  To ensure consistency between main text of protocol and time and events 
schedule.
Original text:
Visit 1 (Screening)
Revised text:
Visit 1 (Pre-Screening Visit 1a and Screening Visit 1b)
Section: Appendix 2 Visit 1b (Placebo-run-in)
Action: To insert that SAEs will be assessed at Visit 1b.
Rationale: This change is to ensure consistency with the Time and Events schedule i.e 
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) 
and the start of placebo run-in medication need to be recorded
Revised Text:
Addition of:
5. Assess SAEs
Section: Appendix 2 Visit1 1, Visit 4, Visit 6 and Visit 10
Action: To correct that the C-SSRS will not be a patient self administered questionnaire
Rationale:  The protocol states that the C-SSRS questionnaires will be patient self 
administered questionnaire. The C-SSRS can only be administered by a trained rater.
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Original text:
Administer patient self-assessment questionnaires: International Prostate Symptom Score 
[IPSS], BHS Q8 BPH Impact Index [BII] and suicidality [C-SSRS]
Revised:
Administer patient self-assessment questionnaires: International Prostate Symptom Score 
[IPSS], BHS Q8 BPH Impact Index [BII]
Administer suicidality questionnaire [C-SSRS]
Section: Appendix 2 Visit 4 and Visit 10
Action: Removal of transition zone volume
Rationale:  Transition zone volume will not be measured within this protocol as not 
required.
Original text: Measure prostate volume (and at selected sites, transition zone volume) by 
transrectal ultrasound (TRUS)
Revised text:
Measure prostate volume by transrectal ultrasound (TRUS)
Section: Time and Events Schedule
Action: Insertion of text to show that if there is a positive Hepatitis C sample, rather than 
a immunoblot RIBA immunoblot assay, a hepatitis C RNA test will be reflexively 
performed to confirm the result.
Rationale: The change is reflective of the procedures at the central lab and consistent 
with the laboratory manual.
Original text:
g. Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, 
a hepatitis C RIBA immunoblot assay should be reflexively performed on the same 
sample to confirm the result.
Revised text:
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, 
a hepatitis C RNA test should be reflexively performed to confirm the result.
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
ARI114265 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for ARI114265: A randomized, 
double-blind, parallel group study to compare the efficacy 
and safety of combination treatment with dutasteride (0.5mg) 
and tamsulosin (0.2mg) with tamsulosin (0.2mg) 
monotherapy, administered once daily for 2 years, on the 
improvement of symptoms and health outcomes in men with 
moderate to severe benign prostatic hyperplasia 
Compound Number  
: GI198745+GI138525 
Effective Date  
: 09-DEC-2016 
 
Description : 
The purpose of this RAP is to describe the planned summaries and statistical analyses to 
be included in the Clinical Study Report (CSR) for Protocol ARI114265. This document 
contains the RAP Amendment 01. 
 
Author’s Name and Functional Area:  
Original 
 
Associate Director, Biostatistics, PAREXEL International 
Employee of PAREXEL on behalf of GSK 
15-DEC-2015 
Amendment 
01 
 
Associate Director, Biostatistics, PAREXEL International 
Employee of PAREXEL on behalf of GSK 
06-DEC-2016 
 
Approved by:  
Original 
 (e-mail approval dated 15-Dec-2015) 
Director Statistics & Programming, GSK 
15-DEC-2015 
Amendment 
01 
 (email approval dated 09-Dec-2016) 
Director Statistics & Programming, GSK 
09-DEC-2016 
 
 
 
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
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)...............................................................8
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analysis .............................................................................................11
3.3.
Targeted Follow-Up Questionnaire (TFUQ) Report.....................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
4.1.1.
Inclusion / Exclusion Criteria Deviations ......................................12
4.1.2.
Important Protocol Deviations......................................................13
4.1.3.
Deviations which Require Exclusion from the Per-Protocol 
Population....................................................................................13
4.1.4.
Deviations which Require Exclusion from the Per-Protocol 
Population but not Tracked or Identified as Important by 
Study Team .................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Analyses ...................................................................16
6.2.
Subject Accountability.................................................................................17
6.3.
Subject Disposition .....................................................................................18
6.4.
Demographic and Baseline Characteristics.................................................18
6.5.
Medical Conditions and Concomitant Medications......................................19
6.6.
Investigational Product Discontinuation, Exposure, and Compliance ..........20
7.
PRIMARY STATISTICAL ANALYSES....................................................................20
7.1.
Primary Efficacy Analyses ..........................................................................20
7.1.1.
Overview of Planned Primary Efficacy Analyses..........................20
7.1.2.
Planned Primary Efficacy Statistical Analyses .............................21
7.1.3.
Supporting and Sensitivity Analyses of Primary Endpoint ............22
8.
SECONDARY STATISTICAL ANALYSES .............................................................24
8.1.
Secondary Efficacy Analyses......................................................................24
8.1.1.
Overview of Planned Secondary Efficacy Analyses .....................24
8.1.2.
IPSS Improvement Levels ...........................................................25
8.1.3.
Prostate Volume ..........................................................................25
8.1.4.
Maximum Urine Flow (Qmax) ......................................................26
8.1.5.
AUR or BPH-Related Surgical Intervention..................................27
8.1.6.
Other Efficacy Measures..............................................................29
8.2.
Safety Analyses..........................................................................................30
 
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8.2.1.
Overview of Adverse Event Tabular Summaries..........................30
8.2.2.
Adverse Events............................................................................32
8.2.3.
Deaths and Serious Adverse Events............................................34
8.2.4.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal From the Study 
and Other Significant Adverse Events..........................................35
8.2.4.1.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from 
the Study....................................................................35
8.2.4.2.
Adverse Events of Special Interest.............................35
8.2.4.3.
Sexual and Breast Tier 1 Adverse Events of 
Special Interest...........................................................35
8.2.4.4.
Prostate Cancer Tier 1 Adverse Events of 
Special Interest...........................................................37
8.2.4.5.
Cardiovascular Tier 1 Adverse Events of 
Special Interest...........................................................37
8.2.4.6.
Infrequent Tier 1 Adverse Events of Special 
Interest .......................................................................37
8.2.5.
Pregnancies.................................................................................38
8.2.6.
Clinical Laboratory Assessments .................................................38
8.2.7.
Serum PSA..................................................................................40
8.2.8.
Post Void Residual Volume .........................................................40
8.2.9.
Gynecomastia Evaluations ..........................................................40
8.2.10.
Digital Rectal Examinations .........................................................41
8.2.11.
Vital Signs....................................................................................41
8.2.12.
Prostate Cancer Biopsies ............................................................42
8.2.13.
Suicidality Assessment ................................................................42
8.3.
Health Outcomes Analyses.........................................................................42
8.3.1.
BPH Impact Index........................................................................42
8.3.2.
BPH-Related Health Status .........................................................43
8.3.3.
Problem Assessment Scale of the Sexual Function 
Inventory (PAS SFI).....................................................................44
9.
COUNTRY-SPECIFIC SUMMARIES AND ANALYSES..........................................45
10. REFERENCES.......................................................................................................46
11. APPENDICES........................................................................................................47
11.1.
Appendix 1: Exclusions from the Per-Protocol Population...........................48
11.2.
Appendix 2: Time & Events.........................................................................52
11.2.1.
Protocol Defined Time & Events ..................................................52
11.3.
Appendix 3: Assessment Windows .............................................................55
11.4.
Appendix 4: Multicenter Studies..................................................................56
11.4.1.
Methods for Handling Centers .....................................................56
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................57
11.5.1.
Study Treatment & Sub-group Display Descriptors......................57
11.5.2.
Reporting Process & Standards...................................................58
11.6.
Appendix 6: Derived and Transformed Data ...............................................60
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............63
11.7.1.
Premature Withdrawals................................................................63
11.7.2.
Handling of Missing Data.............................................................63
11.7.2.1.
Handling of Missing or Partial Dates...........................63
 
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11.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................63
11.7.3.
Questionnaire Total Score Imputation..........................................64
11.8.
Appendix 8: Adverse Event Time Periods and Special Adverse 
Event Definitions.........................................................................................65
11.9.
Appendix 9: Threshold Factors for Clinical Laboratory Tests and 
Vital Signs...................................................................................................78
11.10. Appendix 10: Examination of Covariates and Subgroups............................79
11.11. Appendix 11: Multiple Comparisons and Multiplicity....................................80
11.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................81
11.13. Appendix 13: Mixed-Model Repeated-Measures Analysis ..........................82
11.14. Appendix 14 – Abbreviations & Trade Marks ..............................................83
11.14.1. Abbreviations...............................................................................83
11.14.2. Trademarks .................................................................................84
11.15. Appendix 15: List of Data Displays..............................................................85
11.15.1. Data Display Numbering..............................................................85
11.15.2. Study Population Tables..............................................................86
11.15.3. Efficacy Tables ............................................................................88
11.15.4. Efficacy Figures ...........................................................................97
11.15.5. Safety Tables...............................................................................97
11.15.6. Safety Figures ...........................................................................102
11.15.7. Health Outcome Tables .............................................................103
11.15.8. Health Outcomes Figures ..........................................................106
11.15.9. ICH and Non-ICH Listings..........................................................106
11.16. Appendix 16: Mock Shells for Data Displays.............................................113
11.17. Appendix 17: Amendment 01 Revisions ...................................................114
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose
The purpose of this Reporting and Analysis Plan (RAP) is to describe the planned
summaries and statistical analyses to be included in the Clinical Study Report (CSR) 
for Protocol ARI114265.
Protocol
This RAP is based on the protocol amendment 04 (Republished) (Dated: 
08/JUL/2014) of study ARI114265 [GSK Document No. : RM2010/00134/05]. This 
document contains the RAP amendment 01.
The aim of the study is to investigate whether combination therapy with dutasteride 
and tamsulosin is more effective than tamsulosin monotherapy for the improvement 
of symptoms and health outcomes in a population at increased risk of BPH clinical 
progression including older men (≥50yrs), with moderate-severe symptoms of BPH, 
enlarged prostates (≥30cc) and PSA≥1.5ng/mL.
Primary 
Objective
The primary objective is to assess the efficacy of combination treatment with 
dutasteride 0.5mg and tamsulosin 0.2mg once daily in providing superior 
symptomatic improvement in subjects with BPH compared with once daily 
tamsulosin 0.2mg monotherapy after 2 years of treatment.
Primary 
Endpoint
The primary endpoint is change from baseline IPSS at Year 2 (Month 24 Visit); 
earlier timepoints (Month 21 -> Month 3) are considered secondary endpoints.
Study 
Design
This is a multicenter, randomized, double-blind, parallel group study. Eligible 
subjects will receive placebo tamsulosin and placebo dutasteride for four weeks in a 
single-blind, placebo, run-in period. Each subject will then be randomized to one of 
the following two treatment groups (1:1 ratio) for the double-blind phase (104 weeks) 
of the study:
--Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily or
--Dutasteride placebo once daily + tamsulosin 0.2mg once daily
Subjects will self-administer the study medication once daily for up to 104 weeks 
(2 years). Subjects will return to the clinic at 13 week intervals post-randomization 
during the 2 year treatment period (i.e. at 13, 26, 39, 52, 65, 78, 91, and 104 weeks).
Planned
Analyses
Within this RAP, the following additional references may be made for brevity:
--Full Treatment Description--
--Short Treatment Descriptions--
Dutasteride 0.5mg once daily +
tamsulosin 0.2mg once daily or
-Combination
-Dut 0.5mg + Tam 0.2mg
-Dut + Tam
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
-Tamsulosin Monotherapy
-Tam 0.2mg
-Placebo + Tam 0.2mg
-Tam
The study population, efficacy, safety, and health outcomes summaries and 
analyses will be based on the Intent-to-Treat (ITT) population; few exceptions will be 
 
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Overview
Key Elements of the RAP
noted within the RAP. Summaries and analyses are defined within this RAP. The 
following are high level summary and analyses types.

Study population summaries will be presented overall and by treatment group 
and will include accountability, disposition, demographic characteristics, 
baseline characteristics, protocol deviations, and concomitant medications.

The primary efficacy analyses and treatment group comparisons will be in terms 
of IPSS change from baseline.

Secondary efficacy analyses and treatment group comparisons will be in terms 
of prostate volume, Qmax, IPSS improvement levels (≥2 points, ≥3 points, 
≥25%), Qmax improvement levels (≥3 ml/sec, ≥30%), and time to AUR or 
BPH-related surgery.

Safety summaries will be presented by treatment group and will be in terms of 
study drug exposure, adverse events, clinical laboratory evaluations, serum 
PSA, post void residual volume, qualitative breast examination, digital rectal
examination, vital signs, and suicidality assessment using C-SSRS.

Health Outcomes analyses and treatment group comparisons will be in terms of 
BPH-Related Health Status (IPSS Question 8), BPH Impact Index, and Problem 
Assessment Scale of the Sexual Function Inventory (PAS SFI).
Analysis 
Populations

The ITT Population is comprised of all randomized subjects regardless of 
whether or not treatment was administered.

The Per-Protocol (PP) Population is comprised of all ITT subjects who comply 
closely with the protocol. Specifically this includes ITT subjects who do not have 
a deviation which requires exclusion from the PP population. The PP population 
will not be analyzed if this population comprises more than 80% of the ITT 
population.
Hypothesis
The primary endpoint is change from baseline IPSS at Year 2. Let the following 
represent the mean change from baseline IPSS for each treatment group:
Hdut+tam: Combination (dutasteride 0.5mg and tamsulosin 0.2mg) treatment group
Htam:  
Tamsulosin (tamsulosin 0.2mg treatment group)
Then the primary null and alternative hypotheses to be tested at Year 2 are as 
follows:
Null Hypothesis:
Hdut+tam = Htam
Alternative Hypothesis:
Hdut+tam ≠ Htam
Two-sided tests of the null hypothesis will be conducted at the 0.05 level of 
significance to show superiority of the combination treatment group compared to 
tamsulosin 0.2mg at 2 years of treatment.
Primary 
Analyses
The primary efficacy parameter after two years of study treatment is change from 
baseline IPSS. Change in IPSS from baseline will be compared at each scheduled 
post-baseline visit for combination treatment versus tamsulosin 0.2mg using a 
general linear model with effects for treatment, cluster, and baseline IPSS. 
Secondary 
Secondary efficacy analyses will be in terms of prostate volume, Qmax, IPSS 
 
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Overview
Key Elements of the RAP
Analyses
improvement levels, Qmax improvement levels, and time to AUR or BPH-related 
surgery using appropriate statistical methodology defined within this RAP.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the ARI114265 protocol amendment 04 (Republished) (Dated 08/JUL/2014).
This document contains the RAP amendment 01 which is based on the protocol 
amendment 04 noted above. RAP amendment 01 revisions primarily include 
programming and reporting clarifications, limited expansion of efficacy subgroup 
summaries, and limited expansion of supporting analyses for secondary endpoints.  This 
amendment 01 includes no major changes to the planned analyses. The summary of RAP 
amendment 01 changes is contained in Appendix 17.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the efficacy of 
combination treatment with 
dutasteride 0.5mg and tamsulosin 
0.2mg once daily in providing 
superior symptomatic improvement 
in subjects with BPH compared 
with once daily tamsulosin 0.2mg 
monotherapy after 2 years of 
treatment

Change in IPSS from baseline at Year 2.
Secondary Objectives
Secondary Endpoints

To assess efficacy and safety of 
combination treatment with 
dutasteride 0.5mg and tamsulosin 
0.2mg including the clinical 
outcomes of AUR or BPH-related 
prostatic surgery compared with 
tamsulosin 0.2mg monotherapy 
after 2 years of treatment.
Efficacy

Percent change in prostate volume from baseline

Proportion of subjects with IPSS improvement of ≥2 
points and ≥3 points from baseline and, separately, 
≥25% improvement from baseline

Change in Qmax from baseline

Proportion of subjects with Qmax improvement of 
≥3mL/sec and, separately, ≥30% improvement from 
baseline

Time to event/ proportion of subjects with AUR or 
BPH related prostatic surgery

Time to event/proportion of subjects with AUR

Time to event/proportion of subjects undergoing 
BPH related prostatic surgery
Health Outcome Measures

Change in BPH-Related Health Status (Q8 of 
IPSS) from Baseline

Change in BPH Impact Index (BII) from Baseline
 
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Objectives
Endpoints

Change in Problem Assessment Scale of the 
Sexual Function Inventory (PAS-SFI), from 
Baseline

Resource Use related to AUR and BPH-related 
surgical events. 
Safety

Adverse Events

Change in total serum PSA from baseline

Vital signs

Post-void residual volume

Clinical laboratory measurements (including 
haematology, chemistry)

Physical examination: digital rectal examination 
(DRE) and qualitative  breast examination

Suicidality (C-SSRS)
Exploratory Objectives
Exploratory Endpoints

Pharmacogenetics (PGx) 
Research
Note: PGx planned summaries and 
analyses will be documented 
outside this RAP.

Relationships between genetic variants in DNA from 
patient blood and any unexplained or unexpected 
response to treatment (as monitored by safety, 
tolerability, and efficacy parameters) that may have 
an underlying genetic mechanism.

Population Pharmacokinetics 
(PPK) Research
Note: PPK planned summaries and 
analyses will be documented 
outside this RAP

Characterization of PPK of dutasteride when given in 
combination with tamsulosin to Chinese men with 
BPH.
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multicenter within 4 countries: China, Japan, Korea, and Taiwan.

Randomized, double-blind, parallel group study to assess the efficacy of 
combination treatment with dutasteride 0.5mg and tamsulosin 0.2mg once 
daily in providing superior symptomatic improvement in subjects with BPH 
compared with once daily tamsulosin 0.2mg monotherapy after 2 years of 
treatment.
Dosing / 
Treatment 
Assignment

Placebo tamsulosin and placebo dutasteride for four weeks in a single-blind, 
placebo, run-in period.

Thereafter randomized to one of the following two treatment groups (1:1 ratio) 
for the double-blind phase (104 weeks) of the study:
--Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily or
--Dutasteride placebo once daily + tamsulosin 0.2mg once daily.
Interim 
Analysis
No interim analyses are planned for this study.
2.4.
Statistical Hypotheses
The primary endpoint is change from baseline IPSS. Let the following represent the mean 
change from baseline IPSS for each treatment group:
Hdut+tam: Combination (dutasteride 0.5mg and tamsulosin 0.2mg) treatment group
Htam:  
Tamsulosin 0.2mg treatment group
Then the primary null and alternative hypotheses to be tested at Year 2 are as follows:
Description
Null Hypothesis
Alternative Hypothesis
Combination versus tamsulosin 0.2mg
Hdut+tam = Htam
Hdut+tam ≠ Htam
Two-sided tests of the null hypothesis will be conducted at the 0.05 level of significance 
to show superiority of the combination treatment group compared to tamsulosin 0.2mg at 
2 years of treatment.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses are planned for this study.
 
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3.2.
Final Analysis
The planned primary analyses will be performed after completion of the following 
sequential steps:
1.
All subjects have completed the 104-week study treatment period study as defined in 
the protocol.
2.
All required database cleaning activities have been completed and primary database 
release and primary database freeze have been declared by Data Management. 
Reference ‘primary database’ description below.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
The primary database freeze, using standard Data Management practices, will occur after 
the last subject completes the 104-week randomized treatment phase. Statistical analysis 
and reporting in support of international regulatory submissions will be in terms of this 
primary database freeze and will be referred to as the ‘Final Analysis’ or primary 
‘Statistical Analysis Complete’ (SAC).  Reference Section 9, Country-Specific 
Summaries and Analyses, for a description of a secondary country-based statistical 
analysis complete package.
3.3.
Targeted Follow-Up Questionnaire (TFUQ) Report
As documented in protocol and elsewhere in this RAP, this study includes a Targeted 
Follow-Up Questionnaire (TFUQ) for subjects with sexual function related adverse 
events leading to study withdrawal. Using the TFUQ, subjects will be followed for up to 
6 months after the last dose of study drug. It is anticipated that the final TFUQ data 
component will be included in the above referenced primary database freeze.
However, if there are ongoing TFUQs at the time of primary database freeze, and 
anticipated follow-up and receipt of these data would create a delay in analyzing and 
reporting the study results then the primary freeze may occur with exclusion of 
outstanding TFUQ data. Thereafter, a secondary database freeze will occur in terms of 
newly finalized and recorded TFUQ data (since primary freeze). The decision to perform 
a secondary freeze will be made soon after last subject last visit milestone by Project 
Team with input from Data Management, International Regulatory Affairs, Clinical 
Statistics, Clinical Development, and Clinical Operations.  This secondary freeze will be 
in terms of datasets containing the actual TFUQ and as well as any TFUQ-related 
datasets.  Only TFUQ-related tabular summaries and listings (related to newly frozen 
datasets) will be updated with the secondary freeze.  TFUQ-related summaries and 
listings for this secondary freeze will be referred to as ‘TFUQ Report’.
 
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4.
ANALYSIS POPULATIONS
Analysis populations are defined in the following table.
Population
Definition / Criteria
Analyses Evaluated
Intent-To-Treat
(ITT)

Comprised of all randomized subjects
regardless of whether or not treatment was 
administered

This population will be based on the 
treatment to which the subject was 
randomized.

Any subject who receives a treatment 
randomization number will be considered to 
have been randomized.

All.
Per-Protocol (PP)

Comprised of all ITT subjects who comply 
closely with the protocol. Specifically this 
includes ITT subjects who do not have a 
deviation which requires exclusion from the 
PP population.

Protocol deviations that would exclude 
subjects from the PP population are defined 
in Section 4.1.3 (Deviations which Require 
Exclusion from the Per-Protocol Population) 
and Appendix 1 (Exclusions from the Per-
Protocol Population).

The PP population will not be analyzed if this 
population comprises more than 80% of the 
ITT population. 

Primary efficacy 
endpoint only if this 
population 
comprises 80% or 
less of the ITT 
Population. Details 
on specific 
summaries and 
analyses are 
outlined in Section 7, 
Primary Statistical 
Analyses.
NOTES : 

‘All Enrolled Subjects’ is referenced in at least one tabular summary. Enrolled subjects include those who entered 
placebo run-in phase and/or who were randomized. 
4.1.
Protocol Deviations
4.1.1.
Inclusion / Exclusion Criteria Deviations
All inclusion / exclusion criteria deviations which are recorded on the inclusion / 
exclusion screens of the eCRF will be summarized and listed.  The tabular summary will 
be in terms of number and percent of Intent-to-Treat population subjects violating any 
criterion and violating each criterion. Summaries will be output by each of the two 
randomized treatment groups and overall.
 
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4.1.2.
Important Protocol Deviations
All protocol deviations identified during the course of the study will be tracked and 
reviewed by the study team in accordance with SOP-130050 and the ARI114265 Protocol 
Deviations Management Plan (PDMP). As outlined in the PDMP and Data Management 
procedures, the ARI114265 Study Team will identify protocol deviations which are 
considered to be ‘Important’ and flag on the team’s protocol deviations spreadsheet.  This 
spreadsheet will be subsequently loaded to the Data Management file system and 
formatted for HARP Analysis & Reporting.
Important Deviations will be summarized and listed. The tabular summary will be in 
terms of number and percent of subjects with any Important Deviation and with each 
Important Deviation. Summaries will be output by the eCRF category and subcategories 
for each of the two randomized treatment groups and overall. The eCRF categories and 
subcategories are standardized for this study; examples are provided in the tabular 
summary shells.
4.1.3.
Deviations which Require Exclusion from the Per-Protocol 
Population
In accordance with SOP-130050 and the ARI114265 PDMP, deviations which require 
exclusion from the Per-Protocol population should be identified; the 19 deviations are 
listed in the below table. The historical term used to describe these deviations in 
ARI114265 protocol is ‘major’. In this RAP and for future reporting the phrase 
‘deviations which require exclusion from the Per-Protocol population’ will replace 
‘major’.
Numb
er
Deviations which Require Exclusion from the Per-Protocol Population
01
Missed placebo run-in phase
02
Incorrect study drug (wrong treatment) consumed
03
Randomized but did not consume double-blind study drug
04
Cumulative study drug compliance <75%
05
Cumulative study drug compliance >125%
Violation of Inclusion Criteria (protocol #)
06
Confirmed BPH clinical diagnosis (Inclusion 2)
07
IPSS ≥12 at Screening (Inclusion 3)
08
Prostate volume ≥30cc by TRUS at Screening (Inclusion 4)
09
PSA ≥1.5ng/ml and ≤10ng/mL at Screening (Inclusion 5)
10
Qmax >5 mL/sec and ≤15mL/sec with Voided Volume ≥125mL/sec at Screening (Inclusion 
6)
Violation of Exclusion Criteria (protocol #) 
11
Any conditions other than BPH, which may in the judgement of the investigator, result in 
urinary symptoms or changes in flow rate (Exclusion 6)
12
Use of 5ARI within 6 months of Screening or historical TRUS and throughout the study 
(Exclusion 10a)
13
Use of anabolic steroids within 6 months of Screening and throughout the study (Exclusion 
 
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Numb
er
Deviations which Require Exclusion from the Per-Protocol Population
10b)
14
Use of phytotherapy for BPH within 2 weeks of Screening and throughout the study 
(Exclusion 10c)
15
Use of alpha-adrenoreceptor blockers within 2 weeks of Screening and throughout the study, 
except study meds (Exclusion 10d)
16
Use of alpha-adrenoreceptor agonists or anticholinegics or cholinergics within 48 hours prior 
to all uroflowmetry and IPSS assessments (Exclusion 10e)
17
Use of selective beta 3-adrenoreceptor agonist (mirabegron) within 2 weeks prior to all 
uroflowmetry and IPSS assessments (Exclusion 10f)
18
Prohibited medications and non-drug therapies of Protocol Section 6.2 and not otherwise 
classified above.
Other
19
Any condition which should exclude a subject from the Per-Protocol population which is not 
included above; identified by Study Team.
Please refer to Appendix 1: Exclusions from the Per-Protocol Population for details on 
sources and processing these deviations.
Deviations which require exclusion from the Per-Protocol population will be summarized 
and listed. The Per-Protocol deviations tabular summary will be in terms of number and
percent of subjects with any deviation and for each deviation. Summaries will be output 
by each of the two randomized treatment groups and overall.
4.1.4.
Deviations which Require Exclusion from the Per-Protocol 
Population but not Tracked or Identified as Important by Study 
Team
For brevity, in this section ‘deviations which require exclusion from the per-protocol 
population’, defined in Section 4.1.3, will be referred to as ‘Per-Protocol Deviations’. In 
accordance with SOP-130050 and as clarified in GUI-315049, Per-Protocol Deviations 
are a subset of Important Protocol Deviations. As described in Appendix 1, some Per-
Protocol Deviations may be identified programmatically and/or some may be identified 
post database freeze and unblinding. Therefore, it is not feasible to manually enter all 
Per-Protocol Deviations to the Study Team spreadsheet (referenced in Section 4.1.2) and 
thus not all Per-Protocol Deviations will be tracked or identified as Important by Study 
Team.
Per-Protocol Deviations which were not tracked or identified as Important by Study 
Team will be reported in 1) Listing of Important Deviations and flagged as such, and 2) 
Summary of Important Protocol Deviations. 
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides a list of appendices primarily related to considerations for data analyses
and data handling conventions. A full set of appendices is provided in Section 11.
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Exclusions from the Per-Protocol Population
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Multicenter Studies
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Adverse Event Time Periods and Special Adverse Event Definitions
11.9
Appendix 9: Threshold Factors for Clinical Laboratory Tests and Vital Signs
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified in text or data display shells. 
Table 2 provides an overview of the planned study population summaries and listings. A 
list of planned data displays is in Appendix 15: List of Data Displays.
Reference Section 4 (Analysis Populations) and Appendix 6 (Derived and Transformed 
Data) for supporting definitions on all below subsections.
Formal statistical treatment comparisons will not be performed in terms of the study 
population data.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Listing
Subject Accountability
Numbers of Subjects, including: Enrolled, Placebo Run-In, 
Randomized (ITT Population), Per-Protocol Population
Y
Y
Subject Disposition
Withdrawals During Placebo Run-In
Y
Y
Randomized by Country and Center
Y
Y
Withdrawals During Double-Blind including totals, reasons, 
and by time of discontinuation
Y
Y
Inclusion / Exclusion Criteria Deviations
Y
Y
Important Protocol Deviations
Y
Y
Deviations which Require Exclusion from the Per-Protocol 
Population
Y
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Ethnicity, Race, and Racial Combination Details
Y
Y
Selected Safety Measures at Baseline, Overall and by 
Country
Y
[1]
Selected Efficacy and Health Outcome Measures at Baseline, 
Overall and by Country 
Y
[1]
Medical Conditions and Concomitant Medications
Medical Conditions by Body System
Y
Y
Specific Medical Conditions
Y
Y
BPH History
Y
Y
Alpha-Blocker, 5-Alpha-Reductase Inhibitor, Phytotherapy 
Use [2]
Y
Y
Sexual Function
Y
Y
Family History: Premature Coronary Artery Disease, Breast 
Cancer, Prostate Cancer
Y
Y
Concomitant Medications
Y
Y
 
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Display Type
Data Displays Generated
Table
Listing
Investigational Product Discontinuation, Exposure, Treatment Compliance
Investigational Product Discontinuation
Y
Y
Study Drug Exposure
Y
Y
Study Drug Compliance
Y
Y
Treatment Blind Broken
Y
NOTES :

Y = Yes display generated.

There are no planned Study Population figures.
[1] Reference specific measurement listing in safety, efficacy, and health outcomes
[2] Summaries generated for each Alpha-Blocker, 5-Alpha-Reductase Inhibitor, Phytotherapy Use as well as a) 
Alpha-Blocker or 5-Alpha-Reductase Inhibitor Use and b) Alpha-Blocker or 5-Alpha-Reductase Inhibitor or 
Phytotherapy Use).
6.2.
Subject Accountability
Summaries for the following will be produced in terms of total number overall: 

enrolled subjects

subjects who entered placebo run-in phase

subjects who entered placebo run-in but withdrew prior to randomization.
Enrolled subjects includes those who entered placebo run-in phase and/or who were 
randomized.
Summaries for the following will be produced by treatment and in terms of total number 
overall: 

number of subjects who were randomized to double-blind but missed placebo run-
in

number of subjects who were randomized to double-blind but do not have a 
double-blind treatment start date

number of subjects who have a double-blind treatment start date but were not 
randomized

number of subjects who were randomized to double-blind and did not take at least 
one dose of study medication

number of randomized subjects (ITT population) and defined as subjects with a 
nonmissing treatment number

number of subjects in the Per-Protocol population.
Summaries of the ITT population will be produced by country and center and output by 
randomized treatment and overall. 
A listing of randomized subjects (ITT population) will be produced and will include the 
scheduled randomized treatment and the actual randomized treatment. A flag will be 
included on the listing to indicate if the scheduled treatment differs from the actual 
 
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randomized treatment; as well, any such cases will be included as per-protocol 
deviations.
6.3.
Subject Disposition
A subject may withdraw from the study at any time at the investigator’s discretion or at 
the request of the subject. 
The reason for study withdrawal is recorded in the eCRF for subjects who entered 
placebo run-in but withdrew prior to randomization. A tabular summary will be produced 
for number and percentage of subjects who entered placebo run-in and withdrew prior to 
randomization, overall and by reason. For this summary, the percentages are calculated 
using total subjects who entered placebo run-in as the denominator. 
The reason for study withdrawal is recorded in the eCRF for randomized subjects who 
prematurely withdrew from the study in advance of the Month 24 visit.  A tabular 
summary will be produced for number and percentage of subjects prematurely 
withdrawing from the study, overall and by reason, and will be output by treatment group 
and total.  For this summary, the percentages are calculated using the ITT population as 
the denominator. 
A listing will be produced for the ITT population with key accountability data including 
placebo run-in start and stop dates, randomization date, treatment start and stop dates, 
subject withdrawal (yes or no), completion or withdrawal date, and all visit dates.
ITT population subject discontinuation will be summarized by visit intervals as overall 
totals and by discontinuation reason; these summaries will be output by treatment group 
and total. Visit interval determination used for these summaries is defined in Appendix 3
(Assessment Windows).
6.4.
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized overall and 
by treatment group for the ITT population; summaries will be repeated by country:

sex

age in years

age categories:  <65, ≥65, <75, ≥75 years

ethnicity: Hispanic, Not Hispanic

race / ethnicity: Asian, Hispanic / Latino, White, Not-Hispanic

height

weight

body mass index

history of tobacco use including number of cigarettes smoked per day

alcohol use including number of units per week

baseline safety including ECG, PSA, systolic blood pressure, diastolic blood 
pressure, heart rate, and C-SSRS

baseline efficacy including IPSS, prostate volume, and Qmax
 
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
baseline health outcome measures including BII and QOL Q8

baseline C-SSRS
Race and racial combinations, will be summarized overall and by treatment group for the 
ITT population. Reference Appendix 6 for race and ethnicity details and combinations. 
6.5.
Medical Conditions and Concomitant Medications
The following medical conditions and medication history are GSK standardized data 
collections and/or are of interest in terms of the protocol population, study treatments, 
and indication. These characteristics will be summarized overall and by treatment group 
for the ITT population.

medical conditions by body system (includes GSK standardized collection)

specific medical conditions (more specific or in addition to the above body 
systems)

BPH history including time since first LUTS and time since BPH diagnosis 

alpha-blocker use

5-alpha-reductase inhibitor use

alpha-blocker and 5-alpha-reductase inhibitor use

phytotherapy for BPH use

sexual function including activity status at screening along with impotence and 
lack of libido status of prior 3 months

family history of premature coronary artery disease

family history of breast cancer

family history of prostate cancer
Note:  ARI114265 eCRF is designed to collect affirmative ‘Yes’ responses to the 
following:  Alpha-blocker use, 5-alpha-reductase inhibitor use, and phytotherapy use.  
‘No’ responses are not collected. For purposes of the related summaries, then number of 
subjects with a ‘No’ response will be assumed as the Intent-to-Treat Population treatment 
arm minus the ‘Yes’ responses. Both ‘Yes’ and ‘No’ usage along with (%) of population 
will be presented on relevant tables.
Concomitant medication data are collected on eCRF log forms and will be coded using 
the GSK-Drug Anatomical Therapeutic Chemical (ATC) dictionary. Concomitant 
medications will be defined as any medication documented as such in the database, 
irrespective of start or stop dates or ongoing status.
A summary of concomitant medications will be provided for the ITT population. The 
number and percentage of subjects reporting the use of each concomitant medication will 
be summarized by treatment group and in total, ATC Level 1 and ingredient. A listing of 
the collected concomitant mediations, by treatment and subject, will be provided. A 
listing of the relationship between the ATC Level 1, ingredient and verbatim text for 
concomitant medications will be provided.
 
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6.6.
Investigational Product Discontinuation, Exposure, and 
Compliance
Reasons for investigational product discontinuation are recorded in the eCRF and may 
differ from a subject’s study discontinuation reason. A tabular summary will be produced 
for number and percentage of subjects who prematurely discontinued investigational 
product. Summaries will be produced overall and by reason, and will be output by 
treatment group and total. For this summary, the percentages are calculated using the ITT 
population as the denominator.
A listing of subjects for whom the treatment blind was broken during the study, along 
with the reason, will be produced. 
Study drug exposure (in days) is number of days between (double-blind) treatment start 
date and (double-blind) treatment stop date, both days inclusive. Study drug exposure is 
further explained in Appendix 6. Study drug exposure in days will be summarized by 
treatment group and overall. The number and proportion of subjects exposed to study 
drug will also be summarized by 180-day intervals for each treatment group and overall.
Overall study drug compliance is defined as 100 * Number of Pills Consumed / Number 
of Pills Prescribed.  Compliance for a specific study drug component (e.g. Tamsulosin) is 
defined in the same way. Both of these definitions are explained further in Appendix 6. 
Overall study drug compliance will be summarized by treatment group and across the 
treatment groups. The number and proportion of subjects with overall compliance <75%, 
75-125%, and >125%, will be summarized for each treatment group and across the 
treatment groups. Study drug compliance by component will also be summarized by 
treatment group and across the treatment groups. 
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Overview of Planned Primary Efficacy Analyses
The primary efficacy parameter after the 2nd year of the study is change from baseline 
IPSS (International Prostate Symptom Score). The IPSS questionnaire consists of seven 
questions with each question score ranging from 0 to 5. It is administered at screening, 
baseline, and at each of the scheduled post-baseline treatment phase visits.
IPSS (also called IPSS total score) is the sum of the seven questions. IPSS summaries and 
analyses will be in terms of the total (score); exceptions will be noted such as for 
supporting summaries of individual questions. For calculation of the IPSS total, missing 
individual responses will be imputed when at least four of the seven questions are 
answered (nonmissing). For the imputation, the average of the nonmissing responses will 
be calculated and rounded to the nearest integer. This average will be imputed for the 
original missing response(s). If at least 20% of the subjects have at least one imputed 
IPSS then the statistical analyses will be repeated based on non-imputed scores.
 
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The efficacy analyses will be based on the Intent-to-Treat (ITT) population. Table 3
provides an overview of the planned IPSS summaries and primary efficacy analyses. A 
list of planned data displays is in Appendix 15: List of Data Displays.
Table 3
Overview of Planned Primary Efficacy Analyses
Endpoint
Absolute
Change from Baseline
% Change from Baseline
L
F
T
L
F
T
L
F
T
IPSS (International Prostate Symptom Score) Change from Baseline
Primary Analysis (Month 24 
Visit)
Y[1]
Y
Y[1]
Y
Y[2]
Supporting and Sensitivity Analyses of Primary Endpoint
Mixed-Model Repeated-
Measures (MMRM) 
Analysis (At Visit)
Y
IPSS Change from 
Baseline by Subgroup[3]
Y
Individual IPSS Questions 
Y[1]
Y
Y
IPSS Percentage Change 
from Baseline
Y[1]
Y
IPSS Non-imputed Score 
Analysis[4]
Y
Y
Y
IPSS Per-Protocol 
Population Analysis[5]
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.  All outputs are based on ITT population except [4].

Tables and figures have separate outputs for LOCF and At Visit, except for baseline summaries.
1.
Individual questions 1 – 7 responses, total score, total score change from baseline, and percentage change from 
baseline are combined in a single listing and presented for every visit.
2.
Primary efficacy analyses are presented within this table; details are in the following section.
3.
Subgroups are defined in Section 7.1.3 and Appendix 10: Examination of Covariates and Subgroups.
4.
Analysis is performed only if RAP Section 7.1 imputation conditions are met.
5.
Analysis is performed only if RAP Section 4 per-protocol conditions are met.
7.1.2.
Planned Primary Efficacy Statistical Analyses
Endpoint:  The primary efficacy parameter is the change from baseline IPSS at Year 2 
(Month 24) using the last observation carried forward approach (LOCF) based on the 
Intent-to-Treat (ITT) population.
Table 3 provides an overview of the planned IPSS summaries and primary efficacy 
analyses. A list of planned data displays is in Appendix 15: List of Data Displays.
Baseline and change from baseline are defined in Appendix 6. Last observation carried 
forward (LOCF) and At Visit approaches are defined in Appendix 7.
Note:  IPSS timepoints earlier than Month 24, specifically Month 21 – Month 3, in this 
order, are classified as secondary endpoints. Summaries and analyses of these timepoints 
will be conducted in same manner and on same outputs as the primary analyses. 
Reference Table 4.
 
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Model Specification and Results Presentation:  Change from baseline IPSS at each 
scheduled post-baseline assessment will be compared in terms of combination treatment 
versus tamsulosin treatment using t-tests from a general linear model (GLM) with effects 
for treatment, cluster, and baseline IPSS. Two-sided tests at 0.05 level of significance 
will be conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
IPSS adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Multiple Comparisons and Multiplicity:  Reference Appendix 11, Multiple Comparisons 
and Multiplicity.
Model Checking and Diagnostics: Reference Appendix 12, Model Checking and 
Diagnostics for Statistical Analyses.
7.1.3.
Supporting and Sensitivity Analyses of Primary Endpoint
The following describes supporting and sensitivity analyses of the primary endpoint.
Mixed-Model Repeated-Measures (MMRM) Analysis:  As a supportive analysis, IPSS 
will be analyzed using a mixed-model repeated-measures (MMRM) analysis including 
ITT population data from the scheduled post-baseline assessments. Details are provided 
in Appendix 13, Mixed-Model Repeated-Measures Analysis.
IPSS Change from Baseline by Subgroup: For each subgroup, IPSS change from 
baseline summaries will be output by treatment group at Month 12 and at Month 24 for 
the ITT population using both LOCF and At Visit approaches. No statistical testing will 
be performed. Subgroups are defined in Appendix 10, Examination of Covariates and 
Subgroups.
Individual IPSS Questions 1 – 7:  Each of the 7 IPSS individual question responses will 
be summarized at Baseline, Month 12, and Month 24 by treatment group. Month 12 and 
Month 24 change from baseline will be summarized by treatment group for each of the 7 
questions. The summaries will be based on the ITT population and presented using both 
LOCF and At Visit approaches. No statistical testing will be performed.
IPSS Percentage Change from Baseline: Percentage change from baseline is defined in 
Appendix 6. IPSS percentage change from baseline will be summarized by treatment 
group at each scheduled post-baseline assessment. The summaries will be based on the 
ITT population and presented using both LOCF and At Visit approaches. No statistical 
testing will be performed.
 
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IPSS Non-Imputed Score Analysis:  IPSS missing response imputation procedure is 
described above. If at least 20% of the ITT subjects have at least one imputed IPSS then 
the tables, figures, and analyses described in Section 7.1.2 (Planned Primary Efficacy 
Statistical Analyses) will be repeated using non-imputed scores.
IPSS Per-Protocol Population Analysis:  Per-Protocol (PP) population is defined in 
Section 4. If the PP population comprises 80% or less of the ITT population, then the 
tables, figures, and analyses described in Section 7.1.2 (Planned Primary Efficacy 
Statistical Analyses) will be repeated using the PP population.
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Secondary Efficacy Analyses
8.1.1.
Overview of Planned Secondary Efficacy Analyses
Table 4
Overview of Planned Secondary Efficacy Analyses
Endpoint
Absolute
Change from Baseline
% Change from Baseline
L
F
T
L
F
T
L
F
T
IPSS
IPSS Months 3 – 21 (see 
Section 7.1.2)
Y
Y
Y
Y
Y
Y
Improvement Levels
Y[1]
Y[2]
Prostate Volume
Absolute, Change,
% Change [3]
Y
Y
Y
Y
Y
Y
Y
By Subgroup
Y
Improvement Levels
Y[4]
Maximum Urine Flow (Qmax)
Absolute, Change, 
% Change [5]
Y
Y
Y
Y
Y
Y
Y
By Subgroup
Y
Improvement Levels
Y[6]
Y[7]
AUR or BPH-Related Surgical Intervention[8]
Time to event
Y
Y
Y
Event incidence
Y
Other Efficacy Measures [9]
Urinary tract infection
/ urosepsis
Y
Y
Urinary incontinence
Y
Y
Renal insufficiency
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Tables and figures have separate outputs for LOCF and At Visit, except for baseline summaries and AUR or BPH-
related surgical intervention.
1. IPSS change from baseline five improvement categories are ≥1 point through ≥5 points. ‘No change’ and 
‘worsening’ are also presented. Treatment comparisons are in terms of ≥2 points and separately ≥3 points.
2. IPSS percentage change from baseline seven improvement categories are >0%, ≥10%, ≥20%, ≥25%, ≥30%, 
≥40%, and ≥50%. Treatment comparisons are in terms of ≥25%.
3. Prostate volume printed and summarized for absolute, change from baseline, percentage change from baseline; 
dimensions will be printed. Prostate volume analyses are based on percentage change from baseline.
4. Prostate volume percentage change from baseline seven improvement categories are >0%, ≥10%, ≥20%, ≥25%, 
≥30%, ≥40%, and ≥50%. Treatment comparisons are in terms of ≥25%.
5. Qmax printed and summarized for absolute, change from baseline, percentage change from baseline; total voided 
volume will be printed. Qmax analyses are based on change from baseline.
6. Qmax change from baseline six improvement categories are >0 ml/sec and ≥1 ml/sec through ≥ 5 ml/sec. ‘No 
change’ and ‘worsening’ are also presented. Treatment comparisons are in terms of ≥3 ml/sec.
7. Qmax percentage change from baseline six improvement categories are >0%, ≥10%, ≥20%, ≥30%, ≥40%, and 
≥50%. Treatment comparisons are in terms of ≥30%.
8. Summaries are repeated individually for AUR and BPH-Related Surgical Intervention.
9. Data of other efficacy measures are summarized. No treatment comparisons are performed.
 
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8.1.2.
IPSS Improvement Levels
Symptom improvement is assessed using IPSS continuous data changes as the primary 
efficacy endpoint and using categorical changes as a secondary efficacy endpoint.
Improvement is a post-baseline score which is lower than the baseline score. Worsening 
is a post-baseline score which is higher than the baseline score. The number and 
percentage of subjects with IPSS percentage change from baseline categories of 1) 
improvement, 2) no change, and 3) worsening will be summarized by treatment group 
using both the LOCF and At Visit approaches at each scheduled post-baseline 
assessment.
IPSS change from baseline will be presented using five improvement levels:  ≥1 point 
through ≥5 points.  IPSS percentage change from baseline will be presented using seven 
improvement levels:  >0%, ≥10%, ≥20%, ≥25%, ≥30%, ≥40%, and ≥50%.  Treatment 
comparisons for combination versus tamsulosin will be performed for each ≥ 2 points, ≥3 
points, and ≥25% using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
8.1.3.
Prostate Volume
Prostate dimensions are measured at the second screening visit (1b) and at each Month 12 
and Month 24 (or end of treatment) visits. For analysis and reporting, 

Prostate Volume = 
pi/6 (Anteroposterior Width x Cephalocaudal Width x Transverse Width).
Prostate volume percentage change from baseline is a secondary efficacy endpoint.
Table 4 provides an overview of the planned prostate volume summaries and analyses. A 
list of planned data displays is in Appendix 15: List of Data Displays. Baseline, change 
from baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary. Prostate volume summary statistics will be presented for baseline, 
Month 12 visit, and the Month 24 visit; change from baseline and percentage change 
from baseline summary statistics will be presented for the Month 12 and Month 24 visits. 
Combination treatment and tamsulosin treatment will be compared in terms of prostate 
volume percentage change from baseline at the Month 12 and Month 24 visits using t-
tests from the following general linear model; two-sided tests at 0.05 level of significance 
will be conducted:

log (post baseline prostate volume / baseline prostate volume) = 
log (baseline prostate volume) + treatment + cluster
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of percentage change from baseline will be 
reported. The adjusted mean differences will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
 
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Prostate volume adjusted mean percentage change from baseline will be plotted by 
treatment for each post-baseline scheduled visit in terms of each LOCF and At Visit 
approach.
The number and percentage of subjects with prostate volume percentage change from 
baseline categories of 1) improvement, 2) no change, and 3) worsening will be 
summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment.  Improvement is a post-baseline prostate volume 
which is lower than the baseline prostate volume.  Worsening is a post-baseline prostate 
volume which is higher than the baseline prostate volume.
Prostate volume percentage change from baseline will be presented using seven
improvement levels:  >0%, ≥10%, ≥20%, ≥25%, ≥30%, ≥40%, and ≥50%.  Treatment 
comparisons for combination versus tamsulosin will be performed for ≥25% prostate 
volume improvement using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
Supportive subgroup summaries of prostate volume percentage change from baseline will 
be presented in manner similar to that described for primary efficacy in Appendix 10, 
Examination of Covariates. Reference Appendix 15 for a list of planned prostate volume 
subgroup tables. 
Model checking associated with prostate volume percentage change from baseline will be 
conducted in manner similar to that described for primary efficacy in Appendix 12. 
Reference Appendix 15 for a list of prostate volume model checking outputs.
Reference Appendix 11 for multiplicity considerations.
8.1.4.
Maximum Urine Flow (Qmax)
Qmax and associated total voided volume are measured at screening (Visit 1a with 
possible repeat at Visit 1b), baseline, and at each Month 6, Month 12, Month 18, and 
Month 24 (or end of treatment) visits. Qmax change from baseline is a secondary efficacy 
endpoint. Qmax measurements with voided volumes <125 ml will not be included in the 
analysis.
Table 4 provides an overview of the planned Qmax summaries and analyses. A list of 
planned data displays is in Appendix 15: List of Data Displays. Baseline, change from 
baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary. Qmax summary statistics will be presented for each scheduled visit; 
change from baseline and percentage change from baseline will be presented for each 
scheduled post-baseline visit.
Change from baseline Qmax at each scheduled post-baseline assessment will be 
compared in terms of combination treatment versus tamsulosin treatment using t-tests
from a general linear model (GLM) with effects for treatment, cluster, and baseline 
Qmax.  Two-sided tests at 0.05 level of significance will be conducted.
 
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The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
Qmax adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Qmax improvement is also assessed using categorical changes. Improvement is a post-
baseline Qmax which is higher than the baseline Qmax. Worsening is a post-baseline 
Qmax which is lower than the baseline Qmax. The number and percentage of subjects 
with Qmax percentage change from baseline categories of 1) improvement, 2) no change, 
and 3) worsening will be summarized by treatment group using both the LOCF and At 
Visit approaches at each scheduled post-baseline assessment.
Qmax change from baseline will be presented using six improvement levels: >0 ml/sec 
and ≥1 ml/sec through ≥5ml/sec. Qmax percentage change from baseline will be 
presented using six improvement levels:  >0%, ≥10%, ≥20%, ≥30%, ≥40%, and ≥50%.  
Treatment comparisons for combination versus tamsulosin will be performed for each 
≥3ml/sec and ≥30% using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
Supportive subgroup summaries of Qmax change from baseline will be presented in 
manner similar to that described for primary efficacy in Appendix 10, Examination of 
Covariates. Reference Appendix 15 for a list of planned Qmax subgroup tables. 
Model checking associated with Qmax change from baseline will be conducted in manner 
similar to that described for primary efficacy in Appendix 12. Reference Appendix 15 for 
a list of Qmax model checking outputs. As a supportive analysis, Qmax will be analyzed 
using a mixed-model repeated-measures (MMRM) analysis in a manner similar to that 
described for primary efficacy in Appendix 13.
Reference Appendix 11 for multiplicity considerations.
8.1.5.
AUR or BPH-Related Surgical Intervention
All AUR and BPH-related surgery events during participation in the study are recorded. 
Subjects who discontinue from the study are followed for AUR and BPH-related surgery 
until the 24 month anniversary of randomization. This follow-up is in terms of biannual 
telephone contacts beginning at the first six month scheduled interval after 
discontinuation. Analyses will be in terms of events recorded at clinic visits and also 
collected in the biannual telephone contacts. Table 4 provides an overview of the planned 
summaries and analyses. A list of planned data displays is in Appendix 15: List of Data 
Displays.
 
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Time to first AUR or BPH-related surgery will be defined as the number of days from 
treatment start date to date of the first event (earliest occurring of either AUR or BPH-
related surgery) for each subject. Time to first AUR or BPH-related surgery is classified 
as a secondary efficacy endpoint and will be analyzed in terms of the Intent-to-Treat 
population. 
Censoring will occur at the earliest of the following dates as applicable: the date of 
prostatectomy, the date of last contact for AUR and surgical intervention, and the date of 
death. For censoring, ‘prostatectomy’ will be determined from the eCRF prostatic 
surgical intervention log using the following codes associated with ‘prostatectomy’:  
open, retropubic with or without nerve-sparing, suprapubic, transvesical, perineal, 
salvage, laparoscopic, laparoscopic assisted.  Note this excludes ‘partial prostatectomy’.
The ‘date of last contact for AUR and surgical intervention assessment’ will be assigned 
as the latest of:
--Date of last treatment-phase visit
and
--Date of last successful biannual follow-up telephone contact.
Partial dates will be handled as described in Appendix 7, Premature Withdrawals & 
Handling of Missing Data.
The number of subjects having the first AUR or BPH-related surgery event on or after 
treatment start will be tabulated by treatment, by the two annual time periods (Month 12 
and Month 24), as well as by three month intervals (quarterly) along with the number of 
subjects at risk during each of these time periods.
Note: Cut-off dates are defined in Appendix 6; definition is repeated here:
Month k Cut-off Date (for k= 3, 6, 9, 12, 15, 18, 21, 24):  The maximum of [Month k 
clinic visit date, Month k lab visit date, Baseline Date + (k * 91/3)].
The primary analysis of this endpoint will compare combination treatment versus 
tamsulosin treatment in terms of time to first AUR or BPH-related surgery for the ITT 
population using a log rank test stratified by cluster at the 0.05 level of significance. The 
relative risk (hazard ratio) for the treatment effect and associated two-sided 95% 
confidence intervals will be estimated using a Cox proportional hazards model with 
treatment as the only covariate and stratified by cluster. Estimates and corresponding 
confidence intervals for the relative risk (hazard ratio) and risk reduction (1-hazard ratio) 
of combination treatment versus tamsulosin treatment will be presented along with the 
log rank p-value. Assessment of the Cox modeling procedure will include examination of 
diagnostic plots to assess the assumption of proportional hazards and the review of results 
obtained by fitting separate models by cluster to assess the homogeneity of treatment 
effect across clusters.
Time to first AUR or BPH-related surgery, expressed as months, will be summarized by 
treatment group for the ITT population using product-limit estimates computed by the 
Kaplan-Meier method and displayed graphically as Kaplan-Meier curves.
 
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The number of subjects with at least one AUR or BPH-related surgery will be 
summarized by treatment group across the 2 year period. The crude rate of AUR or BPH-
related surgery incidence will be calculated using the Intent-to-Treat population of each 
treatment as the denominator; the associated 95% confidence interval will be output. This 
crude rate will be compared for combination treatment versus tamsulosin treatment using 
the Mantel-Haenszel test stratified by cluster at the 0.05 level of significance.
AUR or BPH-related surgery event details per subject will be summarized by treatment 
and will include:  event component (first occurring of either AUR or BPH-related 
surgery) and time period of first occurring event (during treatment or after treatment 
stop).  BPH-relatedness (yes/no) and AUR precipitating factors will be summarized by 
treatment for subjects in which AUR is the primary efficacy event’s initial component.  
Types of surgery/intervention will be summarized by treatment for subjects in which 
BPH-related surgery is the primary efficacy event’s initial component.
Time from last dose to first AUR or BPH-related surgery event will be summarized for 
those subjects experiencing the first event after treatment stop.
Hospitalization details for the initial AUR will be summarized by treatment group for 
patient admission status (inpatient or outpatient). For inpatients, the ward type and 
hospitalization days will be summarized by treatment.
The frequency and percentage of subjects with multiple AUR or BPH-related surgery 
events will be summarized by treatment. The frequencies of subjects with 2 events, 3 
events, or ≥4 events will be summarized. Among subjects with both events, the pattern of 
occurrence (AUR/Surgery or Surgery/AUR) will be summarized.
The above described summaries and analyses of AUR or BPH-related surgery will be 
repeated, when applicable, for the individual components 1) AUR and 2) BPH-related 
surgery.
All AUR and surgical intervention data will be listed by treatment and subject.  Time to 
first AUR or BPH-related event will be listed for each subject along with the dates used 
in the computation of these values.
8.1.6.
Other Efficacy Measures
The following are potential BPH disease related events not captured as primary or
secondary endpoints. They are collected in this study for possible comparison to
historical BPH studies and to insure consistency of disease-related adverse event
definition:

Urinary tract infection/urosepsis

Urinary incontinence (overflow/urge)

Renal insufficiency
Each of the three ‘other efficacy measures’ will be summarized by treatment group for 
number of subjects with at least one post-randomization event across the 2-year period. 
The crude rate of each measure will be calculated using the Intent-to-Treat population of 
 
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each treatment as the denominator; the associated 95% confidence interval will be output.
No formal treatment comparisons will be performed.
Data collected in terms of these other efficacy measures will be listed by treatment and 
subject.
8.2.
Safety Analyses
Safety summaries and analyses are reported in terms of the following data classifications:  
adverse events, clinical laboratory assessments (haematology and clinical chemistry), 
total serum prostate specific antigen (PSA), qualitative breast examination, digital rectal
examination, vital signs, suicidality, and post void residual volume.
All safety analyses will be performed using the ITT population unless otherwise specified 
in text or data display shells. Applicable safety analysis and reporting definitions and 
presentations within “Program Safety Analysis Plan (PSAP, 2016) for GI198745 
(dutasteride) and GSK2285985 (fixed dose combination of dutasteride [GI198745] and 
tamsulosin [GI138525]” are utilized within this RAP, with any deviations noted.
8.2.1.
Overview of Adverse Event Tabular Summaries
Table 5 provides an overview of the planned adverse event tabular summaries. A list of 
planned data displays is in Appendix 15: List of Data Displays.
Reference Section 4 (Analysis Populations) and Appendix 6 (Derived and Transformed 
Data) for supporting definitions on all below subsections.
 
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Table 5
Overview of Planned Adverse Event Tabular Summaries
Adverse Event Types, High Level
Any
Drug-
Related
Non-
Serious
Serious
Leading 
to W/D 
from 
Study
Perm. 
D/C of 
Study 
Drug
Fatal
By Type
------------- 3.1 (6 above categories, excluding Non-serious) ------------
Overall
3.2
3.3 [1]
3.4 [2]
3.13 [3]
3.18
3.19 [1]
3.20 [2]
3.5
3.25
3.26 [1]
3.27 [2]
3.35
3.38
3.33
By 6-Month Onset Period
3.6
3.14 [3]
3.21
3.28
By Age (<65, ≥65)
3.7
3.22
3.29
By Age (<75, ≥75)
3.8
3.23
3.30
By Country
3.9
3.24
3.31
By Descending Frequency
3.10
3.12
3.11
By Maximum Intensity
3.15
Most Common
3.16
3.17
Adverse Event Types, Two Levels
Drug-Related
and
Serious
Drug-Related
and
Fatal
Drug-Related
and
Leading to 
W/D from 
Study
Serious
and
Leading to 
W/D from 
Study
Drug-Related
and
Leading to 
Perm D/C of 
Study Drug
Serious
and
Leading to 
Perm D/C of 
Study Drug
Overall
3.32
3.34
3.36
3.37
3.39
3.40
Sexual and Breast Adverse Events of Special Interest
Altered
(Decreased)
Libido
Impotence
Ejaculation
Disorders
Breast Disorders
(includes Enlargement and 
Tenderness)
MedDRA
----------------------------------------------3.41--------------------------------------------
Overall (and by baseline 
characteristics)
3.42
3.43
3.44
3.45, 3.46 [4], 3.47 [5]
By Type
-----------------------------------------------3.48------------------------------------
Not 
Resolved & 
Leading to 
Study 
Withdrawal
Overall
-----------------------------------------------3.49------------------------------------
By Type
3.50
3.51
3.52
3.53
Prostate Cancer Adverse Event of Special Interest
Prostate Cancer Overall
3.54
Cardiovascular Adverse Events of Special Interest
Acute 
Coronary 
Syndrome
Ischemic
Cerebro-
vascular 
Events
Cardiac
Failure
Ischemic
Coronary
[6]
Cardiac
Arrhyth-
mia
Peripheral
Vascular
Disease
Cardio-
vascular
Events
MedDRA
-----------------------------------------------------3.55---------------------------------------------------
Overall
3.56
3.57
3.58
3.59
3.60
3.61
3.62
Infrequent Tier 1 Adverse Events of Special Interest
MedDRA
3.63
Notes:  Summaries are in terms of ‘Starting Post-Randomization’ (defined in Appendix 8) unless otherwise noted as [1] – [3]:
1.
Starting On-Treatment; defined in Appendix 8.
2.
Starting Post-Treatment; defined in Appendix 8. 
 
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3.
Starting On-Treatment and in terms of ‘Study Drug Exposure Basis” in which [Rate] is the number of subjects per 100 person-
years of study drug exposure; adverse events for subjects with missing study drug exposure are excluded.
4.
Breast Disorders: subcategory Breast Enlargement
5.
Breast Disorders: subcategory Breast Tenderness
6.
Ischemic Coronary Artery Disorders / Atherosclerosis
8.2.2.
Adverse Events
Adverse events (AEs) will be coded using the MedDRA (Medical Dictionary for 
Regulatory Activities) coding dictionary. As specified in the protocol, disease related 
events will not be reported as AEs or serious adverse events (SAEs) unless the
investigator assesses the event as more severe than expected for the subject’s condition. 
A mapping of the MedDRA primary system organ class and preferred term to which each 
verbatim term has been coded will be provided in a listing.
Adverse events (AEs) are to be recorded on the electronic case report form (eCRF) from
the start of the placebo run-in phase study treatment until the end of the two year study 
period. Serious AEs (SAEs) are to be recorded over the same time period as non-serious 
AEs. However, any SAEs assessed as related to study participation or related to a GSK 
concomitant medication, will be recorded from the time a subject consents to participate 
in the study up to the end of the two year study period. After discontinuation of study 
treatment, the investigator will monitor all AEs/SAEs that are ongoing until resolution or 
stabilization of the event or until the subject is lost to follow-up. Investigators are not 
required to actively seek information on adverse events occurring after the follow-up 
contact, but may report any adverse event that they believe may be related to 
investigational product regardless of when the event occurs. Adverse events summaries 
will include non-serious as well as serious AEs.
Subjects with sexual function related adverse events leading to study withdrawal, will be 
followed up for up to 6 months after the last dose of study drug using the sexual function 
Targeted Follow-Up Questionnaire (TFUQ). 
If an AE occurs which, in the investigator’s judgment, is possibly related to suicidality, a 
Possible Suicidality-Related Adverse Event (PSRAE) form should be completed by 
investigators or their designated staff.
Each AE will be categorized into the following periods according to its onset date:
pretreatment, post-randomization, on-treatment, post-treatment. These periods are not
mutually exclusive and an AE could be categorized into more than one period. The
definitions of these categories are provided in Appendix 8: Adverse Event Time Periods 
and Special Adverse Event Definitions.
Pre-treatment AEs will not be summarized; they will be included in the AE listing
specified later in this section.
The number of post-randomization adverse events, the number and the percentage of
subjects reporting any post-randomization AE will be summarized by treatment group for
the following:
 
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
All AEs

Drug-related AEs

Serious AEs

AEs leading to study drug discontinuation

AEs leading to withdrawal from study

Fatal AEs
Comparisons of treatment groups for each of these sets of AEs will be performed using 
Fisher’s Exact Test.
Total number of adverse events reported in the study as well as the number and 
percentage of subjects reporting at least one AE will be provided for each treatment 
group. Total number of AEs as well as the number and percentage of subjects reporting 
each AE will be reported by treatment group, primary system organ class and preferred 
term. On-treatment and post-treatment AEs will be summarized separately, as well as 
together as post-randomization AEs. Non-serious post-randomization AEs will be
summarized by treatment group. A summary of post-randomization AEs will be provided
by treatment group and six month time period of onset (Months 1-6, Months 7-12, 
Months 13-18, Months 19-24), by treatment group and age group (<65 years, ≥65 years), 
by treatment group and age group (<75 years, ≥75 years), and by treatment group and 
country.
A summary of post-randomization AEs will be provided by treatment group and
preferred term by descending frequency of preferred term (regardless of system organ
class). In addition, such summaries will be done for serious post-randomization AEs and 
also for non-serious post-randomization AEs. 
For on-treatment AEs, the event rate per 100 person-years of study drug exposure will be 
summarized by treatment group, primary system organ class and preferred term overall 
and by time period (Months 1-6, Months 7-12, Months 13-18, Months 19-24).
A summary of post-randomization AEs will also be provided by treatment group and
maximum intensity. If the same AE occurs on multiple occasions in the same subject, the
AE with the highest intensity will be presented. Intensity will be categorized as mild,
moderate, or severe; a category for missing/not applicable intensity will be included.
The most common AEs (Tier 2 events) are defined as those preferred terms occurring in 
at least 5% of the subjects within any treatment group (non-rounded). The total number 
of events as well as the number and percentage of subjects reporting at least one most 
common AE preferred term starting post-randomization will be provided for each 
treatment group. The number of events, the number and percentage of subjects reporting 
the most common AE preferred terms starting post-randomization will be provided by 
treatment group displayed by decreasing frequency of preferred terms (regardless of 
primary system organ class). For each of these most common AEs, the percentage of 
subjects in the treatment groups will be compared using Fisher’s exact test. In addition, 
the percentage of subjects reporting each AE by treatment group along with the 
corresponding odds ratio and 95% confidence interval for each of the most common AEs 
 
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will be displayed in a figure sorted by odds ratio in descending order, by treatment group. 
The above summary will also be provided for the most common non-serious post-
randomization AEs.
Total number of drug-related adverse events as well as the number and percentage of
subjects reporting at least one drug-related AE will be provided for each treatment group.
Total number of drug-related adverse events as well as the number and percentage of
subjects reporting each drug-related AE will be reported by treatment group, primary
system organ class and preferred term. On-treatment and post-treatment drug-related AEs
will be summarized separately, as well as together as post-randomization drug-related 
AEs. A summary of post-randomization drug-related AEs will be provided by treatment 
group and time period (Months 1-6, Months 7-12, Months 13-18, Months 19-24), by 
treatment group and age group (<65 years, ≥65 years), by treatment group and age group 
(<75 years, ≥75 years) and by treatment group and country.
A listing of all AEs, a listing of AEs by onset period, and a listing of which subjects 
reported specific AEs will be presented. A listing of Possible Suicidality Related Adverse 
Event (PSRAE) data will be provided. A listing of the sexual function Targeted Follow-
Up Questionnaire (TFUQ) data will be provided.
8.2.3.
Deaths and Serious Adverse Events
Total number of serious adverse events as well as the number and percentage of subjects
reporting at least one serious AE will be provided for each treatment group. Total number
of serious adverse events as well as the number and percentage of subjects reporting each
serious AE will be reported by treatment group, primary system organ class and preferred
term. On-treatment and post-treatment serious AEs will be summarized separately, as
well as together as post-randomization serious AEs. A summary of post-randomization
serious AEs will be provided by treatment group and time period (Months 1-6, Months 7-
12, Months 13-18, Months 19-24), by treatment group and age group (<65 years, ≥65
years), by treatment group and age group (<75 years, ≥75 years), and by treatment group 
and country. A summary of all post-randomization drug-related serious AEs, of all post-
randomization fatal AEs, and of all post-randomization drug-related fatal AEs will be 
provided by treatment group. Time to death will be summarized by treatment group using 
Kaplan-Meier estimates and displayed as Kaplan-Meier plots.
Individual subject listings of all non-fatal serious AEs and a separate listing of all fatal
serious AEs will be provided. The listing will indicate the timing of the serious AE with
respect to treatment start date.
 
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8.2.4.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal From the Study and Other Significant 
Adverse Events
8.2.4.1.
Adverse Events Leading to Discontinuation of Investigational Product 
and/or Withdrawal from the Study
A summary of adverse events starting post-randomization and leading to withdrawal
from the study will be provided by treatment group for the following categories:

All AEs

Drug-related AEs

Serious AEs
Similar summaries will be provided for adverse events leading to permanent
discontinuation of the study medication.
Subject listings of AEs leading to withdrawal from the study and AEs leading to
permanent discontinuation of study drug will be provided. The listings will indicate the
timing of the AE with respect to treatment start date.
8.2.4.2.
Adverse Events of Special Interest
Tier 1 adverse events of special interest are pre-specified adverse event preferred terms 
for which there are predefined hypotheses about the existence of a potential treatment 
effect. These events include the following:

Sexual and breast events

Prostate cancer 

Cardiovascular events 

Infrequent events
Summaries for these events are specified in the following sections and will be based on 
post-randomization AEs unless otherwise indicated. A mapping of the MedDRA primary 
system organ class and preferred term to which each verbatim term in the special interest 
AE categories has been coded will be provided in a listing.
8.2.4.3.
Sexual and Breast Tier 1 Adverse Events of Special Interest
Altered (decreased) libido, impotence, ejaculation disorders, and breast disorders, will be
defined as sexual and breast adverse events of special interest. In addition, two subgroups 
of breast disorders (breast disorders: breast enlargement, and breast disorders: breast 
tenderness) are of special interest. MedDRA system organ class and preferred terms 
included in these special interest adverse events are defined in Appendix 8, Table A. 
Total number of, as well as number and percentage of the subjects experiencing, sexual 
and breast adverse events of special interest will be provided by treatment group. In 
addition, for each of the events of special interest, the number and percentage of subjects 
by treatment will be provided for the following:

having an event

having multiple events

having an event in 6-month windows, starting from treatment start date
 
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The following categories are related to the occurrence of the first event of the special
interest AE; number and percentage of subjects in these categories will be provided by
treatment group:

drug-related AE

serious AE

AE leading to withdrawal from the study

AE leading to permanent discontinuation of study drug

AE outcome

AE resolution status (on-therapy vs. off-therapy – see Appendix 8 for definition)

AE maximum intensity
The number and percentage of the subjects experiencing an adverse event of special
interest will be provided by treatment group for the following. The by-baseline 
summaries will be output in the above described overall tabular summaries:

By baseline age group: < 65 years, ≥65 years

By sexual activity at baseline (Yes, No) based on “sexually active” question.  
The number and percentage of subjects experiencing the following types of sexual and 
breast adverse events of special interest will be provided by treatment group:

Any Type (Impotence, Decreased Libido, Ejaculation Disorders, or Breast

Disorders)

One AE Type

Two AE Types

Three AE Types

All Four AE Types
The time to first onset in days will be summarized by treatment group as a continuous
variable as well as by time period of onset. In addition, time to first adverse event of
special interest will be summarized by treatment group using estimates calculated by the
Kaplan-Meier method and displayed graphically as Kaplan-Meier curves. Time to
resolution for the first event in days will be summarized by treatment group.
Duration of adverse events of special interest will be summarized by treatment group for 
uncensored values, censored values, and all values. It is recognized that summary 
statistics such as means and medians involving censored values will be biased (low).
The number of sexual and breast adverse events leading to study withdrawal, as well as 
the number and percentage of subjects reporting at least one such sexual and breast 
adverse event will be provided for all event types and also by event type for each 
treatment group.
Resolution status at end of study (resolved, not resolved) and time from treatment stop 
date to AE resolution will be summarized by treatment group for the sexual and breast 
adverse events leading to study withdrawal and not resolved at Month 24 / End of 
Treatment visit.
 
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Listings of sexual and breast adverse events of special interest will be provided. A listing 
of sexual and breast adverse event status data will be provided. 
A listing of the TFUQ data for sexual and breast adverse events will be provided.
8.2.4.4.
Prostate Cancer Tier 1 Adverse Events of Special Interest
Prostate cancer will be defined as an adverse event of special interest. MedDRA preferred 
terms and codes included in this special interest adverse event are defined in Appendix 8, 
Table B. Prostate cancer events will be summarized separately following the same format 
done for sexual and breast special interest AEs described above. Time to first event for 
prostate cancer events will be summarized separately by treatment group using estimates 
calculated by the Kaplan-Meier method and displayed graphically as Kaplan-Meier 
curves.
Listings of prostate cancer adverse events of special interest will be provided.
8.2.4.5.
Cardiovascular Tier 1 Adverse Events of Special Interest
Cardiovascular adverse events of special interest will be defined as those included in the
following six categories: acute coronary syndrome, ischemic coronary artery
disorders/atherosclerosis, ischemic cerebrovascular events, cardiac failure, cardiac
arrhythmias, and peripheral vascular disease. MedDRA preferred terms and codes
included in these special interest adverse events are defined in Appendix 8, Table C.
Total number of cardiovascular events as well as the number and percentage of subjects 
experiencing cardiovascular events will be provided by treatment group. Each category of
cardiovascular events, and all cardiovascular events as one additional category, will be
summarized separately following the same format done for sexual and breast special 
interest AEs described above. Time to first cardiovascular adverse event of special 
interest will be summarized by treatment group using estimates calculated by the Kaplan-
Meier method and displayed graphically as Kaplan-Meier curves.
Listings of cardiovascular adverse events of special interest will be provided.
Note: The protocol Section 7.4.2.2 (Cardiovascular Events) indicates additional data 
collection required for some cardiovascular events and procedures; these data will be 
output in data listings. Cardiovascular events in protocol Section 7.4.2.2 are not the full 
set of cardiovascular adverse events defined in this RAP section.
8.2.4.6.
Infrequent Tier 1 Adverse Events of Special Interest
Infrequent Tier 1 adverse events of special interest will be defined as those included in 
the following categories: 

Breast cancer

Potential for decreased male fertility due to effects on sperm/semen characteristics 

Interference with formation of external genitalia in a male fetus if a woman 
carrying a male fetus is exposed to dutasteride  
 
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
Hair changes

Allergic reactions

Depressed mood 

Testicular pain and swelling

Intraoperative floppy iris syndrome

Orthostasis 

Priapism

Stevens-Johnson syndrome

Atrial fibrillation, tachycardia, arrhythmias
MedDRA preferred terms and codes included in these special interest adverse events are 
defined in Appendix 8, Table D. Total number of infrequent Tier 1 events as well as the 
number and percentage of subjects with infrequent Tier 1 events will be provided by 
treatment group.
Listings of infrequent Tier 1 adverse events of special interest will be provided.
8.2.5.
Pregnancies
A listing of subjects whose female partner become pregnant during the study will be 
provided if there are any such subjects.
8.2.6.
Clinical Laboratory Assessments
Clinical chemistry and hematology parameters are evaluated from samples scheduled at 
the first screening visit (1a) and at each Month 12 and Month 24 (or end of treatment) 
visits. The following tests will be performed: 
Clinical Chemistry (serum):  Alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin, total protein, sodium, 
potassium, albumin, glucose, creatinine, UREA/BUN (blood urea nitrogen)
Hematology:  Hemoglobin, platelet count, white blood cell count (WBC), red blood cell 
count (RBC)
For purposes of statistical analyses the baseline value of a parameter for each subject will
be defined as the latest laboratory test value on or before the start of the randomized
treatment for that subject.
The final value of a parameter for each subject is defined as the latest post-baseline value
available in the study for that subject. A summary of parameter values, including the
baseline and final value, will be provided by treatment group and scheduled visit. A
summary of change from baseline in parameter values, including the final value, will also
be provided by treatment group and scheduled visit.
 
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A laboratory value that is on or within the normal range is considered normal. A
laboratory value that is above the upper limit of the normal range is considered high
abnormal. A laboratory value that is below the lower limit of the normal range is
considered low abnormal.
The number and percentage of subjects with an abnormal laboratory value at baseline
among subjects with a baseline laboratory value and at least one post baseline laboratory
value will be provided by treatment group and by parameter. The number and percentage
of subjects will be summarized by treatment group for each laboratory test for the
following shift categories:

Normal at baseline to abnormal at any time post-baseline

Normal at baseline to high at any time post-baseline

Normal at baseline to low at any time post-baseline

Normal or low at baseline to high at any time post-baseline

Normal or high at baseline to low at any time post-baseline
Laboratory data transitions from baseline to final assessment will be summarized for each
parameter according to the following categories:

Decrease: High to Low, Normal to Low, High to Normal

No Change: Low to Low, Normal to Normal, High to High

Increase: Low to Normal, Normal to High, Low to High
The threshold laboratory values are defined in terms of a multiplicative factor of the
testing laboratory’s normal range. A laboratory value that is above the upper limit factor
multiplied by the upper limit of the normal range is considered a high threshold value. A
laboratory value that is below the lower limit factor multiplied by the lower limit of the
normal range is considered a low threshold value. Refer to Appendix 9 for a listing of the 
laboratory threshold factors.
The number and percentage of subjects with a threshold laboratory value at baseline
among subjects with a baseline laboratory value and at least one post baseline laboratory
value will be provided by treatment group and by parameter. Subjects with threshold
values any time post-baseline with a non-threshold baseline laboratory value and at least
one post-baseline laboratory value will also be summarized by treatment group and by
parameter.
Listings of hematology and clinical chemistry data will be provided, along with listings 
of hematology and clinical chemistry data exceeding threshold.
The protocol defines possible drug-induced liver injury with hyperbilirubinaemia, for 
laboratory assessments planned in this study, as:
ALT ≥3xULN and Bilirubin ≥2xULN.
A listing of subjects meeting this defined liver function abnormality along with the 
corresponding data will be provided. If no subjects meet the defined criteria, a listing 
(page) will be produced indicating that no subjects met the criteria.
 
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A blood draw for HBsAg and Hepatitis C Antibody is scheduled for Visit 2 (baseline). 
These measurements will be included in a data listing.
8.2.7.
Serum PSA
Serum PSA samples are scheduled at the screening visit, and at each Month 6, Month 12, 
and Month 24 (or end of treatment) visits. Total PSA (absolute values, change from 
baseline values, and percentage change from baseline values) will be summarized by visit 
and treatment group using both the LOCF and At Visit approaches. Change from baseline 
total PSA will be compared in terms of combination treatment versus tamsulosin 
treatment at each scheduled post-baseline assessment using a general linear model with 
effects for treatment and baseline total PSA.
Listings of PSA data will be produced. A listing of PSA data will be provided, along with 
a listing of PSA data exceeding the upper limit of normal.
8.2.8.
Post Void Residual Volume
Total voided volume (in conjunction with Qmax) is measured at screening (Visit 1a with 
possible repeat at Visit 1b), baseline, and at each Month 6, Month 12, Month 18, and 
Month 24 (or end of treatment) visits.
A list of planned data displays is in Appendix 15: List of Data Displays. Baseline, change 
from baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary. Post void residual volume summary statistics will be presented for 
each scheduled visit; change from baseline and percentage change from baseline will be 
presented for each scheduled post-baseline visit.
Post void residual volume change from baseline distribution at each scheduled post-
baseline assessment will be compared in terms of combination treatment versus 
tamsulosin treatment using a nonparametric van Elteren test controlling for cluster at the 
0.05 level of significance.
A listing of post void residual volume data will be provided.
8.2.9.
Gynecomastia Evaluations
A qualitative breast examination is scheduled to be performed at the screening visit, and 
at each Month 6, Month 12, Month 18, and Month 24 (or end of treatment) visits. The
number and percentage of subjects with palpable breast tissue or nipple tenderness and/or
clinically significant palpable breast tissue or nipple tenderness at baseline, at each
scheduled post-baseline assessment and the final assessment (the latest post-baseline
evaluation available) will be presented by treatment. The number and percentage of
subjects changing from ‘no’ at baseline to ‘yes’ at any post-baseline assessment for
 
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palpable breast tissue and for nipple tenderness will be compared in terms of combination 
treatment versus tamsulosin treatment using Fisher’s exact test.
The number and percentage of subjects changing from ‘no’ at baseline in clinical 
significance to ‘yes’ at any post-baseline assessment in clinical significance for palpable 
breast tissue and for nipple tenderness will be presented by treatment group.
A listing of gynecomastia data will be provided.
8.2.10.
Digital Rectal Examinations
A digital rectal examination (DRE) is scheduled to be performed at the screening visit,
and at each Month 6, Month 12, Month 18, and Month 24 (or end of treatment) visits.
The results of normal versus focal abnormality will be summarized by treatment group at 
baseline, at each scheduled post baseline assessment and for the final assessment (the 
latest post-baseline evaluation available). Among subjects with focal abnormalities, 
summaries will include yes/no indication of clinical significance and a yes/no indication 
of biopsy recommendation. The number and percentage of subjects changing from 
‘normal’ at baseline to ‘focal abnormality’ at any post-baseline assessment will be 
compared in terms of combination treatment versus tamsulosin treatment using Fisher’s 
exact test.
A listing of digital rectal examination data will be provided.
8.2.11.
Vital Signs
Vital signs (blood pressure and heart rate) are scheduled to be assessed at screening, 
baseline, and at each of the scheduled post-baseline treatment phase visits. Vital signs 
will be summarized by treatment group for baseline, each scheduled post-baseline 
assessment through Month 24 as well as for the final assessment (the latest post-baseline
value available in the study). Change from baseline vital signs will also be summarized 
for each post-baseline assessment as well as for the final assessment. 
Refer to Appendix 9 for a listing of the vital sign threshold ranges. For threshold vital 
sign summaries, high threshold, low threshold as well as either threshold will be 
presented separately. The number and percentage of subjects with a threshold value at 
baseline among subjects with a baseline and a post baseline value will be presented by 
treatment group. The number and percentage of subjects with at least one post baseline 
value in the threshold range will be presented by treatment group. For each systolic blood 
pressure, diastolic blood pressure, and heart rate, the incidence of exceeding threshold 
will be compared in terms of combination treatment versus tamsulosin treatment using 
Fisher’s exact test.
A listing of vital signs data and a listing of vital signs data exceeding threshold will be 
provided.
 
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8.2.12.
Prostate Cancer Biopsies
A listing of data for biopsies performed to confirm prostate cancer will be provided. 
8.2.13.
Suicidality Assessment 
Assessment of suicidality will be done using the Columbia Suicide Severity Rating Scale (C-
SSRS) and is scheduled to be assessed at each Screening, Month 6, Month 12, and Month 
24 (or end of treatment) visits. Tabular summaries of suicidal ideation and suicidal 
behavior will be produced at each of the scheduled assessments. Along with the 
aforementioned tabular summary, as well, for all subjects with suicidal ideation or 
behavior at any assessment, a listing of C-SSRS data will be provided (as a table), along 
with listings of details of suicidal ideation and suicidal behavior.
In addition a listing of C-SSRS assessments for all subjects will be provided. As noted in 
the adverse event section of this document, the possible suicidality-related adverse events 
will be produced.
8.3.
Health Outcomes Analyses
Health outcomes analyses will be in terms of: BPH Impact Index (BII), BPH-Related 
Health Status (BHS), and the Problem Assessment Scale of the Sexual Function 
Inventory (PAS SFI). Health outcomes analyses will be performed using the ITT 
population unless otherwise specified in text or data display shells.
A list of planned Health Outcomes data displays is in Appendix 15: List of Data 
Displays. Baseline and change from baseline are defined in Appendix 6. Last observation 
carried forward (LOCF) and At Visit approaches are defined in Appendix 7. Reference 
Appendix 11 for descriptions of handling multiplicity.
8.3.1.
BPH Impact Index
The BPH Impact Index (BII) consists of four questions. It is administered at screening, 
baseline and at each of the scheduled post-baseline treatment phase visits. The BII total 
score is the sum of the four questions; the total score range is 0 to 13. BII summaries and 
analyses will be in terms of the total (score); exceptions will be noted such as for 
supporting summaries of individual questions.
For calculation of the BII total, missing individual responses will be imputed when at 
least two of the four questions are answered (nonmissing). For the imputation, the 
average of the nonmissing responses will be calculated and rounded to the nearest 
integer. This average will be imputed for the original missing response(s). If at least 20% 
of the subjects have at least one imputed BII then the statistical analyses will be repeated 
based on non-imputed scores.
Total BII, change from baseline BII, and percentage change from baseline BII will be 
summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment. Change from baseline BII at each scheduled post-
baseline assessment will be compared in terms of combination treatment versus 
 
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tamsulosin treatment using t-tests from a general linear model (GLM) with effects for 
treatment, cluster, and baseline BII. Two-sided tests at 0.05 level of significance will be 
conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
BII adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Each of the four BII individual question responses will be summarized at Baseline, 
Month 12, and Month 24 by treatment group. Month 12 and Month 24 changes from 
baseline will be summarized by treatment group for each of the four questions.  The 
summaries will be based on the ITT population and presented using both LOCF and At 
Visit approaches. No statistical testing will be performed.
Listings of BII individual question and total scores will be presented.
As a supportive analysis, BII will be analyzed using a mixed-model repeated-measures 
(MMRM) analysis in a manner similar to that described for primary efficacy in Appendix 
13.
8.3.2.
BPH-Related Health Status
BPH-Related Health Status (BHS) is collected as Question 8 the IPSS questionnaire and 
ranges from 0 to 6. The IPSS questionnaire is administered, and thus BHS is collected, at 
screening, baseline and at each of the scheduled post-baseline treatment phase visits.
Total BHS, change from baseline BHS, and percentage change from baseline BHS will 
be summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment. Change from baseline BHS at each scheduled post-
baseline assessment will be compared in terms of combination treatment versus 
tamsulosin treatment using t-tests from a general linear model (GLM) with effects for 
treatment, cluster, and baseline BHS. Two-sided tests at 0.05 level of significance will be 
conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
BHS adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
 
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A listing of BHS data will be presented.
As a supportive analysis, BHS will be analyzed using a mixed-model repeated-measures 
(MMRM) analysis in a manner similar to that described for primary efficacy in Appendix 
13.
8.3.3.
Problem Assessment Scale of the Sexual Function Inventory
(PAS SFI)
The Problem Assessment Scale of the Sexual Function Inventory (PAS SFI) consists of 
three questions each with a range of 0 (Big Problem) to 4 (No Problem). It is 
administered at screening, baseline and at each Month 12 and Month 24 (or end of 
treatment) visits. The total PAS SFI is the sum of the three questions; the total score 
range is 0 to 12. PAS SFI summaries and analyses will be in terms of the total (score); 
exceptions will be noted such as for supporting summaries of individual questions.
For a given subject and visit, calculation of the PAS SFI total will not be performed or 
imputed if two or all three individual responses are missing.  For a given subject and 
visit, a single missing individual response will be imputed when two of the three
questions are answered (nonmissing). For the imputation, the average of the nonmissing 
responses will be calculated and rounded to the nearest integer. This average will be 
imputed for the original missing response. If at least 20% of the subjects have at least one 
imputed PAS SFI then the statistical analyses will be repeated based on non-imputed 
scores.
Total PAS SFI and change from baseline PAS SFI will be summarized by treatment 
group using both the LOCF and At Visit approaches at each scheduled post-baseline 
assessment. Change from baseline PAS SFI at each scheduled post-baseline assessment 
will be compared in terms of combination treatment versus tamsulosin treatment using t-
tests from a general linear model (GLM) with effects for treatment, cluster, and baseline 
PAS SFI. Two-sided tests at 0.05 level of significance will be conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
Each of the three PAS SFI individual question responses will be summarized at Baseline, 
Month 12, and Month 24 by treatment group. Month 12 and Month 24 changes from 
baseline will be summarized by treatment group for each of the three questions. The 
summaries will be based on the ITT population and presented using both LOCF and At 
Visit approaches. No statistical testing will be performed.
A listing of PAS SFI data will be presented.
 
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9.
COUNTRY-SPECIFIC SUMMARIES AND ANALYSES
Four countries randomized subjects into this trial and include: China, Japan, Korea, and 
Taiwan. It is anticipated that each of these countries will conduct a regulatory submission 
using planned summaries and analyses of this ARI114265 study.  For primary regulatory 
filings, summaries and analyses will be in terms of the Intent-to-Treat population which 
is based on pooled country data. These regulatory filings may also require complete or 
various sub-levels of data summaries and analyses for (their) specific country.
Each country’s regulatory requirements will be fully defined at a time approaching the 
regulatory filing which will be after RAP finalization. Therefore, to address the potential
requirements for complete country-specific summaries and analyses, all planned tables
and figures, including planned statistical analyses, will be repeated for each of the four 
countries. Cluster (defined earlier in RAP as equal to country) will be excluded from the 
model-based within-country analysis. Exceptions will include planned by-country tabular 
summaries and listings. There will be no across-country multiplicity adjustments. The 
within-country statistical analyses will be underpowered because of their smaller sample 
sizes.
The summaries and analyses for each of the four countries will be provided by Clinical 
Statistics and Programming as part of a secondary (country-based) statistical analysis 
complete (SAC) package. Then, considering country regulatory filing plans and 
requirements, GSK regulatory staff of the individual countries will indicate to medical 
writing staff the summaries, analyses, and formats to be used in final reporting. Non-
reporting of some or all country-based summaries and analyses by the individual 
countries will not result in a RAP revision.  
It is anticipated that analysis and reporting of each country will add up to 2 weeks to the 
initial (Intent-to-Treat Population) SAC.  Therefore, the “Country-specific SAC” will be 
“Primary SAC” plus 8 weeks. The country analysis may be ordered so that the country 
with earliest regulatory requirements will undergo first analysis and reporting. Changes to 
the anticipated ‘8 weeks’ as well as action definition of country reporting order will not 
result in a RAP revision.
 
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10.
REFERENCES
GlaxoSmithKline Document Number RM2010/00134/05 Study ID ARI114265. Protocol 
Amendment 4: A randomized, double-blind, parallel group study to compare the efficacy 
and safety of combination treatment with dutasteride (0.5mg) and tamsulosin (0.2mg) 
with tamsulosin (0.2mg) monotherapy, administered once daily for 2 years, on the 
improvement of symptoms and health outcomes in men with moderate to severe benign 
prostatic hyperplasia. Report Date 08-JUL-2014. 
GlaxoSmithKline Document: Program Safety Analysis Plan (PSAP) for GI198745 
(dutasteride) and GSK2285985 (fixed dose combination of dutasteride [GI198745] and 
tamsulosin [GI138525]); PSAP approval date 09Dec2016.  Note: This reflects PSAP 
version at point of RAP finalization. Any PSAP updates/revisions at point of Statistical 
Analysis Complete (SAC) may be incorporated without a revision to this RAP; in this 
event, PSAP updates impacting analysis and reporting will be described in CSR. 
Mallinckrodt C, Lane P, Schnell D, Peng Y, Mancuso J.  Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Drug 
Information Journal. 2008; 42: 303-319
 
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11.
APPENDICES
Section
Appendix
Section 11.1
Appendix 1: Exclusions from the Per-Protocol Population
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Multicenter Studies
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions
Section 11.6
Appendix 6: Derived and Transformed Data
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 11.8
Appendix 8: Adverse Event Time Periods and Special Adverse Event Definitions
Section 11.9
Appendix 9: Threshold Factors for Clinical Laboratory Tests and Vital Signs
Section 11.10
Appendix 10: Examination of Covariates and Subgroups
Section 11.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Section 11.13
Appendix 13: Mixed-Model Repeated Measures Analysis
Section 11.14
Appendix 14: Abbreviations & Trade Marks
Section 11.15
Appendix 15: List of Data Displays
Section 11.16
Appendix 16: Mock Shells for Data Displays
Section 11.17
Appendix 17: Amendment 01 Revisions
 
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11.1.
Appendix 1: Exclusions from the Per-Protocol Population
In accordance with SOP-130050 and the ARI114265 PDMP, deviations which require 
exclusion from the Per-Protocol population must be identified, when possible, in advance
of treatment unblinding. The deviation review and programming processes, as well as 
spreadsheet and database capabilities, require that deviation identification must be made 
from two sources:
1. Study Team Assessment of deviations tracked on study team’s protocol deviations 
spreadsheet and then indicated as ‘Exclude from Per-Protocol’ 
and 
2. Programmatic Assessment which outputs deviations through Statistics & Programming 
electronic SAS code execution.
The below table lists the 19 deviations which would exclude a subject from the Per-
Protocol population along with identification methods. It is expected that a final analysis 
dataset will be generated with the two sources pooled.  Details on the pooled dataset 
programming and any adjudication process required to reconcile the two sources will be 
defined in advance of database freeze through a RAP amendment or a high level note to 
Study File. If there is inconsistency between the two sources, it is anticipated that the 
programmatic determination will be considered definitive; this will be outlined through a 
RAP amendment or a high level note to Study File.
Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
01
Missed placebo run-in 
phase
Any evidence which 
implies or documents 
that subject missed the 
placebo run-in phase.
1) Placebo run-in treatment 
start and stop dates are missing 
or 
2) Placebo run-in tablets 
consumed = zero
[A5]
02
Incorrect study drug 
(wrong treatment) 
consumed
Any evidence which 
confirms that the 
incorrect container 
contains other-than-
scheduled study 
treatment.
Treatment consumed (from 
incorrect dispensed container)
unequal to treatment planned in 
randomization schedule. Note: 
this can only be determined 
after study unblinding. [A5]
03
Randomized but did not 
consume double-blind 
study drug
Any evidence which 
confirms that the zero 
tablets were consumed 
in double-blind phase
Final nonmissing cumulative 
study drug compliance = zero
[A5]
04
Cumulative study drug 
compliance <75%
Study team is unable to 
calculate RAP-defined 
study drug compliance. 
Therefore, deviation will 
be determined based on 
programmatic 
Final nonmissing cumulative 
study drug compliance < 75%
[A5]
 
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Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
assessment.
05
Cumulative study drug 
compliance >125%
Study team is unable to 
calculate RAP-defined 
study drug compliance. 
Therefore, deviation will 
be determined based on 
programmatic 
assessment.
Final nonmissing cumulative 
study drug compliance > 125%
[A5]
Violation of Inclusion 
Criteria (protocol #)
06
Confirmed BPH clinical 
diagnosis (Inclusion 2)
Any evidence which 
confirms inclusion 
criterion 2 deviation.
Eligibility database indicates 
violation of inclusion criterion 2
[A1]
07
IPSS ≥12 at Screening 
(Inclusion 3)
Any evidence which 
confirms inclusion 
criterion 3 deviation.
Eligibility database indicates  
violation of inclusion criterion 3
[A1]
08
Prostate volume ≥30cc by 
TRUS at Screening 
(Inclusion 4)
Any evidence which 
confirms inclusion 
criterion 4 deviation.
Eligibility database indicates 
violation of inclusion criterion 4
[A1]
09
PSA ≥1.5ng/ml and 
≤10ng/mL at Screening 
(Inclusion 5)
Any evidence which 
confirms inclusion 
criterion 5 deviation.
Eligibility database indicates 
violation of inclusion criterion 5
[A1]
10
Qmax >5 mL/sec and 
≤15mL/sec with Voided 
Volume ≥125mL/sec at 
Screening (Inclusion 6)
Any evidence which 
confirms inclusion 
criterion 6 deviation.
Eligibility database indicates 
violation of inclusion criterion 6
[A1]
Violation of Exclusion 
Criteria (protocol #) 
11
Any conditions other than 
BPH, which may in the 
judgement of the 
investigator, result in 
urinary symptoms or 
changes in flow rate 
(Exclusion 6)
Any evidence which 
confirms exclusion 
criterion 6 deviation.
Eligibility database indicates 
violation of exclusion criterion 6
[A1]
12
Use of 5ARI within 6 
months of Screening or 
historical TRUS and 
throughout the study 
(Exclusion 10a)
Any evidence which 
confirms exclusion 
criterion 10a deviation.
Reference Note b.
[A1]
13
Use of anabolic steroids 
within 6 months of 
Screening and throughout 
the study (Exclusion 10b)
Any evidence which 
confirms exclusion 
criterion 10b deviation.
Reference Note b.
[A1]
14
Use of phytotherapy for 
BPH within 2 weeks of 
Screening and throughout 
the study (Exclusion 10c)
Any evidence which 
confirms exclusion 
criterion 10c deviation.
Reference Note b.
[A1]
 
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Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
15
Use of alpha-
adrenoreceptor blockers 
within 2 weeks of 
Screening and throughout 
the study, except study 
meds (Exclusion 10d)
Any evidence which 
confirms exclusion 
criterion 10d deviation.
Reference Note b.
[A1]
16
Use of alpha-
adrenoreceptor agonists 
or anticholinegics or 
cholinergics within 48 
hours prior to all 
uroflowmetry and IPSS 
assessments (Exclusion 
10e)
Any evidence which 
confirms exclusion 
criterion 10e deviation.
Reference Note b.
[A1]
17
Use of selective beta 3-
adrenoreceptor agonist 
(mirabegron) within 2 
weeks prior to all 
uroflowmetry and IPSS 
assessments (Exclusion 
10f)
Any evidence which 
confirms exclusion 
criterion 10f deviation.
Reference Note b.
[A1]
18
Prohibited medications 
and non-drug therapies of 
Protocol Section 6.2 and 
not otherwise classified 
above.
Study team identification 
of prohibited medication 
or non-drug therapy 
which should require 
exclusion from per-
protocol population and 
not otherwise classified 
above.
[A3]
Other
19
Any condition which 
should exclude a subject 
from the Per-Protocol 
population and is not 
include above.
Study team identification 
through review of 
multiple sources such as 
protocol deviation log 
text, study drug 
compliance outliers, 
concomitant medication 
logs, or site/monitor 
communications. 
NA
Notes: 
a.
Reflects eCRF corresponding code to be applied programmatically; definitions in below table.
b.
Exclusion 10 subsets (a – f) are not individually identified in the INFORM and Analysis & Reporting 
datasets.  Therefore, deviation will be determined based on study team assessment.
 
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Important Deviations Categories, Subcategories, and eCRF Codes
(eCRF Codes define above indicated programmatic assignment)
Category / 
Subcategory
eCRF
Codes
Assessments and/or procedures
Biological specimen sample procedures
6E
Equipment procedures
6G
Failure to comply with dosing procedure
6L
Failure to report SAE, pregnancy, or liver
function abnormalities per-protocol
6B
Informed consent process
6A
Missed assessment or procedure
6I
Randomization procedures
6H
Study blind / unblind procedures
6C
Study treatment supply procedures
6D
Other
6OT
Eligibility criteria not met
A1
Prohibited medication or device
A3
Received wrong treatment or incorrect dose
A5
Visit, assessment or timepoint window
Window for dose administration
4C
Window for efficacy assessments
4A
Window for safety assessments
4B
Other
4OT
 
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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomization)
3 months post 
Randomization
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
ICF
X
Inclusion/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X

X
Physical Examinationa
X
X
X
Xh
X
Vital signsb
X
X
X
X
X
X

X
Haematology/clinical 
chemistry
X
X
X
HBsAg and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
Xh
X
AEs d
X 
X 
X
X
X
X

X
Suicidality (C-SSRS)
X
X
X
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X

X
Prostate Volume (TRUS)
X
X
X
 
 
 
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomization)
3 months post 
Randomization
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
Peak Urine Flow (Qmax)
X
X***
X
X
X
Xh
X
AUR or BPH-related Surgery
X
X
X
X

X
X
Pharmacokineticsj
Serum PK samplesj
X
X
X
Health Outcomes:
BPH Health Status Q 8 IPSS 
(BHS)
X
X
X
X
X
X

X
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X

X
BPH Impact Index (BII) 
X
X
X
X
X
X

X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X

X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X

Compliance check/Collection
X
X
X
X
X

X
Protocol Defined Time & Events, Notes
** This second screening visit is mandatory before dispensing placebo run-in medication. This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
  ongoing assessment
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
 
 
 
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c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RNA test should be reflexively performed to confirm the result)
h.
Only performed at Visit 8 (Month 18)
i.
Performed for End of Study Treatment Assessments as well when a subject discontinues the study treatment.
j.
Serum PK samples are only applicable to subjects of Chinese origin living in China.
 
 
 
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11.3.
Appendix 3: Assessment Windows
Boundaries for the scheduled assessments are defined in the protocol. The data will be 
summarized by nominal visit without regard to window days for all scheduled visits. The 
efficacy, safety, and health outcomes measures collected at nominal visits include IPSS, 
prostate volume, Qmax, PSA, post void residual volume, BII, BPH-related Health Status, 
and PAS-SFI. In order to utilize as much data as possible in these efficacy, safety, and 
health outcomes summaries and analyses, premature withdrawal visit data will be used as 
the scheduled visit data when both of the following criteria are met:

The scheduled visit evaluation is not available, and 

The premature withdrawal visit date falls within 30 days (inclusive) for each of 
the scheduled post baseline visits (i.e., Months 3, 6, 9, 12, 15, 18, 21, and 24), or 
within 15 days (inclusive) of the scheduled Baseline visit (Month 0).  The 
scheduled visit day for month k will be calculated as: 
Baseline Date + (k * 365/12) rounded to the nearest integer.
 
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11.4.
Appendix 4: Multicenter Studies
11.4.1.
Methods for Handling Centers
The 4 countries which randomized subjects into this trial include: China, Japan, Korea, 
and Taiwan. Forty-six centers across these 4 countries randomized subjects into this trial.
Clusters will be used in the exploration of center effect and treatment-by-center 
interaction. 
As stated in the protocol, it was anticipated that randomized subject accrual would be 
spread thinly across centers and summaries of data by center would be unlikely to be 
informative. It was expected that investigative centers would be pooled a priori into 
clusters based on geographic location. As stated in protocol, these clusters would be 
identified once randomization was complete and then used in statistical analyses in the 
exploration of center effects and treatment-by-center interaction.
Based on the actual randomization of sites within countries, it is reasonable and logical to 
assign each country as a single cluster. Therefore, the 4 clusters are the 4 countries:  
China, Japan, Korea, and Taiwan. The countries will be used in summaries of 
randomized subjects, subgroup summaries, and in statistical analyses of efficacy center 
effect and treatment-by-center interaction; these by-country summaries and analyses are 
described in relevant sections.
 
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG [1]
Data Displays for Reporting
Code
Description
Description
Order [2]
A
Dutasteride 0.5mg once daily + 
tamsulosin 0.2mg once daily
Dut 0.5mg + Tam 0.2mg
2
B
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
Placebo + Tam 0.2mg
1
NOTES:
1.
RandAll NG (Next Generation) is a randomization creation and publishing tool for GSK studies.
2.
Order represents treatments being presented in tables, listings, and figures.
Within this RAP, the following additional references may be made for brevity:
--Full Treatment Description--
--Short Treatment Descriptions--
Dutasteride 0.5mg once daily +
tamsulosin 0.2mg once daily or
-Combination
-Dut 0.5mg + Tam 0.2mg
-Dut + Tam
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
-Tamsulosin Monotherapy
-Tam 0.2mg
-Placebo + Tam 0.2mg
-Tam
 
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11.5.2.
Reporting Process & Standards
The following reporting process and reporting standards details apply to all RAP defined 
endpoints.
Reporting Process
Software

SAS software will be used for all analyses except when noted.  It is anticipated that the SAS 
software version 9.3 will be in use at statistical analysis complete; use of a version other than 
9.3 will be documented in IMMS Study File.
Reporting Areas  The following server and areas are identified as of RAP finalization. Revisions
to these areas, for example due to platform / server relocation and/or CDISC reporting standards, 
will be documented in IMMS Study File.
HARP Server
US1SALX00259
HARP Area
The high level area is defined as:  /arenv/arprod/gi198745/ari114265/final.
QC Documentation 
Area
QC process and documentation for analysis and reporting will be maintained 
as a text file on HARP server US1SALX00259 within above noted area.
Analysis Datasets 

Analysis datasets for international regulatory submissions will not be created according to
CDISC standards. GSK exemption for ARI114265 CDISC-based dataset creation and reporting 
was granted in June 2016.
Generation of RTF Files

RTF files will be generated for all tabular summaries with the reporting efforts described in the 
RAP unless clearly stated as not required by the assigned Scientific and Medical Writer(s).   
Reporting Standards
General
The current GSK Integrated Data Standards Library (IDSL) and GSK IDSL Statistical Principles will 
be applied for reporting, unless otherwise stated within RAP text or indicated in table, listing, figure 
shells:

4.03 to 4.24: 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 
From the above standards and principles as well as to be aligned with historical reporting for this 
compound and indication, the key reporting standards to be applied are:

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

Within listings, 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 decimal places.

Within tabular summaries, the minimum and maximum values are presented with the same 
 
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Reporting Standards
number of decimal places as the raw data collected on the eCRF. The mean and percentiles 
(e.g. median, Q1, and Q3) are presented using one additional decimal place. The standard 
deviation and standard error are presented using two additional decimal places.

Continuous variables (e.g., age) will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum.

Categorical variables will be summarized using the number of subjects (n) and percentage (%) 
in each category.

P-values greater than 0.10 will be reported to two decimal accuracy. P-values less than or 
equal to 0.10 will be reported to three decimal accuracy. P-values less than 0.001 will be 
reported as ‘<0.001’.

Applicable safety analysis and reporting definitions and presentations within “Program Safety 
Analysis Plan (PSAP) for GI198745 (dutasteride) and GSK2285985 (fixed dose combination of 
dutasteride [GI198745] and tamsulosin [GI138525]” will be referenced; any deviations will be 
noted within this RAP.
 
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11.6.
Appendix 6: Derived and Transformed Data
(Placebo) Run-In Start and Stop Dates

Placebo run-in start date = Start date of (placebo) study treatment recorded for the run-in 
period. If the recorded start dates for the two study drug containers differ, then select the 
earlier start date.

Placebo run-in stop date = End date of (placebo) study treatment recorded for the run-in 
period. If the recorded stop dates for the two study drug containers differ, then select the later 
stop date.
Note: a subject with a nonmissing placebo run-in start date will be considered as included in the 
Placebo Run-in Phase.
Randomization Date

Randomization date is the randomization telephone call in date which is recorded in the eCRF. 
This date is defined here for completeness and no derivations are made.
Note: a subject with a nonmissing randomization number recorded in eCRF will be considered 
Randomized.
(Double-Blind) Treatment Start and Stop Dates

Treatment start date = Start date of study treatment recorded for the (double-blind) treatment 
period. If the recorded start dates for the two study drug containers differ, then select the 
earlier start date.

Treatment stop date = Stop date of study treatment recorded for the (double-blind) treatment 
period. If the recorded stop dates for the two study drug containers differ, then select the later 
stop date.
 
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Study Drug Exposure and Compliance

As explained in the protocol: 
-Dutasteride study treatment is dispensed as capsules within bottles.
-Tamsulosin study treatment is dispensed as tablets within blister packs.
Within this RAP, the following general terms are used for exposure and compliance:
---“Pill” refers to a capsule or a tablet
---“Container” refers to a bottle or a blister pack.

Study drug exposure (in days) is number of days between (double-blind) treatment start date 
and (double-blind) treatment stop date, both days inclusive (i.e. Study drug exposure 
=Treatment Stop Date – Treatment Start Date +1).

Number of pills consumed during the study is defined for double-blind period as total number of 
pills dispensed (sum over all containers dispensed) minus total number of pills returned (sum 
over all containers dispensed) minus total number of pills lost or wasted (sum over all 
containers dispensed). If any of the containers is not returned or number of pills returned or
wasted is missing for any container, number of pills consumed during the study is missing.

Overall study drug compliance is defined for double-blind period as 100 * Number of Pills 
Consumed / Number of Pills Prescribed.  Number of Pills Prescribed = 2 * Study Drug 
Exposure, since the protocol prescribes that subjects consume 2 pills for each day a subject is 
on treatment (one pill of Placebo or Dutasteride, and one pill of Tamsulosin).  Overall study 
drug compliance is missing if either the number of pills consumed during the study or the study 
drug exposure is missing.

Compliance by study drug component:  Study drug compliance by component will be output 
for:  
--Placebo + Tam 0.2mg for each of the two components:  Placebo and Tam 0.2mg
--Dut 0.5mg + Tam 0.2mg for each of the two components:  Dut 0.5mg and Tam 0.2mg
Compliance is defined as 100 * Number of Pills Consumed / Number of Pills Prescribed, where 
the only pills considered are those for a specific(e.g. Tamsulosin).  Number of Pills Prescribed 
= Study Drug Exposure, since the protocol prescribes that subjects consume 1 pill of any study 
drug component (e.g. Tamsulosin) for each day a subject is on treatment.
Baseline Date

A subject’s baseline date will be the latest non-missing value of either (double-blind) treatment 
start date or randomization date. Baseline date will be used in the derivation of study day 
values and Baseline Values. ‘Baseline date’ may differ from the Visit 2 (Baseline Visit) date 
recorded in eCRF.
Baseline Value

For purposes of data analyses, the subject’s baseline value of an assessment will be defined 
as the latest assessment on or before the Baseline Date.
Change and % Change from Baseline

Change from Baseline = Post-baseline Value – Baseline

% Change from Baseline = 100 x [(Post-baseline Value – Baseline) / Baseline]
 
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Study Day
Study Day is calculated as the number of days from Baseline Date:

Reference Date = Missing
→ Study Day = Missing

Reference Date < Baseline Date
→ Study Day = 
Reference Date – Baseline Date

Reference Date ≥ Baseline Date
→ Study Day = 
Reference Date – (Baseline Date) + 1
Cut-off Dates
-Month k Cut-off Date (for k= 3, 6, 9, 12, 15, 18, 21, 24):  The maximum of [Month k clinic visit date, 
Month k lab visit date, Baseline Date + (k * 91/3)].
Time Since LUTS First Noted (in years)
-Time Since LUTS First Noted = Baseline Date minus Date LUTS First Noted by Patient / 365
Time Since BPH Clinical Diagnosis (in years)
-Time Since BPH Diagnosis = Baseline Date minus Date of BPH Clinical Diagnosis / 365
Age
Only year of birth is collected in the eCRF. For purposes of calculating age for a given subject, date 
of birth will be defined as June 30th of the corresponding year of birth.  Age is calculated in terms of 
Screening (Visit 1b) date and output as a truncated integer. Age categories include <65, ≥65, <75, 
and ≥75 years.
Body Mass Index (BMI) (kg/sq m)
BMI = Weight (kg) / [Height (m)]2
Race / Ethnicity
Race / ethnicity will be determined based on a subject’s reported ethnicity and geographic ancestry 
as defined in the following table.
Race / Ethnicity
Asian
White (But Not Hispanic)
Hispanic
Other
Ethnicity
Not Hispanic or Latino
Not Hispanic or Latino
Hispanic or 
Latino
Not Hispanic 
or Latino
Geographic 
Ancestry
Any combination of 
(restricted to the 
categories below only):
-Asian – East Asian
Heritage
-Asian – Japanese
Heritage
-Asian -  South East
Asian Heritage
-Asian – Central / South
Asian Heritage
Any combination of 
(restricted to the below 
categories only):
-White – Arabic/ North
African Heritage
-White – White/
Caucasian/
European Heritage
Any 
combination
Any 
combination 
not considered 
‘Asian’ or 
‘White (But 
Not Hispanic)’
IPSS (total score)
IPSS (total score) = Sum of IPSS individual questions 1 – 7.  Reference Section 7.1.1 for 
imputation procedure.
Prostate Volume
Prostate Volume = pi/6 (Anteroposterior Width x Cephalocaudal Width x Transverse Width)
 
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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as
completion of the 4-week placebo run-in and the 104-week study treatment 
period.

Withdrawn subjects will not be replaced in the study.

All available data from subjects 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.

Number and percent of ITT population completing the study and those 
withdrawing from the study, along with eCRF recorded reasons for premature 
withdrawals, will be summarized by treatment and overall. 
Note
This section addresses Premature Withdrawals from the study. Premature 
discontinuation of investigational product, along with reasons, is a separate data 
collection and is reported separately.
11.7.2.
Handling of Missing Data
11.7.2.1.
Handling of Missing or Partial Dates
For efficacy time to event endpoints, such as ‘Time to AUR or BPH-Related Surgery’ the 
following approach will be used for unknown event dates unless otherwise indicated. If 
the month and year are known but the day of the month is unknown, then the day of the 
month will be imputed to be the 15th . If the year is known but the month and day are 
unknown then the date will be imputed to be July 2 in that year. In all the preceding 
cases, if it is not definitive that the onset date is on or after the treatment start date based 
on the non-missing (non-imputed) dates, then the date will be imputed to be the treatment 
start date. If the year is unknown then the onset date is considered to be prior to 
treatment start; hence, the event will be excluded from summaries of events on or after 
treatment start.  For subjects without events, the censoring dates will be established using 
non-missing dates, and using dates with only days missing.  Dates with missing months 
and years will not be used in establishing the censoring dates.
Partial adverse event dates will be handled as described in Appendix 8.
11.7.2.2.
Handling of Missing Data for Statistical Analysis
Endpoints measured at specific visits and analyzed in terms of visit numbers include:  
IPSS, prostate volume, Qmax, PSA, post void residual volume, BPH Impact Index (BII), 
BPH-Related Health Status, and PAS-SFI.  Analysis of the data collected in terms of visit 
numbers will be performed using two different approaches to account for missing data.
 
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1. LOCF (Last Observation Carried Forward) analysis:  This involves bringing 
(carrying) forward the last non-missing post-baseline assessment for subjects with 
missing visit data and/or for subjects who discontinued from the study.
2. At Visit analysis:  Missing values at post-baseline assessments are not replaced and 
are regarded as missing.
The LOCF approach will be considered primary for those endpoints in which both LOCF 
and At Visit are used.  If the LOCF and At Visit results are not consistent with regard to 
the statistical analyses and conclusions, then further data analyses will be undertaken. 
11.7.3.
Questionnaire Total Score Imputation
Calculations of IPSS total and BII total, including imputation for missing responses, are 
described in the respective RAP sections.
 
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11.8.
Appendix 8: Adverse Event Time Periods and Special 
Adverse Event Definitions
Date-related derivations and transformations related to adverse events (AEs) are 
described below.
AE Onset Time since First Dose
= AE Onset Date – Treatment Start Date if treatment start date > AE onset date
= AE Onset Date – Treatment Start Date +1 if treatment start date <= AE start date
= missing otherwise
AE Duration (in days) = AE Resolution Date – AE Onset Date + 1
The timing of AEs will be categorized as follows:

An AE is “Pre-Treatment” if the AE onset date is before the treatment start date.

An AE is “On Treatment” if the AE onset date is on or after the treatment start
date (but on or before the treatment stop date, if that is non-missing), or if the 
onset date is missing.

An AE is “Post-Treatment” if the treatment stop date is non-missing, and the AE 
onset date is after the treatment stop date.

An AE is “Post-Randomization” if the AE is either On Treatment or Post-
Treatment.
Note: Cut-off dates are defined in Appendix 6; definition is repeated here, in terms of 6-
month treatment periods, since this is used to determine AE onset period:
Month k Cut-off Date (for k= 6, 12, 18, 24):  The maximum of [Month k clinic visit date, 
Month k lab visit date, Baseline Date + (k * 91/3)].
An on-treatment AE is uniquely identified as having onset within one of the following
four time periods: Months 1-6, Months 7-12, Months 13-18, or Months 19-24. 

An AE is considered to have onset in the Months 1-6 time period if it is an on-
treatment AE and the onset date is on or before the Month 6 cut-off date.

An AE is considered to have onset in the Months 7-12 time period if it is an on-
treatment AE and the onset date is after the Month 6 cut-off date and is on or 
before the Month 12 cut-off date.

An AE is considered to have onset in the Months 13-18 time period if it is an on-
treatment AE and the onset date is after the Month 12 cut-off date and is on or 
before the Month 18 cut-off date.

An AE is considered to have onset in the Months 19-24 time period if it is an on-
treatment AE and the onset date is after the Month 18 cut-off date.
If the AE onset date is partially missing, the timing is determined as follows:
1. If the non-missing parts of the date (either just year or year/month) are unambiguously 
before the start of treatment, the AE is considered Pre-Treatment.
 
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2. If the non-missing parts of the date are unambiguously after the stop of treatment, the
AE is considered Post-Treatment.
3. If #1 or #2 above cannot be assigned, then the AE is considered On-Treatment.
If an on-treatment AE onset date is partially missing, then, for the purpose of assigning 
the 6-month treatment period referenced above, the onset date will be imputed according 
to the algorithm described in the second paragraph below, and the imputed date will be 
used to assign the period.
An AE is considered drug-related if the relationship variable indicates so, or the variable
value is missing. When an AE has an outcome of Resolved/Recovered with or without
sequelae, it may be categorized for resolution status as follows: if resolution date is on or
before treatment stop date, the AE is considered resolved on-therapy, or if either the
resolution date or the treatment stop date is missing and the action taken is not
‘investigational product withdrawn’, the AE is considered resolved on-therapy. If a
resolved AE is not resolved on-therapy, it is considered resolved off-therapy.
For the purpose of Kaplan-Meier estimates for Special Interest AEs, and for categorizing
AEs by time intervals, the following algorithm will be used:
1) If an AE start date is partial, it will be imputed as follows:
a.
If all components of the date (day, month and year) are missing, then the 
date will not be imputed, but the AE will be categorized in the first 6-
month time period.
b. If both day and month are missing, then the day and month will be 
imputed as 01 January.
c.
If only day is missing, then the day will be imputed as 01.
d. Any imputation described in items 1b and 1c above will be revised if it is 
in conflict with the treatment start date: if the month and year of treatment 
start date is same as those in the imputed date, the imputed date will be 
changed to the treatment start date.
2) A subject not having the particular AE will be censored at the latter of the 
following two dates: date of last clinic visit, latest AE start date.
3) If an AE end date is partial, it will be imputed as follows:
a.
If all components of the date (day, month and year) are missing, then the 
end date will be missing.
b. If both day and month are missing, then the day and month will be 
imputed as 31 December.
c.
If only day is missing, then the day will be imputed as the last day of the 
corresponding month.
For computing AE duration, partial AE start and end dates will be imputed as previously 
described, and events with completely unknown (missing) end dates will be censored at 
the latter of the following two dates: date of last clinic visit, latest AE start date. AE 
duration is the total number of non-overlapping days for all events per subject, and will 
be considered censored if any contributing event is censored.
Time to death is defined as (date of death – treatment start date +1). For subjects who do
not experience death, time to death is censored at the date of last clinic visit (if missing, 
 
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the subject will be censored at the treatment start date).
Special interest adverse events, including MedDRA preferred terms and codes, are 
presented below in Table A-Table D:
Table A: Sexual and Breast Adverse Events of Special Interest
Table B: Prostate Cancer Adverse Events of Special Interest
Table C: Cardiovascular Adverse Events of Special Interest
Table D: Infrequent Tier 1 Adverse Events of Special Interest
Table A.  Sexual and Breast Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Altered (Decreased) Libido
Sexual dysfunction
10040477
Male sexual dysfunction
10057672
Libido decreased
10024419
Loss of libido
10024870
Libido disorder
10061221
Impotence
Erectile dysfunction
10061461
Organic erectile dysfunction
10052004
Disturbance in sexual arousal
10058929
Psychogenic erectile dysfunction
10052005
Ejaculation Disorders
Ejaculation delayed
10014325
Ejaculation disorder
10014326
Ejaculation failure
10014328
Retrograde ejaculation
10038967
Anorgasmia
10002652
Orgasm abnormal
10031085
Premature ejaculation
10036596
Male orgasmic disorder
10025513
Orgasmic sensation decreased
10052449
Semen volume decreased
10039944
Breast Disorders
Breast hyperplasia
10006256
Breast enlargement
10006242
Gynaecomastia
10018800
Nipple disorder
10029417
Breast engorgement
10006240
Breast swelling
10006312
Breast pain
10006298
Breast tenderness
10006313
Nipple pain
10029421
Nipple swelling
10058680
Breast discomfort
10049872
Breast Disorders: Breast Enlargement
Breast hyperplasia
10006256
Breast enlargement
10006242
Gynaecomastia
10018800
Nipple disorder
10029417
Breast engorgement
10006240
Breast swelling
10006312
Breast Disorders: Breast Tenderness
Breast pain
10006298
Breast tenderness
10006313
Nipple pain
10029421
Nipple swelling
10058680
Breast discomfort
10049872
 
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Table B.  Prostate Cancer Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Prostate Cancer
Prostate cancer
10060862
Prostate cancer stage 0
10036912
Prostate cancer stage I
10036917
Prostate cancer stage II
10036918
Prostate cancer stage III
10036919
Prostate cancer stage IV
10036920
Prostate cancer recurrent
10036911
Prostate cancer metastatic 
10036909
Table C.  Cardiovascular Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Acute Coronary Syndrome
Acute myocardial infarction 
10000891
Myocardial infarction 
10028596
Silent myocardial infarction  
10049768
Sudden cardiac death
10049418
Angina unstable 
10002388
Cardiac arrest
10007515
Cardio-respiratory arrest
10007617
Cardiac death
10049993
Acute coronary syndrome 
10051592
Ischemic Cerebrovascular Events
Cerebrovascular accident
10008190
Transient ischemic attack
10044390
Cerebral infarction
10008118
Cerebrovascular disorder
10008196
Cerebral artery embolism
10008088
Cerebral artery occlusion
10008089
Cerebral artery thrombosis
10008092
Ischemic stroke
10061256
Cerebral circulatory failure
10008097
Cerebellar infarction
10008034
Thalamic infarction
10064961
Reversible ischemic neurologic deficit
10050496
Thrombotic stroke
10043647
Embolic stroke
10014498
Vertebral artery occlusion
10048965
Carotid arterial embolus
10007684
Carotid artery occlusion
10048964
Carotid artery stenosis
10007687
Carotid artery thrombosis
10007688
Thrombotic cerebral infarction
10067347
Brain stem infarction
10006147
Embolic cerebral infarction
10060839
Lacunar infarction 
10051078
Brain stem stroke
10068644
Stroke in evolution
10059613
Ischaemic cerebral infarction 
10060840
 
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Table C.  Cardiovascular Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes (continued)
Special Interest Event
MedDRA Preferred Term
PT_Code
Cardiac Failure
Cardiac failure congestive
10007559
Cardiac failure 
10007554
Left ventricular failure
10024119
Cardiac failure acute
10007556
Cardiogenic shock
10007625
Left ventricular failure acute
10063081
Right ventricular failure
10039163
Right ventricular failure acute
10063082
Ventricular failure
10060953
Cardiopulmonary failure
10051093
Congestive cardiomyopathy
10056370
Ischemic Coronary Artery Disorders/ 
Atherosclerosis
Coronary artery embolism
10011084
Coronary artery occlusion
10011086
Coronary artery stenosis
10011089
Coronary artery thrombosis
10011091
Myocardial ischemia
10028600
Coronary artery disease
10011078
Arteriosclerosis coronary artery
10003211
Cardiac Arrhythmias
Ventricular extrasystoles
10047289
Torsade de Pointes
10044066
Ventricular  fibrillation
10047290
Cardiac Fibrillation
10061592
Pulseless electrical activity
10058151
Ventricular asystole
10047284
Long QT syndrome
10024803
Ventricular tachycardia
10047302
Ventricular Arrhythmia
10047281
Ventricular flutter  
10047294
Peripheral Vascular Disease
Deep Vein Thrombosis
10051055
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Relevant for dutasteride:  
Allergic reactions 
Anaphylactic reaction
10002198
Anaphylactic shock
10002199
Anaphylactic transfusion reaction
10067113
Anaphylactoid reaction
10002216
Anaphylactoid shock
10063119
Circulatory collapse
10009192
Kounis syndrome
10069167
Shock
10040560
Type I hypersensitivity
10045240
Allergic oedema
10060934
Angioedema
10002424
Circumoral oedema
10052250
Conjunctival oedema
10010726
Corneal oedema
10011033
Epiglottic oedema
10015029
Eye oedema
10052139
Eye swelling
10015967
Eyelid oedema
10015993
Face oedema
10016029
Gingival oedema
10049305
Gingival swelling
10018291
Gleich's syndrome
10066837
Hereditary angioedema
10019860
Idiopathic angioedema
10073257
Idiopathic urticaria
10021247
Laryngeal oedema
10023845
Laryngotracheal oedema
10023893
Limbal swelling
10070492
Lip oedema
10024558
Lip swelling
10024570
Mouth Swelling 
10075203
Oculorespiratory syndrome
10067317
Oedema mouth
10030110
Oropharyngeal swelling
10031118
Palatal oedema
10056998
Palatal swelling
10074403
Periorbital oedema
10034545
Pharyngeal oedema
10034829
Scleral oedema
10057431
Swelling face
10042682
Swollen tongue
10042727
Tongue oedema
10043967
Tracheal oedema
10044296
Urticaria
10046735
Urticaria cholinergic
10046740
Urticaria chronic
10052568
Urticaria papular
10046750
Acquired epidermolysis bullosa
10056508
Blister
10005191
Blister rupture
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Bullous impetigo
10006563
Conjunctivitis
10010741
Corneal exfoliation
10064489
Drug eruption
10013687
Epidermolysis
10053177
Epidermolysis bullosa
10014989
Genital ulceration
10018180
HLA-B*1502 assay positive
10074771
HLA-B*5801 assay positive
10074774
Lip exfoliation
10064482
Mouth ulceration
10028034
Mucocutaneous ulceration
10028084
Mucosa vesicle
10028103
Mucosal erosion
10061297
Mucosal exfoliation
10064486
Mucosal necrosis
10067993
Mucosal ulceration
10028124
Nikolsky's sign
10029415
Noninfective conjunctivitis
10074701
Oral mucosal blistering
10030995
Oral mucosal exfoliation
10064487
Oral papule
10031010
Oropharyngeal blistering
10067950
Pemphigoid
10034277
Pemphigus
10034280
Penile exfoliation
10064485
Skin erosion
10040840
Skin exfoliation
10040844
Staphylococcal scalded skin syndrome
10041929
Stomatitis
10042128
Tongue exfoliation
10064488
Vaginal exfoliation
10064483
Vaginal ulceration
10046943
Vulval ulceration
10047768
Vulvovaginal rash
10071588
Vulvovaginal ulceration
10050181
Application site pruritus
10003053
Aquagenic pruritus
10003071
Injection site pruritus
10022093
Pruritus
10037087
Pruritus genital
10037093
Rash pruritic
10037884
Senile pruritus
10039986
Itching scar
10050818
Eyelids pruritus
10051627
Catheter site pruritus
10052270
Pruritus generalised
10052576
Infusion site pruritus
10053664
Vulvovaginal pruritus
10056530
Incision site pruritus
10059386
Uraemic pruritus
10060875
Pruritus allergic
10063438
Instillation site pruritus
10063763
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Implant site pruritus
10063785
Cholestatic pruritus
10064190
Polymorphic eruption of pregnancy
10066100
Vessel puncture site pruritus
10067254
Vaccination site pruritus
10068881
Brachioradial pruritus
10071443
Notalgia paraesthetica
10072643
Breast Cancer
Apocrine breast carcinoma
10066206
Invasive breast carcinoma
10075713
Triple negative breast cancer
10075566
Breast cancer
10006187
Breast cancer female
10057654
Breast cancer in situ
10006189
Breast cancer male
10061020
Breast cancer metastatic
10055113
Breast cancer recurrent
10006198
Breast cancer stage I
10006199
Breast cancer stage II
10006200
Breast cancer stage III
10006201
Breast cancer stage IV
10006202
Breast sarcoma
10068582
Breast sarcoma metastatic
10068583
Breast sarcoma recurrent
10068584
Electron radiation therapy to breast
10014437
Extended radical mastectomy
10015721
Gamma radiation therapy to breast
10017677
HER-2 positive breast cancer
10065430
Inflammatory carcinoma of breast recurrent
10021977
Inflammatory carcinoma of breast stage III
10021978
Inflammatory carcinoma of breast stage IV
10021979
Inflammatory carcinoma of the breast
10021980
Intraductal papillary breast neoplasm
10073540
Intraductal proliferative breast lesion
10073094
Invasive ductal breast carcinoma
10073095
Invasive lobular breast carcinoma
10073096
Invasive papillary breast carcinoma
10073098
Lobular breast carcinoma in situ
10073099
Malignant nipple neoplasm
10062051
Malignant nipple neoplasm female
10053129
Malignant nipple neoplasm male
10053128
Mastectomy
10026878
Medullary carcinoma of breast
10027095
Metaplastic breast carcinoma
10073100
Modified radical mastectomy
10027799
Mucinous breast carcinoma
10073101
Neuroendocrine breast tumour
10073103
Oestrogen receptor assay positive
10054054
Oestrogen receptor positive breast cancer
10070577
Paget's disease of nipple
10033364
Photon radiation therapy to breast
10034949
Postmastectomy lymphoedema syndrome
10036390
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Progesterone receptor assay positive
10054057
Radical mastectomy
10037773
Radiotherapy to breast
10062090
Simple mastectomy
10040700
Tubular breast carcinoma
10073104
X-ray therapy to breast
10048199
Antioestrogen therapy
10002816
Breast reconstruction
10006305
Breast neoplasm
10006279
Nipple neoplasm
10056286
Phyllodes tumour
10071776
Biopsy breast abnormal
10004745
Breast calcifications
10048782
Breast dysplasia
10006237
Breast prosthesis implantation
10006303
Computerised tomogram breast abnormal
10074534
Depressed mood
Activation syndrome
10066817
Adjustment disorder with depressed mood
10001297
Columbia suicide severity rating scale abnormal
10075616
Adjustment disorder with mixed anxiety and 
depressed mood
10001299
Agitated depression
10001496
Anhedonia
10002511
Antidepressant therapy
10054976
Childhood depression
10068631
Decreased interest
10011971
Depressed mood
10012374
Depression
10012378
Depression postoperative
10012390
Depressive symptom
10054089
Dysphoria
10013954
Electroconvulsive therapy
10014404
Feeling guilty
10049708
Feeling of despair
10016344
Feelings of worthlessness
10016374
Major depression
10057840
Menopausal depression
10067371
Post stroke depression
10070606
Postictal depression
10071324
Perinatal depression
10078366
Completed suicide
10010144
Depression suicidal
10012397
Intentional overdose
10022523
Intentional self-injury
10022524
Poisoning deliberate
10036000
Self-injurious ideation
10051154
Suicidal behaviour
10065604
Suicidal ideation
10042458
Suicide attempt
10042464
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Hair changes
Alopecia
10001760
Alopecia areata
10001761
Alopecia scarring
10001764
Alopecia syphilitic
10001765
Alopecia totalis
10001766
Alopecia universalis
10001767
Hypotrichosis
10021126
Progeria
10036794
Madarosis
10051235
Follicular mucinosis
10056506
Application site alopecia
10059046
Androgenetic alopecia
10068168
Satoyoshi syndrome
10070579
Radiation alopecia
10072045
Diffuse alopecia
10073736
Hypertrichosis
10020864
Interference with formation of external genitalia 
in a male fetus 
Congenital vas deferens absence
10010670
Cryptorchism
10011498
Epispadias
10015088
Hypospadias
10021093
Reproductive tract hypoplasia, male
10057858
Testicular dysplasia
10059271
Congenital genital malformation male
10059492
Penoscrotal fusion
10064951
Sertoli-cell-only syndrome
10066833
Buried penis syndrome
10067131
Penoscrotal transposition
10067287
Penile torsion
10070235
Potential for decreased male fertility 
Infertility tests
10021931
pH semen
10034784
pH semen decreased
10034786
pH semen increased
10034788
pH semen normal
10034790
Red blood cells semen
10038176
Red blood cells semen negative
10038179
Red blood cells semen positive
10038180
Semen liquefaction
10039931
Semen liquefaction normal
10039933
Semen liquefaction prolonged
10039934
Semen liquefaction shortened
10039935
Semen viscosity
10039936
Semen viscosity decreased
10039938
Semen viscosity increased
10039940
Semen viscosity normal
10039942
Semen volume abnormal
10039943
Semen volume decreased
10039944
Semen volume increased
10039946
Semen volume normal
10039948
Sperm analysis
10041476
Sperm analysis abnormal
10041477
Sperm analysis normal
10041478
Spermatozoa abnormal
10041498
Spermatozoa morphology
10041501
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Spermatozoa morphology abnormal
10041502
Spermatozoa morphology normal
10041503
Spermatozoa progressive motility abnormal
10041504
Spermatozoa progressive motility decreased
10041506
Spermatozoa progressive motility normal
10041507
White blood cells semen
10047956
White blood cells semen negative
10047959
White blood cells semen positive
10047960
Fructose semen decreased
10052476
Fructose semen increased
10052477
Prostatic fluid leukocytes increased
10053866
Infertility tests abnormal
10062020
Infertility tests normal
10062021
pH semen abnormal
10062074
Semen liquefaction abnormal
10062159
Semen viscosity abnormal
10062160
Semen analysis normal
10062238
Semen analysis
10068482
Semen analysis abnormal
10068483
Sperm concentration decreased
10070925
Sperm concentration increased
10070926
Sperm concentration abnormal
10070927
Sperm concentration normal
10070928
Sperm concentration
10070929
Sperm concentration zero
10070930
Total sperm count
10070931
Total sperm count decreased
10070932
Infertility
10021926
Infertility male
10021929
Testicular pain and swelling
Anorchism
10002641
Eunuchoidism
10015532
Hypogonadism male
10021011
Testicular atrophy
10043298
Testicular disorder
10043306
Testicular failure
10043315
Testicular failure postoperative
10043317
Testicular failure primary
10043318
Testicular hyperfunction
10043334
Testicular infarction
10043337
Testicular pain
10043345
Testicular retraction
10043348
Testicular swelling
10043354
Testicular torsion
10043356
Testicular necrosis
10049572
Spermatic cord mass
10049792
Testicular appendage torsion
10050476
Spermatic cord pain
10051221
Testicular injury
10051872
Testicular haemorrhage
10051877
Epididymal calculus
10052321
Epididymal enlargement
10052322
Epididymal tenderness
10052323
Testis discomfort
10052531
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Monorchidism
10055002
Epididymal disorder
10055045
Spermatic cord disorder
10056348
Testicular mass
10058901
Testotoxicosis
10063654
Spermatic cord haemorrhage
10065742
Spermatic cord obstruction
10065805
Spermatic cord perforation
10065806
Spermatic cord stenosis
10065807
Testicular perforation
10065808
Testicular hypertrophy
10066101
Testicular oedema
10066769
Sperm granuloma
10067802
Testicular microlithiasis
10067829
Congenital monorchidism
10069505
Testicular autoimmunity
10071574
Relevant for tamsulosin:  
Atrial fibrillation, tachycardia, arrhythmias
Arrhythmia
10003119
Heart alternation
10058155
Heart rate irregular
10019304
Pacemaker generated arrhythmia
10053486
Pacemaker syndrome
10051994
Paroxysmal arrhythmia
10050106
Pulseless electrical activity
10058151
Reperfusion arrhythmia
10058156
Withdrawal arrhythmia
10047997
Arrhythmia supraventricular
10003130
Atrial fibrillation
10003658
Atrial flutter
10003662
Atrial parasystole
10071666
Atrial tachycardia
10003668
Junctional ectopic tachycardia
10074640
Sinus tachycardia
10040752
Supraventricular extrasystoles
10042602
Supraventricular tachyarrhythmia
10065342
Supraventricular tachycardia
10042604
ECG P wave inverted
10057526
Electrocardiogram P wave abnormal
10050384
Retrograde p-waves
10071187
Anomalous atrioventricular excitation
10002611
Cardiac flutter
10052840
Extrasystoles
10015856
Tachyarrhythmia
10049447
Accelerated idioventricular rhythm
10049003
Cardiac fibrillation
10061592
Parasystole
10033929
Rhythm idioventricular
10039111
Torsade de pointes
10044066
Ventricular arrhythmia
10047281
Ventricular extrasystoles
10047289
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular parasystole
10058184
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Ventricular pre-excitation
10049761
Ventricular tachyarrhythmia
10065341
Ventricular tachycardia
10047302
Floppy Iris Syndrome
Floppy iris syndrome
10066373
Orthostasis
Dizziness
10013573
Dizziness postural
10013578
Orthostatic hypotension
10031127
Hypotension
10021097
Syncope
10042772
Presyncope
10036653
Blood pressure orthostatic abnormal
10053354
Blood pressure orthostatic decreased
10053356
Priapism
Priapism
10036661
Stevens-Johnson syndrome
Acute generalised exanthematous pustulosis
10048799
Cutaneous vasculitis
10011686
Dermatitis bullous
10012441
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Drug reaction with eosinophilia and systemic 
symptoms
10073508
Epidermal necrosis
10059284
Erythema multiforme
10015218
Exfoliative rash
10064579
Oculomucocutaneous syndrome
10030081
Skin necrosis
10040893
Stevens-Johnson syndrome
10042033
Toxic epidermal necrolysis
10044223
Toxic skin eruption
10057970
 
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11.9.
Appendix 9: Threshold Factors for Clinical Laboratory Tests 
and Vital Signs
Hematology and Clinical Chemistry Laboratory Tests, Codes and Threshold Factors
LABORATORY TEST
Database
LBTESTCD
Unit
Multiplicative Factors1
Low (x LLN)
High (x ULN)
HEMATOLOGY
-Hemoglobin
HB_BLC
G/L
0.75
-
-Platelet count
PLT_BLC
GI/L
0.75
1.5
-WBC count
WBC_BLC
GI/L
0.5
3.0
-RBC count
RBC_BLC
GI/L
0.5
-
CLINICAL CHEMISTRY
-Albumin
ALB_PLC
G/L
0.9
1.2
-ALT
ALT_PLC
IU/L
-
3.0
-Alkaline Phosphatase
ALP_PLC
IU/L
-
1.5
- AST  
AST_PLC
IU/L
-
3.0
-Creatinine
CRT_PLC
UMOL/L
0.5
3.0
-Glucose
GLUC_PLC
MMOL/L
0.7
1.75
-Potassium
K_PLC
MMOL/L
0.75
1.4
-Sodium
NA_PLC
MMOL/L
0.9
1.15
-Total Bilirubin
BILT_PLC
UMOL/L
-
2.5
-Total Protein
TP_PLC
G/L
0.8
1.15
-Urea/BUN
UREA_PLC
MMOL/L
0.5
2.0
1.
A laboratory value that is above the upper limit factor multiplied by the upper limit of the normal range is 
considered a high threshold value. A laboratory value that is below the lower limit factor multiplied by the 
lower limit of the normal range is considered a low threshold value.
Threshold Ranges for Vital Signs
Threshold Ranges
Vital Sign
Unit
Lower
Upper
Systolic Blood Pressure
mmHg
<80
>165
Diastolic Blood Pressure
mmHg
<40
>105
Heart Rate
bpm
<40
>100
 
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11.10.
Appendix 10: Examination of Covariates and Subgroups
Endpoint(s)
IPSS change from baseline
Analysis
Subgroup Summaries and General Linear Model
A list of subgroups of interest for the primary efficacy endpoint is below. If the categorization 
defining the subgroups results in overly sparse data or if some baseline subgroups are 
homogeneous in response, then particular subgroups may be combined or not reported.
For each subgroup, IPSS change from baseline summaries will be output by treatment group at 
Month 12 and at Month 24 for the ITT population using both LOCF and At Visit approaches. No 
statistical comparisons will be performed.
The effects of baseline subgroups and their interactions with treatment will be assessed. As a 
minimum, these subgroups will include those in the below table except for country and center. 
These effects will be individually explored in terms of: 1) addition of subgroup effect to the model*
and 2) addition of subgroup effect and subgroup effect by treatment interaction to the model*.  
*Refers to primary efficacy General Linear Model (GLM): 
Change from Baseline IPSS = treatment + cluster + baseline IPSS.
In these analyses, continuous variables will be treated as continuous and not as dichotomous 
subgroups. These assessments will focus on Month 24 LOCF, and separately Month 24 At Visit, 
and will be output as listings. Other analyses based on other time points will not be output unless 
substantive finding dictate.
Subgroups Summarized for Primary Efficacy Endpoint
Subgroup
Categorization for Tabular 
Summary Display
Baseline Age 65
<65, ≥65 years
Baseline Age 75
<75, ≥75 years
Baseline IPSS
<20, ≥20
Baseline BPH-Related Health Status 
<4, ≥4
Baseline Prostate Volume
<40, ≥40cc
Baseline Qmax
<10, ≥10ml/sec
Alpha Blocker History
Yes, No
5-Alpha-Reductase Inhibitor History 
Yes, No
Phytotherapy History
Yes, No
Alpha Blocker or 5-Alpha-Reductase 
Inhibitor History
Yes, No
Alpha Blocker or 5-Alpha-Reductase 
Inhibitor or Phytotherapy History
Yes, No
Baseline PSA
<3, ≥3ng/ml
Country (cluster)
China, Japan, Korea, Taiwan
Center
Each center with at least one 
randomized subject.
 
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11.11.
Appendix 11: Multiple Comparisons and Multiplicity
Results of all planned statistical analyses and thus all planned p-values will be reported. P-values 
≤0.05 will be considered formally statistically significant if the below described conditions are 
satisfied for multiple endpoints and multiple time points. Otherwise p-values ≤0.05 will be 
considered nominally significant.
The comparisons are in terms of two treatment arms, Combination and Tamsulosin, so no 
multiplicity adjustment for treatment is necessary. 
Multiplicity adjustment for multiple endpoints is described in this paragraph. For the primary 
efficacy endpoint, IPSS change from baseline at Month 24, if the Month 24 two-sided p-value is 
≤0.05 and the treatment difference supports Combination superiority versus Tamsulosin, then 
formal statistical significance is declared and testing of each secondary endpoint may occur. For 
secondary endpoints evaluated at multiple time points, then the testing will begin at Month 24. For 
purposes of statistical testing, there is no hierarchical order assigned to the set of secondary 
endpoints at Month 24.
Multiplicity adjustment for multiple time points is described in this paragraph. For any endpoint that 
is tested over different visits, a step-down procedure for interpreting the p-values will be adopted. 
The final time point (Month 24) will be tested first. If the Month 24 two-sided p-value is ≤0.05 and 
the treatment difference supports Combination superiority versus Tamsulosin, the time point 
immediately preceding it will be interpreted for formal statistical significance; otherwise formal 
interpretation of significance will stop, but interpretation of nominal significance will continue for 
preceding endpoints. The interpretation of formal statistical significance will continue this way in a 
stepwise manner through all time points. 
As an example, the time point testing visit sequence for the primary efficacy endpoint is: Month 24, 
Month 21, Month 18, Month 15, Month 12, Month 9, Month 6, and (last) Month 3.
 
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11.12.
Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses
Endpoint(s)
IPSS change from baseline
Analysis
General Linear Model

Assessments of the general linear model residuals will be performed. These assessments will 
include reviews of residual by predicted value plots and normal probability plots on residuals.  
This will be in terms of the change from baseline IPSS at Month 24 using the LOCF and At Visit 
approaches.  Similar assessments of other time periods will not be reported unless dictated by 
substantive findings.

If these assumptions are not met, appropriate non-parametric analyses will be performed to test 
the robustness of the results of the parametric analyses. If non-parametric analyses are 
performed further detailed information will be provided in the Statistical Appendix for the Clinical 
Report.

The interaction of cluster with treatment will be assessed by adding the (interaction) term to the 
above planned analysis model at Month 24.

The interaction of baseline IPSS with treatment will be assessed by adding the (interaction) 
term to the above stated model at Month 24.

The effects of baseline subgroups and their interactions with treatment will also be assessed.  
This is described in Appendix 10, Examination of Covariates and Subgroups
 
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11.13.
Appendix 13: Mixed-Model Repeated-Measures Analysis
Mixed-Model Repeated-Measures (MMRM) Analysis:  As a supportive analysis, IPSS change from 
baseline will be analyzed using a mixed-model repeated-measures (MMRM) analysis including 
data from the scheduled post-baseline assessments [Mallinckrodt, 2008]. Analyses will include the 
fixed, categorical effects of treatment, cluster, visit, and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of baseline IPSS and baseline IPSS-by-visit interaction. An 
unstructured covariance structure will be used to model the within-patient errors, shared across 
treatments. PROC MIXED in SAS [Littell, 1996] will be used to fit the model, using the restricted 
maximum likelihood estimation method and the Kenward-Roger option to estimate denominator 
degrees of freedom and standard errors. 
Corresponding SAS output will be provided as a listing. The treatment comparison will be the 
contrast between treatments (Combination minus Tamsulosin) at the Month 24 visit using the two-
sided p-value from the corresponding t-test at α=0.05. In this supportive analysis, superiority of the 
Combination vs. Tamsulosin treatment will be declared if the two-sided p-value for the contrast is 
less than or equal to 0.05 and the observed treatment effect supports superiority. A two-sided 95% 
confidence interval for the estimated treatment difference in the change from baseline at each 
scheduled visit will be computed. Estimated mean change from baseline and standard errors will 
be computed by treatment group and visit. If the model-fitting algorithm fails to converge then 
alternative initial parameter values and/or covariance structures will be considered.
 
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11.14.
Appendix 14 – Abbreviations & Trade Marks
11.14.1.
Abbreviations
Abbreviation
Description
5ARI
5 Alpha-Reductase Inhibitor
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUR
Acute Urinary Retention
A&R
Analysis and Reporting 
BHS
BPH-related Health Status
BII
BPH Impact Index
BPH
Benign Prostatic Hyperplasia
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating
DOB
Date of Birth
DRE
Digital Rectal Examination
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FDC
Fixed Dose Combination
ICH
International Conference on Harmonization
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
LOCF
Last Observation Carried Forward
LUTS
Lower urinary tract symptoms
MMRM
Mixed-Model Repeated- Measures
PAS SFI
Problem Assessment Scale Sexual Function Inventory
PDE-5
Phosphodiesterase-5
PDMP
Protocol Deviation Management Plan
PGx
Pharmacogenetic
PPK
Population Pharmacokinetics
PP
Per-Protocol
PPSM
Patient Perception of Study Medication
PSA
Prostate Specific Antigen
PSAP
Program Safety Analysis Plan
PSRAE
Possible Suicidality Related Adverse Event
QC
Quality Control
Qmax
Maximum (peak) urinary flow rate
RAMOS
Randomization & Medication Ordering System 
 
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Abbreviation
Description
RandAll NG
RandAll is a randomization creation and publishing tool for GSK studies.  NG 
represents Next Generation version.
RAP
Reporting & Analysis Plan
RBC
Red Blood Cell
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TFUQ
Targeted Follow-Up Questionnaire
TRUS
Transrectal ultrasound
UTI
Urinary Tract Infection
WBC
White Blood Cell
11.14.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
AVODART
Flomax
Harnal D
Propecia
Proscar
SAS
WinNonlin
 
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11.15.
Appendix 15: List of Data Displays
11.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays.
Section
Tables
Figures
Study Population
1.1 to 1.32
NA
Efficacy
2.1 to 2.165
2.1 to 2.9
Safety
3.1 to 3.98
3.1 to 3.18
Health Outcomes
4.1 to 4.58
4.1 to 4.4
Section
Listings
ICH Listings (Study Population)
1.1 to 1.14
ICH Listings (Efficacy)
2.1 to 2.8
ICH Listings (Safety)
3.1 to 3.21
ICH Listings (Health Outcomes)
-
Other Listings includes Non-ICH listings
5.1 to 5.64
 
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11.15.2.
Study Population Tables
Study Population Tables (Population=ITT except when noted)
No.
Title
Subject Accountability
1.1
Summary of Subject Accountability   Note: Population = All Enrolled Subjects
Subject Disposition
1.2
Summary of Subject Withdrawals During Placebo Run-in Phase   Note:  Population = Subjects Who Entered Placebo Run-In
1.3
Summary of Randomized Subjects by Country and Center
1.4
Summary of Subject Disposition
1.5
Summary of Subject Discontinuation by Visit
1.6
Summary of Primary Reason for Study Withdrawal, by Period of Discontinuation
1.7
Summary of Inclusion/Exclusion Criteria Deviations
1.8
Summary of Important Protocol Deviations
1.9
Summary of Deviations which Require Exclusion from the Per-Protocol Population
Demographic and Baseline Characteristics
1.10
Summary of Baseline and Demographic Characteristics
1.11
Summary of Baseline and Demographic Characteristics by Country
1.12
Summary of Race and Racial Combinations
1.13
Summary of Race and Racial Combination Details
1.14
Summary of Selected Safety Measures at Baseline 
1.15
Summary of Selected Safety Measures at Baseline by Country
1.16
Summary of Selected Efficacy and Health Outcome Measures at Baseline
1.17
Summary of Selected Efficacy and Health Outcome Measures at Baseline by Country
Medical Conditions and Concomitant Medications
1.18
Summary of Medical Conditions at Screening, by Body System
 
 
 
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Study Population Tables (Population=ITT except when noted)
No.
Title
1.19
Summary of Specific Medical Conditions at Screening
1.20
Summary of BPH History
1.21
Summary of Alpha-Blocker Use
1.22
Summary of 5-Alpha-Reductase Inhibitor Use
Note: Below strikethroughs and data display number revisions are associated with RAP Amendment 01. This approach permanently documents data 
display number revisions for traceability and reference.
1.23  1.24
Summary of Alpha-Blocker, 5-Alpha-Reductase Inhibitor, and Phytotherapy for BPH Use
1.24  1.23
Summary of Phytotherapy for BPH Use
1.25
Summary of Sexual Function at Screening
1.26
Summary of Family History of Premature Coronary Artery Disease
1.27
Summary of Family History of Breast Cancer
1.28
Summary of Family History of Prostate Cancer
1.29
Summary of Concomitant Medications
1.30
Summary of Investigational Product Discontinuation
1.31
Summary of Study Drug Exposure
1.32
Summary of Compliance to Study Drug
 
 
 
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11.15.3.
Efficacy Tables
Efficacy Tables  (Population=ITT)
No.
Title
IPSS Overview and Primary Analysis
2.1
Summary of IPSS Imputations
2.2
Summary of IPSS at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with IPSS at each Month n (3, 6, …24) 
2.3
Summary of IPSS at Each Post-Baseline Visit (LOCF)
2.4
Summary of IPSS at Each Post-Baseline Visit (At Visit)
2.5
Summary of IPSS Change from Baseline (LOCF)
2.6
Summary of IPSS Change from Baseline (At Visit)
IPSS MMRM
2.7
Summary of MMRM Analysis for IPSS Change from Baseline
IPSS Change from Baseline Subgroup Summaries   presented for each Month 12 and Month 24
2.8
Summary of IPSS Change from Baseline, by Age (<65, ≥65 years) (LOCF)
2.9
Summary of IPSS Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.10
Summary of IPSS Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.11
Summary of IPSS Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.12
Summary of IPSS Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.13
Summary of IPSS Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.14
Summary of IPSS Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.15
Summary of IPSS Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.16
Summary of IPSS Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.17
Summary of IPSS Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.18
Summary of IPSS Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.19
Summary of IPSS Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.20
Summary of IPSS Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.21
Summary of IPSS Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.22
Summary of IPSS Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.23
Summary of IPSS Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.24
Summary of IPSS Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.25
Summary of IPSS Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
Note: Below strikethroughs and data display number revisions are associated with RAP Amendment 01. This approach permanently documents data 
display number revisions for traceability and reference.
2.26
Summary of IPSS Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.27
Summary of IPSS Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.28
Summary of IPSS Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History (yes, no) (LOCF)
2.29
Summary of IPSS Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History (yes, no) (At Visit)
2.26  2.30
Summary of IPSS Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
2.27  2.31
Summary of IPSS Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.28  2.32
Summary of IPSS Change from Baseline, by Country (LOCF)
2.29  2.33
Summary of IPSS Change from Baseline, by Country (At Visit)
Note: IPSS change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
Individual IPSS Questions 1 - 7
2.30  2.34
Summary of IPSS at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with IPSS at each Months 12 
and 24
2.31  2.35
Summary of IPSS at Months 12 and 24: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
2.32  2.36
Summary of IPSS at Months 12 and 24: Question 1 (At Visit)
2.33  2.37
Summary of IPSS Change from Baseline at Months 12 and 24: Question 1 (LOCF)
2.34  2.38
Summary of IPSS Change from Baseline at Months 12 and 24: Question 1 (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.35  2.39
Summary of IPSS at Screening and Baseline: Question 2
2.36  2.40
Summary of IPSS at Months 12 and 24: Question 2 (LOCF)
2.37  2.41
Summary of IPSS at Months 12 and 24: Question 2 (At Visit)
2.38  2.42
Summary of IPSS Change from Baseline at Months 12 and 24: Question 2 (LOCF)
2.39  2.43
Summary of IPSS Change from Baseline at Months 12 and 24: Question 2 (At Visit)
2.40  2.44
Summary of IPSS at Screening and Baseline: Question 3
2.41  2.45
Summary of IPSS at Months 12 and 24: Question 3 (LOCF)
2.42  2.46
Summary of IPSS at Months 12 and 24: Question 3 (At Visit)
2.43  2.47
Summary of IPSS Change from Baseline at Months 12 and 24: Question 3 (LOCF)
2.44  2.48
Summary of IPSS Change from Baseline at Months 12 and 24: Question 3 (At Visit)
2.45  2.49
Summary of IPSS at Screening and Baseline: Question 4
2.46  2.50
Summary of IPSS at Months 12 and 24: Question 4 (LOCF)
2.47  2.51
Summary of IPSS at Months 12 and 24: Question 4 (At Visit)
2.48  2.52
Summary of IPSS Change from Baseline at Months 12 and 24: Question 4 (LOCF)
2.49  2.53
Summary of IPSS Change from Baseline at Months 12 and 24: Question 4 (At Visit)
2.50  2.54
Summary of IPSS at Screening and Baseline: Question 5
2.51  2.55
Summary of IPSS at Months 12 and 24: Question 5 (LOCF)
2.52  2.56
Summary of IPSS at Months 12 and 24: Question 5 (At Visit)
2.53  2.57
Summary of IPSS Change from Baseline at Months 12 and 24: Question 5 (LOCF)
2.54  2.58
Summary of IPSS Change from Baseline at Months 12 and 24: Question 5 (At Visit)
2.55  2.59
Summary of IPSS at Screening and Baseline: Question 6
2.56  2.60
Summary of IPSS at Months 12 and 24: Question 6 (LOCF)
2.57  2.61
Summary of IPSS at Months 12 and 24: Question 6 (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.58  2.62
Summary of IPSS Change from Baseline at Months 12 and 24: Question 6 (LOCF)
2.59  2.63
Summary of IPSS Change from Baseline at Months 12 and 24: Question 6 (At Visit)
2.60  2.64
Summary of IPSS at Screening and Baseline: Question 7
2.61  2.65
Summary of IPSS at Months 12 and 24: Question 7 (LOCF)
2.62  2.66
Summary of IPSS at Months 12 and 24: Question 7 (At Visit)
2.63  2.67
Summary of IPSS Change from Baseline at Months 12 and 24: Question 7 (LOCF)
2.64  2.68
Summary of IPSS Change from Baseline at Months 12 and 24: Question 7 (At Visit)
IPSS Percentage Change from Baseline
2.65  2.69
Summary of IPSS Percentage Change from Baseline (LOCF)
2.66  2.70
Summary of IPSS Percentage Change from Baseline (At Visit)
IPSS Non-Imputed Score Analysis
Performed only if RAP Section 7.1 imputation conditions are met; thus, table numbers are not listed.
IPSS Per-Protocol Population Analysis
Performed only if RAP Section 4 per-protocol conditions are met; thus, table numbers are not listed.
IPSS Change-from-Baseline Improvement Levels
2.67  2.71
Summary of IPSS Change-from-Baseline Categories (LOCF)
2.68  2.72
Summary of IPSS Change-from-Baseline Categories (At Visit)
IPSS Percentage Change-from-Baseline Improvement Levels
2.69  2.73
Summary of IPSS Percentage Change-from-Baseline Categories (LOCF)
2.70  2.74
Summary of IPSS Percentage Change-from-Baseline Categories (At Visit)
Prostate Volume
2.71  2.75
Summary of Prostate Volume at Screening and Baseline
2.72  2.76
Summary of Prostate Volume at Each Post-Baseline Visit (LOCF)
2.73  2.77
Summary of Prostate Volume at Each Post-Baseline Visit (At Visit)
2.74  2.78
Summary of Prostate Volume Change from Baseline (LOCF)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.75  2.79
Summary of Prostate Volume Change from Baseline (At Visit)
2.76  2.80
Summary of Prostate Volume Percentage Change from Baseline (LOCF)
2.77  2.81
Summary of Prostate Volume Percentage Change from Baseline (At Visit)
2.78  2.82
Summary of Prostate Volume Percentage Change-from-Baseline Categories (LOCF)
2.79  2.83
Summary of Prostate Volume Percentage Change-from-Baseline Categories (At Visit)
2.80  2.84
Summary of Prostate Volume Percentage Change from Baseline, by Age (<65, ≥65 years) (LOCF)
2.81  2.85
Summary of Prostate Volume Percentage Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.82  2.86
Summary of Prostate Volume Percentage Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.83  2.87
Summary of Prostate Volume Percentage Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.84  2.88
Summary of Prostate Volume Percentage Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.85  2.89
Summary of Prostate Volume Percentage Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.86  2.90
Summary of Prostate Volume Percentage Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.87  2.91
Summary of Prostate Volume Percentage Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.88  2.92
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.89  2.93
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.90  2.94
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.91  2.95
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
2.92  2.96
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.93  2.97
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.94  2.98
Summary of Prostate Volume Percentage Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.95  2.99
Summary of Prostate Volume Percentage Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.96  2.100
Summary of Prostate Volume Percentage Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.97  2.101
Summary of Prostate Volume Percentage Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.102
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.103
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.104
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History 
(yes, no) (LOCF)
2.105
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History 
(yes, no) (At Visit)
2.98  2.106
Summary of Prostate Volume Percentage Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
2.99  2.107
Summary of Prostate Volume Percentage Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.100  2.108
Summary of Prostate Volume Percentage Change from Baseline, by Country (LOCF)
2.101  2.109
Summary of Prostate Volume Percentage Change from Baseline, by Country (At Visit)
Note: Prostate volume percentage change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
Qmax
2.102  2.110
Summary of Qmax at Screening and Baseline
2.103  2.111
Summary of Qmax at Each Post-Baseline Visit (LOCF)
2.104  2.112
Summary of Qmax at Each Post-Baseline Visit (At Visit)
2.105  2.113
Summary of Qmax Change from Baseline (LOCF)
2.106  2.114
Summary of Qmax Change from Baseline (At Visit)
2.115
Summary of MMRM Analysis for Qmax Change from Baseline
2.107  2.116
Summary of Qmax Change from Baseline Categories (LOCF)
2.108  2.117
Summary of Qmax Change from Baseline Categories (At Visit)
2.109  2.118
Summary of Qmax Percentage Change from Baseline (LOCF)
2.110  2.119
Summary of Qmax Percentage Change from Baseline (At Visit)
2.111  2.120
Summary of Qmax Percentage Change-from-Baseline Categories (LOCF)
2.112  2.121
Summary of Qmax Percentage Change-from-Baseline Categories (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.113  2.122
Summary of Qmax Change from Baseline, by Age (<65, ≥65 years) (LOCF)
2.114  2.123
Summary of Qmax Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.115  2.124
Summary of Qmax Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.116  2.125
Summary of Qmax Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.117  2.126
Summary of Qmax Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.118  2.127
Summary of Qmax Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.119  2.128
Summary of Qmax Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.120  2.129
Summary of Qmax Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.121  2.130
Summary of Qmax Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.122  2.131
Summary of Qmax Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.123  2.132
Summary of Qmax Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.124  2.133
Summary of Qmax Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
2.125  2.134
Summary of Qmax Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.126  2.135
Summary of Qmax Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.127  2.136
Summary of Qmax Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.128  2.137
Summary of Qmax Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.129  2.138
Summary of Qmax Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.130  2.139
Summary of Qmax Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
2.140
Summary of Qmax Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.141
Summary of Qmax Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.142
Summary of Qmax Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History (yes, no) (LOCF)
2.143
Summary of Qmax Change from Baseline, by Alpha-Blocker History or 5-Alpha-Reductase Inhibitor or Phytotherapy History (yes, no) (At Visit)
2.131  2.144
Summary of Qmax Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.132  2.145
Summary of Qmax Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.133  2.146
Summary of Qmax Change from Baseline, by Country (LOCF)
2.134  2.147
Summary of Qmax Change from Baseline, by Country (At Visit)
Note: Qmax  change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
 
 
 
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AUR or BPH-Related Surgery
2.135  2.148
Summary of Time to AUR or BPH-Related Surgery
2.136  2.149
Summary of Time to AUR or BPH-Related Surgery by Quarter
2.137  2.150
Summary of AUR or BPH-Related Surgery
2.138  2.151
Summary of Effect of Various Factors on Time to AUR or BPH-Related Surgery
2.139  2.152
Summary of Hospitalization for AUR or BPH-Related Surgery
2.140  2.153
Summary of Time from Treatment Stop to AUR or BPH-Related Surgery
2.141  2.154
Summary of Time to First AUR
2.142  2.155
Summary of Time to First AUR by Quarter
2.143  2.156
Summary of AUR
2.144  2.157
Summary of Hospitalization for AUR
2.145  2.158
Summary of Time to BPH-Related Surgery
2.146  2.159
Summary of Time to BPH-Related Surgery by Quarter
2.147  2.160
Summary of BPH-Related Surgery
2.148  2.161
Summary of Hospitalization for BPH-Related Surgery
2.149  2.162
Summary of Prostatic Surgery
Other Efficacy Measures
2.150  2.163
Summary of Urinary Tract Infection / Urosepsis
2.151  2.164
Summary of Urinary Incontinence
2.152  2.165
Summary of Renal Insufficiency
 
 
 
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11.15.4.
Efficacy Figures
Efficacy Figures  (Population=ITT)
No.
Title
IPSS
2.1
Plot of IPSS Adjusted Mean Change from Baseline (LOCF)
2.2
Plot of IPSS Adjusted Mean Change from Baseline (At Visit)
Prostate Volume
2.3
Plot of Prostate Volume Adjusted Mean Percentage Change from Baseline (LOCF)
2.4
Plot of Prostate Volume Adjusted Mean Percentage Change from Baseline (At Visit)
Qmax
2.5
Plot of Qmax Adjusted Mean Change from Baseline (LOCF)
2.6
Plot of Qmax Adjusted Mean Change from Baseline (At Visit)
AUR or BPH-Related Surgery
2.7
Plot of Kaplan-Meier Estimates of Time to First AUR or BPH-Related Surgery
2.8
Plot of Kaplan-Meier Estimates of Time to First AUR
2.9
Plot of Kaplan-Meier Estimates of Time to First BPH-Related Surgery
11.15.5.
Safety Tables
Safety
3.1
Summary of Adverse Events Starting Post-Randomization by Type
3.2
Summary of Adverse Events Starting Post-Randomization
3.3
Summary of Adverse Events Starting On-Treatment
3.4
Summary of Adverse Events Starting Post-Treatment
3.5
Summary of Non-Serious Adverse Events Starting Post-Randomization
3.6
Summary of Adverse Events Starting Post-Randomization by Time Period of Onset
3.7
Summary of Adverse Events Starting Post-Randomization by Age Group (<65, ≥65)
 
 
 
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Safety
3.8
Summary of Adverse Events Starting Post-Randomization by Age Group (<75, ≥75)
3.9
Summary of Adverse Events Starting Post-Randomization by Country
3.10
Summary of Adverse Events Starting Post-Randomization by Descending Frequency
3.11
Summary of Serious Adverse Events Starting Post-Randomization by Descending Frequency
3.12
Summary of Non-Serious Adverse Events Starting Post-Randomization by Descending Frequency
3.13
Summary of Adverse Events Starting On-Treatment (Study Drug Exposure Basis)
3.14
Summary of Adverse Events Starting On-Treatment by Time Period (Study Drug Exposure Basis)
3.15
Summary of Adverse Events Starting Post-Randomization by Maximum Intensity
3.16
Summary of Most Common Adverse Events Starting Post-Randomization
3.17
Summary of Most Common Non-Serious Adverse Events Starting Post-Randomization
3.18
Summary of Drug-Related Adverse Events Starting Post-Randomization
3.19
Summary of Drug-Related Adverse Events Starting On-Treatment
3.20
Summary of Drug-Related Adverse Events Starting Post-Treatment
3.21
Summary of Drug-Related Adverse Events Starting Post-Randomization by Time Period of Onset
3.22
Summary of Drug-Related Adverse Events Starting Post-Randomization by Age Group (<65, ≥65)
3.23
Summary of Drug-Related Adverse Events Starting Post-Randomization by Age Group (<75, ≥75)
3.24
Summary of Drug-Related Adverse Events Starting Post-Randomization by Country
3.25
Summary of Serious Adverse Events Starting Post-Randomization
3.26
Summary of Serious Adverse Events Starting On-Treatment
3.27
Summary of Serious Adverse Events Starting Post-Treatment
3.28
Summary of Serious Adverse Events Starting Post-Randomization by Time Period of Onset
3.29
Summary of Serious Adverse Events Starting Post-Randomization by Age Group (<65, ≥65)
3.30
Summary of Serious Adverse Events Starting Post-Randomization by Age Group (<75, ≥75)
3.31
Summary of Serious Adverse Events Starting Post-Randomization by Country
3.32
Summary of Drug-Related Serious Adverse Events Starting Post-Randomization
3.33
Summary of Fatal Adverse Events Starting Post-Randomization
3.34
Summary of Drug-Related Fatal Adverse Events Starting Post-Randomization
3.35
Summary of Adverse Events Starting Post-Randomization Leading to Withdrawal from the Study
3.36
Summary of Drug-Related Adverse Events Starting Post-Randomization Leading to Withdrawal from the Study
3.37
Summary of Serious Adverse Events Starting Post-Randomization Leading to Withdrawal from the Study
3.38
Summary of Adverse Events Starting Post-Randomization Leading to Permanent Discontinuation of the Study Drug
 
 
 
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Safety
3.39
Summary of Drug-Related Adverse Events Starting Post-Randomization Leading to Permanent Discontinuation of the Study Drug
3.40
Summary of Serious Adverse Events Starting Post-Randomization Leading to Permanent Discontinuation of the Study Drug
3.41
Summary of Sexual and Breast Adverse Events of Special Interest Starting Post-Randomization
3.42
Summary of Special Interest Adverse Events Starting Post-Randomization: Altered (Decreased) Libido
3.43
Summary of Special Interest Adverse Events Starting Post-Randomization: Impotence
3.44
Summary of Special Interest Adverse Events Starting Post-Randomization: Ejaculation Disorders
3.45
Summary of Special Interest Adverse Events Starting Post-Randomization: Breast Disorders
3.46
Summary of Special Interest Adverse Events Starting Post-Randomization: Breast Disorders: Breast Enlargement
3.47
Summary of Special Interest Adverse Events Starting Post-Randomization: Breast Disorders: Breast Tenderness
Note: Below strikethroughs and data display number revisions are associated with RAP Amendment 01. This approach permanently documents 
data display number revisions for traceability and reference.
3.48
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics: Altered (Decreased) Libido
3.49
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics: Impotence
3.50
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics: Ejaculation Disorders
3.51
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics : Breast Disorders
3.52
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics: Breast Disorders: Breast Enlargement
3.53
Summary of Special Interest Adverse Events Starting Post-randomization By Baseline Characteristics: Breast Disorders: Breast Tenderness
3.54  3.48
Summary of Special Interest Sexual and Breast Adverse Events Starting Post-Randomization
3.55  3.49
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal
3.56  3.50
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal: Altered (Decreased) Libido
3.57  3.51
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal: Impotence
3.58  3.52
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal: Ejaculation Disorders
3.59  3.53
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal: Breast Disorders
3.60  3.54
Summary of Special Interest Adverse Events Starting Post-Randomization: Prostate Cancer
3.61  3.55
Summary of Cardiovascular Adverse Events of Special Interest Starting Post-Randomization
3.62  3.56
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Acute Coronary Syndrome 
3.63  3.57
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Ischemic Cerebrovascular Events 
3.64  3.58
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Cardiac Failure 
3.65  3.59
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Ischemic Coronary Artery Disorders/Atherosclerosis 
3.66  3.60
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization : Cardiac Arrhythmia 
3.67  3.61
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Peripheral Vascular Disease 
 
 
 
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Safety
3.68  3.62
Summary of Special Interest Cardiovascular Adverse Events Starting Post-Randomization: Cardiovascular Events
3.69  3.63
Summary of Infrequent Tier 1 Adverse Events of Special Interest Starting Post-Randomization   
3.70  3.64
Summary of Laboratory Data
3.71  3.65
Summary of Change from Baseline Laboratory Data
3.72  3.66
Summary of Baseline Abnormal Laboratory Values
3.73  3.67
Summary of Shift in Laboratory Values: Normal at Baseline to Abnormal at Any Time Post-Baseline
3.74  3.68
Summary of Shift in Laboratory Values: Normal at Baseline to High at Any Time Post-Baseline
3.75  3.69
Summary of Shift in Laboratory Values: Normal at Baseline to Low at Any Time Post-Baseline
3.76  3.70
Summary of Shift in Laboratory Values: Normal or Low at Baseline to High at Any Time Post-Baseline
3.77  3.71
Summary of Shift in Laboratory Values: Normal or High at Baseline to Low at Any Time Post-Baseline
3.78  3.72
Summary of Laboratory Data Transitions: Change From Baseline to Final Assessment
3.79  3.73
Summary of Baseline Threshold Laboratory Values
3.80  3.74
Summary of Threshold Laboratory Values at Any Time Post-Baseline
3.81  3.75
Summary of Baseline Total PSA Values (ng/ml)
3.82  3.76
Summary of Total PSA (ng/ml) at Post-Baseline Visits (LOCF)
3.83  3.77
Summary of Total PSA (ng/ml) at Post-Baseline Visits (At Visit)
3.84  3.78
Summary of Total PSA Change From Baseline (ng/ml) (LOCF)
3.85  3.79
Summary of Total PSA Change From Baseline (ng/ml) (At Visit)
3.86  3.80
Summary of Total PSA Percentage Change From Baseline (LOCF)
3.87  3.81
Summary of Total PSA Percentage Change From Baseline (At Visit)
3.88  3.82
Summary of Post-Void Residual Volume at Screening and Baseline
3.89  3.83
Summary of Post-Void Residual Volume at Each Post-Baseline Visit (LOCF)
3.90  3.84
Summary of Post-Void Residual Volume at Each Post-Baseline Visit (At Visit)
3.91  3.85
Summary of Post-Void Residual Volume Change from Baseline (LOCF)
3.92  3.86
Summary of Post-Void Residual Volume Change from Baseline (At Visit)
3.93  3.87
Summary of Post-Void Residual Volume Percentage Change from Baseline  (LOCF)
3.94  3.88
Summary of Post-Void Residual Volume Percentage Change from Baseline (At Visit)
3.95  3.89
Summary of Gynecomastia Evaluation
3.96  3.90
Summary of Change from Baseline Gynecomastia Evaluation
3.97  3.91
Summary of Digital Rectal Examination
 
 
 
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Safety
3.98  3.92
Summary of Change from Baseline Digital Rectal Examination
3.99  3.93
Summary of Vital Signs
3.100  3.94
Summary of Change from Baseline Vital Signs
3.101  3.95
Summary of Vital Signs Exceeding Threshold at Baseline
3.102  3.96
Summary of Vital Signs Exceeding Threshold at Any Post-Baseline Visit
3.103  3.97
Summary of C-SSRS Data
3.104  3.98
Listing of C-SSRS Data for Subjects With Suicidal Ideation and/or Behavior
 
 
 
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11.15.6.
Safety Figures
3.1
Plot of Study Drug Exposure
3.2
Plot of Power to Detect a Difference in Adverse Event Rate for Combination versus Tamsulosin
3.3
Most Common Adverse Events Starting Post-Randomization, Sorted by Odds Ratio
3.4
Plot of Kaplan-Meier Estimates of Time to First Altered (Decreased) Libido Adverse Event
3.5
Plot of Kaplan-Meier Estimates of Time to First Impotence Adverse Event
3.6
Plot of Kaplan-Meier Estimates of Time to First Ejaculation Disorder Adverse Event
3.7
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder Adverse Event
3.8
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder: Breast Enlargement Adverse Event
3.9
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder: Breast Tenderness Adverse Event
3.10
Plot of Kaplan-Meier Estimates of Time to First Prostate Cancer Adverse Event
3.11
Plot of Kaplan-Meier Estimates of Time to First Acute Coronary Syndrome  Adverse Event
3.12
Plot of Kaplan-Meier Estimates of Time to First Ischemic Cerebrovascular Adverse Event
3.13
Plot of Kaplan-Meier Estimates of Time to First Cardiac Failure Adverse Event
3.14
Plot of Kaplan-Meier Estimates of Time to First Ischemic CAD/Atherosclerosis Adverse Event
3.15
Plot of Kaplan-Meier Estimates of Time to First Cardiac Arrhythmia Adverse Event
3.16
Plot of Kaplan-Meier Estimates of Time to First Peripheral Vascular Disease Adverse Event
3.17
Plot of Kaplan-Meier Estimates of Time to First Cardiovascular Adverse Event
3.18
Plot of Kaplan-Meier Estimates of Time to Death
 
 
 
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11.15.7.
Health Outcome Tables
Health Outcomes Tables  (Population=ITT)
No.
Title
BII Overview and Primary Analysis
4.1
Summary of BII Imputations
4.2
Summary of BII at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Month n (3, 6, …24) 
4.3
Summary of BII at Each Post-Baseline Visit (LOCF)
4.4
Summary of BII at Each Post-Baseline Visit (At Visit)
4.5
Summary of BII Change from Baseline (LOCF)
4.6
Summary of BII Change from Baseline (At Visit)
4.7
Summary of MMRM Analysis for BII Change from Baseline
Individual BII Questions 1 - 4
4.7  4.8
Summary of BII at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Months 12 and 24
4.8  4.9
Summary of BII at Months 12 and 24: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
4.9  4.10
Summary of BII at Months 12 and 24: Question 1 (At Visit)
4.10  4.11
Summary of BII Change from Baseline at Months 12 and 24: Question 1 (LOCF)
4.11  4.12
Summary of BII Change from Baseline at Months 12 and 24: Question 1 (At Visit)
4.12  4.13
Summary of BII at Screening and Baseline: Question 2
4.13  4.14
Summary of BII at Months 12 and 24: Question 2 (LOCF)
4.14  4.15
Summary of BII at Months 12 and 24: Question 2 (At Visit)
4.15  4.16
Summary of BII at Months 12 and 24: Change from Baseline: Question 2 (LOCF)
4.16  4.17
Summary of BII Change from Baseline at Months 12 and 24: Question 2 (At Visit)
4.17  4.18
Summary of BII at Screening and Baseline: Question 3
4.18  4.19
Summary of BII at Months 12 and 24: Question 3 (LOCF)
4.19  4.20
Summary of BII at Months 12 and 24: Question 3 (At Visit)
 
 
 
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Health Outcomes Tables  (Population=ITT)
No.
Title
4.20  4.21
Summary of BII Change from Baseline at Months 12 and 24: Question 3 (LOCF)
4.21  4.22
Summary of BII Change from Baseline at Months 12 and 24: Question 3 (At Visit)
4.22  4.23
Summary of BII at Screening and Baseline: Question 4
4.23  4.24
Summary of BII at Months 12 and 24: Question 4 (LOCF)
4.24  4.25
Summary of BII at Months 12 and 24: Question 4 (At Visit)
4.25  4.26
Summary of BII Change from Baseline at Months 12 and 24: Question 4 (LOCF)
4.26  4.27
Summary of BII Change from Baseline at Months 12 and 24: Question 4 (At Visit)
BII Percentage Change from Baseline
4.27  4.28
Summary of BII Percentage Change from Baseline (LOCF)
4.28  4.29
Summary of BII Percentage Change from Baseline (At Visit)
BII Non-Imputed Score Analysis
Performed only if RAP Section11.7 imputation conditions are met; thus, table numbers are not listed.
BPH-Related Health Status
4.29  4.30
Summary of BPH-Related Health Status at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Month n 
(3, 6, …24) 
4.30  4.31
Summary of BPH-Related Health Status at Each Post-Baseline Visit (LOCF)
4.31  4.32
Summary of BPH-Related Health Status at Each Post-Baseline Visit (At Visit)
4.32  4.33
Summary of BPH-Related Health Status Change from Baseline (LOCF)
4.33  4.34
Summary of BPH-Related Health Status Change from Baseline (At Visit)
4.35
Summary of MMRM Analysis for BPH-Related Health Status Change from Baseline
4.34  4.36
Summary of BPH-Related Health Status Percentage Change from Baseline (LOCF)
4.35  4.37
Summary of BPH-Related Health Status Percentage Change from Baseline (At Visit)
 
 
 
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Health Outcomes Tables  (Population=ITT)
No.
Title
PAS SFI Overview and Primary Analysis
4.36  4.38
Summary of PAS SFI Imputations
4.37  4.39
Summary of PAS SFI at Screening and Baseline  includes Visit 1b, Visit 2, Baseline, Baseline for Subjects with PAS SFI at each Month n (12 and 24) 
4.38  4.40
Summary of PAS SFI at Each Post-Baseline Visit (LOCF)
4.39  4.41
Summary of PAS SFI at Each Post-Baseline Visit (At Visit)
4.40  4.42
Summary of PAS SFI Change from Baseline (LOCF)
4.41  4.43
Summary of PAS SFI Change from Baseline (At Visit)
Individual PAS SFI Questions 1 - 3
4.42  4.44
Summary of PAS SFI at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with PAS SFI at each Months 12 
and 24
4.43  4.45
Summary of PAS SFI: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
4.44  4.46
Summary of PAS SFI: Question 1 (At Visit)
4.45  4.47
Summary of PAS SFI Change from Baseline: Question 1 (LOCF)
4.46  4.48
Summary of PAS SFI Change from Baseline: Question 1 (At Visit)
4.47  4.49
Summary of PAS SFI at Screening and Baseline: Question 2
4.48  4.50
Summary of PAS SFI: Question 2 (LOCF)
4.49  4.51
Summary of PAS SFI: Question 2 (At Visit)
4.50  4.52
Summary of PAS SFI Change from Baseline: Question 2 (LOCF)
4.51  4.53
Summary of PAS SFI Change from Baseline: Question 2 (At Visit)
4.52  4.54
Summary of PAS SFI at Screening and Baseline: Question 3
4.53  4.55
Summary of PAS SFI: Question 3 (LOCF)
4.54  4.56
Summary of PAS SFI: Question 3 (At Visit)
4.55  4.57
Summary of PAS SFI Change from Baseline: Question 3 (LOCF)
4.56  4.58
Summary of PAS SFI Change from Baseline: Question 3 (At Visit)
 
 
 
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11.15.8.
Health Outcomes Figures
Health Outcomes Figures  (Population=ITT)
No.
Title
4.1
Plot of BII Adjusted Mean Change from Baseline (LOCF)
4.2
Plot of BII Adjusted Mean Change from Baseline (At Visit)
4.3
Plot of BPH-Related Health Status Adjusted Mean Change from Baseline (LOCF)
4.4
Plot of BPH-Related Health Status Adjusted Mean Change from Baseline (At Visit)
11.15.9.
ICH and Non-ICH Listings
The following categorizes data listings as ICH (International Conference on Harmonization) used to support critical analyses or non-ICH. 
The two classifications are assigned with consideration for general regulatory requirements across countries at point of RAP finalization. 
Changes to these classifications may occur at point of reporting as a result of specific country requirements or requests and will not result 
in a RAP revision.
 
 
 
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ICH
Non-ICH
Title
Study Population
-
5.1
Listing of Subject Withdrawals During Placebo Run-in Phase
1.1
Listing of Randomized and Actual Treatments
1.2
Listing of Subject Accountability
1.3
Listing of Reasons for Study Withdrawal
1.4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
1.5
Listing of Important Protocol Deviations
1.6
Listing of Deviations which Require Exclusion from the Per-Protocol Population
1.7
Listing of Demographic Characteristics
1.8
Listing of Race Details
5.2
Listing of Substance Use at Screening
5.3
Listing of Medical Conditions at Screening
5.4
Listing of Sexual Function at Screening
5.5
Listing of Family History of Premature Coronary Artery Disease
5.6
Listing of Electrocardiogram Results
5.7
Listing of BPH History
5.8
Listing of Alpha-Blocker, 5-Alpha-Reductase Inhibitor, and Phytotherapy Usage History
5.9
Listing of Family History of Breast Cancer and Prostate Cancer 
1.9
Listing of Concomitant Medications  
1.10
Listing of Relationship Between ATC Level 1, Ingredient, and Verbatim Text 
1.11
Listing of Investigational Product Discontinuation
1.12
Listing of Exposure to Study Drug
5.10
Listing of Study Drug Dispensing
1.13
Listing of Study Drug Compliance
 
 
 
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ICH
Non-ICH
Title
Study Population
1.14
Listing of Subjects for Whom the Treatment Blind was Broken During the Study
ICH
Non-ICH
Title
Efficacy Listings
IPSS
2.1
Listing of IPSS
5.11
Listing of IPSS MMRM Analysis: SAS Output
5.12
GLM Analysis and Diagnostics for IPSS Change from Baseline at Month 24 (LOCF): SAS Output
5.13
GLM Analysis and Diagnostics for IPSS Change from Baseline at Month 24 (At Visit): SAS Output
5.14
Assessment of Subgroup Effects for IPSS Change from Baseline at Month 24 (LOCF)
5.15
Assessment of Subgroup Effects for IPSS Change from Baseline at Month 24 (At Visit)
5.16
Summary of IPSS Change from Baseline, by Center, at Months 12 and 24 (LOCF): SAS Output
Note, this LOCF table and below At Visit table are in Non-ICH listing rather than a table due to high number of centers, many with low 
enrollment. Output can be moved at point of CSR if necessary.
5.17
Summary of IPSS Change from Baseline, by Center, at Months 12 and 24 (At Visit) 
Prostate Volume
2.2
Listing of Prostate Volume
5.18
GLM Analysis and Diagnostics for Prostate Volume Percentage Change from Baseline at Month 24 (LOCF): SAS Output
5.19
GLM Analysis and Diagnostics for Prostate Volume Percentage Change from Baseline at Month 24 (At Visit): SAS Output
5.20
Assessment of Subgroup Effects for Prostate Volume Percentage Change from Baseline at Month 24 (LOCF)
5.21
Assessment of Subgroup Effects for Prostate Volume Percentage Change from Baseline at Month 24 (At Visit)
5.22
Summary of Prostate Volume Percentage Change from Baseline, by Center, at Months 12 and 24 (LOCF)
5.23
Summary of Prostate Volume Percentage Change from Baseline, by Center, at Months 12 and 24 (At Visit) 
 
 
 
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ICH
Non-ICH
Title
Efficacy Listings
Qmax
2.3
Listing of Subjects with Voided Volume less than 125ml
2.4
Listing of Qmax and Voided Volume
5.24
GLM Analysis and Diagnostics for Qmax Change from Baseline at Month 24 (LOCF): SAS Output
5.25
GLM Analysis and Diagnostics for Qmax Change from Baseline at Month 24 (At Visit): SAS Output
5.26
Assessment of Subgroup Effects for Qmax Change from Baseline at Month 24 (LOCF)
5.27
Assessment of Subgroup Effects for Qmax Change from Baseline at Month 24 (At Visit)
5.28
Summary of Qmax Change from Baseline, by Center, at Months 12 and 24 (LOCF)
5.29
Summary of Qmax Change from Baseline, by Center, at Months 12 and 24 (At Visit)
2.5
Listing of Biannual Follow-Up Telephone Contacts
2.6
Listing of Subjects with AUR
2.7
Listing of Subjects with Prostatic Surgery
2.8
Listing of Subjects with Non-Surgical Intervention for BPH
5.30
Listing of Time to First AUR or BPH-Related Surgery Event
5.31
Listing of Analysis of Time to First AUR or BPH-Related Surgery: SAS Output
5.32
Listing of Time to First AUR
5.33
Listing of Analysis of Time to First AUR: SAS Output
5.34
Listing of Time to First BPH-Related Surgery Event
5.35
Listing of Analysis of Time to First BPH-Related Surgery: SAS Output
5.36
Listing of Subjects With Urinary Tract Infection / Urosepsis
5.37
Listing of Subjects With Urinary Incontinence
5.38
Listing of Subjects With Renal Insufficiency
 
 
 
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ICH
Non-ICH
Title
Safety
3.1
Listing of Relationship between System Organ Class and Verbatim Text
3.2
Listing of All Adverse Events
3.3
Listing of All Adverse Events by Onset Period
3.4
Listing of Subject Numbers for Specific Adverse Events
3.5
Listing of Fatal Adverse Events
3.6
Listing of Non-Fatal Serious Adverse Events
3.7
Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug
3.8
Listing of Adverse Events Leading to Withdrawal from the Study
3.9
Listing of Possible Suicidality-Related Adverse Events
3.10
Listing of Possible Suicidality-Related Adverse Event Comments
Note: Below strikethroughs and data display number revisions are associated with RAP Amendment 01. This approach permanently 
documents data display number revisions for traceability and reference.
3.11
Listing of Possible Suicidality-Related Adverse Event Data (Section 4)
3.12
Listing of Possible Suicidality-Related Adverse Event Data (Sections 5-8)
3.13  3.11
Listing of Relationship between Special Interest Adverse Events and Verbatim Text
3.14  3.12
Listing of Adverse Events of Special Interest
5.39
Listing of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal
5.40
Listing of Targeted Follow-Up Questionnaire Data
3.15  3.13
Listing of Pregnancies in Female Partners of Male Study Participants
5.41
Listing of Clinical Chemistry Data
5.42
Listing of Hematology Data
3.16  3.14
Listing of Clinical Chemistry Data Exceeding Threshold
3.17  3.15
Listing of Hematology Data Exceeding Threshold
 
 
 
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ICH
Non-ICH
Title
Safety
5.43
Listing of Baseline Hepatitis B Surface Antigen and Hepatitis C Antibody Data
5.44
Listing of Serum PSA (ng/ml)
3.18  3.16
Listing of Serum PSA Data Exceeding Upper Limit of Normal
3.19  3.17
Listing of Subjects with ALT ≥3 times ULN and Bilirubin ≥2 times ULN
5.45
Listing of Post-Void Residual Volume
5.46
Listing of Gynecomastia Data
5.47
Listing of Digital Rectal Examination Data
5.48
Listing of Vital Signs Data
3.20  3.18
Listing of Vital Signs Exceeding Threshold
3.21  3.19
Listing of For-Cause Biopsy Results
5.49
Listing of C-SSRS Data
3.22  3.20
Listing of C-SSRS Suicidal Behavior Details for Subjects With Suicidal Behavior
3.23  3.21
Listing of Details of Most Severe Suicidal Ideation at Each C-SSRS Assessment for Subjects With Suicidal Ideation
5.50
Listing of Cardiovascular Events Recorded in the eCRF Log
5.51
Listing of Cardiovascular Event Findings Recorded in the eCRF Log
5.52
Listing of Cardiovascular Event Diagnostic Tests Recorded in the eCRF Log
5.53
Listing of Health Resource Utilization Recorded in the eCRF Log
5.54
Listing of Physical Evidence Recorded in the eCRF Log
5.55
Listing of Surgery and Medical Procedures Related to Cardiovascular Events
5.56
Listing of Risk Factors Recorded in the eCRF Log
5.57
Listing of Labs Related to Cardiovascular Events Recorded in the eCRF Log
5.58
Listing of Vital Signs Related to Cardiovascular Events Recorded in the eCRF Log
 
 
 
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ICH
Non-ICH
Title
Safety
5.59
Listing of ECGs Related to Cardiovascular Events Recorded in the eCRF Log
5.60
Listing of Status Variables Related to Cardiovascular Events Recorded in the eCRF Log
5.61
Listing of Subjects Recorded on Surgery File Related to Cardiovascular Events, But with No Surgery Performed
Health Outcomes
5.50  5.62
Listing of BPH Impact Index (BII)
5.51  5.63
Listing of BPH-Related Health Status
5.52  5.64
Listing of Problem Assessment Scale of the Sexual Function Inventory (PAS SFI)
 
 
 
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11.16.
Appendix 16: Mock Shells for Data Displays
Mock table shells are stored in IMMS, within same directory/cabinet as RAP, as separate documents.
 
 
 
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11.17.
Appendix 17: Amendment 01 Revisions
Item
RAP Revision General Description
RAP Section
01
Indicate RAP “Amendment Number 01” with administrative details including revision 
number, copyright year, effective date, description, author, and approver.
-Cover page
-Document header
-Document footer
-Section 1: Key Elements of the RAP
-Section 2.1: Changes to the Protocol Defined Statistical 
Analysis Plan
02
Clarify:
-“IPSS primary analysis” is in terms of the Month 24 timepoint only.
-Analyses of IPSS timepoints earlier than Month 24, specifically Month 21 – Month 
3, in this order, are classified as secondary endpoints.
-Section 1: Synopsis
-Table 3: Overview of Planned Primary Efficacy Analyses
-Section 7.1.2: Planned Primary Efficacy Statistical 
Analyses
-Table 4: Overview of Planned Secondary Efficacy 
Analyses
03
For each Alpha-Blocker, 5-Alpha-Reductase Inhibitor, and Phytotherapy for BPH 
prior use, document the eCRF collection of affirmative ‘Yes’ responses only.  
Indicate assumptions for ‘No’ responses and related tabular summary 
presentations.
-Section 6.5: Medical Conditions and Concomitant 
Medications
04
In addition to study population summaries of Alpha-Blocker, 5-Alpha-Reductase 
Inhibitor, and Phytotherapy for BPH prior use, expand summaries to include prior 
use of:
[a] Alpha-Blocker OR 5-Alpha-Reductase Inhibitor Use
[b] Alpha-Blocker OR 5-Alpha-Reductase Inhibitor OR Phytotherapy for BPH Use.
-Table 2: Overview of Planned Study Population 
Analyses
-Section 11.15.2: Study Population Tables
 
 
 
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Item
RAP Revision General Description
RAP Section
05
Within “Examination of Covariates and Subgroups”, expand the list of subgroups to 
include:
[a] Alpha-Blocker OR 5-Alpha-Reductase Inhibitor Use
[b] Alpha-Blocker OR 5-Alpha-Reductase Inhibitor OR Phytotherapy for BPH Use.
This is applicable for IPSS, prostate volume, and Qmax summaries.
-Appendix 10: Examination of Covariates
-Section 11.15.3: Efficacy Tables
06
As a supporting analysis include a mixed-model repeated measures (MMRM) 
analysis to be conducted and output in a manner similar to the primary efficacy 
endpoint for:  Qmax, BPH Impact Index, and BPH-Related Health Status.
-Section 8.1.4: Maximum, Urine Flow (Qmax)
-Section 8.3.1: BPH Impact Index
-Section 8.3.2: BPH-Related Health Status
-Appendix 15: List of Data Displays
07
Improve format and conciseness of AE special interest tables by moving original “by 
baseline” age and sexual function summaries of Tables 3.48 – 3.53 into Tables 
3.42-3.47.  Therefore, Tables 3.48 – 3.53 are deleted and subsequent safety tables 
are renumbered accordingly.
-Table 5: Overview of Planned Adverse Event Tabular 
Summaries
-Section 8.2.4.3: Sexual and Breast Tier 1 Adverse 
Events of Special Interest
-11.15:  Appendix 15: List of Data Displays
08
Update terms and MedDRA codes for AEs of Special Interest (due to MedDRA and 
Global Safety Team since original RAP).  Revise the following within Table D, 
Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms 
and Codes using MedDRA version 19.1
Allergic reactions:
-delete “First use syndrome”, code 10068159
-delete “Small bowel angioedema”, code 10051401
Breast cancer:
-delete “Contralateral breast cancer”, code 10054784
Depressed mood:
-Appendix 8: Adverse Event Time Period and Special 
Adverse Event Definitions
 
 
 
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Item
RAP Revision General Description
RAP Section
-delete “Dysthymic disorder”, code 10013982
-replace “Postpartum depression” with “Perinatal depression”, code 10078366
-delete “Self injurious behavior”, code 10063495. Note this was replaced with, 
already included, “Intentional self-injury”.
09
Revise title of Figure 2.1 – Figure 2.6 from “Figure of” to “Plot of”
-Section 11.15.4: Efficacy Figures
10
Expand IDSL list of principles from “4.23” to “4.24” to account for IDSL Jul2016 
addition.
-Section 11.5.2: Reporting Process & Standards
11
Expand list of “Exclusions from the Per-Protocol Population” to account for relevant 
prohibited medications and non-drug therapies of Protocol Section 6.2 which are 
not otherwise classified in Appendix 1.
-Section 4.1.3: Deviations which Require Exclusion from 
the Per-Protocol Population
-Appendix 1: Exclusions from the Per-Protocol 
Population
12
Improve format and conciseness of Possible Suicidality-Related Adverse Event 
Listings.  This reduces the number of associated listings from four to two.  
Therefore, Listings 3.11 and 3.12 are deleted and subsequent listings are 
renumbered accordingly.
-11.15: Appendix 15: List of Data Displays
13
Apply proper and consistent first letter capitalization to data display titles; as an 
example revise “On-treatment” to “On-Treatment”.
-11.15: Appendix 15: List of Data Displays
14
Include reference to cardiovascular event data collection of protocol section 7.4.2.2. 
Insert additional associated data listings; renumber subsequent listings accordingly.
-Section 8.2.4.5: Cardiovascular Tier 1 Adverse Events 
of Special Interest
-11.15:  Appendix 15: List of Data Displays
15
Remove reference to CDISC-based dataset creation and reporting. Document that 
GSK exemption for ARI114265 CDISC-based dataset creation and reporting was 
-Section 11.5.2: Reporting Process & Standards
 
 
 
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Item
RAP Revision General Description
RAP Section
granted June 2016.
16
Clarify study drug compliance definition and calculations by treatment group and 
across the treatment groups.
-Section 6.6:   Investigational Product Discontinuation, 
Exposure, and Compliance
-Appendix 6: Derived and Transformed Data
 
 
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
ARI114265
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for ARI114265: A randomized, 
double-blind, parallel group study to compare the efficacy 
and safety of combination treatment with dutasteride (0.5mg) 
and tamsulosin (0.2mg) with tamsulosin (0.2mg) 
monotherapy, administered once daily for 2 years, on the 
improvement of symptoms and health outcomes in men with 
moderate to severe benign prostatic hyperplasia
Compound Number 
:
GI198745+GI138525
Effective Date 
:
15-DEC-2015
Description :
The purpose of this RAP is to describe the planned summaries and statistical analyses to 
be included in the Clinical Study Report (CSR) for Protocol ARI114265.
Author’s Name and Functional Area: 
Associate Director, Biostatistics, PAREXEL International
Employee of PAREXEL on behalf of GSK
15-DEC-2015
Approved by: 
(e-mail approval dated 15-Dec-2015)
Director Statistics & Programming, GSK
15-DEC-2015
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PPD
PPD


CONFIDENTIAL
ARI114265
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses...................................................................................9
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analysis .............................................................................................10
3.3.
Targeted Follow-Up Questionnaire (TFUQ) Report.....................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
4.1.1.
Inclusion / Exclusion Criteria Deviations ......................................11
4.1.2.
Important Protocol Deviations......................................................12
4.1.3.
Deviations which Require Exclusion from the Per-Protocol 
Population....................................................................................12
4.1.4.
Deviations which Require Exclusion from the Per-Protocol 
Population but not Tracked or Identified as Important by 
Study Team .................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
6.2.
Subject Accountability.................................................................................16
6.3.
Subject Disposition .....................................................................................17
6.4.
Demographic and Baseline Characteristics.................................................17
6.5.
Medical Conditions and Concomitant Medications......................................18
6.6.
Investigational Product Discontinuation, Exposure, and Compliance ..........18
7.
PRIMARY STATISTICAL ANALYSES....................................................................19
7.1.
Primary Efficacy Analyses ..........................................................................19
7.1.1.
Overview of Planned Primary Efficacy Analyses..........................19
7.1.2.
Planned Primary Efficacy Statistical Analyses .............................20
7.1.3.
Supporting and Sensitivity Analyses of Primary Endpoint ............21
8.
SECONDARY STATISTICAL ANALYSES .............................................................22
8.1.
Secondary Efficacy Analyses......................................................................22
8.1.1.
Overview of Planned Secondary Efficacy Analyses .....................22
8.1.2.
IPSS Improvement Levels ...........................................................23
8.1.3.
Prostate Volume ..........................................................................23
8.1.4.
Maximum Urine Flow (Qmax) ......................................................24
8.1.5.
AUR or BPH-Related Surgical Intervention..................................25
8.1.6.
Other Efficacy Measures..............................................................27
8.2.
Safety Analyses..........................................................................................28
 
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3
8.2.1.
Overview of Adverse Event Tabular Summaries..........................28
8.2.2.
Adverse Events............................................................................30
8.2.3.
Deaths and Serious Adverse Events............................................32
8.2.4.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal From the Study 
and Other Significant Adverse Events..........................................33
8.2.4.1.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from 
the Study....................................................................33
8.2.4.2.
Adverse Events of Special Interest.............................33
8.2.4.3.
Sexual and Breast Tier 1 Adverse Events of 
Special Interest...........................................................33
8.2.4.4.
Prostate Cancer Tier 1 Adverse Events of 
Special Interest...........................................................35
8.2.4.5.
Cardiovascular Tier 1 Adverse Events of 
Special Interest...........................................................35
8.2.4.6.
Infrequent Tier 1 Adverse Events of Special 
Interest .......................................................................35
8.2.5.
Pregnancies.................................................................................36
8.2.6.
Clinical Laboratory Assessments .................................................36
8.2.7.
Serum PSA..................................................................................38
8.2.8.
Post Void Residual Volume .........................................................38
8.2.9.
Gynecomastia Evaluations ..........................................................38
8.2.10.
Digital Rectal Examinations .........................................................39
8.2.11.
Vital Signs....................................................................................39
8.2.12.
Prostate Cancer Biopsies ............................................................40
8.2.13.
Suicidality Assessment ................................................................40
8.3.
Health Outcomes Analyses.........................................................................40
8.3.1.
BPH Impact Index........................................................................40
8.3.2.
BPH-Related Health Status .........................................................41
8.3.3.
Problem Assessment Scale of the Sexual Function
Inventory (PAS SFI).....................................................................42
9.
COUNTRY-SPECIFIC SUMMARIES AND ANALYSES..........................................43
10. REFERENCES.......................................................................................................44
11. APPENDICES........................................................................................................45
11.1.
Appendix 1: Exclusions from the Per-Protocol Population...........................46
11.2.
Appendix 2: Time & Events.........................................................................50
11.2.1.
Protocol Defined Time & Events ..................................................50
11.3.
Appendix 3: Assessment Windows .............................................................53
11.4.
Appendix 4: Multicenter Studies..................................................................54
11.4.1.
Methods for Handling Centers .....................................................54
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................55
11.5.1.
Study Treatment & Sub-group Display Descriptors......................55
11.5.2.
Reporting Process & Standards...................................................55
11.6.
Appendix 6: Derived and Transformed Data ...............................................57
11.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............60
11.7.1.
Premature Withdrawals................................................................60
11.7.2.
Handling of Missing Data.............................................................60
11.7.2.1.
Handling of Missing or Partial Dates...........................60
 
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11.7.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................60
11.7.3.
Questionnaire Total Score Imputation..........................................61
11.8.
Appendix 8: Adverse Event Time Periods and Special Adverse 
Event Definitions.........................................................................................62
11.9.
Appendix 9: Threshold Factors for Clinical Laboratory Tests and 
Vital Signs...................................................................................................75
11.10. Appendix 10: Examination of Covariates and Subgroups............................76
11.11. Appendix 11: Multiple Comparisons and Multiplicity....................................77
11.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................78
11.13. Appendix 13: Mixed-Model Repeated-Measures Analysis ..........................79
11.14. Appendix 14 – Abbreviations & Trade Marks ..............................................80
11.14.1. Abbreviations...............................................................................80
11.14.2. Trademarks .................................................................................81
11.15. Appendix 15: List of Data Displays..............................................................82
11.15.1. Data Display Numbering..............................................................82
11.15.2. Study Population Tables..............................................................83
11.15.3. Efficacy Tables ............................................................................85
11.15.4. Efficacy Figures ...........................................................................93
11.15.5. Safety Tables...............................................................................93
11.15.6. Safety Figures .............................................................................99
11.15.7. Health Outcome Tables .............................................................101
11.15.8. Health Outcomes Figures ..........................................................104
11.15.9. ICH and Non-ICH Listings..........................................................104
11.16. Appendix 16: Mock Shells for Data Displays.............................................110
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose
The purpose of this Reporting and Analysis Plan (RAP) is to describe the planned
summaries and statistical analyses to be included in the Clinical Study Report (CSR) 
for Protocol ARI114265.
Protocol
This RAP is based on the protocol amendment 04 (Republished) (Dated: 
08/JUL/2014) of study ARI114265 [GSK Document No. : RM2010/00134/05].
The aim of the study is to investigate whether combination therapy with dutasteride 
and tamsulosin is more effective than tamsulosin monotherapy for the improvement 
of symptoms and health outcomes in a population at increased risk of BPH clinical 
progression including older men (≥50yrs), with moderate-severe symptoms of BPH, 
enlarged prostates (≥30cc) and PSA≥1.5ng/mL.
Primary 
Objective
The primary objective is to assess the efficacy of combination treatment with 
dutasteride 0.5mg and tamsulosin 0.2mg once daily in providing superior 
symptomatic improvement in subjects with BPH compared with once daily 
tamsulosin 0.2mg monotherapy after 2 years of treatment.
Primary 
Endpoint
The primary endpoint is change from baseline IPSS at Year 2.
Study 
Design
This is a multicenter, randomized, double-blind, parallel group study. Eligible 
subjects will receive placebo tamsulosin and placebo dutasteride for four weeks in a 
single-blind, placebo, run-in period. Each subject will then be randomized to one of 
the following two treatment groups (1:1 ratio) for the double-blind phase (104 weeks) 
of the study:
--Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily or
--Dutasteride placebo once daily + tamsulosin 0.2mg once daily
Subjects will self-administer the study medication once daily for up to 104 weeks 
(2 years). Subjects will return to the clinic at 13 week intervals post-randomization 
during the 2 year treatment period (i.e. at 13, 26, 39, 52, 65, 78, 91, and 104 weeks).
Planned
Analyses
Within this RAP, the following additional references may be made for brevity:
--Full Treatment Description--
--Short Treatment Descriptions--
Dutasteride 0.5mg once daily +
tamsulosin 0.2mg once daily or
-Combination
-Dut 0.5mg + Tam 0.2mg
-Dut + Tam
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
-Tamsulosin Monotherapy
-Tam 0.2mg
-Placebo + Tam 0.2mg
-Tam
The study population, efficacy, safety, and health outcomes summaries and 
analyses will be based on the Intent-to-Treat (ITT) population; few exceptions will be 
noted within the RAP. Summaries and analyses are defined within this RAP. The 
following are high level summary and analyses types.
 
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Overview
Key Elements of the RAP

Study population summaries will be presented overall and by treatment group 
and will include accountability, disposition, demographic characteristics, 
baseline characteristics, protocol deviations, and concomitant medications.

The primary efficacy analyses and treatment group comparisons will be in terms 
of IPSS change from baseline.

Secondary efficacy analyses and treatment group comparisons will be in terms 
of prostate volume, Qmax, IPSS improvement levels (≥2 points, ≥3 points, 
≥25%), Qmax improvement levels (≥3 ml/sec, ≥30%), and time to AUR or 
BPH-related surgery.

Safety summaries will be presented by treatment group and will be in terms of 
study drug exposure, adverse events, clinical laboratory evaluations, serum 
PSA, post void residual volume, qualitative breast examination, digital rectal 
examination, vital signs, and suicidality assessment using C-SSRS.

Health Outcomes analyses and treatment group comparisons will be in terms of 
BPH-Related Health Status (IPSS Question 8), BPH Impact Index, and Problem 
Assessment Scale of the Sexual Function Inventory (PAS SFI).
Analysis 
Populations

The ITT Population is comprised of all randomized subjects regardless of 
whether or not treatment was administered.

The Per-Protocol (PP) Population is comprised of all ITT subjects who comply 
closely with the protocol. Specifically this includes ITT subjects who do not have 
a deviation which requires exclusion from the PP population. The PP population 
will not be analyzed if this population comprises more than 80% of the ITT 
population.
Hypothesis
The primary endpoint is change from baseline IPSS at Year 2. Let the following 
represent the mean change from baseline IPSS for each treatment group:
Hdut+tam: Combination (dutasteride 0.5mg and tamsulosin 0.2mg) treatment group
Htam:  
Tamsulosin (tamsulosin 0.2mg treatment group)
Then the primary null and alternative hypotheses to be tested at Year 2 are as 
follows:
Null Hypothesis:
Hdut+tam = Htam
Alternative Hypothesis:
Hdut+tam ≠ Htam
Two-sided tests of the null hypothesis will be conducted at the 0.05 level of 
significance to show superiority of the combination treatment group compared to 
tamsulosin 0.2mg at 2 years of treatment.
Primary 
Analyses
The primary efficacy parameter after two years of study treatment is change from 
baseline IPSS. Change in IPSS from baseline will be compared at each scheduled 
post-baseline visit for combination treatment versus tamsulosin 0.2mg using a 
general linear model with effects for treatment, cluster, and baseline IPSS. 
Secondary 
Analyses
Secondary efficacy analyses will be in terms of prostate volume, Qmax, IPSS 
improvement levels, Qmax improvement levels, and time to AUR or BPH-related 
surgery using appropriate statistical methodology defined within this RAP.
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the ARI114265 protocol amendment 04 (Republished) (Dated 08/JUL/2014).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the efficacy of 
combination treatment with 
dutasteride 0.5mg and tamsulosin 
0.2mg once daily in providing 
superior symptomatic improvement 
in subjects with BPH compared 
with once daily tamsulosin 0.2mg 
monotherapy after 2 years of 
treatment

Change in IPSS from baseline at Year 2.
Secondary Objectives
Secondary Endpoints

To assess efficacy and safety of 
combination treatment with 
dutasteride 0.5mg and tamsulosin 
0.2mg including the clinical 
outcomes of AUR or BPH-related 
prostatic surgery compared with 
tamsulosin 0.2mg monotherapy 
after 2 years of treatment.
Efficacy

Percent change in prostate volume from baseline

Proportion of subjects with IPSS improvement of ≥2 
points and ≥3 points from baseline and, separately, 
≥25% improvement from baseline

Change in Qmax from baseline

Proportion of subjects with Qmax improvement of 
≥3mL/sec and, separately, ≥30% improvement from 
baseline

Time to event/ proportion of subjects with AUR or 
BPH related prostatic surgery

Time to event/proportion of subjects with AUR

Time to event/proportion of subjects undergoing 
BPH related prostatic surgery
Health Outcome Measures

Change in BPH-Related Health Status (Q8 of 
IPSS) from Baseline

Change in BPH Impact Index (BII) from Baseline

Change in Problem Assessment Scale of the 
Sexual Function Inventory (PAS-SFI), from 
Baseline

Resource Use related to AUR and BPH-related 
surgical events. 
 
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Objectives
Endpoints
Safety

Adverse Events

Change in total serum PSA from baseline

Vital signs

Post-void residual volume

Clinical laboratory measurements (including 
haematology, chemistry)

Physical examination: digital rectal examination 
(DRE) and qualitative  breast examination

Suicidality (C-SSRS)
Exploratory Objectives
Exploratory Endpoints

Pharmacogenetics (PGx) 
Research
Note: PGx planned summaries and 
analyses will be documented 
outside this RAP.

Relationships between genetic variants in DNA from 
patient blood and any unexplained or unexpected 
response to treatment (as monitored by safety, 
tolerability, and efficacy parameters) that may have 
an underlying genetic mechanism.

Population Pharmacokinetics 
(PPK) Research
Note: PPK planned summaries and 
analyses will be documented 
outside this RAP

Characterization of PPK of dutasteride when given in 
combination with tamsulosin to Chinese men with 
BPH.
 
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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Multicenter within 4 countries: China, Japan, Korea, and Taiwan.

Randomized, double-blind, parallel group study to assess the efficacy of 
combination treatment with dutasteride 0.5mg and tamsulosin 0.2mg once 
daily in providing superior symptomatic improvement in subjects with BPH 
compared with once daily tamsulosin 0.2mg monotherapy after 2 years of 
treatment.
Dosing / 
Treatment 
Assignment

Placebo tamsulosin and placebo dutasteride for four weeks in a single-blind, 
placebo, run-in period.

Thereafter randomized to one of the following two treatment groups (1:1 ratio) 
for the double-blind phase (104 weeks) of the study:
--Dutasteride 0.5mg once daily + tamsulosin 0.2mg once daily or
--Dutasteride placebo once daily + tamsulosin 0.2mg once daily.
Interim 
Analysis
No interim analyses are planned for this study.
2.4.
Statistical Hypotheses
The primary endpoint is change from baseline IPSS. Let the following represent the mean 
change from baseline IPSS for each treatment group:
Hdut+tam: Combination (dutasteride 0.5mg and tamsulosin 0.2mg) treatment group
Htam:  
Tamsulosin 0.2mg treatment group
Then the primary null and alternative hypotheses to be tested at Year 2 are as follows:
Description
Null Hypothesis
Alternative Hypothesis
Combination versus tamsulosin 0.2mg
Hdut+tam = Htam
Hdut+tam ≠ Htam
Two-sided tests of the null hypothesis will be conducted at the 0.05 level of significance 
to show superiority of the combination treatment group compared to tamsulosin 0.2mg at 
2 years of treatment.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses are planned for this study.
 
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3.2.
Final Analysis
The planned primary analyses will be performed after completion of the following 
sequential steps:
1.
All subjects have completed the 104-week study treatment period study as defined in 
the protocol.
2.
All required database cleaning activities have been completed and primary database 
release and primary database freeze have been declared by Data Management. 
Reference ‘primary database’ description below.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.
The primary database freeze, using standard Data Management practices, will occur after 
the last subject completes the 104-week randomized treatment phase. Statistical analysis 
and reporting in support of international regulatory submissions will be in terms of this 
primary database freeze and will be referred to as the ‘Final Analysis’ or primary 
‘Statistical Analysis Complete’ (SAC).  Reference Section 9, Country-Specific 
Summaries and Analyses, for a description of a secondary country-based statistical 
analysis complete package.
3.3.
Targeted Follow-Up Questionnaire (TFUQ) Report
As documented in protocol and elsewhere in this RAP, this study includes a Targeted 
Follow-Up Questionnaire (TFUQ) for subjects with sexual function related adverse 
events leading to study withdrawal. Using the TFUQ, subjects will be followed for up to 
6 months after the last dose of study drug. It is anticipated that the final TFUQ data 
component will be included in the above referenced primary database freeze.
However, if there are ongoing TFUQs at the time of primary database freeze, and 
anticipated follow-up and receipt of these data would create a delay in analyzing and 
reporting the study results then the primary freeze may occur with exclusion of 
outstanding TFUQ data. Thereafter, a secondary database freeze will occur in terms of 
newly finalized and recorded TFUQ data (since primary freeze). The decision to perform 
a secondary freeze will be made soon after last subject last visit milestone by Project 
Team with input from Data Management, International Regulatory Affairs, Clinical 
Statistics, Clinical Development, and Clinical Operations.  This secondary freeze will be 
in terms of datasets containing the actual TFUQ and as well as any TFUQ-related 
datasets.  Only TFUQ-related tabular summaries and listings (related to newly frozen 
datasets) will be updated with the secondary freeze.  TFUQ-related summaries and 
listings for this secondary freeze will be referred to as ‘TFUQ Report’.
 
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4.
ANALYSIS POPULATIONS
Analysis populations are defined in the following table.
Population
Definition / Criteria
Analyses Evaluated
Intent-To-Treat
(ITT)

Comprised of all randomized subjects
regardless of whether or not treatment was 
administered

This population will be based on the 
treatment to which the subject was 
randomized.

Any subject who receives a treatment 
randomization number will be considered to 
have been randomized.

All.
Per-Protocol (PP)

Comprised of all ITT subjects who comply 
closely with the protocol. Specifically this 
includes ITT subjects who do not have a 
deviation which requires exclusion from the 
PP population.

Protocol deviations that would exclude 
subjects from the PP population are defined 
in Section 4.1.3 (Deviations which Require 
Exclusion from the Per-Protocol Population) 
and Appendix 1 (Exclusions from the Per-
Protocol Population).

The PP population will not be analyzed if this 
population comprises more than 80% of the 
ITT population. 

Primary efficacy 
endpoint only if this 
population 
comprises 80% or 
less of the ITT 
Population. Details 
on specific 
summaries and 
analyses are 
outlined in Section 7, 
Primary Statistical 
Analyses.
NOTES : 

‘All Enrolled Subjects’ is referenced in at least one tabular summary. Enrolled subjects include those who entered 
placebo run-in phase and/or who were randomized. 
4.1.
Protocol Deviations
4.1.1.
Inclusion / Exclusion Criteria Deviations
All inclusion / exclusion criteria deviations which are recorded on the inclusion / 
exclusion screens of the eCRF will be summarized and listed.  The tabular summary will 
be in terms of number and percent of Intent-to-Treat population subjects violating any
criterion and violating each criterion. Summaries will be output by each of the two 
randomized treatment groups and overall.
 
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4.1.2.
Important Protocol Deviations
All protocol deviations identified during the course of the study will be tracked and 
reviewed by the study team in accordance with SOP-130050 and the ARI114265 Protocol 
Deviations Management Plan (PDMP). As outlined in the PDMP and Data Management 
procedures, the ARI114265 Study Team will identify protocol deviations which are 
considered to be ‘Important’ and flag on the team’s protocol deviations spreadsheet.  This 
spreadsheet will be subsequently loaded to the Data Management file system and 
formatted for HARP Analysis & Reporting.
Important Deviations will be summarized and listed. The tabular summary will be in 
terms of number and percent of subjects with any Important Deviation and with each 
Important Deviation. Summaries will be output by the eCRF category and subcategories 
for each of the two randomized treatment groups and overall. The eCRF categories and 
subcategories are standardized for this study; examples are provided in the tabular 
summary shells.
4.1.3.
Deviations which Require Exclusion from the Per-Protocol 
Population
In accordance with SOP-130050 and the ARI114265 PDMP, deviations which require 
exclusion from the Per-Protocol population should be identified; the 18 deviations are 
listed in the below table. The historical term used to describe these deviations in 
ARI114265 protocol is ‘major’. In this RAP and for future reporting the phrase 
‘deviations which require exclusion from the Per-Protocol population’ will replace 
‘major’.
Number
Deviations which Require Exclusion from the Per-Protocol Population
01
Missed placebo run-in phase
02
Incorrect study drug (wrong treatment) consumed
03
Randomized but did not consume double-blind study drug
04
Cumulative study drug compliance <75%
05
Cumulative study drug compliance >125%
Violation of Inclusion Criteria (protocol #)
06
Confirmed BPH clinical diagnosis (Inclusion 2)
07
IPSS ≥12 at Screening (Inclusion 3)
08
Prostate volume ≥30cc by TRUS at Screening (Inclusion 4)
09
PSA ≥1.5ng/ml and ≤10ng/mL at Screening (Inclusion 5)
10
Qmax >5 mL/sec and ≤15mL/sec with Voided Volume ≥125mL/sec at Screening (Inclusion 
6)
Violation of Exclusion Criteria (protocol #) 
11
Any conditions other than BPH, which may in the judgement of the investigator, result in 
urinary symptoms or changes in flow rate (Exclusion 6)
12
Use of 5ARI within 6 months of Screening or historical TRUS and throughout the study 
(Exclusion 10a)
13
Use of anabolic steroids within 6 months of Screening and throughout the study (Exclusion 
10b)
 
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Number
Deviations which Require Exclusion from the Per-Protocol Population
14
Use of phytotherapy for BPH within 2 weeks of Screening and throughout the study 
(Exclusion 10c)
15
Use of alpha-adrenoreceptor blockers within 2 weeks of Screening and throughout the study, 
except study meds (Exclusion 10d)
16
Use of alpha-adrenoreceptor agonists or anticholinegics or cholinergics within 48 hours prior 
to all uroflowmetry and IPSS assessments (Exclusion 10e)
17
Use of selective beta 3-adrenoreceptor agonist (mirabegron) within 2 weeks prior to all 
uroflowmetry and IPSS assessments (Exclusion 10f)
Other
18
Any condition which should exclude a subject from the Per-Protocol population which is not 
included above; identified by Study Team.
Please refer to Appendix 1: Exclusions from the Per-Protocol Population for details on 
sources and processing these deviations.
Deviations which require exclusion from the Per-Protocol population will be summarized 
and listed. The Per-Protocol deviations tabular summary will be in terms of number and 
percent of subjects with any deviation and for each deviation. Summaries will be output 
by each of the two randomized treatment groups and overall.
4.1.4.
Deviations which Require Exclusion from the Per-Protocol 
Population but not Tracked or Identified as Important by Study 
Team
For brevity, in this section ‘deviations which require exclusion from the per-protocol 
population’, defined in Section 4.1.3, will be referred to as ‘Per-Protocol Deviations’. In 
accordance with SOP-130050 and as clarified in GUI-315049, Per-Protocol Deviations 
are a subset of Important Protocol Deviations. As described in Appendix 1, some Per-
Protocol Deviations may be identified programmatically and/or some may be identified 
post database freeze and unblinding. Therefore, it is not feasible to manually enter all 
Per-Protocol Deviations to the Study Team spreadsheet (referenced in Section 4.1.2) and 
thus not all Per-Protocol Deviations will be tracked or identified as Important by Study 
Team.
Per-Protocol Deviations which were not tracked or identified as Important by Study 
Team will be reported in 1) Listing of Important Deviations and flagged as such, and 2) 
Summary of Important Protocol Deviations. 
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides a list of appendices primarily related to considerations for data analyses
and data handling conventions. A full set of appendices is provided in Section 11.
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Exclusions from the Per-Protocol Population
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Multicenter Studies
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
11.8
Appendix 8: Adverse Event Time Periods and Special Adverse Event Definitions
11.9
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified in text or data display shells. 
Table 2 provides an overview of the planned study population summaries and listings. A 
list of planned data displays is in Appendix 15: List of Data Displays.
Reference Section 4 (Analysis Populations) and Appendix 6 (Derived and Transformed 
Data) for supporting definitions on all below subsections.
Formal statistical treatment comparisons will not be performed in terms of the study 
population data.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Listing
Subject Accountability
Numbers of Subjects, including: Enrolled, Placebo Run-In, 
Randomized (ITT Population), Per-Protocol Population
Y
Y
Subject Disposition
Withdrawals During Placebo Run-In
Y
Y
Randomized by Country and Center
Y
Y
Withdrawals During Double-Blind including totals, reasons, 
and by time of discontinuation
Y
Y
Inclusion / Exclusion Criteria Deviations
Y
Y
Important Protocol Deviations
Y
Y
Deviations which Require Exclusion from the Per-Protocol 
Population
Y
Y
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Ethnicity, Race, and Racial Combination Details
Y
Y
Selected Safety Measures at Baseline, Overall and by 
Country
Y
[1]
Selected Efficacy and Health Outcome Measures at Baseline, 
Overall and by Country 
Y
[1]
Medical Conditions and Concomitant Medications
Medical Conditions by Body System
Y
Y
Specific Medical Conditions
Y
Y
BPH History
Y
Y
Alpha-Blocker, 5-Alpha-Reductase Inhibitor, Phytotherapy 
Use
Y
Y
Sexual Function
Y
Y
Family History: Premature Coronary Artery Disease, Breast 
Cancer, Prostate Cancer
Y
Y
Concomitant Medications
Y
Y
 
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Display Type
Data Displays Generated
Table
Listing
Investigational Product Discontinuation, Exposure, Treatment Compliance
Investigational Product Discontinuation
Y
Y
Study Drug Exposure
Y
Y
Study Drug Compliance
Y
Y
Treatment Blind Broken
Y
NOTES :

Y = Yes display generated.

There are no planned Study Population figures.
[1] Reference specific measurement listing in safety, efficacy, and health outcomes.
6.2.
Subject Accountability
Summaries for the following will be produced in terms of total number overall: 

enrolled subjects

subjects who entered placebo run-in phase

subjects who entered placebo run-in but withdrew prior to randomization.
Enrolled subjects includes those who entered placebo run-in phase and/or who were 
randomized.
Summaries for the following will be produced by treatment and in terms of total number 
overall: 

number of subjects who were randomized to double-blind but missed placebo run-
in

number of subjects who were randomized to double-blind but do not have a 
double-blind treatment start date

number of subjects who have a double-blind treatment start date but were not 
randomized

number of subjects who were randomized to double-blind and did not take at least 
one dose of study medication

number of randomized subjects (ITT population) and defined as subjects with a 
nonmissing treatment number

number of subjects in the Per-Protocol population.
Summaries of the ITT population will be produced by country and center and output by 
randomized treatment and overall. 
A listing of randomized subjects (ITT population) will be produced and will include the 
scheduled randomized treatment and the actual randomized treatment. A flag will be 
included on the listing to indicate if the scheduled treatment differs from the actual 
randomized treatment; as well, any such cases will be included as per-protocol 
deviations.
 
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6.3.
Subject Disposition
A subject may withdraw from the study at any time at the investigator’s discretion or at 
the request of the subject. 
The reason for study withdrawal is recorded in the eCRF for subjects who entered 
placebo run-in but withdrew prior to randomization. A tabular summary will be produced 
for number and percentage of subjects who entered placebo run-in and withdrew prior to 
randomization, overall and by reason. For this summary, the percentages are calculated 
using total subjects who entered placebo run-in as the denominator. 
The reason for study withdrawal is recorded in the eCRF for randomized subjects who 
prematurely withdrew from the study in advance of the Month 24 visit.  A tabular 
summary will be produced for number and percentage of subjects prematurely 
withdrawing from the study, overall and by reason, and will be output by treatment group 
and total.  For this summary, the percentages are calculated using the ITT population as 
the denominator. 
A listing will be produced for the ITT population with key accountability data including 
placebo run-in start and stop dates, randomization date, treatment start and stop dates, 
subject withdrawal (yes or no), completion or withdrawal date, and all visit dates.
ITT population subject discontinuation will be summarized by visit intervals as overall 
totals and by discontinuation reason; these summaries will be output by treatment group 
and total. Visit interval determination used for these summaries is defined in Appendix 3
(Assessment Windows).
6.4.
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized overall and 
by treatment group for the ITT population; summaries will be repeated by country:

sex

age in years

age categories:  <65, ≥65, <75, ≥75 years

ethnicity: Hispanic, Not Hispanic

race / ethnicity: Asian, Hispanic / Latino, White, Not-Hispanic

height

weight

body mass index

history of tobacco use including number of cigarettes smoked per day

alcohol use including number of units per week

baseline safety including ECG, PSA, systolic blood pressure, diastolic blood 
pressure, heart rate, and C-SSRS

baseline efficacy including IPSS, prostate volume, and Qmax

baseline health outcome measures including BII and QOL Q8

baseline C-SSRS
 
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Race and racial combinations, will be summarized overall and by treatment group for the 
ITT population. Reference Appendix 6 for race and ethnicity details and combinations. 
6.5.
Medical Conditions and Concomitant Medications
The following medical conditions and medication history are GSK standardized data 
collections and/or are of interest in terms of the protocol population, study treatments, 
and indication. These characteristics will be summarized overall and by treatment group 
for the ITT population.

medical conditions by body system (includes GSK standardized collection)

specific medical conditions (more specific or in addition to the above body 
systems)

BPH history including time since first LUTS and time since BPH diagnosis 

alpha-blocker use

5-alpha-reductase inhibitor use

alpha-blocker and 5-alpha-reductase inhibitor use

phytotherapy for BPH use

sexual function including activity status at screening along with impotence and 
lack of libido status of prior 3 months

family history of premature coronary artery disease

family history of breast cancer

family history of prostate cancer
Concomitant medication data are collected on eCRF log forms and will be coded using 
the GSK-Drug Anatomical Therapeutic Chemical (ATC) dictionary. Concomitant 
medications will be defined as any medication documented as such in the database, 
irrespective of start or stop dates or ongoing status.
A summary of concomitant medications will be provided for the ITT population. The 
number and percentage of subjects reporting the use of each concomitant medication will 
be summarized by treatment group and in total, ATC Level 1 and ingredient. A listing of 
the collected concomitant mediations, by treatment and subject, will be provided. A 
listing of the relationship between the ATC Level 1, ingredient and verbatim text for 
concomitant medications will be provided.
6.6.
Investigational Product Discontinuation, Exposure, and 
Compliance
Reasons for investigational product discontinuation are recorded in the eCRF and may 
differ from a subject’s study discontinuation reason. A tabular summary will be produced 
for number and percentage of subjects who prematurely discontinued investigational 
product. Summaries will be produced overall and by reason, and will be output by 
treatment group and total. For this summary, the percentages are calculated using the ITT 
population as the denominator.
A listing of subjects for whom the treatment blind was broken during the study, along 
with the reason, will be produced. 
 
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Study drug exposure (in days) is number of days between (double-blind) treatment start 
date and (double-blind) treatment stop date, both days inclusive Study drug exposure is 
further explained in Appendix 6. Study drug exposure in days will be summarized by 
treatment group and overall. The number and proportion of subjects exposed to study 
drug will also be summarized by 180-day intervals for each treatment group and overall.
Overall study drug compliance is defined as 100* (number of capsules consumed during 
the study) / (study drug exposure) / 2. Division by 2 is required since subjects were 
scheduled to consume 2 tablets per day. Overall study drug compliance as well as 
compliance by study drug component are further explained in Appendix 6. Overall study 
drug compliance will be summarized by treatment group and across the treatment groups. 
The number and proportion of subjects with overall compliance <75%, 75-125%, and 
>125%, will be summarized for each treatment group and across the treatment groups. 
Study drug compliance by component will be summarized by each treatment. 
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Primary Efficacy Analyses
7.1.1.
Overview of Planned Primary Efficacy Analyses
The primary efficacy parameter after the 2nd year of the study is change from baseline 
IPSS (International Prostate Symptom Score). The IPSS questionnaire consists of seven 
questions with each question score ranging from 0 to 5. It is administered at screening, 
baseline, and at each of the scheduled post-baseline treatment phase visits.
IPSS (also called IPSS total score) is the sum of the seven questions. IPSS summaries and 
analyses will be in terms of the total (score); exceptions will be noted such as for 
supporting summaries of individual questions. For calculation of the IPSS total, missing 
individual responses will be imputed when at least four of the seven questions are 
answered (nonmissing). For the imputation, the average of the nonmissing responses will 
be calculated and rounded to the nearest integer. This average will be imputed for the 
original missing response(s). If at least 20% of the subjects have at least one imputed 
IPSS then the statistical analyses will be repeated based on non-imputed scores.
The efficacy analyses will be based on the Intent-to-Treat (ITT) population. Table 3
provides an overview of the planned IPSS summaries and primary efficacy analyses. A 
list of planned data displays is in Appendix 15: List of Data Displays.
 
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Table 3
Overview of Planned Primary Efficacy Analyses
Endpoint
Absolute
Change from Baseline
% Change from Baseline
L
F
T
L
F
T
L
F
T
IPSS (International Prostate Symptom Score) Change from Baseline
Primary Analysis
Y[1]
Y
Y[1]
Y
Y[2]
Supporting and Sensitivity Analyses of Primary Endpoint
Mixed-Model Repeated-
Measures (MMRM) 
Analysis (At Visit)
Y
IPSS Change from 
Baseline by Subgroup[3]
Y
Individual IPSS Questions 
Y[1]
Y
Y
IPSS Percentage Change 
from Baseline
Y[1]
Y
IPSS Non-imputed Score 
Analysis[4]
Y
Y
Y
IPSS Per-Protocol 
Population Analysis[5]
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.  All outputs are based on ITT population except [4].

Tables and figures have separate outputs for LOCF and At Visit, except for baseline summaries.
1.
Individual questions 1 – 7 responses, total score, total score change from baseline, and percentage change from 
baseline are combined in a single listing and presented for every visit.
2.
Primary efficacy analyses are presented within this table; details are in the following section.
3.
Subgroups are defined in Section 7.1.3 and Appendix 10: Examination of Covariates and Subgroups.
4.
Analysis is performed only if RAP Section 7.1 imputation conditions are met.
5.
Analysis is performed only if RAP Section 4 per-protocol conditions are met.
7.1.2.
Planned Primary Efficacy Statistical Analyses
Endpoint:  The primary efficacy parameter is the change from baseline IPSS at Year 2 
(Month 24) using the last observation carried forward approach (LOCF) based on the 
Intent-to-Treat (ITT) population.
Table 3 provides an overview of the planned IPSS summaries and primary efficacy 
analyses. A list of planned data displays is in Appendix 15: List of Data Displays.
Baseline and change from baseline are defined in Appendix 6. Last observation carried 
forward (LOCF) and At Visit approaches are defined in Appendix 7.
Model Specification and Results Presentation:  Change from baseline IPSS at each 
scheduled post-baseline assessment will be compared in terms of combination treatment 
versus tamsulosin treatment using t-tests from a general linear model (GLM) with effects 
for treatment, cluster, and baseline IPSS. Two-sided tests at 0.05 level of significance 
will be conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
 
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the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
IPSS adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Multiple Comparisons and Multiplicity:  Reference Appendix 11, Multiple Comparisons 
and Multiplicity.
Model Checking and Diagnostics: Reference Appendix 12, Model Checking and 
Diagnostics for Statistical Analyses.
7.1.3.
Supporting and Sensitivity Analyses of Primary Endpoint
The following describes supporting and sensitivity analyses of the primary endpoint.
Mixed-Model Repeated-Measures (MMRM) Analysis:  As a supportive analysis, IPSS 
will be analyzed using a mixed-model repeated-measures (MMRM) analysis including 
ITT population data from the scheduled post-baseline assessments. Details are provided 
in Appendix 13, Mixed-Model Repeated-Measures Analysis.
IPSS Change from Baseline by Subgroup: For each subgroup, IPSS change from 
baseline summaries will be output by treatment group at Month 12 and at Month 24 for 
the ITT population using both LOCF and At Visit approaches. No statistical testing will 
be performed. Subgroups are defined in Appendix 10, Examination of Covariates and 
Subgroups.
Individual IPSS Questions 1 – 7:  Each of the 7 IPSS individual question responses will 
be summarized at Baseline, Month 12, and Month 24 by treatment group. Month 12 and 
Month 24 change from baseline will be summarized by treatment group for each of the 7 
questions. The summaries will be based on the ITT population and presented using both 
LOCF and At Visit approaches. No statistical testing will be performed.
IPSS Percentage Change from Baseline: Percentage change from baseline is defined in 
Appendix 6. IPSS percentage change from baseline will be summarized by treatment 
group at each scheduled post-baseline assessment. The summaries will be based on the 
ITT population and presented using both LOCF and At Visit approaches. No statistical 
testing will be performed.
IPSS Non-Imputed Score Analysis:  IPSS missing response imputation procedure is 
described above. If at least 20% of the ITT subjects have at least one imputed IPSS then 
the tables, figures, and analyses described in Section 7.1.2 (Planned Primary Efficacy 
Statistical Analyses) will be repeated using non-imputed scores.
IPSS Per-Protocol Population Analysis:  Per-Protocol (PP) population is defined in 
Section 4. If the PP population comprises 80% or less of the ITT population, then the 
tables, figures, and analyses described in Section 7.1.2 (Planned Primary Efficacy 
Statistical Analyses) will be repeated using the PP population.
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Secondary Efficacy Analyses
8.1.1.
Overview of Planned Secondary Efficacy Analyses
Table 4
Overview of Planned Secondary Efficacy Analyses
Endpoint
Absolute
Change from Baseline
% Change from Baseline
L
F
T
L
F
T
L
F
T
IPSS
Improvement Levels
Y[1]
Y[2]
Prostate Volume
Absolute, Change,
% Change [3]
Y
Y
Y
Y
Y
Y
Y
By Subgroup
Y
Improvement Levels
Y[4]
Maximum Urine Flow (Qmax)
Absolute, Change, 
% Change [5]
Y
Y
Y
Y
Y
Y
Y
By Subgroup
Y
Improvement Levels
Y[6]
Y[7]
AUR or BPH-Related Surgical Intervention[8]
Time to event
Y
Y
Y
Event incidence
Y
Other Efficacy Measures [9]
Urinary tract infection
/ urosepsis
Y
Y
Urinary incontinence
Y
Y
Renal insufficiency
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Tables and figures have separate outputs for LOCF and At Visit, except for baseline summaries and AUR or BPH-
related surgical intervention.
1. IPSS change from baseline five improvement categories are ≥1 point through ≥5 points. ‘No change’ and 
‘worsening’ are also presented. Treatment comparisons are in terms of ≥2 points and separately ≥3 points.
2. IPSS percentage change from baseline seven improvement categories are >0%, ≥10%, ≥20%, ≥25%, ≥30%, 
≥40%, and ≥50%. Treatment comparisons are in terms of ≥25%.
3. Prostate volume printed and summarized for absolute, change from baseline, percentage change from baseline; 
dimensions will be printed. Prostate volume analyses are based on percentage change from baseline.
4. Prostate volume percentage change from baseline seven improvement categories are >0%, ≥10%, ≥20%, ≥25%, 
≥30%, ≥40%, and ≥50%. Treatment comparisons are in terms of ≥25%.
5. Qmax printed and summarized for absolute, change from baseline, percentage change from baseline; total voided 
volume will be printed. Qmax analyses are based on change from baseline.
6. Qmax change from baseline six improvement categories are >0 ml/sec and ≥1 ml/sec through ≥ 5 ml/sec. ‘No 
change’ and ‘worsening’ are also presented. Treatment comparisons are in terms of ≥3 ml/sec.
7. Qmax percentage change from baseline six improvement categories are >0%, ≥10%, ≥20%, ≥30%, ≥40%, and 
≥50%. Treatment comparisons are in terms of ≥30%.
8. Summaries are repeated individually for AUR and BPH-Related Surgical Intervention.
9. Data of other efficacy measures are summarized. No treatment comparisons are performed.
 
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8.1.2.
IPSS Improvement Levels
Symptom improvement is assessed using IPSS continuous data changes as the primary 
efficacy endpoint and using categorical changes as a secondary efficacy endpoint.
Improvement is a post-baseline score which is lower than the baseline score. Worsening 
is a post-baseline score which is higher than the baseline score. The number and 
percentage of subjects with IPSS percentage change from baseline categories of 1) 
improvement, 2) no change, and 3) worsening will be summarized by treatment group 
using both the LOCF and At Visit approaches at each scheduled post-baseline 
assessment.
IPSS change from baseline will be presented using five improvement levels:  ≥1 point 
through ≥5 points.  IPSS percentage change from baseline will be presented using seven 
improvement levels:  >0%, ≥10%, ≥20%, ≥25%, ≥30%, ≥40%, and ≥50%.  Treatment 
comparisons for combination versus tamsulosin will be performed for each ≥ 2 points, ≥3 
points, and ≥25% using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
8.1.3.
Prostate Volume
Prostate dimensions are measured at the second screening visit (1b) and at each Month 12 
and Month 24 (or end of treatment) visits. For analysis and reporting, 

Prostate Volume = 
pi/6 (Anteroposterior Width x Cephalocaudal Width x Transverse Width).
Prostate volume percentage change from baseline is a secondary efficacy endpoint.
Table 4 provides an overview of the planned prostate volume summaries and analyses. A 
list of planned data displays is in Appendix 15: List of Data Displays. Baseline, change 
from baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary. Prostate volume summary statistics will be presented for baseline, 
Month 12 visit, and the Month 24 visit; change from baseline and percentage change 
from baseline summary statistics will be presented for the Month 12 and Month 24 visits. 
Combination treatment and tamsulosin treatment will be compared in terms of prostate 
volume percentage change from baseline at the Month 12 and Month 24 visits using t-
tests from the following general linear model; two-sided tests at 0.05 level of significance 
will be conducted:

log (post baseline prostate volume / baseline prostate volume) = 
log (baseline prostate volume) + treatment + cluster
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of percentage change from baseline will be 
reported. The adjusted mean differences will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
 
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Prostate volume adjusted mean percentage change from baseline will be plotted by 
treatment for each post-baseline scheduled visit in terms of each LOCF and At Visit 
approach.
The number and percentage of subjects with prostate volume percentage change from 
baseline categories of 1) improvement, 2) no change, and 3) worsening will be 
summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment.  Improvement is a post-baseline prostate volume 
which is lower than the baseline prostate volume.  Worsening is a post-baseline prostate 
volume which is higher than the baseline prostate volume.
Prostate volume percentage change from baseline will be presented using seven
improvement levels:  >0%, ≥10%, ≥20%, ≥25%, ≥30%, ≥40%, and ≥50%.  Treatment 
comparisons for combination versus tamsulosin will be performed for ≥25% prostate 
volume improvement using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
Supportive subgroup summaries of prostate volume percentage change from baseline will 
be presented in manner similar to that described for primary efficacy in Appendix 10, 
Examination of Covariates. Reference Appendix 15 for a list of planned prostate volume 
subgroup tables. 
Model checking associated with prostate volume percentage change from baseline will be 
conducted in manner similar to that described for primary efficacy in Appendix 12. 
Reference Appendix 15 for a list of prostate volume model checking outputs.
Reference Appendix 11 for multiplicity considerations.
8.1.4.
Maximum Urine Flow (Qmax)
Qmax and associated total voided volume are measured at screening (Visit 1a with 
possible repeat at Visit 1b), baseline, and at each Month 6, Month 12, Month 18, and 
Month 24 (or end of treatment) visits. Qmax change from baseline is a secondary efficacy 
endpoint. Qmax measurements with voided volumes <125 ml will not be included in the 
analysis.
Table 4 provides an overview of the planned Qmax summaries and analyses. A list of 
planned data displays is in Appendix 15: List of Data Displays. Baseline, change from 
baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary.  Qmax summary statistics will be presented for each scheduled visit; 
change from baseline and percentage change from baseline will be presented for each 
scheduled post-baseline visit.
Change from baseline Qmax at each scheduled post-baseline assessment will be 
compared in terms of combination treatment versus tamsulosin treatment using t-tests
from a general linear model (GLM) with effects for treatment, cluster, and baseline 
Qmax.  Two-sided tests at 0.05 level of significance will be conducted.
 
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The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
Qmax adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Qmax improvement is also assessed using categorical changes. Improvement is a post-
baseline Qmax which is higher than the baseline Qmax. Worsening is a post-baseline 
Qmax which is lower than the baseline Qmax. The number and percentage of subjects 
with Qmax percentage change from baseline categories of 1) improvement, 2) no change, 
and 3) worsening will be summarized by treatment group using both the LOCF and At 
Visit approaches at each scheduled post-baseline assessment.
Qmax change from baseline will be presented using six improvement levels: >0 ml/sec 
and ≥1 ml/sec through ≥5ml/sec. Qmax percentage change from baseline will be 
presented using six improvement levels:  >0%, ≥10%, ≥20%, ≥30%, ≥40%, and ≥50%.  
Treatment comparisons for combination versus tamsulosin will be performed for each 
≥3ml/sec and ≥30% using a Mantel-Haenszel test controlling for cluster at alpha=0.05.
Supportive subgroup summaries of Qmax change from baseline will be presented in 
manner similar to that described for primary efficacy in Appendix 10, Examination of 
Covariates. Reference Appendix 15 for a list of planned Qmax subgroup tables. 
Model checking associated with Qmax change from baseline will be conducted in manner 
similar to that described for primary efficacy in Appendix 12. Reference Appendix 15 for 
a list of Qmax model checking outputs.
Reference Appendix 11 for multiplicity considerations.
8.1.5.
AUR or BPH-Related Surgical Intervention
All AUR and BPH-related surgery events during participation in the study are recorded. 
Subjects who discontinue from the study are followed for AUR and BPH-related surgery 
until the 24 month anniversary of randomization. This follow-up is in terms of biannual 
telephone contacts beginning at the first six month scheduled interval after 
discontinuation. Analyses will be in terms of events recorded at clinic visits and also 
collected in the biannual telephone contacts. Table 4 provides an overview of the planned 
summaries and analyses. A list of planned data displays is in Appendix 15: List of Data 
Displays.
Time to first AUR or BPH-related surgery will be defined as the number of days from 
treatment start date to date of the first event (earliest occurring of either AUR or BPH-
related surgery) for each subject. Time to first AUR or BPH-related surgery is classified 
 
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as a secondary efficacy endpoint and will be analyzed in terms of the Intent-to-Treat 
population. 
Censoring will occur at the earliest of the following dates as applicable: the date of 
prostatectomy, the date of last contact for AUR and surgical intervention, and the date of 
death. For censoring, ‘prostatectomy’ will be determined from the eCRF prostatic 
surgical intervention log using the following codes associated with ‘prostatectomy’:  
open, retropubic with or without nerve-sparing, suprapubic, transvesical, perineal, 
salvage, laparoscopic, laparoscopic assisted.  Note this excludes ‘partial prostatectomy’.
The ‘date of last contact for AUR and surgical intervention assessment’ will be assigned 
as the latest of:
--Date of last treatment-phase visit
and
--Date of last successful biannual follow-up telephone contact.
Partial dates will be handled as described in Appendix 7, Premature Withdrawals & 
Handling of Missing Data.
The number of subjects having the first AUR or BPH-related surgery event on or after 
treatment start will be tabulated by treatment, by the two annual time periods (Month 12 
and Month 24), as well as by three month intervals (quarterly) along with the number of 
subjects at risk during each of these time periods.
Note: Cut-off dates are defined in Appendix 6; definition is repeated here:
Month k Cut-off Date (for k= 3, 6, 9, 12, 15, 18, 21, 24):  The maximum of [Month k 
clinic visit date, Month k lab visit date, Baseline Date + (k * 91/3)].
The primary analysis of this endpoint will compare combination treatment versus 
tamsulosin treatment in terms of time to first AUR or BPH-related surgery for the ITT 
population using a log rank test stratified by cluster at the 0.05 level of significance. The 
relative risk (hazard ratio) for the treatment effect and associated two-sided 95% 
confidence intervals will be estimated using a Cox proportional hazards model with 
treatment as the only covariate and stratified by cluster. Estimates and corresponding 
confidence intervals for the relative risk (hazard ratio) and risk reduction (1-hazard ratio) 
of combination treatment versus tamsulosin treatment will be presented along with the 
log rank p-value. Assessment of the Cox modeling procedure will include examination of 
diagnostic plots to assess the assumption of proportional hazards and the review of results 
obtained by fitting separate models by cluster to assess the homogeneity of treatment 
effect across clusters.
Time to first AUR or BPH-related surgery, expressed as months, will be summarized by 
treatment group for the ITT population using product-limit estimates computed by the 
Kaplan-Meier method and displayed graphically as Kaplan-Meier curves.
The number of subjects with at least one AUR or BPH-related surgery will be 
summarized by treatment group across the 2 year period. The crude rate of AUR or BPH-
related surgery incidence will be calculated using the Intent-to-Treat population of each 
 
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treatment as the denominator; the associated 95% confidence interval will be output. This 
crude rate will be compared for combination treatment versus tamsulosin treatment using 
the Mantel-Haenszel test stratified by cluster at the 0.05 level of significance.
AUR or BPH-related surgery event details per subject will be summarized by treatment 
and will include:  event component (first occurring of either AUR or BPH-related 
surgery) and time period of first occurring event (during treatment or after treatment 
stop).  BPH-relatedness (yes/no) and AUR precipitating factors will be summarized by 
treatment for subjects in which AUR is the primary efficacy event’s initial component.  
Types of surgery/intervention will be summarized by treatment for subjects in which 
BPH-related surgery is the primary efficacy event’s initial component.
Time from last dose to first AUR or BPH-related surgery event will be summarized for 
those subjects experiencing the first event after treatment stop.
Hospitalization details for the initial AUR will be summarized by treatment group for 
patient admission status (inpatient or outpatient). For inpatients, the ward type and 
hospitalization days will be summarized by treatment.
The frequency and percentage of subjects with multiple AUR or BPH-related surgery 
events will be summarized by treatment. The frequencies of subjects with 2 events, 3 
events, or ≥4 events will be summarized. Among subjects with both events, the pattern of 
occurrence (AUR/Surgery or Surgery/AUR) will be summarized.
The above described summaries and analyses of AUR or BPH-related surgery will be 
repeated, when applicable, for the individual components 1) AUR and 2) BPH-related 
surgery.
All AUR and surgical intervention data will be listed by treatment and subject.  Time to 
first AUR or BPH-related event will be listed for each subject along with the dates used 
in the computation of these values.
8.1.6.
Other Efficacy Measures
The following are potential BPH disease related events not captured as primary or
secondary endpoints. They are collected in this study for possible comparison to
historical BPH studies and to insure consistency of disease-related adverse event
definition:

Urinary tract infection/urosepsis

Urinary incontinence (overflow/urge)

Renal insufficiency
Each of the three ‘other efficacy measures’ will be summarized by treatment group for 
number of subjects with at least one post-randomization event across the 2-year period. 
The crude rate of each measure will be calculated using the Intent-to-Treat population of 
each treatment as the denominator; the associated 95% confidence interval will be output.
No formal treatment comparisons will be performed.
 
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Data collected in terms of these other efficacy measures will be listed by treatment and 
subject.
8.2.
Safety Analyses
Safety summaries and analyses are reported in terms of the following data classifications:  
adverse events, clinical laboratory assessments (haematology and clinical chemistry), 
total serum prostate specific antigen (PSA), qualitative breast examination, digital rectal
examination, vital signs, suicidality, and post void residual volume.
All safety analyses will be performed using the ITT population unless otherwise specified 
in text or data display shells. Applicable safety analysis and reporting definitions and 
presentations within “Program Safety Analysis Plan (PSAP) for GI198745 (dutasteride) 
and GSK2285985 (fixed dose combination of dutasteride [GI198745] and tamsulosin 
[GI138525]” are utilized within this RAP, with any deviations noted.
8.2.1.
Overview of Adverse Event Tabular Summaries
Table 5 provides an overview of the planned adverse event tabular summaries. A list of 
planned data displays is in Appendix 15: List of Data Displays.
Reference Section 4 (Analysis Populations) and Appendix 6 (Derived and Transformed 
Data) for supporting definitions on all below subsections.
 
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Table 5
Overview of Planned Adverse Event Tabular Summaries
Adverse Event Types, High Level
Any
Drug-
Related
Non-
Serious
Serious
Leading 
to W/D 
from 
Study
Perm. 
D/C of 
Study 
Drug
Fatal
By Type
------------- 3.1 (6 above categories, excluding Non-serious) ------------
Overall
3.2
3.3 [1]
3.4 [2]
3.13 [3]
3.18
3.19 [1]
3.20 [2]
3.5
3.25
3.26 [1]
3.27 [2]
3.35
3.38
3.33
By 6-Month Onset Period
3.6
3.14 [3]
3.21
3.28
By Age (<65, ≥65)
3.7
3.22
3.29
By Age (<75, ≥75)
3.8
3.23
3.30
By Country
3.9
3.24
3.31
By Descending Frequency
3.10
3.12
3.11
By Maximum Intensity
3.15
Most Common
3.16
3.17
Adverse Event Types, Two Levels
Drug-Related
and
Serious
Drug-Related
and
Fatal
Drug-Related
and
Leading to 
W/D from 
Study
Serious
and
Leading to 
W/D from 
Study
Drug-Related
and
Leading to 
Perm D/C of 
Study Drug
Serious
and
Leading to 
Perm D/C of 
Study Drug
Overall
3.32
3.34
3.36
3.37
3.39
3.40
Sexual and Breast Adverse Events of Special Interest
Altered
(Decreased)
Libido
Impotence
Ejaculation
Disorders
Breast Disorders
(includes Enlargement and 
Tenderness)
MedDRA
----------------------------------------------3.41--------------------------------------------
Overall
3.42
3.43
3.44
3.45, 3.46 [4], 3.47 [5]
By Baseline 
Characteristics
3.48
3.49
3.50
3.51, 3.52 [4],3.53 [5]
By Type
-----------------------------------------------3.54------------------------------------
Not 
Resolved & 
Leading to 
Study 
Withdrawal
Overall
-----------------------------------------------3.55------------------------------------
By Type
3.56
3.57
3.58
3.59
Prostate Cancer Adverse Event of Special Interest
Prostate Cancer Overall
3.60
Cardiovascular Adverse Events of Special Interest
Acute 
Coronary 
Syndrome
Ischemic
Cerebro-
vascular 
Events
Cardiac
Failure
Ischemic
Coronary
[6]
Cardiac
Arrythmia
Peripheral
Vascular
Disease
Cardio-
vascular
Events
MedDRA
-----------------------------------------------------3.61---------------------------------------------------
Overall
3.62
3.63
3.64
3.65
3.66
3.67
3.68
Infrequent Tier 1 Adverse Events of Special Interest
MedDRA
3.41
 
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Notes:  Summaries are in terms of ‘Starting Post-Randomization’ (defined in Appendix 8) unless otherwise noted as [1] – [3]:
1.
Starting On-Treatment; defined in Appendix 8.
2.
Starting Post-Treatment; defined in Appendix 8. 
3.
Starting On-Treatment and in terms of ‘Study Drug Exposure Basis” in which [Rate] is the number of subjects per 100 person-
years of study drug exposure; adverse events for subjects with missing study drug exposure are excluded.
4.
Breast Disorders: subcategory Breast Enlargement
5.
Breast Disorders: subcategory Breast Tenderness
6.
Ischemic Coronary Artery Disorders / Atherosclerosis
8.2.2.
Adverse Events
Adverse events (AEs) will be coded using the MedDRA (Medical Dictionary for 
Regulatory Activities) coding dictionary. As specified in the protocol, disease related 
events will not be reported as AEs or serious adverse events (SAEs) unless the
investigator assesses the event as more severe than expected for the subject’s condition. 
A mapping of the MedDRA primary system organ class and preferred term to which each 
verbatim term has been coded will be provided in a listing.
Adverse events (AEs) are to be recorded on the electronic case report form (eCRF) from
the start of the placebo run-in phase study treatment until the end of the two year study 
period. Serious AEs (SAEs) are to be recorded over the same time period as non-serious 
AEs. However, any SAEs assessed as related to study participation or related to a GSK 
concomitant medication, will be recorded from the time a subject consents to participate 
in the study up to the end of the two year study period. After discontinuation of study 
treatment, the investigator will monitor all AEs/SAEs that are ongoing until resolution or 
stabilization of the event or until the subject is lost to follow-up. Investigators are not 
required to actively seek information on adverse events occurring after the follow-up 
contact, but may report any adverse event that they believe may be related to 
investigational product regardless of when the event occurs. Adverse events summaries 
will include non-serious as well as serious AEs.
Subjects with sexual function related adverse events leading to study withdrawal, will be 
followed up for up to 6 months after the last dose of study drug using the sexual function 
Targeted Follow-Up Questionnaire (TFUQ). 
If an AE occurs which, in the investigator’s judgment, is possibly related to suicidality, a 
Possible Suicidality-Related Adverse Event (PSRAE) form should be completed by 
investigators or their designated staff.
Each AE will be categorized into the following periods according to its onset date:
pretreatment, post-randomization, on-treatment, post-treatment. These periods are not
mutually exclusive and an AE could be categorized into more than one period. The
definitions of these categories are provided in Appendix 8: Adverse Event Time Periods 
and Special Adverse Event Definitions.
Pre-treatment AEs will not be summarized; they will be included in the AE listing
specified later in this section.
 
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The number of post-randomization adverse events, the number and the percentage of
subjects reporting any post-randomization AE will be summarized by treatment group for
the following:

All AEs

Drug-related AEs

Serious AEs

AEs leading to study drug discontinuation

AEs leading to withdrawal from study

Fatal AEs
Comparisons of treatment groups for each of these sets of AEs will be performed using
Fisher’s Exact Test.
Total number of adverse events reported in the study as well as the number and
percentage of subjects reporting at least one AE will be provided for each treatment
group. Total number of AEs as well as the number and percentage of subjects reporting
each AE will be reported by treatment group, primary system organ class and preferred
term. On-treatment and post-treatment AEs will be summarized separately, as well as
together as post-randomization AEs. Non-serious post-randomization AEs will be
summarized by treatment group. A summary of post-randomization AEs will be provided
by treatment group and six month time period of onset (Months 1-6, Months 7-12, 
Months 13-18, Months 19-24), by treatment group and age group (<65 years, ≥65 years), 
by treatment group and age group (<75 years, ≥75 years), and by treatment group and 
country.
A summary of post-randomization AEs will be provided by treatment group and
preferred term by descending frequency of preferred term (regardless of system organ
class). In addition, such summaries will be done for serious post-randomization AEs and 
also for non-serious post-randomization AEs. 
For on-treatment AEs, the event rate per 100 person-years of study drug exposure will be 
summarized by treatment group, primary system organ class and preferred term overall 
and by time period (Months 1-6, Months 7-12, Months 13-18, Months 19-24).
A summary of post-randomization AEs will also be provided by treatment group and
maximum intensity. If the same AE occurs on multiple occasions in the same subject, the
AE with the highest intensity will be presented. Intensity will be categorized as mild,
moderate, or severe; a category for missing/not applicable intensity will be included.
The most common AEs (Tier 2 events) are defined as those preferred terms occurring in 
at least 5% of the subjects within any treatment group (non-rounded). The total number 
of events as well as the number and percentage of subjects reporting at least one most 
common AE preferred term starting post-randomization will be provided for each 
treatment group. The number of events, the number and percentage of subjects reporting 
the most common AE preferred terms starting post-randomization will be provided by 
treatment group displayed by decreasing frequency of preferred terms (regardless of 
primary system organ class). For each of these most common AEs, the percentage of 
 
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subjects in the treatment groups will be compared using Fisher’s exact test. In addition, 
the percentage of subjects reporting each AE by treatment group along with the 
corresponding odds ratio and 95% confidence interval for each of the most common AEs 
will be displayed in a figure sorted by odds ratio in descending order, by treatment group. 
The above summary will also be provided for the most common non-serious post-
randomization AEs.
Total number of drug-related adverse events as well as the number and percentage of
subjects reporting at least one drug-related AE will be provided for each treatment group.
Total number of drug-related adverse events as well as the number and percentage of
subjects reporting each drug-related AE will be reported by treatment group, primary
system organ class and preferred term. On-treatment and post-treatment drug-related AEs
will be summarized separately, as well as together as post-randomization drug-related 
AEs. A summary of post-randomization drug-related AEs will be provided by treatment 
group and time period (Months 1-6, Months 7-12, Months 13-18, Months 19-24), by 
treatment group and age group (<65 years, ≥65 years), by treatment group and age group 
(<75 years, ≥75 years) and by treatment group and country.
A listing of all AEs, a listing of AEs by onset period, and a listing of which subjects 
reported specific AEs will be presented. A listing of Possible Suicidality Related Adverse 
Event (PSRAE) data will be provided. A listing of the sexual function Targeted Follow-
Up Questionnaire (TFUQ) data will be provided.
8.2.3.
Deaths and Serious Adverse Events
Total number of serious adverse events as well as the number and percentage of subjects
reporting at least one serious AE will be provided for each treatment group. Total number
of serious adverse events as well as the number and percentage of subjects reporting each
serious AE will be reported by treatment group, primary system organ class and preferred
term. On-treatment and post-treatment serious AEs will be summarized separately, as
well as together as post-randomization serious AEs. A summary of post-randomization
serious AEs will be provided by treatment group and time period (Months 1-6, Months 7-
12, Months 13-18, Months 19-24), by treatment group and age group (<65 years, ≥65
years), by treatment group and age group (<75 years, ≥75 years), and by treatment group 
and country. A summary of all post-randomization drug-related serious AEs, of all post-
randomization fatal AEs, and of all post-randomization drug-related fatal AEs will be 
provided by treatment group. Time to death will be summarized by treatment group using 
Kaplan-Meier estimates and displayed as Kaplan-Meier plots.
Individual subject listings of all non-fatal serious AEs and a separate listing of all fatal
serious AEs will be provided. The listing will indicate the timing of the serious AE with
respect to treatment start date.
 
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8.2.4.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal From the Study and Other Significant 
Adverse Events
8.2.4.1.
Adverse Events Leading to Discontinuation of Investigational Product 
and/or Withdrawal from the Study
A summary of adverse events starting post-randomization and leading to withdrawal
from the study will be provided by treatment group for the following categories:

All AEs

Drug-related AEs

Serious AEs
Similar summaries will be provided for adverse events leading to permanent
discontinuation of the study medication.
Subject listings of AEs leading to withdrawal from the study and AEs leading to
permanent discontinuation of study drug will be provided. The listings will indicate the
timing of the AE with respect to treatment start date.
8.2.4.2.
Adverse Events of Special Interest
Tier 1 adverse events of special interest are pre-specified adverse event preferred terms 
for which there are predefined hypotheses about the existence of a potential treatment 
effect. These events include the following:

Sexual and breast events

Prostate cancer 

Cardiovascular events 

Infrequent events
Summaries for these events are specified in the following sections and will be based on 
post-randomization AEs unless otherwise indicated. A mapping of the MedDRA primary 
system organ class and preferred term to which each verbatim term in the special interest 
AE categories has been coded will be provided in a listing.
8.2.4.3.
Sexual and Breast Tier 1 Adverse Events of Special Interest
Altered (decreased) libido, impotence, ejaculation disorders, and breast disorders, will be
defined as sexual and breast adverse events of special interest. In addition, two subgroups 
of breast disorders (breast disorders: breast enlargement, and breast disorders: breast 
tenderness) are of special interest. MedDRA system organ class and preferred terms 
included in these special interest adverse events are defined in Appendix 8, Table A. 
Total number of, as well as number and percentage of the subjects experiencing, sexual 
and breast adverse events of special interest will be provided by treatment group. In 
addition, for each of the events of special interest, the number and percentage of subjects 
by treatment will be provided for the following:

having an event
 
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
having multiple events

having an event in 6-month windows, starting from treatment start date
The following categories are related to the occurrence of the first event of the special
interest AE; number and percentage of subjects in these categories will be provided by
treatment group:

drug-related AE

serious AE

AE leading to withdrawal from the study

AE leading to permanent discontinuation of study drug

AE outcome

AE resolution status (on-therapy vs. off-therapy – see Appendix 8 for definition)

AE maximum intensity
The number and percentage of the subjects experiencing an adverse event of special
interest will be provided by treatment group for the following:

Overall

By age group: < 65 years, ≥65 years

By sexual activity at baseline (Yes, No) based on “sexually active” question.  
The number and percentage of subjects experiencing the following types of sexual and 
breast adverse events of special interest will be provided by treatment group:

Any Type (Impotence, Decreased Libido, Ejaculation Disorders, or Breast

Disorders)

One AE Type

Two AE Types

Three AE Types

All Four AE Types
The time to first onset in days will be summarized by treatment group as a continuous
variable as well as by time period of onset. In addition, time to first adverse event of
special interest will be summarized by treatment group using estimates calculated by the
Kaplan-Meier method and displayed graphically as Kaplan-Meier curves. Time to
resolution for the first event in days will be summarized by treatment group.
Duration of adverse events of special interest will be summarized by treatment group for 
uncensored values, censored values, and all values. It is recognized that summary 
statistics such as means and medians involving censored values will be biased (low).
The number of sexual and breast adverse events leading to study withdrawal, as well as 
the number and percentage of subjects reporting at least one such sexual and breast 
adverse event will be provided for all event types and also by event type for each 
treatment group.
Resolution status at end of study (resolved, not resolved) and time from treatment stop 
date to AE resolution will be summarized by treatment group for the sexual and breast 
 
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adverse events leading to study withdrawal and not resolved at Month 24 / End of 
Treatment visit.
Listings of sexual and breast adverse events of special interest will be provided. A listing 
of sexual and breast adverse event status data will be provided. 
A listing of the TFUQ data for sexual and breast adverse events will be provided.
8.2.4.4.
Prostate Cancer Tier 1 Adverse Events of Special Interest
Prostate cancer will be defined as an adverse event of special interest. MedDRA preferred 
terms and codes included in this special interest adverse event are defined in Appendix 8, 
Table B. Prostate cancer events will be summarized separately following the same format 
done for sexual and breast special interest AEs described above. Time to first event for 
prostate cancer events will be summarized separately by treatment group using estimates 
calculated by the Kaplan-Meier method and displayed graphically as Kaplan-Meier 
curves.
Listings of prostate cancer adverse events of special interest will be provided.
8.2.4.5.
Cardiovascular Tier 1 Adverse Events of Special Interest
Cardiovascular adverse events of special interest will be defined as those included in the
following six categories: acute coronary syndrome, ischemic coronary artery
disorders/atherosclerosis, ischemic cerebrovascular events, cardiac failure, cardiac
arrhythmias, and peripheral vascular disease. MedDRA preferred terms and codes
included in these special interest adverse events are defined in Appendix 8, Table C.
Total number of cardiovascular events as well as the number and percentage of subjects 
experiencing cardiovascular events will be provided by treatment group. Each category of
cardiovascular events, and all cardiovascular events as one additional category, will be
summarized separately following the same format done for sexual and breast special 
interest AEs described above. Time to first cardiovascular adverse event of special 
interest will be summarized by treatment group using estimates calculated by the Kaplan-
Meier method and displayed graphically as Kaplan-Meier curves.
Listings of cardiovascular adverse events of special interest will be provided.
8.2.4.6.
Infrequent Tier 1 Adverse Events of Special Interest
Infrequent Tier 1 adverse events of special interest will be defined as those included in 
the following categories: 

Breast cancer

Potential for decreased male fertility due to effects on sperm/semen characteristics 

Interference with formation of external genitalia in a male fetus if a woman 
carrying a male fetus is exposed to dutasteride  
 
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
Hair changes

Allergic reactions

Depressed mood 

Testicular pain and swelling

Intraoperative floppy iris syndrome

Orthostasis 

Priapism

Stevens-Johnson syndrome

Atrial fibrillation, tachycardia, arrhythmias
MedDRA preferred terms and codes included in these special interest adverse events are 
defined in Appendix 8, Table D. Total number of infrequent Tier 1 events as well as the 
number and percentage of subjects with infrequent Tier 1 events will be provided by 
treatment group.
Listings of infrequent Tier 1 adverse events of special interest will be provided.
8.2.5.
Pregnancies
A listing of subjects whose female partner become pregnant during the study will be 
provided if there are any such subjects.
8.2.6.
Clinical Laboratory Assessments
Clinical chemistry and hematology parameters are evaluated from samples scheduled at 
the first screening visit (1a) and at each Month 12 and Month 24 (or end of treatment) 
visits. The following tests will be performed: 
Clinical Chemistry (serum):  Alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin, total protein, sodium, 
potassium, albumin, glucose, creatinine, UREA/BUN (blood urea nitrogen)
Hematology:  Hemoglobin, platelet count, white blood cell count (WBC), red blood cell 
count (RBC)
For purposes of statistical analyses the baseline value of a parameter for each subject will
be defined as the latest laboratory test value on or before the start of the randomized
treatment for that subject.
The final value of a parameter for each subject is defined as the latest post-baseline value
available in the study for that subject. A summary of parameter values, including the
baseline and final value, will be provided by treatment group and scheduled visit. A
 
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summary of change from baseline in parameter values, including the final value, will also
be provided by treatment group and scheduled visit.
A laboratory value that is on or within the normal range is considered normal. A
laboratory value that is above the upper limit of the normal range is considered high
abnormal. A laboratory value that is below the lower limit of the normal range is
considered low abnormal.
The number and percentage of subjects with an abnormal laboratory value at baseline
among subjects with a baseline laboratory value and at least one post baseline laboratory
value will be provided by treatment group and by parameter. The number and percentage
of subjects will be summarized by treatment group for each laboratory test for the
following shift categories:

Normal at baseline to abnormal at any time post-baseline

Normal at baseline to high at any time post-baseline

Normal at baseline to low at any time post-baseline

Normal or low at baseline to high at any time post-baseline

Normal or high at baseline to low at any time post-baseline
Laboratory data transitions from baseline to final assessment will be summarized for each
parameter according to the following categories:

Decrease: High to Low, Normal to Low, High to Normal

No Change: Low to Low, Normal to Normal, High to High

Increase: Low to Normal, Normal to High, Low to High
The threshold laboratory values are defined in terms of a multiplicative factor of the
testing laboratory’s normal range. A laboratory value that is above the upper limit factor
multiplied by the upper limit of the normal range is considered a high threshold value. A
laboratory value that is below the lower limit factor multiplied by the lower limit of the
normal range is considered a low threshold value. Refer to Appendix 9 for a listing of the 
laboratory threshold factors.
The number and percentage of subjects with a threshold laboratory value at baseline
among subjects with a baseline laboratory value and at least one post baseline laboratory
value will be provided by treatment group and by parameter. Subjects with threshold
values any time post-baseline with a non-threshold baseline laboratory value and at least
one post-baseline laboratory value will also be summarized by treatment group and by
parameter.
Listings of hematology and clinical chemistry data will be provided, along with listings 
of hematology and clinical chemistry data exceeding threshold.
The protocol defines possible drug-induced liver injury with hyperbilirubinaemia, for 
laboratory assessments planned in this study, as:
ALT ≥3xULN and Bilirubin ≥2xULN.
 
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A listing of subjects meeting this defined liver function abnormality along with the 
corresponding data will be provided. If no subjects meet the defined criteria, a listing 
(page) will be produced indicating that no subjects met the criteria.
A blood draw for HBsAg and Hepatitis C Antibody is scheduled for Visit 2 (baseline). 
These measurements will be included in a data listing.
8.2.7.
Serum PSA
Serum PSA samples are scheduled at the screening visit, and at each Month 6, Month 12, 
and Month 24 (or end of treatment) visits. Total PSA (absolute values, change from 
baseline values, and percentage change from baseline values) will be summarized by visit 
and treatment group using both the LOCF and At Visit approaches. Change from baseline 
total PSA will be compared in terms of combination treatment versus tamsulosin 
treatment at each scheduled post-baseline assessment using a general linear model with 
effects for treatment and baseline total PSA.
Listings of PSA data will be produced. A listing of PSA data will be provided, along with 
a listing of PSA data exceeding the upper limit of normal.
8.2.8.
Post Void Residual Volume
Total voided volume (in conjunction with Qmax) is measured at screening (Visit 1a with 
possible repeat at Visit 1b), baseline, and at each Month 6, Month 12, Month 18, and 
Month 24 (or end of treatment) visits.
A list of planned data displays is in Appendix 15: List of Data Displays. Baseline, change 
from baseline, and percentage change from baseline are defined in Appendix 6. Last 
observation carried forward (LOCF) and At Visit approaches are defined in Appendix 7. 
Summaries and analyses will be in terms of the ITT population; LOCF approach will be 
considered primary. Post void residual volume summary statistics will be presented for 
each scheduled visit; change from baseline and percentage change from baseline will be 
presented for each scheduled post-baseline visit.
Post void residual volume change from baseline distribution at each scheduled post-
baseline assessment will be compared in terms of combination treatment versus 
tamsulosin treatment using a nonparametric van Elteren test controlling for cluster at the 
0.05 level of significance.
A listing of post void residual volume data will be provided.
8.2.9.
Gynecomastia Evaluations
A qualitative breast examination is scheduled to be performed at the screening visit, and 
at each Month 6, Month 12, Month 18, and Month 24 (or end of treatment) visits. The
number and percentage of subjects with palpable breast tissue or nipple tenderness and/or
clinically significant palpable breast tissue or nipple tenderness at baseline, at each
 
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scheduled post-baseline assessment and the final assessment (the latest post-baseline
evaluation available) will be presented by treatment. The number and percentage of
subjects changing from ‘no’ at baseline to ‘yes’ at any post-baseline assessment for
palpable breast tissue and for nipple tenderness will be compared in terms of combination 
treatment versus tamsulosin treatment using Fisher’s exact test.
The number and percentage of subjects changing from ‘no’ at baseline in clinical 
significance to ‘yes’ at any post-baseline assessment in clinical significance for palpable 
breast tissue and for nipple tenderness will be presented by treatment group.
A listing of gynecomastia data will be provided.
8.2.10.
Digital Rectal Examinations
A digital rectal examination (DRE) is scheduled to be performed at the screening visit,
and at each Month 6, Month 12, Month 18, and Month 24 (or end of treatment) visits.
The results of normal versus focal abnormality will be summarized by treatment group at 
baseline, at each scheduled post baseline assessment and for the final assessment (the 
latest post-baseline evaluation available). Among subjects with focal abnormalities, 
summaries will include yes/no indication of clinical significance and a yes/no indication 
of biopsy recommendation. The number and percentage of subjects changing from 
‘normal’ at baseline to ‘focal abnormality’ at any post-baseline assessment will be 
compared in terms of combination treatment versus tamsulosin treatment using Fisher’s 
exact test.
A listing of digital rectal examination data will be provided.
8.2.11.
Vital Signs
Vital signs (blood pressure and heart rate) are scheduled to be assessed at screening, 
baseline, and at each of the scheduled post-baseline treatment phase visits. Vital signs 
will be summarized by treatment group for baseline, each scheduled post-baseline 
assessment through Month 24 as well as for the final assessment (the latest post-baseline
value available in the study). Change from baseline vital signs will also be summarized 
for each post-baseline assessment as well as for the final assessment. 
Refer to Appendix 9 for a listing of the vital sign threshold ranges. For threshold vital 
sign summaries, high threshold, low threshold as well as either threshold will be 
presented separately. The number and percentage of subjects with a threshold value at 
baseline among subjects with a baseline and a post baseline value will be presented by 
treatment group. The number and percentage of subjects with at least one post baseline 
value in the threshold range will be presented by treatment group. For each systolic blood 
pressure, diastolic blood pressure, and heart rate, the incidence of exceeding threshold 
will be compared in terms of combination treatment versus tamsulosin treatment using 
Fisher’s exact test.
A listing of vital signs data and a listing of vital signs data exceeding threshold will be 
provided.
 
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8.2.12.
Prostate Cancer Biopsies
A listing of data for biopsies performed to confirm prostate cancer will be provided. 
8.2.13.
Suicidality Assessment 
Assessment of suicidality will be done using the Columbia Suicide Severity Rating Scale (C-
SSRS) and is scheduled to be assessed at each Screening, Month 6, Month 12, and Month 
24 (or end of treatment) visits. Tabular summaries of suicidal ideation and suicidal 
behavior will be produced at each of the scheduled assessments. Along with the 
aforementioned tabular summary, as well, for all subjects with suicidal ideation or 
behavior at any assessment, a listing of C-SSRS data will be provided (as a table), along 
with listings of details of suicidal ideation and suicidal behavior.
In addition a listing of C-SSRS assessments for all subjects will be provided. As noted in 
the adverse event section of this document, the possible suicidality-related adverse events 
will be produced.
8.3.
Health Outcomes Analyses
Health outcomes analyses will be in terms of: BPH Impact Index (BII), BPH-Related 
Health Status (BHS), and the Problem Assessment Scale of the Sexual Function 
Inventory (PAS SFI). Health outcomes analyses will be performed using the ITT 
population unless otherwise specified in text or data display shells.
A list of planned Health Outcomes data displays is in Appendix 15: List of Data 
Displays. Baseline and change from baseline are defined in Appendix 6. Last observation 
carried forward (LOCF) and At Visit approaches are defined in Appendix 7. Reference 
Appendix 11 for descriptions of handling multiplicity.
8.3.1.
BPH Impact Index
The BPH Impact Index (BII) consists of four questions. It is administered at screening, 
baseline and at each of the scheduled post-baseline treatment phase visits. The BII total 
score is the sum of the four questions; the total score range is 0 to 13. BII summaries and 
analyses will be in terms of the total (score); exceptions will be noted such as for 
supporting summaries of individual questions.
For calculation of the BII total, missing individual responses will be imputed when at 
least two of the four questions are answered (nonmissing). For the imputation, the 
average of the nonmissing responses will be calculated and rounded to the nearest 
integer. This average will be imputed for the original missing response(s). If at least 20% 
of the subjects have at least one imputed BII then the statistical analyses will be repeated 
based on non-imputed scores.
Total BII, change from baseline BII, and percentage change from baseline BII will be 
summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment. Change from baseline BII at each scheduled post-
 
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baseline assessment will be compared in terms of combination treatment versus 
tamsulosin treatment using t-tests from a general linear model (GLM) with effects for 
treatment, cluster, and baseline BII. Two-sided tests at 0.05 level of significance will be 
conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
BII adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
Each of the four BII individual question responses will be summarized at Baseline, 
Month 12, and Month 24 by treatment group. Month 12 and Month 24 changes from
baseline will be summarized by treatment group for each of the four questions.  The 
summaries will be based on the ITT population and presented using both LOCF and At 
Visit approaches. No statistical testing will be performed.
Listings of BII individual question and total scores will be presented.
8.3.2.
BPH-Related Health Status
BPH-Related Health Status (BHS) is collected as Question 8 the IPSS questionnaire and 
ranges from 0 to 6. The IPSS questionnaire is administered, and thus BHS is collected, at 
screening, baseline and at each of the scheduled post-baseline treatment phase visits.
Total BHS, change from baseline BHS, and percentage change from baseline BHS will 
be summarized by treatment group using both the LOCF and At Visit approaches at each 
scheduled post-baseline assessment. Change from baseline BHS at each scheduled post-
baseline assessment will be compared in terms of combination treatment versus 
tamsulosin treatment using t-tests from a general linear model (GLM) with effects for 
treatment, cluster, and baseline BHS. Two-sided tests at 0.05 level of significance will be 
conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
BHS adjusted mean change from baseline will be plotted by treatment for each post-
baseline scheduled visit in terms of each LOCF and At Visit approach.
A listing of BHS data will be presented.
 
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8.3.3.
Problem Assessment Scale of the Sexual Function Inventory
(PAS SFI)
The Problem Assessment Scale of the Sexual Function Inventory (PAS SFI) consists of 
three questions each with a range of 0 (Big Problem) to 4 (No Problem). It is 
administered at screening, baseline and at each Month 12 and Month 24 (or end of 
treatment) visits. The total PAS SFI is the sum of the three questions; the total score 
range is 0 to 12. PAS SFI summaries and analyses will be in terms of the total (score); 
exceptions will be noted such as for supporting summaries of individual questions.
For a given subject and visit, calculation of the PAS SFI total will not be performed or 
imputed if two or all three individual responses are missing.  For a given subject and 
visit, a single missing individual response will be imputed when two of the three
questions are answered (nonmissing). For the imputation, the average of the nonmissing 
responses will be calculated and rounded to the nearest integer. This average will be 
imputed for the original missing response. If at least 20% of the subjects have at least one 
imputed PAS SFI then the statistical analyses will be repeated based on non-imputed 
scores.
Total PAS SFI and change from baseline PAS SFI will be summarized by treatment 
group using both the LOCF and At Visit approaches at each scheduled post-baseline 
assessment. Change from baseline PAS SFI at each scheduled post-baseline assessment 
will be compared in terms of combination treatment versus tamsulosin treatment using t-
tests from a general linear model (GLM) with effects for treatment, cluster, and baseline 
PAS SFI. Two-sided tests at 0.05 level of significance will be conducted.
The adjusted mean estimates (mean and standard error), the adjusted mean difference, 
and the 95% confidence interval in terms of the adjusted mean difference will be 
presented. The adjusted mean difference will be in terms of combination treatment minus 
tamsulosin treatment. The model results will be presented on same tabular summary as 
the arithmetic mean, standard deviation, median, minimum and maximum. The results 
will be presented by treatment for each scheduled post-baseline assessment.
Each of the three PAS SFI individual question responses will be summarized at Baseline, 
Month 12, and Month 24 by treatment group. Month 12 and Month 24 changes from 
baseline will be summarized by treatment group for each of the three questions. The 
summaries will be based on the ITT population and presented using both LOCF and At 
Visit approaches. No statistical testing will be performed.
A listing of PAS SFI data will be presented.
 
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9.
COUNTRY-SPECIFIC SUMMARIES AND ANALYSES
Four countries randomized subjects into this trial and include: China, Japan, Korea, and 
Taiwan. It is anticipated that each of these countries will conduct a regulatory submission 
using planned summaries and analyses of this ARI114265 study.  For primary regulatory 
filings, summaries and analyses will be in terms of the Intent-to-Treat population which 
is based on pooled country data. These regulatory filings may also require complete or 
various sub-levels of data summaries and analyses for (their) specific country.
Each country’s regulatory requirements will be fully defined at a time approaching the 
regulatory filing which will be after RAP finalization. Therefore, to address the potential
requirements for complete country-specific summaries and analyses, all planned tables
and figures, including planned statistical analyses, will be repeated for each of the four 
countries. Cluster (defined earlier in RAP as equal to country) will be excluded from the 
model-based within-country analysis. Exceptions will include planned by-country tabular 
summaries and listings. There will be no across-country multiplicity adjustments. The 
within-country statistical analyses will be underpowered because of their smaller sample 
sizes.
The summaries and analyses for each of the four countries will be provided by Clinical 
Statistics and Programming as part of a secondary (country-based) statistical analysis 
complete (SAC) package. Then, considering country regulatory filing plans and 
requirements, GSK regulatory staff of the individual countries will indicate to medical 
writing staff the summaries, analyses, and formats to be used in final reporting. Non-
reporting of some or all country-based summaries and analyses by the individual 
countries will not result in a RAP revision.  
It is anticipated that analysis and reporting of each country will add up to 2 weeks to the 
initial (Intent-to-Treat Population) SAC.  Therefore, the “Country-specific SAC” will be 
“Primary SAC” plus 8 weeks. The country analysis may be ordered so that the country 
with earliest regulatory requirements will undergo first analysis and reporting. Changes to 
the anticipated ‘8 weeks’ as well as action definition of country reporting order will not 
result in a RAP revision.
 
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10.
REFERENCES
GlaxoSmithKline Document Number RM2010/00134/05 Study ID ARI114265. Protocol 
Amendment 4: A randomized, double-blind, parallel group study to compare the efficacy 
and safety of combination treatment with dutasteride (0.5mg) and tamsulosin (0.2mg) 
with tamsulosin (0.2mg) monotherapy, administered once daily for 2 years, on the 
improvement of symptoms and health outcomes in men with moderate to severe benign 
prostatic hyperplasia. Report Date 08-JUL-2014.
GlaxoSmithKline Document: Program Safety Analysis Plan (PSAP) for GI198745 
(dutasteride) and GSK2285985 (fixed dose combination of dutasteride [GI198745] and 
tamsulosin [GI138525]); PSAP approval date 09Dec2015.  Note: This reflects PSAP 
version at point of RAP finalization. Any PSAP updates/revisions at point of Statistical 
Analysis Complete (SAC) may be incorporated without a revision to this RAP; in this 
event, PSAP updates impacting analysis and reporting will be described in CSR.
Mallinckrodt C, Lane P, Schnell D, Peng Y, Mancuso J. Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. Drug 
Information Journal. 2008; 42: 303-319. 
 
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11.
APPENDICES
Section
Appendix
Section 11.1
Appendix 1: Exclusions from the Per-Protocol Population
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Multicenter Studies
Section 11.5
Appendix 5: Data Display Standards & Handling Conventions
Section 11.6
Appendix 6: Derived and Transformed Data
Section 11.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 11.8
Appendix 8: Adverse Event Time Periods and Special Adverse Event Definitions
Section 11.9
Appendix 9: Threshold Factors for Clinical Laboratory Tests and Vital Signs
Section 11.10
Appendix 10: Examination of Covariates and Subgroups
Section 11.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 11.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Section 11.13
Appendix 13: Mixed-Model Repeated Measures Analysis
Section 11.14
Appendix 14: Abbreviations & Trade Marks
Section 11.15
Appendix 15: List of Data Displays
Section 11.16
Appendix 16: Mock Shells for Data Displays
 
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11.1.
Appendix 1: Exclusions from the Per-Protocol Population
In accordance with SOP-130050 and the ARI114265 PDMP, deviations which require 
exclusion from the Per-Protocol population must be identified, when possible, in advance
of treatment unblinding. The deviation review and programming processes, as well as 
spreadsheet and database capabilities, require that deviation identification must be made 
from two sources:
1. Study Team Assessment of deviations tracked on study team’s protocol deviations 
spreadsheet and then indicated as ‘Exclude from Per-Protocol’ 
and 
2. Programmatic Assessment which outputs deviations through Statistics & Programming 
electronic SAS code execution.
The below table lists the 18 deviations which would exclude a subject from the Per-
Protocol population along with identification methods. It is expected that a final analysis 
dataset will be generated with the two sources pooled.  Details on the pooled dataset 
programming and any adjudication process required to reconcile the two sources will be 
defined in advance of database freeze through a RAP amendment or a high level note to 
Study File. If there is inconsistency between the two sources, it is anticipated that the 
programmatic determination will be considered definitive; this will be outlined through a 
RAP amendment or a high level note to Study File.
Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
01
Missed placebo run-in 
phase
Any evidence which 
implies or documents 
that subject missed the 
placebo run-in phase
1) Placebo run-in treatment 
start and stop dates are missing 
or 
2) Placebo run-in tablets 
consumed = zero
[A5]
02
Incorrect study drug 
(wrong treatment) 
consumed
Any evidence which 
confirms that the 
incorrect container 
contains other-than-
scheduled study 
treatment.
Treatment consumed (from 
incorrect dispensed container)
unequal to treatment planned in 
randomization schedule. Note: 
this can only be determined 
after study unblinding. [A5]
03
Randomized but did not 
consume double-blind 
study drug
Any evidence which 
confirms that the zero 
tablets were consumed 
in double-blind phase
Final nonmissing cumulative 
study drug compliance = zero
[A5]
04
Cumulative study drug 
compliance <75%
Study team is unable to 
calculate RAP-defined 
study drug compliance. 
Therefore, deviation will 
be determined based on 
programmatic 
Final nonmissing cumulative 
study drug compliance < 75%
[A5]
 
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Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
assessment.
05
Cumulative study drug 
compliance >125%
Study team is unable to 
calculate RAP-defined 
study drug compliance. 
Therefore, deviation will 
be determined based on 
programmatic 
assessment.
Final nonmissing cumulative 
study drug compliance > 125%
[A5]
Violation of Inclusion 
Criteria (protocol #)
06
Confirmed BPH clinical 
diagnosis (Inclusion 2)
Any evidence which 
confirms inclusion 
criterion 2 deviation.
Eligibility database indicates 
violation of inclusion criterion 2
[A1]
07
IPSS ≥12 at Screening 
(Inclusion 3)
Any evidence which 
confirms inclusion 
criterion 3 deviation.
Eligibility database indicates  
violation of inclusion criterion 3
[A1]
08
Prostate volume ≥30cc by 
TRUS at Screening 
(Inclusion 4)
Any evidence which 
confirms inclusion 
criterion 4 deviation.
Eligibility database indicates 
violation of inclusion criterion 4
[A1]
09
PSA ≥1.5ng/ml and 
≤10ng/mL at Screening 
(Inclusion 5)
Any evidence which 
confirms inclusion 
criterion 5 deviation.
Eligibility database indicates 
violation of inclusion criterion 5
[A1]
10
Qmax >5 mL/sec and 
≤15mL/sec with Voided
Volume ≥125mL/sec at 
Screening (Inclusion 6)
Any evidence which 
confirms inclusion 
criterion 6 deviation.
Eligibility database indicates 
violation of inclusion criterion 6
[A1]
Violation of Exclusion 
Criteria (protocol #) 
11
Any conditions other than 
BPH, which may in the 
judgement of the 
investigator, result in 
urinary symptoms or 
changes in flow rate 
(Exclusion 6)
Any evidence which 
confirms exclusion 
criterion 6 deviation.
Eligibility database indicates 
violation of exclusion criterion 6
[A1]
12
Use of 5ARI within 6 
months of Screening or 
historical TRUS and 
throughout the study 
(Exclusion 10a)
Any evidence which 
confirms exclusion 
criterion 10a deviation.
Reference Note b.
[A1]
13
Use of anabolic steroids 
within 6 months of 
Screening and throughout 
the study (Exclusion 10b)
Any evidence which 
confirms exclusion 
criterion 10b deviation.
Reference Note b.
[A1]
14
Use of phytotherapy for 
BPH within 2 weeks of 
Screening and throughout 
the study (Exclusion 10c)
Any evidence which 
confirms exclusion 
criterion 10c deviation.
Reference Note b.
[A1]
 
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Number
Per-Protocol Deviation
Study Team 
Assessment
Programmatic Assessment
[eCRF Code Note a]
15
Use of alpha-
adrenoreceptor blockers 
within 2 weeks of 
Screening and throughout 
the study, except study 
meds (Exclusion 10d)
Any evidence which 
confirms exclusion 
criterion 10d deviation.
Reference Note b.
[A1]
16
Use of alpha-
adrenoreceptor agonists 
or anticholinegics or 
cholinergics within 48 
hours prior to all 
uroflowmetry and IPSS 
assessments (Exclusion 
10e)
Any evidence which 
confirms exclusion 
criterion 10e deviation.
Reference Note b.
[A1]
17
Use of selective beta 3-
adrenoreceptor agonist 
(mirabegron) within 2 
weeks prior to all 
uroflowmetry and IPSS 
assessments (Exclusion 
10f)
Any evidence which 
confirms exclusion 
criterion 10f deviation.
Reference Note b.
[A1]
Other
18
Any condition which 
should exclude a subject 
from the Per-Protocol 
population and is not 
include above.
Study team identification 
through review of 
multiple sources such as 
protocol deviation log 
text, study drug 
compliance outliers, 
concomitant medication 
logs, or site/monitor 
communications. 
NA
Notes: 
a.
Reflects eCRF corresponding code to be applied programmatically; definitions in below table.
b.
Exclusion 10 subsets (a – f) are not individually identified in the INFORM and Analysis & Reporting 
datasets.  Therefore, deviation will be determined based on study team assessment.
 
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Important Deviations Categories, Subcategories, and eCRF Codes
(eCRF Codes define above indicated programmatic assignment)
Category / 
Subcategory
eCRF
Codes
Assessments and/or procedures
Biological specimen sample procedures
6E
Equipment procedures
6G
Failure to comply with dosing procedure
6L
Failure to report SAE, pregnancy, or liver
function abnormalities per-protocol
6B
Informed consent process
6A
Missed assessment or procedure
6I
Randomization procedures
6H
Study blind / unblind procedures
6C
Study treatment supply procedures
6D
Other
6OT
Eligibility criteria not met
A1
Prohibited medication or device
A3
Received wrong treatment or incorrect dose
A5
Visit, assessment or timepoint window
Window for dose administration
4C
Window for efficacy assessments
4A
Window for safety assessments
4B
Other
4OT
 
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11.2.
Appendix 2: Time & Events
11.2.1.
Protocol Defined Time & Events
Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomization)
3 months post 
Randomization
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
ICF
X
Inclusion/Exclusion
X
X
Medical Hx/ Demog/CV Hx/
X
ECG (12-lead)
X
Collection of PGx Sample
X
Safety evaluations
Concomitant medication
X
X
X
X
X
X
X

X
Physical Examinationa
X
X
X
Xh
X
Vital signsb
X
X
X
X
X
X

X
Haematology/clinical 
chemistry
X
X
X
HBsAg and Hepatitis C 
Antibody g
X
Total serum PSAc
X
X
X
X
Post-void residual volume 
(PVR)
X
X***
X
X
X
Xh
X
AEs d
X 
X 
X
X
X
X

X
Suicidality (C-SSRS)
X
X
X
X
Efficacy:
BPH symptoms (IPSS)
X
X
X
X
X
X

X
Prostate Volume (TRUS)
X
X
X
 
 
 
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Study Procedures
Visit 1a 
Pre-
Screen
Visit 1b** 
Screening
(V1a +  14 
days)
Visit 2
Baseline (V1b + 
28d ± 4 days)
Visit 3
(Baseline + 
13 wks
± 14 days)
Visit 4
(Baseline + 
26 wks
± 14  days)
Visit 5
(Baseline + 
39 wks 
± 14 days)
Visit 6
(Baseline + 
52 wks
± 14 days)
Visits 7 - 9
(Years 2, repeat 
as for V3-V5 of 
Year 1)
Visit 10
(Baseline + 
104 wks
± 14 days)
Pre-Screen 
Visit
Start of 
Placebo  
run-in
Start of 
Treatment 
Phase Baseline
(Randomization)
3 months post 
Randomization
(Rand)
6 months 
post Rand
9 months 
post Rand
12 months 
post Rand 
15,18 & 21 
months post 
Rand 
respectively
End of 
Treatment 
Phase 24 
months post 
Randi
Peak Urine Flow (Qmax)
X
X***
X
X
X
Xh
X
AUR or BPH-related Surgery
X
X
X
X

X
X
Pharmacokineticsj
Serum PK samplesj
X
X
X
Health Outcomes:
BPH Health Status Q 8 IPSS 
(BHS)
X
X
X
X
X
X

X
AUR or BPH-related Surgery 
Medical Resource Utilisation
X
X
X
X
X

X
BPH Impact Index (BII) 
X
X
X
X
X
X

X
PAS-SFI
X
X
X
X
Other Efficacy Measures
UTI /Incontinence / Renal 
Insufficiency
X
X
X
X
X

X
Register in RAMOS
X
Study Medication:
Call RAMOS/DispenseMeds
X e
X f
X
X
X
X

Compliance check/Collection
X
X
X
X
X

X
 
 
 
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Protocol Defined Time & Events, Notes
** This second screening visit is mandatory before dispensing placebo run-in medication. This additional screen visit is designed to allow time for PSA/haem/biochem results to be 
returned from the laboratory, and repeat Qmax/PVR (if required) before performing TRUS on patients who may not otherwise be eligible for the study.
***REPEAT ONLY IF QMAX inclusion criteria NOT MET at Visit 1a
  ongoing assessment
a.
Including DRE and qualitative breast examination
b.
Blood pressure and pulse to be taken after sitting quietly for 5 minutes
c.
PSA sample must be taken before TRUS
d.
Only Serious AEs (related to study participation) occurring between Screening (Visit 1a) and the start of placebo run-in medication need to be recorded
e.
Single-blind medication to be dispensed at Visit 1b only
f.
Double-blind medication dispensed from Visit 2 onwards.
g.
Hepatitis B surface antigen and hepatitis C antibody (if hepatitis C antibody positive, a hepatitis C RNA test should be reflexively performed to confirm the result)
h.
Only performed at Visit 8 (Month 18)
i.
Performed for End of Study Treatment Assessments as well when a subject discontinues the study treatment.
j.
Serum PK samples are only applicable to subjects of Chinese origin living in China.
 
 
 
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11.3.
Appendix 3: Assessment Windows
Boundaries for the scheduled assessments are defined in the protocol. The data will be 
summarized by nominal visit without regard to window days for all scheduled visits. The 
efficacy, safety, and health outcomes measures collected at nominal visits include IPSS, 
prostate volume, Qmax, PSA, post void residual volume, BII, BPH-related Health Status, 
and PAS-SFI. In order to utilize as much data as possible in these efficacy, safety, and 
health outcomes summaries and analyses, premature withdrawal visit data will be used as 
the scheduled visit data when both of the following criteria are met:

The scheduled visit evaluation is not available, and 

The premature withdrawal visit date falls within 30 days (inclusive) for each of 
the scheduled post baseline visits (i.e., Months 3, 6, 9, 12, 15, 18, 21, and 24), or 
within 15 days (inclusive) of the scheduled Baseline visit (Month 0).  The 
scheduled visit day for month k will be calculated as: 
Baseline Date + (k * 365/12) rounded to the nearest integer.
 
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11.4.
Appendix 4: Multicenter Studies
11.4.1.
Methods for Handling Centers
The 4 countries which randomized subjects into this trial include: China, Japan, Korea, 
and Taiwan. Forty-six centers across these 4 countries randomized subjects into this trial.
Clusters will be used in the exploration of center effect and treatment-by-center 
interaction. 
As stated in the protocol, it was anticipated that randomized subject accrual would be 
spread thinly across centers and summaries of data by center would be unlikely to be 
informative. It was expected that investigative centers would be pooled a priori into 
clusters based on geographic location. As stated in protocol, these clusters would be 
identified once randomization was complete and then used in statistical analyses in the 
exploration of center effects and treatment-by-center interaction.
Based on the actual randomization of sites within countries, it is reasonable and logical to 
assign each country as a single cluster. Therefore, the 4 clusters are the 4 countries:  
China, Japan, Korea, and Taiwan. The countries will be used in summaries of 
randomized subjects, subgroup summaries, and in statistical analyses of efficacy center 
effect and treatment-by-center interaction; these by-country summaries and analyses are 
described in relevant sections.
 
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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG [1]
Data Displays for Reporting
Code
Description
Description
Order [2]
A
Dutasteride 0.5mg once daily + 
tamsulosin 0.2mg once daily
Dut 0.5mg + Tam 0.2mg
2
B
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
Placebo + Tam 0.2mg
1
NOTES:
1.
RandAll NG (Next Generation) is a randomization creation and publishing tool for GSK studies.
2.
Order represents treatments being presented in tables, listings, and figures.
Within this RAP, the following additional references may be made for brevity:
--Full Treatment Description--
--Short Treatment Descriptions--
Dutasteride 0.5mg once daily +
tamsulosin 0.2mg once daily or
-Combination
-Dut 0.5mg + Tam 0.2mg
-Dut + Tam
Dutasteride placebo once daily + 
tamsulosin 0.2mg once daily
-Tamsulosin Monotherapy
-Tam 0.2mg
-Placebo + Tam 0.2mg
-Tam
11.5.2.
Reporting Process & Standards
The following reporting process and reporting standards details apply to all RAP defined 
endpoints.
Reporting Process
Software

SAS software will be used for all analyses except when noted.  It is anticipated that the SAS 
software version 9.3 will be in use at statistical analysis complete; use of a version other than 
9.3 will be documented in IMMS Study File.
Reporting Areas  The following server and areas are identified as of RAP finalization. Revisions
to these areas, for example due to platform / server relocation and/or CDISC reporting standards, 
will be documented in IMMS Study File.
HARP Server
US1SALX00259
HARP Area
The high level area is defined as:  /arenv/arprod/gi198745/ari114265/final.
QC Documentation 
Area
QC process and documentation for analysis and reporting will be maintained 
as a text file on HARP server US1SALX00259 within above noted area.
 
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Reporting Process
Analysis Datasets 

Analysis datasets for international regulatory submissions will be created according to CDISC 
standards.  The SDTM IG Version & AdaM IG Version will be defined in IMMS Study File when 
CDISC standards are implemented.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM; changes will be documented in IMMS Study 
File.
Generation of RTF Files

RTF files will be generated for all tabular summaries with the reporting efforts described in the 
RAP unless clearly stated as not required by the assigned Scientific and Medical Writer(s).   
Reporting Standards
General
The current GSK Integrated Data Standards Library (IDSL) and GSK IDSL Statistical Principles will 
be applied for reporting, unless otherwise stated within RAP text or indicated in table, listing, figure 
shells:

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 
From the above standards and principles as well as to be aligned with historical reporting for this 
compound and indication, the key reporting standards to be applied are:

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

Within listings, 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 decimal places.

Within tabular summaries, the minimum and maximum values are presented with the same 
number of decimal places as the raw data collected on the eCRF. The mean and percentiles 
(e.g. median, Q1, and Q3) are presented using one additional decimal place. The standard 
deviation and standard error are presented using two additional decimal places.

Continuous variables (e.g., age) will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum.

Categorical variables will be summarized using the number of subjects (n) and percentage (%) 
in each category.

P-values greater than 0.10 will be reported to two decimal accuracy. P-values less than or 
equal to 0.10 will be reported to three decimal accuracy. P-values less than 0.001 will be 
reported as ‘<0.001’.

Applicable safety analysis and reporting definitions and presentations within “Program Safety 
Analysis Plan (PSAP) for GI198745 (dutasteride) and GSK2285985 (fixed dose combination of 
dutasteride [GI198745] and tamsulosin [GI138525]” will be referenced; any deviations will be 
oted within this RAP.
 
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11.6.
Appendix 6: Derived and Transformed Data
(Placebo) Run-In Start and Stop Dates

Placebo run-in start date = Start date of (placebo) study treatment recorded for the run-in 
period. If the recorded start dates for the two study drug containers differ, then select the 
earlier start date.

Placebo run-in stop date = End date of (placebo) study treatment recorded for the run-in 
period. If the recorded stop dates for the two study drug containers differ, then select the later 
stop date.
Note: a subject with a nonmissing placebo run-in start date will be considered as included in the 
Placebo Run-in Phase.
Randomization Date

Randomization date is the randomization telephone call in date which is recorded in the eCRF. 
This date is defined here for completeness and no derivations are made.
Note: a subject with a nonmissing randomization number recorded in eCRF will be considered 
Randomized.
(Double-Blind) Treatment Start and Stop Dates

Treatment start date = Start date of study treatment recorded for the (double-blind) treatment 
period. If the recorded start dates for the two study drug containers differ, then select the 
earlier start date.

Treatment stop date = Stop date of study treatment recorded for the (double-blind) treatment 
period. If the recorded stop dates for the two study drug containers differ, then select the later 
stop date.
 
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Study Drug Exposure and Compliance

As explained in the protocol: 
-Dutasteride study treatment is dispensed as capsules within bottles.
-Tamsulosin study treatment is dispensed as tablets within blister packs.
Within this RAP, the following general terms are used for exposure and compliance:
---“Pill” refers to a capsule or a tablet
---“Container” refers to a bottle or a blister pack.

Study drug exposure (in days) is number of days between (double-blind) treatment start date 
and (double-blind) treatment stop date, both days inclusive (i.e. Study drug exposure 
=Treatment Stop Date – Treatment Start Date +1).

Number of pills consumed during the study is defined for double-blind period as total number of 
pills dispensed (sum over all containers dispensed) minus total number of pills returned (sum 
over all containers dispensed) minus total number of pills lost or wasted (sum over all 
containers dispensed). If any of the containers is not returned or number of pills returned or
wasted is missing for any container, number of pills consumed during the study is missing.

Overall study drug compliance is defined for double-blind period as 100 * (number of pills
consumed during the study / study drug exposure) / 2.  Division by 2 is required since subjects 
were scheduled to consume 2 pills per day. Overall study drug compliance is missing if either 
the number of pills consumed during the study or the study drug exposure is missing.

Compliance by study drug component:  Study drug compliance by component will be output 
for:  
--Placebo + Tam 0.2mg for each of the two components:  Placebo and Tam 0.2mg
--Dut 0.5mg + Tam 0.2mg for each of the two components:  Dut 0.5mg and Tam 0.2mg
Compliance is defined as 100 * (number of pills consumed during the study / study drug 
exposure for that drug component) / 1. Note that division by 2 is not applicable for the study 
drug components. Number of pills and exposure are defined in terms of each drug component 
and not the overall.
Baseline Date

A subject’s baseline date will be the latest non-missing value of either (double-blind) treatment 
start date or randomization date. Baseline date will be used in the derivation of study day 
values and Baseline Values. ‘Baseline date’ may differ from the Visit 2 (Baseline Visit) date 
recorded in eCRF.
Baseline Value

For purposes of data analyses, the subject’s baseline value of an assessment will be defined 
as the latest assessment on or before the Baseline Date.
Change and % Change from Baseline

Change from Baseline = Post-baseline Value – Baseline

% Change from Baseline = 100 x [(Post-baseline Value – Baseline) / Baseline]
Study Day
Study Day is calculated as the number of days from Baseline Date:

Reference Date = Missing
→ Study Day = Missing

Reference Date < Baseline Date
→ Study Day = 
Reference Date – Baseline Date

Reference Date ≥ Baseline Date
→ Study Day = 
Reference Date – (Baseline Date) + 1
 
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Cut-off Dates
-Month k Cut-off Date (for k= 3, 6, 9, 12, 15, 18, 21, 24): The maximum of [Month k clinic visit date, 
Month k lab visit date, Baseline Date + (k * 91/3)].
Time Since LUTS First Noted (in years)
-Time Since LUTS First Noted = Baseline Date minus Date LUTS First Noted by Patient / 365
Time Since BPH Clinical Diagnosis (in years)
-Time Since BPH Diagnosis = Baseline Date minus Date of BPH Clinical Diagnosis / 365
Age
Only year of birth is collected in the eCRF. For purposes of calculating age for a given subject, date 
of birth will be defined as June 30th of the corresponding year of birth.  Age is calculated in terms of 
Screening (Visit 1b) date and output as a truncated integer. Age categories include <65, ≥65, <75, 
and ≥75 years.
Body Mass Index (BMI) (kg/sq m)
BMI = Weight (kg) / [Height (m)]2
Race / Ethnicity
Race / ethnicity will be determined based on a subject’s reported ethnicity and geographic ancestry 
as defined in the following table.
Race / Ethnicity
Asian
White (But Not Hispanic)
Hispanic
Other
Ethnicity
Not Hispanic or Latino
Not Hispanic or Latino
Hispanic or 
Latino
Not Hispanic 
or Latino
Geographic 
Ancestry
Any combination of 
(restricted to the 
categories below only):
-Asian – East Asian
Heritage
-Asian – Japanese
Heritage
-Asian -  South East
Asian Heritage
-Asian – Central / South
Asian Heritage
Any combination of 
(restricted to the below 
categories only):
-White – Arabic/ North
African Heritage
-White – White/
Caucasian/
European Heritage
Any 
combination
Any 
combination 
not considered 
‘Asian’ or 
‘White (But 
Not Hispanic)’
IPSS (total score)
IPSS (total score) = Sum of IPSS individual questions 1 – 7.  Reference Section 7.1.1 for 
imputation procedure.
Prostate Volume
Prostate Volume = pi/6 (Anteroposterior Width x Cephalocaudal Width x Transverse Width)
 
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11.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) is defined as
completion of the 4-week placebo run-in and the 104-week study treatment 
period.

Withdrawn subjects will not be replaced in the study.

All available data from subjects 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.

Number and percent of ITT population completing the study and those 
withdrawing from the study, along with eCRF recorded reasons for premature 
withdrawals, will be summarized by treatment and overall. 
Note
This section addresses Premature Withdrawals from the study. Premature 
discontinuation of investigational product, along with reasons, is a separate data 
collection and is reported separately.
11.7.2.
Handling of Missing Data
11.7.2.1.
Handling of Missing or Partial Dates
For efficacy time to event endpoints, such as ‘Time to AUR or BPH-Related Surgery’ the 
following approach will be used for unknown event dates unless otherwise indicated. If 
the month and year are known but the day of the month is unknown, then the day of the 
month will be imputed to be the 15th . If the year is known but the month and day are 
unknown then the date will be imputed to be July 2 in that year. In all the preceding 
cases, if it is not definitive that the onset date is on or after the treatment start date based 
on the non-missing (non-imputed) dates, then the date will be imputed to be the treatment 
start date. If the year is unknown then the onset date is considered to be prior to 
treatment start; hence, the event will be excluded from summaries of events on or after 
treatment start.  For subjects without events, the censoring dates will be established using 
non-missing dates, and using dates with only days missing.  Dates with missing months 
and years will not be used in establishing the censoring dates.
Partial adverse event dates will be handled as described in Appendix 8.
11.7.2.2.
Handling of Missing Data for Statistical Analysis
Endpoints measured at specific visits and analyzed in terms of visit numbers include:  
IPSS, prostate volume, Qmax, PSA, post void residual volume, BPH Impact Index (BII), 
BPH-Related Health Status, and PAS-SFI.  Analysis of the data collected in terms of visit 
numbers will be performed using two different approaches to account for missing data.
 
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1. LOCF (Last Observation Carried Forward) analysis:  This involves bringing 
(carrying) forward the last non-missing post-baseline assessment for subjects with 
missing visit data and/or for subjects who discontinued from the study.
2. At Visit analysis:  Missing values at post-baseline assessments are not replaced and 
are regarded as missing.
The LOCF approach will be considered primary for those endpoints in which both LOCF 
and At Visit are used.  If the LOCF and At Visit results are not consistent with regard to 
the statistical analyses and conclusions, then further data analyses will be undertaken. 
11.7.3.
Questionnaire Total Score Imputation
Calculations of IPSS total and BII total, including imputation for missing responses, are 
described in the respective RAP sections.
 
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11.8.
Appendix 8: Adverse Event Time Periods and Special 
Adverse Event Definitions
Date-related derivations and transformations related to adverse events (AEs) are 
described below.
AE Onset Time since First Dose
= AE Onset Date – Treatment Start Date if treatment start date > AE onset date
= AE Onset Date – Treatment Start Date +1 if treatment start date <= AE start date
= missing otherwise
AE Duration (in days) = AE Resolution Date – AE Onset Date + 1
The timing of AEs will be categorized as follows:

An AE is “Pre-Treatment” if the AE onset date is before the treatment start date.

An AE is “On Treatment” if the AE onset date is on or after the treatment start
date (but on or before the treatment stop date, if that is non-missing), or if the 
onset date is missing.

An AE is “Post-Treatment” if the treatment stop date is non-missing, and the AE 
onset date is after the treatment stop date.

An AE is “Post-Randomization” if the AE is either On Treatment or Post-
Treatment.
Note: Cut-off dates are defined in Appendix 6; definition is repeated here, in terms of 6-
month treatment periods, since this is used to determine AE onset period:
Month k Cut-off Date (for k= 6, 12, 18, 24):  The maximum of [Month k clinic visit date, 
Month k lab visit date, Baseline Date + (k * 91/3)].
An on-treatment AE is uniquely identified as having onset within one of the following
four time periods: Months 1-6, Months 7-12, Months 13-18, or Months 19-24. 

An AE is considered to have onset in the Months 1-6 time period if it is an on-
treatment AE and the onset date is on or before the Month 6 cut-off date.

An AE is considered to have onset in the Months 7-12 time period if it is an on-
treatment AE and the onset date is after the Month 6 cut-off date and is on or 
before the Month 12 cut-off date.

An AE is considered to have onset in the Months 13-18 time period if it is an on-
treatment AE and the onset date is after the Month 12 cut-off date and is on or 
before the Month 18 cut-off date.

An AE is considered to have onset in the Months 19-24 time period if it is an on-
treatment AE and the onset date is after the Month 18 cut-off date.
If the AE onset date is partially missing, the timing is determined as follows:
1. If the non-missing parts of the date (either just year or year/month) are unambiguously 
before the start of treatment, the AE is considered Pre-Treatment.
 
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2. If the non-missing parts of the date are unambiguously after the stop of treatment, the
AE is considered Post-Treatment.
3. If #1 or #2 above cannot be assigned, then the AE is considered On-Treatment.
If an on-treatment AE onset date is partially missing, then, for the purpose of assigning 
the 6-month treatment period referenced above, the onset date will be imputed according 
to the algorithm described in the second paragraph below, and the imputed date will be 
used to assign the period.
An AE is considered drug-related if the relationship variable indicates so, or the variable
value is missing. When an AE has an outcome of Resolved/Recovered with or without
sequelae, it may be categorized for resolution status as follows: if resolution date is on or
before treatment stop date, the AE is considered resolved on-therapy, or if either the
resolution date or the treatment stop date is missing and the action taken is not
‘investigational product withdrawn’, the AE is considered resolved on-therapy. If a
resolved AE is not resolved on-therapy, it is considered resolved off-therapy.
For the purpose of Kaplan-Meier estimates for Special Interest AEs, and for categorizing
AEs by time intervals, the following algorithm will be used:
1) If an AE start date is partial, it will be imputed as follows:
a.
If all components of the date (day, month and year) are missing, then the 
date will not be imputed, but the AE will be categorized in the first 6-
month time period.
b. If both day and month are missing, then the day and month will be 
imputed as 01 January.
c.
If only day is missing, then the day will be imputed as 01.
d. Any imputation described in items 1b and 1c above will be revised if it is 
in conflict with the treatment start date: if the month and year of treatment 
start date is same as those in the imputed date, the imputed date will be 
changed to the treatment start date.
2) A subject not having the particular AE will be censored at the latter of the 
following two dates: date of last clinic visit, latest AE start date.
3) If an AE end date is partial, it will be imputed as follows:
a.
If all components of the date (day, month and year) are missing, then the 
end date will be missing.
b. If both day and month are missing, then the day and month will be 
imputed as 31 December.
c.
If only day is missing, then the day will be imputed as the last day of the 
corresponding month.
For computing AE duration, partial AE start and end dates will be imputed as previously 
described, and events with completely unknown (missing) end dates will be censored at 
the latter of the following two dates: date of last clinic visit, latest AE start date. AE 
duration is the total number of non-overlapping days for all events per subject, and will 
be considered censored if any contributing event is censored.
 
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Time to death is defined as (date of death – treatment start date +1). For subjects who do
not experience death, time to death is censored at the date of last clinic visit (if missing, 
the subject will be censored at the treatment start date).
Special interest adverse events, including MedDRA preferred terms and codes, are 
presented below in Table A - Table D:
Table A: Sexual and Breast Adverse Events of Special Interest
Table B: Prostate Cancer Adverse Events of Special Interest
Table C: Cardiovascular Adverse Events of Special Interest
Table D: Infrequent Tier 1 Adverse Events of Special Interest
Table A.  Sexual and Breast Adverse Events of Special Interest:  MedDRA Preferred Terms and 
Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Altered (Decreased) Libido
Sexual dysfunction
10040477
Male sexual dysfunction
10057672
Libido decreased
10024419
Loss of libido
10024870
Libido disorder
10061221
Impotence
Erectile dysfunction
10061461
Organic erectile dysfunction
10052004
Disturbance in sexual arousal
10058929
Psychogenic erectile dysfunction
10052005
Ejaculation Disorders
Ejaculation delayed
10014325
Ejaculation disorder
10014326
Ejaculation failure
10014328
Retrograde ejaculation
10038967
Anorgasmia
10002652
Orgasm abnormal
10031085
Premature ejaculation
10036596
Male orgasmic disorder
10025513
Orgasmic sensation decreased
10052449
Semen volume decreased
10039944
Breast Disorders
Breast hyperplasia
10006256
Breast enlargement
10006242
Gynaecomastia
10018800
Nipple disorder
10029417
Breast engorgement
10006240
Breast swelling
10006312
Breast pain
10006298
Breast tenderness
10006313
Nipple pain
10029421
Nipple swelling
10058680
Breast discomfort
10049872
Breast Disorders: Breast Enlargement
Breast hyperplasia
10006256
Breast enlargement
10006242
Gynaecomastia
10018800
Nipple disorder
10029417
Breast engorgement
10006240
Breast swelling
10006312
Breast Disorders: Breast Tenderness
Breast pain
10006298
Breast tenderness
10006313
Nipple pain
10029421
Nipple swelling
10058680
Breast discomfort
10049872
 
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Table B.  Prostate Cancer Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Prostate Cancer
Prostate cancer
10060862
Prostate cancer stage 0
10036912
Prostate cancer stage I
10036917
Prostate cancer stage II
10036918
Prostate cancer stage III
10036919
Prostate cancer stage IV
10036920
Prostate cancer recurrent
10036911
Prostate cancer metastatic 
10036909
 
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Table C.  Cardiovascular Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Acute Coronary Syndrome
Acute myocardial infarction 
10000891
Myocardial infarction 
10028596
Silent myocardial infarction  
10049768
Sudden cardiac death
10049418
Angina unstable 
10002388
Cardiac arrest
10007515
Cardio-respiratory arrest
10007617
Cardiac death
10049993
Acute coronary syndrome 
10051592
Ischemic Cerebrovascular Events
Cerebrovascular accident
10008190
Transient ischemic attack
10044390
Cerebral infarction
10008118
Cerebrovascular disorder
10008196
Cerebral artery embolism
10008088
Cerebral artery occlusion
10008089
Cerebral artery thrombosis
10008092
Ischemic stroke
10061256
Cerebral circulatory failure
10008097
Cerebellar infarction
10008034
Thalamic infarction
10064961
Reversible ischemic neurologic deficit
10050496
Thrombotic stroke
10043647
Embolic stroke
10014498
Vertebral artery occlusion
10048965
Carotid arterial embolus
10007684
Carotid artery occlusion
10048964
Carotid artery stenosis
10007687
Carotid artery thrombosis
10007688
Thrombotic cerebral infarction
10067347
Brain stem infarction
10006147
Embolic cerebral infarction
10060839
Lacunar infarction 
10051078
Brain stem stroke
10068644
Stroke in evolution
10059613
Ischaemic cerebral infarction 
10060840
 
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Table C.  Cardiovascular Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes 
(continued)
Special Interest Event
MedDRA Preferred Term
PT_Code
Cardiac Failure
Cardiac failure congestive
10007559
Cardiac failure 
10007554
Left ventricular failure
10024119
Cardiac failure acute
10007556
Cardiogenic shock
10007625
Left ventricular failure acute
10063081
Right ventricular failure
10039163
Right ventricular failure acute
10063082
Ventricular failure
10060953
Cardiopulmonary failure
10051093
Congestive cardiomyopathy
10056370
Ischemic Coronary Artery Disorders/ 
Atherosclerosis
Coronary artery embolism
10011084
Coronary artery occlusion
10011086
Coronary artery stenosis
10011089
Coronary artery thrombosis
10011091
Myocardial ischemia
10028600
Coronary artery disease
10011078
Arteriosclerosis coronary artery
10003211
Cardiac Arrhythmias
Ventricular extrasystoles
10047289
Torsade de Pointes
10044066
Ventricular  fibrillation
10047290
Cardiac Fibrillation
10061592
Pulseless electrical activity
10058151
Ventricular asystole
10047284
Long QT syndrome
10024803
Ventricular tachycardia
10047302
Ventricular Arrhythmia
10047281
Ventricular flutter  
10047294
Peripheral Vascular Disease
Deep Vein Thrombosis
10051055
 
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Table D.  Infrequent Tier 1 Adverse Events of Special Interest:  MedDRA Preferred Terms and Codes
Special Interest Event
MedDRA Preferred Term
PT_Code
Relevant for dutasteride:  
Allergic reactions 
Anaphylactic reaction
10002198
Anaphylactic shock
10002199
Anaphylactic transfusion reaction
10067113
Anaphylactoid reaction
10002216
Anaphylactoid shock
10063119
Circulatory collapse
10009192
First use syndrome
10068158
Kounis syndrome
10069167
Shock
10040560
Type I hypersensitivity
10045240
Allergic oedema
10060934
Angioedema
10002424
Circumoral oedema
10052250
Conjunctival oedema
10010726
Corneal oedema
10011033
Epiglottic oedema
10015029
Eye oedema
10052139
Eye swelling
10015967
Eyelid oedema
10015993
Face oedema
10016029
Gingival oedema
10049305
Gingival swelling
10018291
Gleich's syndrome
10066837
Hereditary angioedema
10019860
Idiopathic angioedema
10073257
Idiopathic urticaria
10021247
Laryngeal oedema
10023845
Laryngotracheal oedema
10023893
Limbal swelling
10070492
Lip oedema
10024558
Lip swelling
10024570
Mouth Swelling 
10075203
Oculorespiratory syndrome
10067317
Oedema mouth
10030110
Oropharyngeal swelling
10031118
Palatal oedema
10056998
Palatal swelling
10074403
Periorbital oedema
10034545
Pharyngeal oedema
10034829
Scleral oedema
10057431
Small bowel angioedema
10051401
Swelling face
10042682
Swollen tongue
10042727
Tongue oedema
10043967
Tracheal oedema
10044296
Urticaria
10046735
Urticaria cholinergic
10046740
Urticaria chronic
10052568
Urticaria papular
10046750
Acquired epidermolysis bullosa
10056508
Blister
10005191
Blister rupture
10073385
Bullous impetigo
10006563
Conjunctivitis
10010741
Corneal exfoliation
10064489
Drug eruption
10013687
Epidermolysis
10053177
Epidermolysis bullosa
10014989
 
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Genital ulceration
10018180
HLA-B*1502 assay positive
10074771
HLA-B*5801 assay positive
10074774
Lip exfoliation
10064482
Mouth ulceration
10028034
Mucocutaneous ulceration
10028084
Mucosa vesicle
10028103
Mucosal erosion
10061297
Mucosal exfoliation
10064486
Mucosal necrosis
10067993
Mucosal ulceration
10028124
Nikolsky's sign
10029415
Noninfective conjunctivitis
10074701
Oral mucosal blistering
10030995
Oral mucosal exfoliation
10064487
Oral papule
10031010
Oropharyngeal blistering
10067950
Pemphigoid
10034277
Pemphigus
10034280
Penile exfoliation
10064485
Skin erosion
10040840
Skin exfoliation
10040844
Staphylococcal scalded skin syndrome
10041929
Stomatitis
10042128
Tongue exfoliation
10064488
Vaginal exfoliation
10064483
Vaginal ulceration
10046943
Vulval ulceration
10047768
Vulvovaginal rash
10071588
Vulvovaginal ulceration
10050181
Application site pruritus
10003053
Aquagenic pruritus
10003071
Injection site pruritus
10022093
Pruritus
10037087
Pruritus genital
10037093
Rash pruritic
10037884
Senile pruritus
10039986
Itching scar
10050818
Eyelids pruritus
10051627
Catheter site pruritus
10052270
Pruritus generalised
10052576
Infusion site pruritus
10053664
Vulvovaginal pruritus
10056530
Incision site pruritus
10059386
Uraemic pruritus
10060875
Pruritus allergic
10063438
Instillation site pruritus
10063763
Implant site pruritus
10063785
Cholestatic pruritus
10064190
Polymorphic eruption of pregnancy
10066100
Vessel puncture site pruritus
10067254
Vaccination site pruritus
10068881
Brachioradial pruritus
10071443
Notalgia paraesthetica
10072643
Breast Cancer
Apocrine breast carcinoma
10066206
Invasive breast carcinoma
10075713
Triple negative breast cancer
10075566
Breast cancer
10006187
Breast cancer female
10057654
Breast cancer in situ
10006189
Breast cancer male
10061020
 
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Breast cancer metastatic
10055113
Breast cancer recurrent
10006198
Breast cancer stage I
10006199
Breast cancer stage II
10006200
Breast cancer stage III
10006201
Breast cancer stage IV
10006202
Breast sarcoma
10068582
Breast sarcoma metastatic
10068583
Breast sarcoma recurrent
10068584
Contralateral breast cancer
10054784
Electron radiation therapy to breast
10014437
Extended radical mastectomy
10015721
Gamma radiation therapy to breast
10017677
HER-2 positive breast cancer
10065430
Inflammatory carcinoma of breast recurrent
10021977
Inflammatory carcinoma of breast stage III
10021978
Inflammatory carcinoma of breast stage IV
10021979
Inflammatory carcinoma of the breast
10021980
Intraductal papillary breast neoplasm
10073540
Intraductal proliferative breast lesion
10073094
Invasive ductal breast carcinoma
10073095
Invasive lobular breast carcinoma
10073096
Invasive papillary breast carcinoma
10073098
Lobular breast carcinoma in situ
10073099
Malignant nipple neoplasm
10062051
Malignant nipple neoplasm female
10053129
Malignant nipple neoplasm male
10053128
Mastectomy
10026878
Medullary carcinoma of breast
10027095
Metaplastic breast carcinoma
10073100
Modified radical mastectomy
10027799
Mucinous breast carcinoma
10073101
Neuroendocrine breast tumour
10073103
Oestrogen receptor assay positive
10054054
Oestrogen receptor positive breast cancer
10070577
Paget's disease of nipple
10033364
Photon radiation therapy to breast
10034949
Postmastectomy lymphoedema syndrome
10036390
Progesterone receptor assay positive
10054057
Radical mastectomy
10037773
Radiotherapy to breast
10062090
Simple mastectomy
10040700
Tubular breast carcinoma
10073104
X-ray therapy to breast
10048199
Antioestrogen therapy
10002816
Breast reconstruction
10006305
Breast neoplasm
10006279
Nipple neoplasm
10056286
Phyllodes tumour
10071776
Biopsy breast abnormal
10004745
Breast calcifications
10048782
Breast dysplasia
10006237
Breast prosthesis implantation
10006303
Computerised tomogram breast abnormal
10074534
Depressed mood
Activation syndrome
10066817
Adjustment disorder with depressed mood
10001297
Columbia suicide severity rating scale abnormal
10075616
Adjustment disorder with mixed anxiety and 
depressed mood
10001299
 
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Agitated depression
10001496
Anhedonia
10002511
Antidepressant therapy
10054976
Childhood depression
10068631
Decreased interest
10011971
Depressed mood
10012374
Depression
10012378
Depression postoperative
10012390
Depressive symptom
10054089
Dysphoria
10013954
Dysthymic disorder
10013982
Electroconvulsive therapy
10014404
Feeling guilty
10049708
Feeling of despair
10016344
Feelings of worthlessness
10016374
Major depression
10057840
Menopausal depression
10067371
Post stroke depression
10070606
Postictal depression
10071324
Postpartum depression
10056393
Completed suicide
10010144
Depression suicidal
10012397
Intentional overdose
10022523
Intentional self-injury
10022524
Poisoning deliberate
10036000
Self injurious behaviour
10063495
Self-injurious ideation
10051154
Suicidal behaviour
10065604
Suicidal ideation
10042458
Suicide attempt
10042464
Hair changes
Alopecia
10001760
Alopecia areata
10001761
Alopecia scarring
10001764
Alopecia syphilitic
10001765
Alopecia totalis
10001766
Alopecia universalis
10001767
Hypotrichosis
10021126
Progeria
10036794
Madarosis
10051235
Follicular mucinosis
10056506
Application site alopecia
10059046
Androgenetic alopecia
10068168
Satoyoshi syndrome
10070579
Radiation alopecia
10072045
Diffuse alopecia
10073736
Hypertrichosis
10020864
Interference with formation of external genitalia in 
a male fetus 
Congenital vas deferens absence
10010670
Cryptorchism
10011498
Epispadias
10015088
Hypospadias
10021093
Reproductive tract hypoplasia, male
10057858
Testicular dysplasia
10059271
Congenital genital malformation male
10059492
Penoscrotal fusion
10064951
Sertoli-cell-only syndrome
10066833
Buried penis syndrome
10067131
Penoscrotal transposition
10067287
Penile torsion
10070235
Infertility tests
10021931
pH semen
10034784
pH semen decreased
10034786
 
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Potential for decreased male fertility 
pH semen increased
10034788
pH semen normal
10034790
Red blood cells semen
10038176
Red blood cells semen negative
10038179
Red blood cells semen positive
10038180
Semen liquefaction
10039931
Semen liquefaction normal
10039933
Semen liquefaction prolonged
10039934
Semen liquefaction shortened
10039935
Semen viscosity
10039936
Semen viscosity decreased
10039938
Semen viscosity increased
10039940
Semen viscosity normal
10039942
Semen volume abnormal
10039943
Semen volume decreased
10039944
Semen volume increased
10039946
Semen volume normal
10039948
Sperm analysis
10041476
Sperm analysis abnormal
10041477
Sperm analysis normal
10041478
Spermatozoa abnormal
10041498
Spermatozoa morphology
10041501
Spermatozoa morphology abnormal
10041502
Spermatozoa morphology normal
10041503
Spermatozoa progressive motility abnormal
10041504
Spermatozoa progressive motility decreased
10041506
Spermatozoa progressive motility normal
10041507
White blood cells semen
10047956
White blood cells semen negative
10047959
White blood cells semen positive
10047960
Fructose semen decreased
10052476
Fructose semen increased
10052477
Prostatic fluid leukocytes increased
10053866
Infertility tests abnormal
10062020
Infertility tests normal
10062021
pH semen abnormal
10062074
Semen liquefaction abnormal
10062159
Semen viscosity abnormal
10062160
Semen analysis normal
10062238
Semen analysis
10068482
Semen analysis abnormal
10068483
Sperm concentration decreased
10070925
Sperm concentration increased
10070926
Sperm concentration abnormal
10070927
Sperm concentration normal
10070928
Sperm concentration
10070929
Sperm concentration zero
10070930
Total sperm count
10070931
Total sperm count decreased
10070932
Infertility
10021926
Infertility male
10021929
Testicular pain and swelling
Anorchism
10002641
Eunuchoidism
10015532
Hypogonadism male
10021011
Testicular atrophy
10043298
Testicular disorder
10043306
Testicular failure
10043315
Testicular failure postoperative
10043317
Testicular failure primary
10043318
Testicular hyperfunction
10043334
Testicular infarction
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Testicular pain
10043345
Testicular retraction
10043348
Testicular swelling
10043354
Testicular torsion
10043356
Testicular necrosis
10049572
Spermatic cord mass
10049792
Testicular appendage torsion
10050476
Spermatic cord pain
10051221
Testicular injury
10051872
Testicular haemorrhage
10051877
Epididymal calculus
10052321
Epididymal enlargement
10052322
Epididymal tenderness
10052323
Testis discomfort
10052531
Monorchidism
10055002
Epididymal disorder
10055045
Spermatic cord disorder
10056348
Testicular mass
10058901
Testotoxicosis
10063654
Spermatic cord haemorrhage
10065742
Spermatic cord obstruction
10065805
Spermatic cord perforation
10065806
Spermatic cord stenosis
10065807
Testicular perforation
10065808
Testicular hypertrophy
10066101
Testicular oedema
10066769
Sperm granuloma
10067802
Testicular microlithiasis
10067829
Congenital monorchidism
10069505
Testicular autoimmunity
10071574
Relevant for tamsulosin:  
Atrial fibrillation, tachycardia, arrhythmias
Arrhythmia
10003119
Heart alternation
10058155
Heart rate irregular
10019304
Pacemaker generated arrhythmia
10053486
Pacemaker syndrome
10051994
Paroxysmal arrhythmia
10050106
Pulseless electrical activity
10058151
Reperfusion arrhythmia
10058156
Withdrawal arrhythmia
10047997
Arrhythmia supraventricular
10003130
Atrial fibrillation
10003658
Atrial flutter
10003662
Atrial parasystole
10071666
Atrial tachycardia
10003668
Junctional ectopic tachycardia
10074640
Sinus tachycardia
10040752
Supraventricular extrasystoles
10042602
Supraventricular tachyarrhythmia
10065342
Supraventricular tachycardia
10042604
ECG P wave inverted
10057526
Electrocardiogram P wave abnormal
10050384
Retrograde p-waves
10071187
Anomalous atrioventricular excitation
10002611
Cardiac flutter
10052840
Extrasystoles
10015856
Tachyarrhythmia
10049447
Accelerated idioventricular rhythm
10049003
Cardiac fibrillation
10061592
Parasystole
10033929
Rhythm idioventricular
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Torsade de pointes
10044066
Ventricular arrhythmia
10047281
Ventricular extrasystoles
10047289
Ventricular fibrillation
10047290
Ventricular flutter
10047294
Ventricular parasystole
10058184
Ventricular pre-excitation
10049761
Ventricular tachyarrhythmia
10065341
Ventricular tachycardia
10047302
Floppy Iris Syndrome
Floppy iris syndrome
10066373
Orthostasis
Dizziness
10013573
Dizziness postural
10013578
Orthostatic hypotension
10031127
Hypotension
10021097
Syncope
10042772
Presyncope
10036653
Blood pressure orthostatic abnormal
10053354
Blood pressure orthostatic decreased
10053356
Priapism
Priapism
10036661
Stevens-Johnson syndrome
Acute generalised exanthematous pustulosis
10048799
Cutaneous vasculitis
10011686
Dermatitis bullous
10012441
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Drug reaction with eosinophilia and systemic 
symptoms
10073508
Epidermal necrosis
10059284
Erythema multiforme
10015218
Exfoliative rash
10064579
Oculomucocutaneous syndrome
10030081
Skin necrosis
10040893
Stevens-Johnson syndrome
10042033
Toxic epidermal necrolysis
10044223
Toxic skin eruption
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11.9.
Appendix 9: Threshold Factors for Clinical Laboratory Tests 
and Vital Signs
Hematology and Clinical Chemistry Laboratory Tests, Codes and Threshold Factors
LABORATORY TEST
Database
LBTESTCD
Unit
Multiplicative Factors1
Low (x LLN)
High (x ULN)
HEMATOLOGY
-Hemoglobin
HB_BLC
G/L
0.75
-
-Platelet count
PLT_BLC
GI/L
0.75
1.5
-WBC count
WBC_BLC
GI/L
0.5
3.0
-RBC count
RBC_BLC
GI/L
0.5
-
CLINICAL CHEMISTRY
-Albumin
ALB_PLC
G/L
0.9
1.2
-ALT
ALT_PLC
IU/L
-
3.0
-Alkaline Phosphatase
ALP_PLC
IU/L
-
1.5
- AST  
AST_PLC
IU/L
-
3.0
-Creatinine
CRT_PLC
UMOL/L
0.5
3.0
-Glucose
GLUC_PLC
MMOL/L
0.7
1.75
-Potassium
K_PLC
MMOL/L
0.75
1.4
-Sodium
NA_PLC
MMOL/L
0.9
1.15
-Total Bilirubin
BILT_PLC
UMOL/L
-
2.5
-Total Protein
TP_PLC
G/L
0.8
1.15
-Urea/BUN
UREA_PLC
MMOL/L
0.5
2.0
1.
A laboratory value that is above the upper limit factor multiplied by the upper limit of the normal range is 
considered a high threshold value. A laboratory value that is below the lower limit factor multiplied by the 
lower limit of the normal range is considered a low threshold value.
Threshold Ranges for Vital Signs
Threshold Ranges
Vital Sign
Unit
Lower
Upper
Systolic Blood Pressure
mmHg
<80
>165
Diastolic Blood Pressure
mmHg
<40
>105
Heart Rate
bpm
<40
>100
 
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11.10.
Appendix 10: Examination of Covariates and Subgroups
Endpoint(s)
IPSS change from baseline
Analysis
Subgroup Summaries and General Linear Model
A list of subgroups of interest for the primary efficacy endpoint is below. If the categorization 
defining the subgroups results in overly sparse data or if some baseline subgroups are 
homogeneous in response, then particular subgroups may be combined or not reported.
For each subgroup, IPSS change from baseline summaries will be output by treatment group at 
Month 12 and at Month 24 for the ITT population using both LOCF and At Visit approaches. No 
statistical comparisons will be performed.
The effects of baseline subgroups and their interactions with treatment will be assessed. As a 
minimum, these subgroups will include those in the below table except for country and center. 
These effects will be individually explored in terms of: 1) addition of subgroup effect to the model*
and 2) addition of subgroup effect and subgroup effect by treatment interaction to the model*.  
*Refers to primary efficacy General Linear Model (GLM): 
Change from Baseline IPSS = treatment + cluster + baseline IPSS.
In these analyses, continuous variables will be treated as continuous and not as dichotomous 
subgroups. These assessments will focus on Month 24 LOCF, and separately Month 24 At Visit, 
and will be output as listings. Other analyses based on other time points will not be output unless 
substantive finding dictate.
Subgroups Summarized for Primary Efficacy Endpoint
Subgroup
Categorization for Tabular 
Summary Display
Baseline Age 65
<65, ≥65 years
Baseline Age 75
<75, ≥75 years
Baseline IPSS
<20, ≥20
Baseline BPH-Related Health Status 
<4, ≥4
Baseline Prostate Volume
<40, ≥40cc
Baseline Qmax
<10, ≥10ml/sec
Alpha Blocker History
Yes, No
5-Alpha-Reductase Inhibitor History 
Yes, No
Phytotherapy History
Yes, No
Baseline PSA
<3, ≥3ng/ml
Country (cluster)
China, Japan, Korea, Taiwan
Center
Each center with at least one 
randomized subject.
 
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11.11.
Appendix 11: Multiple Comparisons and Multiplicity
Results of all planned statistical analyses and thus all planned p-values will be reported. P-values 
≤0.05 will be considered formally statistically significant if the below described conditions are 
satisfied for multiple endpoints and multiple time points. Otherwise p-values ≤0.05 will be 
considered nominally significant.
The comparisons are in terms of two treatment arms, Combination and Tamsulosin, so no 
multiplicity adjustment for treatment is necessary. 
Multiplicity adjustment for multiple endpoints is described in this paragraph. For the primary 
efficacy endpoint, IPSS change from baseline at Month 24, if the Month 24 two-sided p-value is 
≤0.05 and the treatment difference supports Combination superiority versus Tamsulosin, then 
formal statistical significance is declared and testing of each secondary endpoint may occur. For 
secondary endpoints evaluated at multiple time points, then the testing will begin at Month 24. For 
purposes of statistical testing, there is no hierarchical order assigned to the set of secondary 
endpoints at Month 24.
Multiplicity adjustment for multiple time points is described in this paragraph. For any endpoint that 
is tested over different visits, a step-down procedure for interpreting the p-values will be adopted. 
The final time point (Month 24) will be tested first. If the Month 24 two-sided p-value is ≤0.05 and 
the treatment difference supports Combination superiority versus Tamsulosin, the time point 
immediately preceding it will be interpreted for formal statistical significance; otherwise formal 
interpretation of significance will stop, but interpretation of nominal significance will continue for 
preceding endpoints. The interpretation of formal statistical significance will continue this way in a 
stepwise manner through all time points. 
As an example, the time point testing visit sequence for the primary efficacy endpoint is: Month 24, 
Month 21, Month 18, Month 15, Month 12, Month 9, Month 6, and (last) Month 3.
 
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11.12.
Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses
Endpoint(s)
IPSS change from baseline
Analysis
General Linear Model

Assessments of the general linear model residuals will be performed. These assessments will 
include reviews of residual by predicted value plots and normal probability plots on residuals.  
This will be in terms of the change from baseline IPSS at Month 24 using the LOCF and At Visit 
approaches.  Similar assessments of other time periods will not be reported unless dictated by 
substantive findings.

If these assumptions are not met, appropriate non-parametric analyses will be performed to test 
the robustness of the results of the parametric analyses. If non-parametric analyses are 
performed further detailed information will be provided in the Statistical Appendix for the Clinical 
Report.

The interaction of cluster with treatment will be assessed by adding the (interaction) term to the 
above planned analysis model at Month 24.

The interaction of baseline IPSS with treatment will be assessed by adding the (interaction) 
term to the above stated model at Month 24.

The effects of baseline subgroups and their interactions with treatment will also be assessed.  
This is described in Appendix 10, Examination of Covariates and Subgroups
 
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11.13.
Appendix 13: Mixed-Model Repeated-Measures Analysis
Mixed-Model Repeated-Measures (MMRM) Analysis:  As a supportive analysis, IPSS change from 
baseline will be analyzed using a mixed-model repeated-measures (MMRM) analysis including 
data from the scheduled post-baseline assessments [Mallinckrodt, 2008]. Analyses will include the 
fixed, categorical effects of treatment, cluster, visit, and treatment-by-visit interaction, as well as the 
continuous, fixed covariates of baseline IPSS and baseline IPSS-by-visit interaction. An 
unstructured covariance structure will be used to model the within-patient errors, shared across 
treatments. PROC MIXED in SAS [Littell, 1996] will be used to fit the model, using the restricted 
maximum likelihood estimation method and the Kenward-Roger option to estimate denominator 
degrees of freedom and standard errors. 
Corresponding SAS output will be provided as a listing. The treatment comparison will be the 
contrast between treatments (Combination minus Tamsulosin) at the Month 24 visit using the two-
sided p-value from the corresponding t-test at α=0.05. In this supportive analysis, superiority of the 
Combination vs. Tamsulosin treatment will be declared if the two-sided p-value for the contrast is 
less than or equal to 0.05 and the observed treatment effect supports superiority. A two-sided 95% 
confidence interval for the estimated treatment difference in the change from baseline at each 
scheduled visit will be computed. Estimated mean change from baseline and standard errors will 
be computed by treatment group and visit. If the model-fitting algorithm fails to converge then 
alternative initial parameter values and/or covariance structures will be considered.
 
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11.14.
Appendix 14 – Abbreviations & Trade Marks
11.14.1.
Abbreviations
Abbreviation
Description
5ARI
5 Alpha-Reductase Inhibitor
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUR
Acute Urinary Retention
A&R
Analysis and Reporting 
BHS
BPH-related Health Status
BII
BPH Impact Index
BPH
Benign Prostatic Hyperplasia
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating
DOB
Date of Birth
DRE
Digital Rectal Examination
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
FDC
Fixed Dose Combination
ICH
International Conference on Harmonization
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
LOCF
Last Observation Carried Forward
LUTS
Lower urinary tract symptoms
MMRM
Mixed-Model Repeated- Measures
PAS SFI
Problem Assessment Scale Sexual Function Inventory
PDE-5
Phosphodiesterase-5
PDMP
Protocol Deviation Management Plan
PGx
Pharmacogenetic
PPK
Population Pharmacokinetics
PP
Per-Protocol
PPSM
Patient Perception of Study Medication
PSA
Prostate Specific Antigen
PSAP
Program Safety Analysis Plan
PSRAE
Possible Suicidality Related Adverse Event
QC
Quality Control
Qmax
Maximum (peak) urinary flow rate
RAMOS
Randomization & Medication Ordering System 
 
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Abbreviation
Description
RandAll NG
RandAll is a randomization creation and publishing tool for GSK studies.  NG 
represents Next Generation version.
RAP
Reporting & Analysis Plan
RBC
Red Blood Cell
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TFUQ
Targeted Follow-Up Questionnaire
TRUS
Transrectal ultrasound
UTI
Urinary Tract Infection
WBC
White Blood Cell
11.14.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
AVODART
Flomax
Harnal D
Propecia
Proscar
SAS
WinNonlin
 
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11.15.
Appendix 15: List of Data Displays
11.15.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays.
Section
Tables
Figures
Study Population
1.1 to 1.32
NA
Efficacy
2.1 to 2.152
2.1 to 2.9
Safety
3.1 to 3.104
3.1 to 3.18
Health Outcomes
4.1 to 4.56
4.1 to 4.4
Section
Listings
ICH Listings (Study Population)
1.1 to 1.14
ICH Listings (Efficacy)
2.1 to 2.8
ICH Listings (Safety)
3.1 to 3.23
ICH Listings (Health Outcomes)
-
Other Listings includes Non-ICH listings
5.1 to 5.52
 
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11.15.2.
Study Population Tables
Study Population Tables (Population=ITT except when noted)
No.
Title
Subject Accountability
1.1.
Summary of Subject Accountability   Note: Population = All Enrolled Subjects
Subject Disposition
1.2.
Summary of Subject Withdrawals During Placebo Run-in Phase   Note:  Population = Subjects Who Entered Placebo Run-In
1.3.
Summary of Randomized Subjects by Country and Center
1.4.
Summary of Subject Disposition
1.5.
Summary of Subject Discontinuation by Visit
1.6.
Summary of Primary Reason for Study Withdrawal, by Period of Discontinuation
1.7.
Summary of Inclusion/Exclusion Criteria Deviations
1.8.
Summary of Important Protocol Deviations
1.9.
Summary of Deviations which Require Exclusion from the Per-Protocol Population
Demographic and Baseline Characteristics
1.10.
Summary of Baseline and Demographic Characteristics
1.11.
Summary of Baseline and Demographic Characteristics by Country
1.12.
Summary of Race and Racial Combinations
1.13.
Summary of Race and Racial Combination Details
1.14.
Summary of Selected Safety Measures at Baseline 
1.15.
Summary of Selected Safety Measures at Baseline by Country
1.16.
Summary of Selected Efficacy and Health Outcome Measures at Baseline
1.17.
Summary of Selected Efficacy and Health Outcome Measures at Baseline by Country
Medical Conditions and Concomitant Medications
1.18.
Summary of Medical Conditions at Screening, by Body System
 
 
 
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Study Population Tables (Population=ITT except when noted)
No.
Title
1.19.
Summary of Specific Medical Conditions at Screening
1.20.
Summary of BPH History
1.21.
Summary of Alpha-Blocker Use
1.22.
Summary of 5-Alpha-Reductase Inhibitor Use
1.23.
Summary of Alpha-Blocker and 5-Alpha-Reductase Inhibitor Use
1.24.
Summary of Phytotherapy for BPH Use
1.25.
Summary of Sexual Function at Screening
1.26.
Summary of Family History of Premature Coronary Artery Disease
1.27.
Summary of Family History of Breast Cancer
1.28.
Summary of Family History of Prostate Cancer
1.29.
Summary of Concomitant Medications
1.30.
Summary of Investigational Product Discontinuation
1.31.
Summary of Study Drug Exposure
1.32.
Summary of Compliance to Study Drug
 
 
 
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11.15.3.
Efficacy Tables
Efficacy Tables  (Population=ITT)
No.
Title
IPSS Overview and Primary Analysis
2.1.
Summary of IPSS Imputations
2.2.
Summary of IPSS at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with IPSS at each Month n (3, 6, …24) 
2.3.
Summary of IPSS at Each Post-Baseline Visit (LOCF)
2.4.
Summary of IPSS at Each Post-Baseline Visit (At Visit)
2.5.
Summary of IPSS Change from Baseline (LOCF)
2.6.
Summary of IPSS Change from Baseline (At Visit)
IPSS MMRM
2.7.
Summary of IPSS MMRM Analysis
IPSS Change from Baseline Subgroup Summaries   presented for each Month 12 and Month 24
2.8.
Summary of IPSS Change from Baseline, by Age (<65, ≥65 years) (LOCF)
2.9.
Summary of IPSS Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.10.
Summary of IPSS Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.11.
Summary of IPSS Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.12.
Summary of IPSS Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.13.
Summary of IPSS Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.14.
Summary of IPSS Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.15.
Summary of IPSS Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.16.
Summary of IPSS Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.17.
Summary of IPSS Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.18.
Summary of IPSS Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.19.
Summary of IPSS Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.20.
Summary of IPSS Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.21.
Summary of IPSS Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.22.
Summary of IPSS Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.23.
Summary of IPSS Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.24.
Summary of IPSS Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.25.
Summary of IPSS Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
2.26.
Summary of IPSS Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
2.27.
Summary of IPSS Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.28.
Summary of IPSS Change from Baseline, by Country (LOCF)
2.29.
Summary of IPSS Change from Baseline, by Country (At Visit)
Note: IPSS change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
Individual IPSS Questions 1 - 7
2.30.
Summary of IPSS at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with IPSS at each Months 12 and 24
2.31.
Summary of IPSS: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
2.32.
Summary of IPSS: Question 1 (At Visit)
2.33.
Summary of IPSS Change from Baseline: Question 1 (LOCF)
2.34.
Summary of IPSS Change from Baseline: Question 1 (At Visit)
2.35.
Summary of IPSS at Screening and Baseline: Question 2
2.36.
Summary of IPSS: Question 2 (LOCF)
2.37.
Summary of IPSS: Question 2 (At Visit)
2.38.
Summary of IPSS Change from Baseline: Question 2 (LOCF)
2.39.
Summary of IPSS Change from Baseline: Question 2 (At Visit)
2.40.
Summary of IPSS at Screening and Baseline: Question 3
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.41.
Summary of IPSS: Question 3 (LOCF)
2.42.
Summary of IPSS: Question 3 (At Visit)
2.43.
Summary of IPSS Change from Baseline: Question 3 (LOCF)
2.44.
Summary of IPSS Change from Baseline: Question 3 (At Visit)
2.45.
Summary of IPSS at Screening and Baseline: Question 4
2.46.
Summary of IPSS: Question 4 (LOCF)
2.47.
Summary of IPSS: Question 4 (At Visit)
2.48.
Summary of IPSS Change from Baseline: Question 4 (LOCF)
2.49.
Summary of IPSS Change from Baseline: Question 4 (At Visit)
2.50.
Summary of IPSS at Screening and Baseline: Question 5
2.51.
Summary of IPSS: Question 5 (LOCF)
2.52.
Summary of IPSS: Question 5 (At Visit)
2.53.
Summary of IPSS Change from Baseline: Question 5 (LOCF)
2.54.
Summary of IPSS Change from Baseline: Question 5 (At Visit)
2.55.
Summary of IPSS at Screening and Baseline: Question 6
2.56.
Summary of IPSS: Question 6 (LOCF)
2.57.
Summary of IPSS: Question 6 (At Visit)
2.58.
Summary of IPSS Change from Baseline: Question 6 (LOCF)
2.59.
Summary of IPSS Change from Baseline: Question 6 (At Visit)
2.60.
Summary of IPSS at Screening and Baseline: Question 7
2.61.
Summary of IPSS: Question 7 (LOCF)
2.62.
Summary of IPSS: Question 7 (At Visit)
2.63.
Summary of IPSS Change from Baseline: Question 7 (LOCF)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.64.
Summary of IPSS Change from Baseline: Question 7 (At Visit)
IPSS Percentage Change from Baseline
2.65.
Summary of IPSS Percentage Change from Baseline (LOCF)
2.66.
Summary of IPSS Percentage Change from Baseline (At Visit)
IPSS Non-Imputed Score Analysis
Performed only if RAP Section 7.1 imputation conditions are met; thus, table numbers are not listed.
IPSS Per-Protocol Population Analysis
Performed only if RAP Section 4 per-protocol conditions are met; thus, table numbers are not listed.
IPSS Change-from-Baseline Improvement Levels
2.67.
Summary of IPSS Change-from-Baseline Categories (LOCF)
2.68.
Summary of IPSS Change-from-Baseline Categories (At Visit)
IPSS Percentage Change-from-Baseline Improvement Levels
2.69.
Summary of IPSS Percentage Change-from-Baseline Categories (LOCF)
2.70.
Summary of IPSS Percentage Change-from-Baseline Categories (At Visit)
Prostate Volume
2.71.
Summary of Prostate Volume at Screening and Baseline
2.72.
Summary of Prostate Volume at Each Post-Baseline Visit (LOCF)
2.73.
Summary of Prostate Volume at Each Post-Baseline Visit (At Visit)
2.74.
Summary of Prostate Volume Change from Baseline (LOCF)
2.75.
Summary of Prostate Volume Change from Baseline (At Visit)
2.76.
Summary of Prostate Volume Percentage Change from Baseline (LOCF)
2.77.
Summary of Prostate Volume Percentage Change from Baseline (At Visit)
2.78.
Summary of Prostate Volume Percentage Change-from-Baseline Categories (LOCF)
2.79.
Summary of Prostate Volume Percentage Change-from-Baseline Categories (At Visit)
2.80.
Summary of Prostate Volume Percentage Change from Baseline, by Age (<65, ≥65 years) (LOCF)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.81.
Summary of Prostate Volume Percentage Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.82.
Summary of Prostate Volume Percentage Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.83.
Summary of Prostate Volume Percentage Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.84.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.85.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.86.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.87.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.88.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.89.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.90.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.91.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
2.92.
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.93.
Summary of Prostate Volume Percentage Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.94.
Summary of Prostate Volume Percentage Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.95.
Summary of Prostate Volume Percentage Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.96.
Summary of Prostate Volume Percentage Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.97.
Summary of Prostate Volume Percentage Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
2.98.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
2.99.
Summary of Prostate Volume Percentage Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.100.
Summary of Prostate Volume Percentage Change from Baseline, by Country (LOCF)
2.101.
Summary of Prostate Volume Percentage Change from Baseline, by Country (At Visit)
Note: Prostate volume percentage change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
Qmax
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.102.
Summary of Qmax at Screening and Baseline
2.103.
Summary of Qmax at Each Post-Baseline Visit (LOCF)
2.104.
Summary of Qmax at Each Post-Baseline Visit (At Visit)
2.105.
Summary of Qmax Change from Baseline (LOCF)
2.106.
Summary of Qmax Change from Baseline (At Visit)
2.107.
Summary of Qmax Change from Baseline Categories (LOCF)
2.108.
Summary of Qmax Change from Baseline Categories (At Visit)
2.109.
Summary of Qmax Percentage Change from Baseline (LOCF)
2.110.
Summary of Qmax Percentage Change from Baseline (At Visit)
2.111.
Summary of Qmax Percentage Change from Baseline Categories (LOCF)
2.112.
Summary of Qmax Percentage Change from Baseline Categories (At Visit)
2.113.
Summary of Qmax Change from Baseline, by Age (<65, ≥65 years) (LOCF)
2.114.
Summary of Qmax Change from Baseline, by Age (<65, ≥65 years) (At Visit)
2.115.
Summary of Qmax Change from Baseline, by Age (<75, ≥75 years) (LOCF)
2.116.
Summary of Qmax Change from Baseline, by Age (<75, ≥75 years) (At Visit)
2.117.
Summary of Qmax Change from Baseline, by Baseline IPSS (<20, ≥20) (LOCF)
2.118.
Summary of Qmax Change from Baseline, by Baseline IPSS (<20, ≥20) (At Visit)
2.119.
Summary of Qmax Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (LOCF)
2.120.
Summary of Qmax Change from Baseline, by Baseline BPH-Related Health Status (<4, ≥4) (At Visit)
2.121.
Summary of Qmax Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (LOCF)
2.122.
Summary of Qmax Change from Baseline, by Baseline Prostate Volume (<40, ≥40cc) (At Visit)
2.123.
Summary of Qmax Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (LOCF)
2.124.
Summary of Qmax Change from Baseline, by Baseline Qmax (<10, ≥10ml/sec) (At Visit)
 
 
 
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Efficacy Tables  (Population=ITT)
No.
Title
2.125.
Summary of Qmax Change from Baseline, by Alpha-Blocker History (yes, no) (LOCF)
2.126.
Summary of Qmax Change from Baseline, by Alpha-Blocker History (yes, no) (At Visit)
2.127.
Summary of Qmax Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (LOCF)
2.128.
Summary of Qmax Change from Baseline, by 5-Alpha-Reductase Inhibitor History (yes, no) (At Visit)
2.129.
Summary of Qmax Change from Baseline, by Phytotherapy History (yes, no) (LOCF)
2.130.
Summary of Qmax Change from Baseline, by Phytotherapy History (yes, no) (At Visit)
2.131.
Summary of Qmax Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (LOCF)
2.132.
Summary of Qmax Change from Baseline, by Baseline PSA (<3,  ≥3ng/ml) (At Visit)
2.133.
Summary of Qmax Change from Baseline, by Country (LOCF)
2.134.
Summary of Qmax Change from Baseline, by Country (At Visit)
Note: Qmax  change from baseline summaries by center are output in Non-ICH Listings rather than in Tables.
 
 
 
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AUR or BPH-Related Surgery
2.135.
Summary of Time to AUR or BPH-Related Surgery
2.136.
Summary of Time to AUR or BPH-Related Surgery by Quarter
2.137.
Summary of AUR or BPH-Related Surgery
2.138.
Summary of Effect of Various Factors on Time to AUR or BPH-Related Surgery
2.139.
Summary of Hospitalization for AUR or BPH-Related Surgery
2.140.
Summary of Time from Treatment Stop to AUR or BPH-Related Surgery
2.141.
Summary of Time to First AUR
2.142.
Summary of Time to First AUR by Quarter
2.143.
Summary of AUR
2.144.
Summary of Hospitalization for AUR
2.145.
Summary of Time to BPH-Related Surgery
2.146.
Summary of Time to BPH-Related Surgery by Quarter
2.147.
Summary of BPH-Related Surgery
2.148.
Summary of Hospitalization for BPH-Related Surgery
2.149.
Summary of Prostatic Surgery
Other Efficacy Measures
2.150.
Summary of Urinary Tract Infection / Urosepsis
2.151.
Summary of Urinary Incontinence
2.152.
Summary of Renal Insufficiency
 
 
 
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11.15.4.
Efficacy Figures
Efficacy Figures  (Population=ITT)
No.
Title
IPSS
2.1.
Figure of IPSS Adjusted Mean Change from Baseline (LOCF)
2.2.
Figure of IPSS Adjusted Mean Change from Baseline (At Visit)
Prostate Volume
2.3.
Figure of Prostate Volume Adjusted Mean Percentage Change from Baseline (LOCF)
2.4.
Figure of Prostate Volume Adjusted Mean Percentage Change from Baseline (At Visit)
Qmax
2.5.
Figure of Qmax Adjusted Mean Change from Baseline (LOCF)
2.6.
Figure of Qmax Adjusted Mean Change from Baseline (At Visit)
AUR or BPH-Related Surgery
2.7.
Plot of Kaplan-Meier Estimates of Time to First AUR or BPH-Related Surgery
2.8.
Plot of Kaplan-Meier Estimates of Time to First AUR
2.9.
Plot of Kaplan-Meier Estimates of Time to First BPH-Related Surgery
11.15.5.
Safety Tables
Safety
3.1
Summary of Adverse Events Starting Post-randomization by Type
3.2
Summary of Adverse Events Starting Post-randomization
3.3
Summary of Adverse Events Starting On-Treatment
3.4
Summary of Adverse Events Starting Post-Treatment
3.5
Summary of Non-serious Adverse Events Starting Post-randomization
3.6
Summary of Adverse Events Starting Post-randomization by Time Period of Onset
3.7
Summary of Adverse Events Starting Post-randomization by Age Group (<65, ≥65)
3.8
Summary of Adverse Events Starting Post-randomization by Age Group (<75, ≥75)
 
 
 
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3.9
Summary of Adverse Events Starting Post-randomization by Country
3.10
Summary of Adverse Events Starting Post-randomization by Descending Frequency
3.11
Summary of Serious Adverse Events Starting Post-randomization by Descending 
Frequency
3.12
Summary of Non-serious Adverse Events Starting Post-randomization by 
Descending Frequency
3.13
Summary of Adverse Events Starting On-Treatment (Study Drug Exposure Basis)
3.14
Summary of Adverse Events Starting On-Treatment by Time Period (Study Drug 
Exposure Basis)
3.15
Summary of Adverse Events Starting Post-Randomization by Maximum Intensity
3.16
Summary of Most Common Adverse Events Starting Post-Randomization
3.17
Summary of Most Common Nonserious Adverse Events Starting Post-
Randomization
3.18
Summary of Drug-related Adverse Events Starting Post-randomization
3.19
Summary of Drug-related Adverse Events Starting On-treatment
3.20
Summary of Drug-related Adverse Events Starting Post-treatment
3.21
Summary of Drug-related Adverse Events Starting Post-randomization by Time 
Period of Onset
3.22
Summary of Drug-related Adverse Events Starting Post-randomization by Age Group 
(<65, ≥65)
3.23
Summary of Drug-related Adverse Events Starting Post-randomization by Age Group 
(<75, ≥75)
3.24
Summary of Drug-related Adverse Events Starting Post-randomization by Country
3.25
Summary of Serious Adverse Events Starting Post-randomization
3.26
Summary of Serious Adverse Events Starting On-treatment
3.27
Summary of Serious Adverse Events Starting Post-treatment
3.28
Summary of Serious Adverse Events Starting Post-randomization by Time Period of 
Onset
3.29
Summary of Serious Adverse Events Starting Post-randomization by Age Group 
(<65, ≥65)
3.30
Summary of Serious Adverse Events Starting Post-randomization by Age Group 
(<75, ≥75)
3.31
Summary of Serious Adverse Events Starting Post-randomization by Country
 
 
 
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3.32
Summary of Drug-related Serious Adverse Events Starting Post-randomization
3.33
Summary of Fatal Adverse Events Starting Post-randomization
3.34
Summary of Drug-related Fatal Adverse Events Starting Post-randomization
3.35
Summary of Adverse Events Starting Post-randomization Leading to Withdrawal 
from the Study
3.36
Summary of Drug-related Adverse Events Starting Post-randomization Leading to 
Withdrawal from the Study
3.37
Summary of Serious Adverse Events Starting Post-randomization Leading to 
Withdrawal from the Study
3.38
Summary of Adverse Events Starting Post-randomization Leading to Permanent 
Discontinuation of the Study Drug
3.39
Summary of Drug-related Adverse Events Starting Post-randomization Leading to 
Permanent Discontinuation of the Study Drug
3.40
Summary of Serious Adverse Events Starting Post-randomization Leading to 
Permanent Discontinuation of the Study Drug
3.41
Summary of Sexual and Breast Adverse Events of Special Interest Starting Post-
randomization
3.42
Summary of Special Interest Adverse Events Starting Post-randomization: Altered 
(Decreased) Libido
3.43
Summary of Special Interest Adverse Events Starting Post-randomization: Impotence
3.44
Summary of Special Interest Adverse Events Starting Post-randomization: 
Ejaculation Disorders
3.45
Summary of Special Interest Adverse Events Starting Post-randomization: Breast 
Disorders
3.46
Summary of Special Interest Adverse Events Starting Post-randomization: Breast 
Disorders: Breast Enlargement
3.47
Summary of Special Interest Adverse Events Starting Post-randomization: Breast 
Disorders: Breast Tenderness
3.48
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics: Altered (Decreased) Libido
3.49
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics: Impotence
 
 
 
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3.50
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics: Ejaculation Disorders
3.51
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics : Breast Disorders
3.52
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics: Breast Disorders: Breast Enlargement
3.53
Summary of Special Interest Adverse Events Starting Post-randomization By 
Baseline Characteristics: Breast Disorders: Breast Tenderness
3.54
Summary of Special Interest Sexual and Breast Adverse Events Starting Post-
randomization
3.55
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study 
Withdrawal
3.56
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study 
Withdrawal: Altered (Decreased) Libido
3.57
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study 
Withdrawal: Impotence
3.58
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study 
Withdrawal: Ejaculation Disorders
3.59
Summary of Sexual and Breast Adverse Events of Special Interest Leading to Study 
Withdrawal: Breast Disorders
3.60
Summary of Special Interest Adverse Events Starting Post-randomization: Prostate 
Cancer
3.61
Summary of Cardiovascular Adverse Events of Special Interest Starting Post-
randomization
3.62
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Acute Coronary Syndrome 
3.63
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Ischemic Cerebrovascular Events 
3.64
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Cardiac Failure 
3.65
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Ischemic Coronary Artery Disorders/Atherosclerosis 
 
 
 
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3.66
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization : Cardiac Arrythmia 
3.67
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Peripheral Vascular Disease 
3.68
Summary of Special Interest Cardiovascular Adverse Events Starting Post-
randomization: Cardiovascular Events
3.69
Summary of Infrequent Tier 1 Adverse Events of Special Interest Starting Post-
randomization   
3.70
Summary of Laboratory Data
3.71
Summary of Change from Baseline Laboratory Data
3.72
Summary of Baseline Abnormal Laboratory Values
3.73
Summary of Shift in Laboratory Values: Normal at Baseline to Abnormal at Any Time 
Post-baseline
3.74
Summary of Shift in Laboratory Values: Normal at Baseline to High at Any Time 
Post-baseline
3.75
Summary of Shift in Laboratory Values: Normal at Baseline to Low at Any Time Post-
baseline
3.76
Summary of Shift in Laboratory Values: Normal or Low at Baseline to High at Any 
Time Post-baseline
3.77
Summary of Shift in Laboratory Values: Normal or High at Baseline to Low at Any 
Time Post-baseline
3.78
Summary of Laboratory Data Transitions: Change From Baseline to Final 
Assessment
3.79
Summary of Baseline Threshold Laboratory Values
3.80
Summary of Threshold Laboratory Values at Any Time Post-baseline
3.81
Summary of Baseline Total PSA Values (ng/ml)
3.82
Summary of Total PSA (ng/ml) at Post-Baseline Visits (LOCF)
3.83
Summary of Total PSA (ng/ml) at Post-Baseline Visits (At Visit)
3.84
Summary of Total PSA Change From Baseline (ng/ml) (LOCF)
3.85
Summary of Total PSA Change From Baseline (ng/ml) (At Visit)
3.86
Summary of Total PSA Percentage Change From Baseline (LOCF)
3.87
Summary of Total PSA Percentage Change From Baseline (At Visit)
3.88
Summary of Post Void Residual Volume at Screening and Baseline
 
 
 
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3.89
Summary of Post Void Residual Volume at Each Post-Baseline Visit (LOCF)
3.90
Summary of Post Void Residual Volume at Each Post-Baseline Visit (At Visit)
3.91
Summary of Post Void Residual Volume Change from Baseline (LOCF)
3.92
Summary of Post Void Residual Volume Change from Baseline (At Visit)
3.93
Summary of Post Void Residual Volume Percentage Change from Baseline  (LOCF)
3.94
Summary of Post Void Residual Volume Percentage Change from Baseline (At Visit)
3.95
Summary of Gynecomastia Evaluation
3.96
Summary of Change from Baseline Gynecomastia Evaluation
3.97
Summary of Digital Rectal Examination
3.98
Summary of Change from Baseline Digital Rectal Examination
3.99
Summary of Vital Signs
3.100
Summary of Change from Baseline Vital Signs
3.101
Summary of Vital Signs Exceeding Threshold at Baseline
3.102
Summary of Vital Signs Exceeding Threshold at Any Post-Baseline Visit
3.103
Summary of C-SSRS Data
3.104
Listing of C-SSRS Data for Subjects With Suicidal Ideation and/or Behavior
 
 
 
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11.15.6.
Safety Figures
3.1
Plot of Study Drug Exposure
3.2
Plot of Power to Detect a Difference in Adverse Event Rate for Combination 
versus Tamsulosin
3.3
Most Common Adverse Events Sorted by Odds Ratio
3.4
Plot of Kaplan-Meier Estimates of Time to First Altered (Decreased) Libido 
Adverse Event
3.5
Plot of Kaplan-Meier Estimates of Time to First Impotence Adverse Event
3.6
Plot of Kaplan-Meier Estimates of Time to First Ejaculation Disorder Adverse 
Event
3.7
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder Adverse 
Event
3.8
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder: Breast 
Enlargement Adverse Event
3.9
Plot of Kaplan-Meier Estimates of Time to First Breast Disorder: Breast 
Tenderness Adverse Event
3.10
Plot of Kaplan-Meier Estimates of Time to First Prostate Cancer Adverse 
Event
3.11
Plot of Kaplan-Meier Estimates of Time to First Acute Coronary Syndrome  
Adverse Event
3.12
Plot of Kaplan-Meier Estimates of Time to First Ischemic Cerebrovascular 
Adverse Event
3.13
Plot of Kaplan-Meier Estimates of Time to First Cardiac Failure Adverse Event
3.14
Plot of Kaplan-Meier Estimates of Time to First Ischemic Coronary Artery 
Disorders/Atherosclerosis Adverse Event
3.15
Plot of Kaplan-Meier Estimates of Time to First Cardiac Arrythmia Adverse 
Event
3.16
Plot of Kaplan-Meier Estimates of Time to First Peripheral Vascular Disease 
Adverse Event
 
 
 
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3.17
Plot of Kaplan-Meier Estimates of Time to First Cardiovascular Adverse Event
3.18
Plot of Kaplan-Meier Estimates of Time to Death
 
 
 
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11.15.7.
Health Outcome Tables
Health Outcomes Tables  (Population=ITT)
No.
Title
BII Overview and Primary Analysis
4.1
Summary of BII Imputations
4.2
Summary of BII at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Month n (3, 6, …24) 
4.3
Summary of BII at Each Post-Baseline Visit (LOCF)
4.4
Summary of BII at Each Post-Baseline Visit (At Visit)
4.5
Summary of BII Change from Baseline (LOCF)
4.6
Summary of BII Change from Baseline (At Visit)
Individual BII Questions 1 - 4
4.7
Summary of BII at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Months 12 and 24
4.8
Summary of BII: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
4.9
Summary of BII: Question 1 (At Visit)
4.10
Summary of BII Change from Baseline: Question 1 (LOCF)
4.11
Summary of BII Change from Baseline: Question 1 (At Visit)
4.12
Summary of BII at Screening and Baseline: Question 2
4.13
Summary of BII: Question 2 (LOCF)
4.14
Summary of BII: Question 2 (At Visit)
4.15
Summary of BII Change from Baseline: Question 2 (LOCF)
4.16
Summary of BII Change from Baseline: Question 2 (At Visit)
4.17
Summary of BII at Screening and Baseline: Question 3
4.18
Summary of BII: Question 3 (LOCF)
4.19
Summary of BII: Question 3 (At Visit)
4.20
Summary of BII Change from Baseline: Question 3 (LOCF)
 
 
 
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Health Outcomes Tables  (Population=ITT)
No.
Title
4.21
Summary of BII Change from Baseline: Question 3 (At Visit)
4.22
Summary of BII at Screening and Baseline: Question 4
4.23
Summary of BII: Question 4 (LOCF)
4.24
Summary of BII: Question 4 (At Visit)
4.25
Summary of BII Change from Baseline: Question 4 (LOCF)
4.26
Summary of BII Change from Baseline: Question 4 (At Visit)
BII Percentage Change from Baseline
4.27
Summary of BII Percentage Change from Baseline (LOCF)
4.28
Summary of BII Percentage Change from Baseline (At Visit)
BII Non-Imputed Score Analysis
Performed only if RAP Section 11.7 imputation conditions are met; thus, table numbers are not listed.
BPH-Related Health Status
4.29
Summary of BPH-Related Health Status at Screening and Baseline  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with BII at each Month n (3, 6, 
…24) 
4.30
Summary of BPH-Related Health Status at Each Post-Baseline Visit (LOCF)
4.31
Summary of BPH-Related Health Status at Each Post-Baseline Visit (At Visit)
4.32
Summary of BPH-Related Health Status Change from Baseline (LOCF)
4.33
Summary of BPH-Related Health Status Change from Baseline (At Visit)
4.34
Summary of BPH-Related Health Status Percentage Change from Baseline (LOCF)
4.35
Summary of BPH-Related Health Status Percentage Change from Baseline (At Visit)
PAS SFI Overview and Primary Analysis
4.36
Summary of PAS SFI Imputations
4.37
Summary of PAS SFI at Screening and Baseline  includes Visit 1b, Visit 2, Baseline, Baseline for Subjects with PAS SFI at each Month n (12 and 24) 
4.38
Summary of PAS SFI at Each Post-Baseline Visit (LOCF)
 
 
 
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Health Outcomes Tables  (Population=ITT)
No.
Title
4.39
Summary of PAS SFI at Each Post-Baseline Visit (At Visit)
4.40
Summary of PAS SFI Change from Baseline (LOCF)
4.41
Summary of PAS SFI Change from Baseline (At Visit)
Individual PAS SFI Questions 1 - 3
4.42
Summary of PAS SFI at Screening and Baseline: Question 1  includes Visit 1a, Visit 2, Baseline, Baseline for Subjects with PAS SFI at each Months 12 and 
24
4.43
Summary of PAS SFI: Question 1 (LOCF)    each of the below individual question summaries is in terms of Months 12 and 24 only.
4.44
Summary of PAS SFI: Question 1 (At Visit)
4.45
Summary of PAS SFI Change from Baseline: Question 1 (LOCF)
4.46
Summary of PAS SFI Change from Baseline: Question 1 (At Visit)
4.47
Summary of PAS SFI at Screening and Baseline: Question 2
4.48
Summary of PAS SFI: Question 2 (LOCF)
4.49
Summary of PAS SFI: Question 2 (At Visit)
4.50
Summary of PAS SFI Change from Baseline: Question 2 (LOCF)
4.51
Summary of PAS SFI Change from Baseline: Question 2 (At Visit)
4.52
Summary of PAS SFI at Screening and Baseline: Question 3
4.53
Summary of PAS SFI: Question 3 (LOCF)
4.54
Summary of PAS SFI: Question 3 (At Visit)
4.55
Summary of PAS SFI Change from Baseline: Question 3 (LOCF)
4.56
Summary of PAS SFI Change from Baseline: Question 3 (At Visit)
 
 
 
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11.15.8.
Health Outcomes Figures
Health Outcomes Figures  (Population=ITT)
No.
Title
4.1
Plot of BII Adjusted Mean Change from Baseline (LOCF)
4.2
Plot of BII Adjusted Mean Change from Baseline (At Visit)
4.3
Plot of BPH-Related Health Status Adjusted Mean Change from Baseline (LOCF)
4.4
Plot of BPH-Related Health Status Adjusted Mean Change from Baseline (At Visit)
11.15.9.
ICH and Non-ICH Listings
The following categorizes data listings as ICH (International Conference on Harmonization) used to support critical analyses or non-ICH. 
The two classifications are assigned with consideration for general regulatory requirements across countries at point of RAP finalization. 
Changes to these classifications may occur at point of reporting as a result of specific country requirements or requests and will not result 
in a RAP revision.
ICH
Non-ICH
Title
Study Population
-
5.1
Listing of Subject Withdrawals During Placebo Run-in Phase
1.1
Listing of Randomized and Actual Treatments
1.2
Listing of Subject Accountability
1.3
Listing of Reasons for Study Withdrawal
1.4
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
1.5
Listing of Important Protocol Deviations
1.6
Listing of Deviations which Require Exclusion from the Per-Protocol Population
1.7
Listing of Demographic Characteristics
 
 
 
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ICH
Non-ICH
Title
1.8
Listing of Race Details
5.2
Listing of Substance Use at Screening
5.3
Listing of Medical Conditions at Screening
5.4
Listing of Sexual Function at Screening
5.5
Listing of Family History of Premature Coronary Artery Disease
5.6
Listing of Electrocardiogram Results
5.7
Listing of BPH History
5.8
Listing of Alpha-Blocker, 5-Alpha-Reductase Inhibitor, and Phytotherapy Usage History
5.9
Listing of Family History of Breast Cancer and Prostate Cancer 
1.9
Listing of Concomitant Medications  
1.10
Listing of Relationship Between ATC Level 1, Ingredient, and Verbatim Text 
1.11
Listing of Investigational Product Discontinuation
1.12
Listing of Exposure to Study Drug
5.10
Listing of Study Drug Dispensing
1.13
Listing of Study Drug Compliance
1.14
Listing of Subjects for Whom the Treatment Blind was Broken During the Study
 
 
 
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ICH
Non-ICH
Title
Efficacy Listings
IPSS
2.1
Listing of IPSS
5.11
Listing of IPSS MMRM Analysis: SAS Output
5.12
Listing of IPSS Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (LOCF)
5.13
Listing of IPSS Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (At Visit)
5.14
Listing of IPSS Change from Baseline Subgroup Analyses: SAS Output for Month 24 (LOCF)
5.15
Listing of IPSS Change from Baseline Subgroup Analyses: SAS Output for Month 24 (At Visit)
5.16
Summary of IPSS Change from Baseline by Center for Months 12 and 24 (LOCF)  Note, this LOCF table and below At Visit table are in 
Non-ICH listing rather than a table due to high number of centers, many with low enrollment. Output can be moved at point of CSR if 
necessary.
5.17
Summary of IPSS Change from Baseline by Center for Months 12 and 24 (At Visit) 
Prostate Volume
2.2
Listing of Prostate Volume
5.18
Listing of Prostate Volume Percentage Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (LOCF)
5.19
Listing of Prostate Volume Percentage Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (At Visit)
5.20
Listing of Prostate Volume Percentage Change from Baseline Subgroup Analyses: SAS Output for Month 24 (LOCF)
5.21
Listing of Prostate Volume Percentage Change from Baseline Subgroup Analyses: SAS Output for Month 24 (At Visit)
5.22
Summary of Prostate Volume Percentage Change from Baseline by Center for Months 12 and 24 (LOCF)
5.23
Summary of Prostate Volume Percentage Change from Baseline by Center for Months 12 and 24 (At Visit) 
Qmax
 
 
 
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ICH
Non-ICH
Title
2.3
Listing of Subjects with Voided Volume less than 125ml
2.4
Listing of Qmax and Voided Volume
5.24
Listing of Qmax Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (LOCF)
5.25
Listing of Qmax Change from Baseline GLM and Diagnostics: SAS Output for Month 24 (At Visit)
5.26
Listing of Qmax Change from Baseline Subgroup Analyses: SAS Output for Month 24 (LOCF)
5.27
Listing of Qmax Change from Baseline Subgroup Analyses: SAS Output for Month 24 (At Visit)
5.28
Summary of Qmax Change from Baseline by Center for Months 12 and 24 (LOCF)
5.29
Summary of Qmax Change from Baseline by Center for Months 12 and 24 (At Visit) 
2.5
Listing of Biannual Follow-Up Telephone Contacts
2.6
Listing of Subjects with AUR
2.7
Listing of Subjects with Prostatic Surgery
2.8
Listing of Subjects with Non-Surgical Intervention for BPH
5.30
Listing of Time to First AUR or BPH-Related Surgery Event
5.31
Listing of Analysis of Time to First AUR or BPH-Related Surgery: SAS Output
5.32
Listing of Time to First AUR
5.33
Listing of Analysis of Time to First AUR: SAS Output
5.34
Listing of Time to First BPH-Related Surgery Event
5.35
Listing of Analysis of Time to First BPH-Related Surgery: SAS Output
5.36
Listing of Subjects With Urinary Tract Infection / Urosepsis
5.37
Listing of Subjects With Urinary Incontinence
5.38
Listing of Subjects With Renal Insufficiency
 
 
 
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ICH
Non-ICH
Title
Safety
3.1
Listing of Relationship between System Organ Class and Verbatim Text
3.2
Listing of All Adverse Events
3.3
Listing of All Adverse Events by Onset Period
3.4
Listing of Subject Numbers for Specific Adverse Events
3.5
Listing of Fatal Adverse Events
3.6
Listing of Non-Fatal Serious Adverse Events
3.7
Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug
3.8
Listing of Adverse Events Leading to Withdrawal from the Study
3.9
Listing of Possible Suicidality-Related Adverse Event Data: Event and Description (Section 1 - Section 2)
3.10
Listing of Possible Suicidality-Related Adverse Event Data: Possible Cause(s)  (Section 3)
3.11
Listing of Possible Suicidality-Related Adverse Event Data (Section 4)
3.12
Listing of Possible Suicidality-Related Adverse Event Data (Section 5 – Section 8)
3.13
Listing of Relationship between Special Interest Adverse Events and Verbatim Text
3.14
Listing of Adverse Events of Special Interest
5.39
Listing of Sexual and Breast Adverse Events of Special Interest Leading to Study Withdrawal
5.40
Listing of Targeted Followup Questionnaire Data
3.15
Listing of Pregnancies in Female Partners of Male Study Participants
5.41
Listing of Clinical Chemistry Data
5.42
Listing of Hematology Data
3.16
Listing of Clinical Chemistry Data Exceeding Threshold
3.17
Listing of Hematology Data Exceeding Threshold
5.43
Listing of Baseline HBsAg and Hepatitis C Antibody Data
5.44
Listing of Serum PSA Data
 
 
 
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ICH
Non-ICH
Title
3.18
Listing of Serum PSA Data Exceeding Upper Limit of Normal
3.19
Listing of Subjects with ALT ≥3 times ULN and Bilirubin ≥2 times ULN
5.45
Listing of Post Void Residual Volume
5.46
Listing of Gynecomastia Data
5.47
Listing of Digital Rectal Examination Data
5.48
Listing of Vital Signs Data
3.20
Listing of Vital Signs Exceeding Threshold
3.21
Listing of For-Cause Biopsy Results
5.49
Listing of C-SSRS Data
3.22
Listing of C-SSRS Suicidal Behavior Details for Subjects With Suicidal Behavior
3.23
Listing of Details of Most Severe Suicidal Ideation at Each C-SSRS  Assessment for Subjects With Suicidal Ideation
Health Outcomes
5.50
Listing of BPH Impact Index (BII)
5.51
Listing of BPH-Related Health Status
5.52
Listing of Problem Assessment Scale of the Sexual Function Inventory (PAS SFI)
 
 
 
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11.16.
Appendix 16: Mock Shells for Data Displays
Mock table shells are stored in IMMS, within same directory/cabinet as RAP, as separate 
documents.
 
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