Implementation of a Screening Tool for Subjects With Benign Prostatic Enlargement/Obstruction to Identify Men >=50 Years Presenting in General Practice With Other Co-morbidities Who Should be Assessed for BPH
Phase: PHASE4
Conditions: Prostatic Hyperplasia
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
FDC116114
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Implementation of a screening tool for subjects with benign 
prostatic enlargement/obstruction to identify men ≥50 years 
presenting in General Practice with other co-morbidities who 
should be assessed for BPH
Compound Number:
None
Development Phase:
NA
Effective Date:
18-JAN-2016
Protocol Amendment Number:  02
Author (s):
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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The GlaxoSmithKline group of companies
FDC116114
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2012N140248_00
2015-SEP-30
Original
2012N140248_01
2015-DEC-02
Amendment No. 1

Deletion of compound numbers on the title page and the entering of “None”.

Deletion of the development status on the title page and entering “NA”.

Changing the study to an interventional study from non-interventional (Section 4).

Deletion of the collection of race and ethnicity (Section 6.2).
2012N140248_02
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Amendment No. 2

Clarification of digital rectal exam throughout the protocol.

Addition of criteria for probable BPH (Study 4).

Addition to concomitant medications - exclusion criteria (Section 5.2.).

Addition of footnotes to Time and Events Table. (Section 6.1.).

Deletion of text referring to GSK product. (Section 6.3.1.1. and Section 6.3.1.3.).
 
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Mobile/
Pager Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
MD
Mobile:
Email: 
Mobile: 
N/A
GlaxoSmithKline
(GSK)
5 Moore Drive, PO 
Box 13398, RTP, 
NC 27709-3398, 
United States
Secondary 
Medical 
Monitor
Mobile:
Phone:
Email: 
Mobile:
N/A
Istanbul, Turkey
SAE 
contact 
information 
Medical 
monitor as 
above: 
 
MD
Mobile:
Email: 
Mobile
N/A
GSK
5 Moore Drive, PO 
Box 13398, RTP, 
NC 27709-3398, 
United States
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number FDC116114
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY FDC116114.................................................8
2.
INTRODUCTION....................................................................................................10
2.1.
Study Rationale ..........................................................................................10
2.2.
Brief Background ........................................................................................11
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................12
4.
STUDY DESIGN ....................................................................................................12
4.1.
Overall Design ............................................................................................13
4.2.
Treatment Arms and Duration.....................................................................16
4.3.
Type and Number of Subjects.....................................................................17
4.4.
Design Justification.....................................................................................17
4.5.
Dose Justification........................................................................................17
4.6.
Benefit:Risk Assessment ............................................................................17
4.6.1.
Risk Assessment .........................................................................18
4.6.2.
Benefit Assessment.....................................................................19
4.6.3.
Overall Benefit:Risk Conclusion...................................................19
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............19
5.1.
Inclusion Criteria.........................................................................................19
5.2.
Exclusion Criteria........................................................................................20
5.3.
Screening/Baseline/Run-in Failures............................................................20
5.4.
Withdrawal/Stopping Criteria.......................................................................21
5.5.
Subject and Study Completion....................................................................21
5.6.
Concomitant Medications and Non-Drug Therapies....................................21
5.6.1.
Permitted Medications and Non-Drug Therapies..........................21
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................21
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................22
6.1.
Time and Events Table...............................................................................23
6.2.
Screening and Critical Baseline Assessments ............................................24
6.3.
Safety .........................................................................................................24
6.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........24
6.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................24
6.3.1.2.
Follow-up of AEs and SAEs........................................25
6.3.1.3.
Regulatory Reporting Requirements for SAEs............25
6.3.2.
Physical Exams ...........................................................................25
6.3.3.
Clinical Safety Laboratory Assessments ......................................25
6.3.4.
Urine Sample Collection ..............................................................26
7.
DATA MANAGEMENT ...........................................................................................26
8.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................27
8.1.
Hypotheses.................................................................................................27
8.2.
Sample Size Considerations.......................................................................27
8.3.
Data Analysis Considerations .....................................................................27
 
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8.3.1.
Analysis Populations....................................................................27
8.3.2.
Interim Analysis ...........................................................................28
8.3.3.
Multiplicity....................................................................................28
8.4.
Key Elements of Analysis Plan ...................................................................28
8.4.1.
Population Descriptive Statistics..................................................28
8.4.2.
Primary Analyses.........................................................................28
8.4.3.
Secondary Analyses ....................................................................29
9.
STUDY GOVERNANCE CONSIDERATIONS........................................................30
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............30
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................30
9.3.
Quality Control (Study Monitoring) ..............................................................31
9.4.
Quality Assurance.......................................................................................31
9.5.
Study and Site Closure ...............................................................................32
9.6.
Records Retention......................................................................................32
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................33
10. REFERENCES.......................................................................................................34
11. APPENDICES........................................................................................................35
11.1.
Appendix 1 – Abbreviations and Trademarks..............................................35
11.2.
Appendix 2: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................36
11.2.1.
Definition of Adverse Events........................................................36
11.2.2.
Definition of Serious Adverse Events...........................................37
11.2.3.
Recording of AEs and SAEs ........................................................38
11.2.4.
Evaluating AEs and SAEs............................................................39
11.2.5.
Reporting of SAEs to GSK...........................................................40
11.3.
Appendix 3 - Country Specific Requirements..............................................42
11.4.
Appendix 4 – IPSS SCREENING TOOL.....................................................43
11.5.
Appendix 5 – SCREENER FOR PATIENTS WITH BENIGN 
PROSTATIC ENLARGEMENT/OBSTRUCTION (BPE/BPO)......................44
11.6.
Appendix 6 - Protocol Changes ..................................................................45
 
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1.
PROTOCOL SYNOPSIS FOR STUDY FDC116114
Rationale
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is that it may 
help a General Practitioners (GP) to identify patients who may have BPH for further tests 
and improve the speed of referrals to specialists when this is appropriate. Symptomatic 
BPH is present in 40 – 60% of men over the age of 50 and prevalence rises with age. It is 
known that men with LUTS may be reluctant to discuss these symptoms with their GP, 
and that GPs do not routinely proactively ask about LUTS when men present for other 
complaints.  As a result, many men with BPH present late with more severe symptoms.  
As a result up to 70% of men may have moderate to severe BPH at their initial diagnosis.
The recent D-IMPACT study confirmed that GPs can accurately diagnose BPH in around 
75% of men presenting with LUTS, using simple tests.  A Benign Prostatic Enlargement 
(BPE)/Benign Prostatic Obstruction (BPO) screening tool which identifies LUTS 
probably due to BPH in men not yet presenting with LUTS would provide an opportunity 
to proactively assess men who do not present with LUTS. BPH is a progressive condition 
and identifying men at risk of progression is important to allow their treatment to be 
optimised.  Furthermore the utility of the screening tool will be compared to the validated 
tool in wide clinical use, the International Prostate Symptom Score (IPSS).
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To assess the utility of a BPE/BPO screening 
tool in conjunction with serum prostate 
specific antigen (PSA) in finding men 
confirmed to have BPH on full urologist 
assessment of diagnostic test results.
Proportion of men that are confirmed to have 
BPH based on full urologist assessment of 
diagnostic test results among men with a 
positive result on the BPE/BPO screening 
tool (score ≥3) and serum PSA ≥2 ng/mL.
Secondary

To assess the utility of a BPE/BPO 
screening tool in conjunction with serum 
PSA in finding men with risk of BPH 
Progression on full urologist assessment of 
diagnostic test results.

To assess the utility of a BPE/BPO 
screening tool in finding men diagnosed with 
probable BPH as assessed by the GP.

Compare the utility of the BPE/BPO 
screening tool with the International Prostate 
Symptom Score (IPSS) screening tool.

Proportion of men that are confirmed to be a 
risk for BPH progression based upon full 
urologist assessment among men with a 
positive result on the BPE/BPO screening 
tool (score ≥3) and serum PSA ≥2 ng/mL.

Proportion of men that are diagnosed with 
probable BPH1 as assessed by the GP 
among men with a positive result on the 
BPE/BPO screening tool (score ≥3).

Agreement (using Kappa statistic for 
categories) between the BPE/BPO 
screening tool assessment (score ≥3) and 
an IPSS score approach (score ≥8) in 
selecting men to investigate for BPH).
1Probable BPH is the presumptive diagnosis of urinary tract obstruction from an enlarged prostate
based on clinical symptoms and findings where urinary symptoms are not apparently related to any 
other cause.
 
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Overall Design

This study will evaluate the utility of the Benign Prostatic Enlargement (BPE)/
Benign Prostatic Obstruction (BPO) screening tool in a general practice setting 
where the results of this screening tool will be used for further investigation. 
Therefore in this study, all men testing positive on the BPE/BPO screening tool 
(score ≥3) tool or on the IPSS (score ≥8) will be enrolled and offered a prostate 
specific antigen (PSA) test and urinalysis to establish a diagnosis of probable benign 
prostatic hyperplasia (BPH) (Part I – Visit 1).  The General Practitioner (GP) may 
perform a DRE (digital rectal examination), however the DRE will be repeated by 
the urologist to confirm the diagnosis and to rule out an abnormality suggesting 
prostate cancer.  The GP will make a diagnosis of probable BPH based upon 
screening results and lab tests which suggest that they are related to BPH and not 
other causes of such symptoms.

The GP will phone the subject to report yes or no for probable BPH Part II (Visit 2). 
If the subject has probable BPH, the GP will schedule the subject for Visit 3 with a 
urologist.  If the subject does not have probable BPH, then the subject has completed 
the study.

Subjects that proceed to Part II (Visit 3) will be scheduled for a urology assessment 
performed by a urologist.  This assessment includes a DRE and a brief physical exam 
and review of the PSA test, for a confirmatory diagnosis of BPH and estimation of 
risk of progression of BPH.
Treatment Arms and Duration

Approximately 1,500 males presenting to a GP with a primary complaint other than
LUTS will be screened for probable BPH to yield 500 subjects being referred to a 
urologist.

The duration of the study will be 1 week (4 days) and up to 6 weeks to allow for 
GP and urologist visit scheduling.

There is no study drug in this study.
Type and Number of Subjects

Approximately 1,500 males 50 years presenting to a GP for reasons unrelated to 
this study will be screened for probable BPH to yield 500 subjects being referred to a 
urologist.
Analysis

The primary endpoint is defined as the proportion of men that are confirmed to have 
BPH based on full urologist assessment of diagnostic test results among men with a 
positive result on the BPE/BPO screening tool and probable BPH diagnosis as 
assessed by the GP.  For this proportion, the numerator is number of subjects 
diagnosed with BPH by a urologist; denominator is number of subjects with a 
positive result on the BPE/BPO screening tool and a probable BPH assessment by 
 
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the GP and a BPH assessment by the urologist.  The 95% confidence interval for this 
proportion will be presented.

Sufficient general practice centres (50 consecutive men per centre) in various 
markets will be recruited to administer the BPE/BPO screening tool to 1,500 men 
(using protocol defined criteria) presenting to clinic for reasons unrelated to the 
study.  It is expected that 33% of the 1,500 presenting (or approximately 500) will
have a positive result on the BPE/BPO screening tool and a probable BPH 
assessment by GP and thus will be assessed by a urologist.

Due to the design of the study and types of endpoints incorporated, ‘observed cases’ 
will be summarized for a subset of subjects in study Parts I and II.  There will be no 
imputations for missing data or for discontinued subjects.

An interim analysis is not planned for this study.
2.
INTRODUCTION

This study will evaluate the utility of the Benign Prostatic Enlargement (BPE)/
Benign Prostatic Obstruction (BPO) screening tool in a general practice setting 
where the results of the BPE/BPO screening tool will be used for further 
investigation. Therefore in this study, all men testing positive with the BPE/BPO tool 
(score ≥3) and/or on the IPSS (score ≥8) will be enrolled and offered a prostate 
specific antigen (PSA) test and urinalysis to help establish a diagnosis of probable
benign prostatic hyperplasia (BPH) (Part I – Visit 1).  The GP may perform a DRE, 
however the DRE will be repeated by the urologist to confirm the diagnosis and to 
rule out an abnormality suggesting prostate cancer.  

The GP will phone the subject to report yes or no for probable benign prostatic 
hyperplasia (BPH) Part II (Visit 2). If the subject has probable BPH, the GP will 
schedule the subject for Visit 3 with a urologist. If the subject does not have probable 
BPH, then the subject has completed the study.

For those subjects that proceed to Part II (Visit 3) they will be scheduled for a 
urology assessment performed by a urologist. This assessment includes DRE and a 
brief physical exam with review of the PSA test, for a confirmatory diagnosis of 
BPH and estimation of risk of progression of BPH.
2.1.
Study Rationale
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to BPH is that it may help a GP to identify patients 
who may have BPH for further tests and improve the speed of referrals to specialists 
when this is appropriate. Symptomatic BPH is present in 40 – 60% of men over the age 
of 50 and prevalence rises with age (Emberton, 2003). It is known that men with lower 
urinary tract symptoms (LUTS) may be reluctant to discuss these symptoms with their 
GP , and that GPs do not routinely proactively ask about LUTS when men present for 
other complaints.  As a result, many men with BPH present late with more serve 
symptoms. As a result, up to 70% of men may have moderate to severe BPH at their 
initial diagnosis. The recent D-IMPACT study confirmed that GPs can accurately 
 
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diagnose BPH in around 75% of men presenting with LUTS, using simple tests 
(Carballido, 2011).  A simple screening tool which identifies LUTS probably due to BPH 
in men not yet presenting with LUTS would provide an opportunity to proactively 
identify and potentially treat men who do not present with LUTS as their primary 
complaint. It is important to identify BPH early.  BPH is a progressive condition and 
identifying men at risk of progression is important to allow their treatment to be 
optimised (Fitzpatrick, 2006).  Furthermore the utility of screening tool will be compared 
to a validated tool in wide clinical use, the International Prostate Symptom Score (IPSS).
2.2.
Brief Background
Symptomatic BPH is present in 40 – 60% of men over the age of 50 and prevalence rises 
with age (Emberton, 2003). It is known that men with LUTS may be reluctant to consult, 
and that GPs do not proactively ask about LUTS when men present for other co-
morbidities. As a result many men present late, and up to 70% of men may have 
moderate to severe BPH at diagnosis. Some of these men may have an increased prostate 
volume (>30 cc) and a prostate specific antigen (PSA) ≥1.5 ng/mL, and therefore be at 
risk of progression (Roehrborn, 2007). Under European Association of Urology (EAU)
guidelines, these men may be suitable for treatments targeted to the underlying cause of 
the disease.
The International Prostate Symptom Score (IPSS) score is well validated as a tool to 
assess the severity of LUTS symptoms, and has similarly been used for assessing 
symptomatic efficacy of treatments for BPH (Roehrborn, 2008). Nevertheless this tool 
was not developed as a diagnostic tool for BPH. Furthermore, GPs are reluctant to use the 
IPSS because it takes time away from other problems and extends the patient visit time 
and may require other staff to implement. An abbreviated diagnostic tool would therefore 
assist the GP in diagnosis and timely referral to a urologist.
A screening tool which identifies LUTS probably due to BPH in men presenting for 
reasons unrelated to the study would provide an opportunity to proactively assess men 
who may not consider presenting with these symptoms. BPH is a progressive condition 
and identifying men at risk of progression is important to allow their treatment to be 
optimised (Fitzpatrick, 2006).
 
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary
To assess the utility of a BPE/BPO 
screening tool in conjunction with PSA in 
finding men confirmed to have BPH on full 
urologist assessment of diagnostic test 
results.
Proportion of men that are confirmed to have 
BPH based on full urologist assessment of 
diagnostic test results among men with a 
positive result on the BPE/BPO screening 
tool and tool (score ≥3) and serum PSA 
≥2 ng/mL.
Secondary

To assess the utility of a BPE/BPO 
screening tool in conjunction with PSA in 
finding men with risk of BPH Progression on 
full urologist assessment of diagnostic test 
results.

To assess the utility of a BPE/BPO 
screening tool in finding men diagnosed with 
probable BPH as assessed by the GP.

Compare the utility of the BPE/BPO 
screening tool with the IPSS screening tool.

Proportion of men that are confirmed to be a 
risk for BPH progression based upon full 
urologist assessment among men with a 
positive result on the BPE/BPO screening 
tool and probable GP BPH diagnosis.

Proportion of men that are diagnosed with 
probable BPH1 as assessed by the GP 
among men with a positive result on the 
BPE/BPO screening tool (score ≥3).

Agreement (using Kappa statistic for 
categories) between the BPE/BPO 
screening tool assessment (score ≥3) and 
an IPSS score approach (score ≥8) in 
selecting men to investigate for BPH.
1 Probable BPH is the presumptive diagnosis of urinary tract obstruction from an enlarged 
prostate based on clinical symptoms and findings where urinary symptoms are not 
apparently related to any other cause.
4.
STUDY DESIGN
This non-randomized, interventional study utilizing a questionnaire-based assessment of 
men in General Practice. Validation of the tool was performed in a previous 
GlaxoSmithKline (GSK) study (FDC116700: Quick Question Tool Development and 
Linguistic Validation). Men who sign the informed consent form and meet the eligibility 
criteria will be enrolled and complete the Part I diagnostic tests at the GP clinic.  If the 
GP determines that the subject has probable BPH (IPSS ≥8 and/or BPE/BPO 
questionnaire ≥3 with a PSA ≥2 ng/ml), the subject proceeds to Part II and is scheduled 
for a urologist assessment and diagnostic tests to confirm or refute a BPH diagnosis and 
to assess risk of progression of BPH.
 
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4.1.
Overall Design
This study is intended to reproduce the circumstances in which the BPH quick tool will 
be used in General Practice, i.e., in men that may have ‘hidden’ LUTS symptoms. To 
reproduce these circumstances of opportunistic screening, men will not be invited to 
attend their GP but must attend spontaneously with for reasons that are not related to 
this study. At this point they will be invited to participate in the study.
GPs participating in the study will recruit men ≥50 years that present in their clinic for 
reasons that are not related to this study. 
After obtaining informed consent, the GP will initially assess all inclusion and exclusion 
criteria except for the questionnaire inclusion criterion.  If the subject meets those 
eligibility requirements, the GP administers the BPE/BPO and IPSS screening tools. 
Subjects who have a positive score on the BPE/BPO screening tool (total score 3) 
and/or the IPSS tool (score ≥8) and meet all other eligibility requirements will be enrolled 
in Part I of the study.  The GP then performs the following diagnostic tests for Part I of 
the study: urinalysis (sample sent to local lab if the strip test is positive) and Prostate 
Specific Antigen (PSA) blood test. If the serum PSA result is ≥2 ng/mL, the GP will 
make a diagnosis of ‘probable BPH (subjects with symptoms likely to be related to 
BPH)’ or not.  All men with ‘probable BPH’ will proceed to Part II and will be scheduled 
for Visit 3 with a urologist for confirmation of the GP’s findings plus a brief physical 
exam and DRE.  Additional testing may be performed as per standard of care to assist 
with a confirmatory diagnosis such as a DRE, however this is not required by the 
protocol.
The urologist is to:
1) Establish a clinical diagnosis of BPH
AND
2) Estimate whether the patient is at risk of progression of BPH (PSA ≥2.0 ng/mL 
and other testing).
For the purposes of this study the diagnosis of the urologist (BPH yes/no) is the 
operational definition of confirmed BPH. Those men refusing referral to the 
urologist, but considered by a GP to have BPH (after the tests specified above) 
will be classified as ‘probable BPH’.
 
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Description of Visits:
VISIT 1 (primary care clinic)

Males ≥50 years visiting GP for reasons unrelated to the study

Patient provides informed consent

Inclusion/exclusion criteria confirmation

Medical history and demography

BPE/BPO and IPSS screening tools
ENROLLED: Subject is enrolled and proceeds to Part I (GP 
Assessment) of the study.  If the GP diagnoses probable BPH, the 
subject will proceed to Part II (urologist assessment).
PART I: GP Assessment
After being enrolled, complete the following at Visit 1:

Urinalysis strip test.

If strip test is positive, send urine sample to local lab 
urinalysis.

PSA blood test

Additional testing may be performed as per standard of care to assist 
with a confirmatory diagnosis such as a DRE, however this is not 
required.
If subject meets entry criteria, 
including a positive IPSS (score 
≥8) and/or BPE/BPO (score 
≥3).
Eligible to participate
 
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VISIT 2 (telephone call)

GP reviews urinalysis and PSA lab results.

Call subject: If lab results show NO probable BPH, then subject 
will not continue in the study.  If PSA lab results show 
PROBABLE BPH (≥2 ng/mL), subject proceeds to Part II and Visit 
3 is scheduled for the urologist assessment.
 
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VISIT 3 (Part II – urologist clinic visit)

Urologist reviews medical history and symptoms

Brief physical examination

DRE

Review previous tests (BPE/BPO screening tool, IPSS screening 
tool, urinalysis, PSA)

NOTE: Urologist may need to perform additional diagnostic 
testing as per standard of care and as needed to assess the 
BPH diagnosis. This follow-up is not prescribed by this 
protocol, however, any data collected that is used for the final 
diagnosis will be entered in the study case report form (CRF).  
Advice or treatment post study will be discretion of the GP or 
Urologist. 
4.2.
Treatment Arms and Duration

Approximately 1,500 males presenting to a GP for a reason that is not related to this 
study will be screened for probable BPH to yield 500 subjects being referred to a 
urologist.

The duration of the study will be 1 week (4 days) and up to 6 weeks to allow for GP 
and urologist visit scheduling.
There is no study drug in this study.
Urologist provides:

Confirmation of clinical diagnosis of BPH 
(or confirmation the subject does NOT 
have BPH).

Estimate whether the patient is at risk of 
progression of BPH (PSA≥2.0ng/mL and 
other tests).
 
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4.3.
Type and Number of Subjects
Approximately 1,500 males presenting to a GP for reasons unrelated to this study will be 
screened for probable BPH to yield 500 subjects being referred to a urologist.
4.4.
Design Justification
The BPE/BPO screening tool has been developed using the currently recommended FDA 
guidelines (Food and Drug Administration, 2009) for developing patient-completed 
questionnaires such as Patient Reported Outcomes. The tool to be used in this study in the 
General Practice setting has undergone validation in a urology setting to demonstrate the 
validity of the tool in populations with and without a definite diagnosis of BPH (GSK 
Study FDC116700). The FDC116700 study demonstrated that the most effective have 
been observed by screening patients with BPE/BPO items with a threshold score ≥3 and 
then testing such patients with PSA. With total PSA greater than or equal to 2 the 
combination screener/PSA shows a sensitivity of 83.8% and a specificity of 74.0%, with 
an accuracy of 80.1%.
4.5.
Dose Justification
No investigational study drug will be used in this study.
4.6.
Benefit:Risk Assessment
The following section outlines the risk assessment and mitigation strategy for this 
protocol: 
 
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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Urine strip test
Routine and minimal risk
Serious adverse events (SAEs) are 
monitored via automated emails and adverse 
events (AEs) are reviewed on a routine basis 
to identify any procedure related events.
PSA blood test:
The risks of taking blood include pain, a 
bruise at the point where the blood is taken, 
redness and swelling of the vein and 
infection, and a rare risk of fainting.
Routine and minimal risk
SAEs are monitored via automated emails 
and AEs are reviewed on a routine basis to 
identify any procedure related events.
DRE:
Routine and minimal risk. Procedure used in 
evaluation for BPH.
SAEs are monitored via automated emails 
and AEs are reviewed on a routine basis to 
identify any procedure related events.
Urologist physical examination
Routine and minimal risk. Procedure used in 
evaluation for BPH.
Performed by a urologist.  
SAEs are monitored via automated emails 
and AEs are reviewed on a routine basis to 
identify any procedure related events.
 
 
 
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4.6.2.
Benefit Assessment
Subjects could benefit from this study by having the protocol-specified assessments and 
procedures performed.  It is possible that undiagnosed BPH could be identified.
4.6.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with the procedures to be performed in 
this study are justified by the anticipated benefits that may be afforded to subjects who 
may have undiagnosed BPH.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Informed Consent Form.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply: 
AGE
1. Greater than or equal to 50 (50) years of age at the time of signing the informed 
consent form.
SEX
2. Male
INFORMED CONSENT
3. Capable of giving signed informed consent as described in Section 9.2 which includes 
compliance with the requirements and restrictions listed in the consent form and in 
this protocol.
OTHER
4. Present in a General Practice setting for a reason unrelated to this study.
5. Positive IPSS score (8) and/or positive BPE/BPO screening tool score (≥3).
 
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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. History of BPH for which they have received test procedures, medical intervention 
and/or medicine.
2. History of prostate-related LUTS for which they have received test procedures, 
medical intervention and/or medicine.
3. History of prostatic surgery (including transurethral resection of the prostate [TURP], 
balloon dilatation, thermotherapy, and/or stent replacement) or other invasive or 
minimally invasive procedures to treat BPH.
4. Has other conditions that may cause urinary symptoms (e.g., neurogenic bladder, 
bladder neck contracture, urethral stricture, bladder malignancy, acute or chronic 
prostatitis, or acute or chronic urinary tract infections, etc.).
5. History or evidence of prostate cancer (e.g., positive biopsy or ultrasound, suspicious
DRE and/or rising PSA).
CONCOMITANT MEDICATIONS
6. Current or prior use of the following: 
a.
5α-reductase inhibitors (finasteride or dutasteride), 
b. anti-cholinergics (e.g. oxybutynin, propantheline, tolterodine, solifenacin, 
darifenacin, mirabegron) alpha-adrenoreceptor blockers (i.e., indoramin, 
prazosin, terazosin, tamsulosin, alfuzosin, doxazosin and silodosin), herbal 
products for urinary symptoms. 
c.
Use of any investigational study drug within 30 days or 5 half-lives of the 
drug in question, (whichever is longer), preceding the first study visit.
7. Use within previous 30 days at Visit 1 of:
a.
PDE-5 inhibitors for erectile dysfunction
b. anabolic steroids
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
do not meet eligibility criteria and are not subsequently enrolled. In order to ensure 
transparent reporting of screen failure subjects, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and respond to queries from 
Regulatory authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse Events (see 
Section 6.3.1.3).  Data for screen failures will be collected in source information at the 
site and will be transmitted to GSK.
 
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Subjects will be screen failures if they do not meet inclusion/exclusion criteria and do not 
have a qualifying score on at least one of the two questionnaires (BPE/BPO and/or IPSS 
screening tools).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he may request destruction 
of any samples taken, and the investigator must document this in the site study records. 
5.5.
Subject and Study Completion
A completed subject is one who has completed all study visits.
The end of the study is defined as the last subject’s last visit.
5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
All medications taken during the study will be recorded in the CRF with indication, dose 
information, and dates of administration.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Use of prohibited medications, as stated in the exclusion criteria, could potentially affect 
the value of the data collected. If there is no option other than to administer a prohibited 
medication, please if possible discuss the procedure with your monitor before 
administration.
 
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Prohibited medications:

5α-reductase inhibitors (finasteride or dutasteride), 

anti-cholinergics (e.g. oxybutynin, propantheline, tolterodine, solifenacin, 
darifenacin, mirabegron) alpha-adrenoreceptor blockers (i.e., indoramin, prazosin, 
terazosin, tamsulosin, alfuzosin, doxazosin and silodosin), herbal products for 
urinary symptoms.

PDE-5 inhibitors for erectile dysfunction

anabolic steroids
6.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 6.1
 
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6.1.
Time and Events Table
Procedure
VISIT 1:
Screening/
Enrolment at GP Clinic
Study Period
(1 week 4 days to 6 weeks)
VISIT 2 (phone call): 
GP
VISIT 3: Urologist6
(up to 6 weeks after V1)
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history
X
Concomitant medications (all ongoing and within 30 days prior to  
Visit 1)
X
IPSS screening tool
X
BPE/BPO screening tool
X
PROCEDURES AFTER SUBJECT IS ENROLLED1:
Urine strip test2
X
Urinalysis (only if urine strip test is positive)2
X
PSA blood test3
X
Results phone call to subject4
X
Digital rectal exam (DRE)5
X
X
Brief physical examination
X
Enter prostate-related results in the CRF from non-protocol required 
procedures
X
AE/SAE review (related to study procedures and/or participation)
==========================================
Concomitant medication review
==========================================
1.
Subject is enrolled after meeting eligibility requirements, which includes a positive BPE/BPO screening tool and/or positive IPSS screening tool.
2.
Urinalysis sent to local laboratory only if urine strip test is positive.
3.
PSA blood test sent to local lab.  Local lab results and reference ranges are entered in the CRF.
4.
For Visit 2, the GP calls the subject to report yes or no for probable BPH. If the subject has probable BPH, the GP schedules the subject for Visit 3 with the urologist.  If the 
subject does not have probable BPH, then the subject has completed the study.
5.
DRE is performed by the urologist. The GP may conduct a DRE at visit 1 however the DRE will be repeated by the urologist to confirm the diagnosis and to rule out an 
abnormality suggesting prostate cancer..
6.
Information collected during visit 3 will be entered into the eCRF by the Principal Investigator. 
 
 
 
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6.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, and sex.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Patient Reported Outcomes questionnaires should be completed by subjects before any 
other assessment at a clinic visit, in the order specified.
6.3.
Safety
6.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 11.2. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
6.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) will be recorded from the 
time a subject consents to participate in the study up to and including any follow-up 
contact. 

Medical occurrences that begin after obtaining informed consent may be recorded on 
the Medical History/Current Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 11.2.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he considers the event 
reasonably related to the study treatment or study participation, the investigator must 
promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 11.2.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
 
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6.3.1.2.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs (as defined in Section 6.3.1) will be 
followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.4). Further 
information on follow-up procedures is given in Section 11.2.
6.3.1.3.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment  or related to a GSK product 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.
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.
6.3.2.
Physical Exams

The urologist will perform a brief physical exam.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses
6.3.3.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, must be conducted in accordance with the 
local laboratory requirements and Protocol Time and Events Schedule.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the study reference manual (SRM) for appropriate processing and handling of 
samples to avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a local laboratory, apart 
from:
 
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
Urinalysis strip test
If the urinalysis test strip is positive, then the sample is sent to a local lab for urinalysis.
The results of each test and reference ranges must be entered in the CRF.
PSA chemistry and urinalysis are listed in Table 1. 
Table 1
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Urinalysis strip test

If strip test is positive, send sample to local lab for urinalysis
PSA 
Chemistry

Submit blood sample to local lab for PSA analysis.
6.3.4.
Urine Sample Collection
A urine strip test will be performed at screening.  If the dipstick is positive, a urine 
sample will be submitted to the local laboratory for urinalysis. Please see the time points 
listed in Section 6.1 Time and Events Table.  Results and reference ranges will be entered 
in the CRF.
7.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined electronic CRFs, 
transmitted electronically to GSK or designee, and combined with data provided 
from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

Adverse events terms and concomitant medications will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
 
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8.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
8.1.
Hypotheses
The primary endpoint is defined as the proportion of men confirmed to have BPH based 
on full urologist diagnostic testing in men with a positive result on the BPE/BPO 
screening tool and a probable BPH assessment by GP. Primary endpoint summaries will 
be descriptively presented in terms of the calculated proportion, described below, and 
95% confidence interval on the proportion. Formal hypothesis testing will not be 
conducted in terms of the primary and secondary endpoint proportions.
8.2.
Sample Size Considerations
Sufficient general practice centres (approximately 50 subjects per centre) in the various 
markets will be recruited to administer the BPE/BPO screening tool to 1,500 men using 
protocol defined criteria presenting to clinic. It is expected that 33% of the 1,500 
presenting (or approximately 500) will have a positive result on the BPE/BPO and/or 
IPSS screening tools and a probable BPH assessment by GP and thus will be assessed by 
a urologist.
Evaluation of 500 subjects by a urologist will allow estimation of a 95% confidence 
interval on the primary endpoint proportion with a maximum width of ±0.044. Sample 
size assumptions are in terms of the binominal distribution with the proportion of 
urologist confirmed BPH diagnosis most conservatively assigned at 0.50.  Using these 
assumptions, the following provides an overview of other possible sample sizes along 
with projected 95% confidence interval maximum width.
Number of Subjects 
Evaluated by Urologist
Maximum Width of a 95% 
Confidence Interval
300
±0.057
500
±0.044
700
±0.037
Sample size re-estimation is not planned.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
Subjects are not randomized or dispensed study treatment. As designed in the protocol,
the number of subjects will decrease from the screening period to GP Assessment (Part I) 
and then again in the subsequent Urologist Assessment (Part II) either due to not 
qualifying for progression to the next part of the study or due to any withdrawal. 
The decreases, along with planned multiple summary and analysis types, will impact and 
restrict the evaluable population for a given endpoint. Therefore, populations are not 
defined in the traditional sense. Rather, for each reported summary statistic and analyses, 
 
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the subset of subjects and/or denominators will be clearly defined in the Reporting and 
Analysis Plan (RAP).

Due to the design of the study and types of endpoints incorporated, ‘observed cases’ 
will be summarized. For the primary analyses, there will be no imputations for 
missing data, no imputations for missing responses within the BPE/BPO or IPSS 
screening tools, and no imputations for subjects withdrawing from the study or not 
qualifying for a subsequent part of the study.
Any pre-planned exclusions from analysis, such as for protocol deviations, will be 
defined in the RAP.
8.3.2.
Interim Analysis
An interim analysis is not planned for this study.
8.3.3.
Multiplicity
All pre-planned summary statistics and hypothesis testing results will be presented. There 
are no established controls for interpretation of the multiple outputs.
8.4.
Key Elements of Analysis Plan
Data will be listed and summarized according to 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 the protocol will be documented in 
the RAP and final study report.
8.4.1.
Population Descriptive Statistics
Numbers of subjects participating in the study will be summarized for each study period: 
Screening, GP Assessment (Part I), and Urologist Assessment (Part II). Numbers of 
subjects who do not continue to a subsequent study period, along with reason, will be 
summarized.
Summary statistics for CRF collected demography, medical history, and medical 
evaluations collected by the GP and urologist will be summarized, as applicable, for each 
study period.
8.4.2.
Primary Analyses
The primary endpoint is defined as the proportion of men confirmed to have BPH based 
on full urologist diagnostic testing among men with a positive result on the BPE/BPO 
screening tool (score ≥3) and serum PSA ≥2 ng/mL. Primary endpoint summaries will be 
descriptively presented in terms of the calculated proportion, described below, and 95% 
confidence interval on the proportion. Formal hypothesis testing will not be conducted.
 
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Tool
Proportion
Numerator
Denominator
BPE/
BPO
BPH Diagnosis by 
Urologist based upon 
BPE/BPO screening tool
(score ≥3) and serum 
PSA ≥2 ng/mL  
Number of subjects 
diagnosed with BPH
based on full urologist 
diagnostic testing
Number of subjects with a positive 
result on the BPE/BPO screening 
tool (score ≥3) and serum PSA 
≥2 ng/mL and a BPH assessment by 
urologist
8.4.3.
Secondary Analyses
Secondary endpoints and other measures of interest are defined in terms of proportions 
for each: probable BPH diagnosis by GP, BPH diagnosis by urologist, and BPH 
progression risk by urologist along with use of 1) BPE/BPO screening tool and 2) IPSS 
screening tool. These proportions will be calculated in terms of the numerators and 
denominators shown below; the 95% confidence intervals for these proportions will be 
presented.
Secondary Endpoints: Proportions only in terms of the BPE/BPO tool
Tool
Proportion
Numerator
Denominator
BPE/
BPO
BPH Progression Risk by 
Urologist based upon 
BPE/BPO screening tool
(score ≥3)  and serum 
PSA ≥2 ng/mL
Number of subjects 
diagnosed with BPH 
progression risk by 
urologist
Number of subjects with a positive 
result on the BPE/BPO screening 
tool (score ≥3) and serum PSA 
≥2 ng/mL and a BPH progression 
risk assessment by urologist
BPE/
BPO
Probable BPH Diagnosis 
by GP based upon 
BPE/BPO screening tool
(score ≥3) 
Number of subjects 
diagnosed with ‘probable 
BPH’ by GP
Number of subjects with a positive 
result on the BPE/BPO screening 
tool (score ≥3) and a BPH 
assessment by GP
Secondary Endpoints: Proportions only in terms of the IPSS screening tool
Tool
Proportion
Numerator
Denominator
IPSS
BPH Diagnosis by 
urologist based upon 
IPSS (score ≥8) and 
serum PSA ≥2 ng/mL
Number of subjects 
diagnosed with BPH
based on full urologist 
diagnostic testing
Number of subjects with a positive 
result on the IPSS (score ≥8) and 
serum PSA ≥2 ng/mL and a BPH 
assessment by urologist
IPSS
BPH Progression Risk by 
urologist based upon 
IPSS (score ≥8) and 
serum PSA ≥2 ng/mL
Number of subjects 
diagnosed with BPH 
progression risk by 
urologist
Number of subjects with a positive 
result on the IPSS (score ≥8) and 
serum PSA ≥2 ng/mL and a BPH 
progression risk assessment by 
urologist
IPSS
Probable BPH Diagnosis 
by GP based upon IPSS 
(score ≥8) 
Number of subjects 
diagnosed with ‘probable 
BPH’ by GP
Number of subjects with a positive 
result on the IPSS (score ≥8) and a 
BPH assessment by GP
Additional summaries, proportions and related 95% confidence intervals, will be 
generated as outlined above, but in terms of a positive result for both the BPE/BPO and 
the IPSS screening tools.
 
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Another secondary endpoint of this study is to assess the level of agreement between the
BPE/BPO and/or IPSS screening tools for selecting men to investigate for BPH. The 
number and proportion of subjects with a positive or with a negative response to both the 
BPE/BPO and IPSS screening tools at screening will be summarized.
Agreement of the BPE/BPO and the IPSS screening tools will be assessed using the 
kappa coefficient. The simple kappa coefficient along with the 95% confidence interval 
will be generated using SAS along with hypothesis testing. The associated null 
hypothesis is that the two measures (BPE/BPO and IPSS screening tools) are 
independent, i.e., kappa = 0. The alternative hypothesis is that the agreement of the two 
measures is better than one would expect by chance. Two-sided tests of the null 
hypothesis will be conducted at the 0.05 level of significance.
The above defined kappa coefficient will be characterized as proposed by Landis and 
Koch (Landis, 1977) with <0 indicating no agreement, 0-0.20 as slight, 0.21-0.40 as fair, 
0.41-0.60 as moderate, 0.61-0.80 as substantial, and 0.81 – 1 as almost perfect agreement.
The proportion of men refusing further GP investigation among subjects with a positive 
BPE/BPO screening tool will be summarized.  The proportion of subjects refusing 
referral to an urologist among subjects with a positive BPE/BPO screening tool and 
probable GP BPH diagnosis will be summarized.
The above described proportions, for both primary and secondary endpoints, will also be 
summarized by country.  
9.
STUDY GOVERNANCE CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable
 
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
Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GPs and Urologists will be selected based on their medical qualifications and the 
capacity to perform study procedures per the protocol.  No bias is expected as a 
result of this selection.

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study 

As a non-randomized study, subjects will be selected by the inclusion/exclusion 
criteria.  No bias is expected as a result of this selection. 
9.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements. When reviewing data collection 
procedures, the discussion will also include identification, agreement and 
documentation of data items for which the CRF will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
9.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. In the event of an assessment, audit or inspection, the 
investigator (and institution) must agree to grant the advisor(s), auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss the conduct of the study, any findings/relevant issues 
and to implement any corrective and/or preventative actions to address any 
findings/issues identified.
 
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9.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
9.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
 
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institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
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10.
REFERENCES
Carballido J, Fourcade R, Pagliarulo A, et al. Can benign prostatic hyperplasia be 
identified in the primary care setting using only simple tests? Results of the Diagnosis 
IMprovement in PrimAry Care Trial. Int J Clin Pract. 2011;65(9):989-96.
Emberton M, Andriole GL et al. Benign prostatic hyperplasia: a progressive disease of 
aging men. Urology. 2003;61:267–273.
Fitzpatrick JM. The natural history of benign prostatic hyperplasia. BJU Int. 2006;97 
Suppl 2:3-6; discussion 21-22. 
Landis, J.R.; Koch, G.G. The measurement of observer agreement for categorical data. 
Biometrics. 1977;33 (1): 159-174.
Roehrborn CG, Nuckolls JG, Wei JT, et al. The Benign Prostatic Hyperplasia Registry 
and Patient Survey: study design, methods and patient baseline characteristics. BJU Int. 
2007;100:813-819.
Roehrborn CG, Siami P, Barkin J, et al. The effects of dutasteride, tamsulosin and 
combination therapy on lower urinary tract symptoms in men with benign prostatic 
hyperplasia and prostatic enlargement: 2-year results from the CombAT study. Urol. 
2008;179(2):616-21; discussion 621. Epub 2007. Erratum in:Urol. 2008;180(3):1191.
U.S. Department of Health and Human Services Food and Drug Administration. 
Guidance for industry: Patient-reported outcome measures: Use in medical product 
development to support labeling claims. Health and Quality of Life Outcomes. 2009.
 
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11.
APPENDICES
11.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
BPH
Benign prostatic hyperplasia
BPE
Benign prostatic enlargement
BPO
Benign prostatic obstruction
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
DRE
Digital rectal examination
EAU
European Association of Urology
GSK
GlaxoSmithKline
GP
General Practitioner
IPSS
International Prostate Symptom Score (Version 2), I-PSS2
LUTS
Lower urinary tract symptoms
PSA
Prostate specific antigen
RAP
Reporting and analysis plan
SAE
Serious adverse event
SRM
Study reference manual
TURP
Transurethral resection of the prostate
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
 
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11.2.
Appendix 2: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.2.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
 
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Events NOT meeting definition of an AE include:
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.
11.2.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
 
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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
11.2.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
 
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AEs and SAE Recording:
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
11.2.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
 
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Assessment of Causality
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his assessment.

For each AE/SAE the investigator must document in the medical notes that he has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.2.5.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
 
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SAE reporting to GSK via electronic data collection tool
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the CRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
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11.3.
Appendix 3 - Country Specific Requirements
No country-specific requirements exist.
 
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11.4.
Appendix 4 – IPSS SCREENING TOOL
 
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11.5.
Appendix 5 – SCREENER FOR PATIENTS WITH BENIGN 
PROSTATIC ENLARGEMENT/OBSTRUCTION (BPE/BPO)
 
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11.6.
Appendix 6 - Protocol Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Changes with Rationale

Deletion of compound numbers on the title page and the entering of “None”

Deletion of the development status on the title page and entering “NA”

Changing the study to an interventional study from non-interventional (Section 4)

Deletion of the collection of race and ethnicity (Section 6.2)
List of Specific Changes
Changes are struck through and additions are underlined:
TITLE PAGE
PREVIOUS TEXT
Compound Number:
GI198745+GI138525
Development Phase:
IV
REVISED TEXT 
Compound Number:
GI198745+GI138525 None
Development Phase:
IVNA
Rationale for the changes: There are no compound numbers cited in the text, hence the 
value ‘None’ is used.
 
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Section 4 - Study Design
PREVIOUS TEXT
This non-randomized, non-interventional study utilizing a questionnaire-based 
assessment of men in General Practice. Validation of the tool was performed in a 
previous GlaxoSmithKline (GSK) study (FDC116700: Quick Question Tool 
Development and Linguistic Validation).
REVISED TEXT
This non-randomized, non-interventional study utilizing a questionnaire-based 
assessment of men in General Practice. Validation of the tool was performed in a 
previous GlaxoSmithKline (GSK) study (FDC116700: Quick Question Tool 
Development and Linguistic Validation).
Rationale for the change: The study was changed from non-interventional to 
interventional based on the collection of urine and blood samples which is outside of 
normal medical practice for subjects presenting to their physician reasons that are not 
related to this study.
Section 6.2 - Screening and Critical Baseline Assessments
PREVIOUS TEXT
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
REVISED TEXT
The following demographic parameters will be captured: year of birth, and sex. , race and 
ethnicity.
Rationale for the change: Collection of this information is not required for the analysis of 
the study end points and therefore will not be collected.
 
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AMENDMENT 2
Where the Amendment Applies
This amendment applies to all sites participating in this study.
Summary of Changes with Rationale

The study title has been revised to indicate the specific age criteria for men to be 
involved in the study.

Deletion of phase IV to maintain consistency with title page.

Included the DRE at all applicable sections of the protocol to confirm the diagnosis 
and to rule out an abnormality suggesting prostate cancer by urologist.

Included the probable BPH criteria for clarity and to maintain consistency with other 
sections of protocol.

Addition of herbal products for urinary symptoms under prohibited medications to 
exclude subjects that are receiving treatment of BPH symptoms.

Modified the regulatory reporting requirements for SAEs to exclude GSK product as 
no product is be investigated. 

Minor corrections and edits have been made throughout the protocol.
List of Specific Changes
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
TITLE PAGE
PREVIOUS TEXT
Title:
Implementation of a screening tool for subjects with benign 
prostatic enlargement/obstruction to identify men 50 years 
presenting in General Practice with other co-morbidities who 
should be assessed for BPH
REVISED TEXT
Title:
Implementation of a screening tool for subjects with benign 
prostatic enlargement/obstruction to identify men ≥50 years 
presenting in General Practice with other co-morbidities who 
should be assessed for BPH
 
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Rationale for the changes: The change has been made for clarification of men age 
criteria.
Protocol Synopsis
Rationale
PREVIOUS TEXT
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is that it may 
help General Practitioners (GPs) identify patients who may have BPH for further tests 
and improve the speed of referrals to specialists when this is appropriate.
REVISED TEXT
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is that it may 
help a General Practitioners (GPs) to identify patients who may have BPH for further 
tests and improve the speed of referrals to specialists when this is appropriate.
Overall Design
PREVIOUS TEXT

This is a Phase IV study that will test the utility of the Benign Prostatic Enlargement 
(BPE)/ Benign Prostatic Obstruction (BPO) screening tool in a general practice
setting where the results of this screening tool will be used for further investigation. 
Therefore in this study, all men testing positive on the BPE/BPO screening tool 
(score ≥3) tool or on the IPSS (score ≥8) will be enrolled and offered a prostate 
specific antigen (PSA) test and urinalysis to establish a diagnosis of probable benign 
prostatic hyperplasia (BPH) (Part I – Visit 1).  A GP makes a diagnosis of probable 
BPH based upon screening results and lab tests which suggest that they are related to 
BPH and not other causes of such symptoms.

The General Practitioners (GPs) will phone the subject to report yes or no for 
probable BPH Part II (Visit 2). If the subject has probable BPH, the GP schedules the 
subject for Visit 3 with a urologist.  If the subject does not have probable BPH, then 
the subject has completed the study.

Subjects that proceed to Part II (Visit 3) will be scheduled for a urology assessment 
performed by a urologist.  This assessment includes digital rectal examination (DRE) 
and a brief physical exam and review of the PSA test, for a confirmatory diagnosis of 
BPH and estimation of risk of progression of BPH.
REVISED TEXT

This is a Phase IV study that will test evaluate the utility of the Benign Prostatic 
Enlargement (BPE)/ Benign Prostatic Obstruction (BPO) screening tool in a general 
practice setting where the results of this screening tool will be used for further 
investigation. Therefore in this study, all men testing positive on the BPE/BPO 
 
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screening tool (score ≥3) tool or on the IPSS (score ≥8) will be enrolled and offered a 
prostate specific antigen (PSA) test and urinalysis to establish a diagnosis of 
probable benign prostatic hyperplasia (BPH) (Part I – Visit 1).  The General 
Practitioner (GP) may perform a DRE (digital rectal examination), however the DRE 
will be repeated by the urologist to confirm the diagnosis and to rule out an 
abnormality suggesting prostate cancer.  A The GP will makes a diagnosis of 
probable BPH based upon screening results and lab tests which suggest that they are 
related to BPH and not other causes of such symptoms.

The General Practitioners (GPs) will phone the subject to report yes or no for 
probable BPH Part II (Visit 2). If the subject has probable BPH, the GP will
schedules the subject for Visit 3 with a urologist.  If the subject does not have 
probable BPH, then the subject has completed the study.

Subjects that proceed to Part II (Visit 3) will be scheduled for a urology assessment 
performed by a urologist.  This assessment includes a digital rectal examination 
(DRE) and a brief physical exam and review of the PSA test, for a confirmatory 
diagnosis of BPH and estimation of risk of progression of BPH.
Analysis
PREVIOUS TEXT

The primary endpoint is defined as the proportion of men that are confirmed to have 
BPH based on full urologist assessment of diagnostic test results among men with a 
positive result on the BPE/BPO screening tool and probable GP BPH diagnosis.  For 
this proportion, the numerator is number of subjects diagnosed with BPH by a 
urologist; denominator is number of subjects with a positive result on the BPE/BPO 
screening tool and a probable BPH assessment by the GP and a BPH assessment by 
the urologist.  The 95% confidence interval for this proportion will be presented.

Sufficient general practice centres (50 consecutive men per centre) in the top 5 
European markets will be recruited to administer the BPE/BPO screening tool to 
1,500 men (using protocol defined criteria) presenting to clinic for reasons unrelated 
to the study.  It is expected that 33% of the 1,500 presenting (or approximately 500) 
will have a positive result on the BPE/BPO screening tool and a probable BPH 
assessment by GP and thus will be assessed by a urologist.
REVISED TEXT

The primary endpoint is defined as the proportion of men that are confirmed to have 
BPH based on full urologist assessment of diagnostic test results among men with a 
positive result on the BPE/BPO screening tool and probable GP BPH diagnosis as
assessed by the GP.  For this proportion, the numerator is number of subjects 
diagnosed with BPH by a urologist; denominator is number of subjects with a 
positive result on the BPE/BPO screening tool and a probable BPH assessment by 
the GP and a BPH assessment by the urologist.  The 95% confidence interval for this 
proportion will be presented.

Sufficient general practice centres (50 consecutive men per centre) in the top various
5 European markets will be recruited to administer the BPE/BPO screening tool to 
 
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1,500 men (using protocol defined criteria) presenting to clinic for reasons unrelated 
to the study.  It is expected that 33% of the 1,500 presenting (or approximately 500) 
will have a positive result on the BPE/BPO screening tool and a probable BPH 
assessment by GP and thus will be assessed by a urologist.
Rationale for the changes: The changes have been made to maintained consistency with
other sections of protocol.
2.
INTRODUCTION
PREVIOUS TEXT

This Phase IV study will test the utility of the Benign Prostatic Enlargement (BPE)/
Benign Prostatic Obstruction (BPO) screening tool in a general practice setting 
where the results of the BPE/BPO screening tool will be used for further 
investigation. Therefore in this study, all men testing positive with the BPE/BPO tool 
(score ≥3) and/or on the IPSS (score ≥8) will be enrolled and offered a prostate 
specific antigen (PSA) test and urinalysis to help establish a diagnosis of probable
benign prostatic hyperplasia (BPH) (Part I – Visit 1).

The General Practitioners (GPs) will phone the subject to report yes or no for 
probable benign prostatic hyperplasia (BPH) Part II (Visit 2). If the subject has 
probable BPH, the GP schedules the subject for Visit 3 with a urologist. If the 
subject does not have probable BPH, then the subject has completed the study.

For those subjects that proceed to Part II (Visit 3) they will be scheduled for a 
urology assessment performed by a urologist. This assessment includes digital rectal 
examination (DRE) and a brief physical exam with review of the PSA test, for a 
confirmatory diagnosis of BPH and estimation of risk of progression of BPH.
REVISED TEXT

This Phase IV study will test evaluate the utility of the Benign Prostatic Enlargement 
(BPE)/ Benign Prostatic Obstruction (BPO) screening tool in a general practice 
setting where the results of the BPE/BPO screening tool will be used for further 
investigation. Therefore in this study, all men testing positive with the BPE/BPO tool 
(score ≥3) and/or on the IPSS (score ≥8) will be enrolled and offered a prostate 
specific antigen (PSA) test and urinalysis to help establish a diagnosis of probable 
benign prostatic hyperplasia (BPH) (Part I – Visit 1).  The GP may perform a DRE, 
however the DRE will be repeated by the urologist to confirm the diagnosis and to 
rule out an abnormality suggesting prostate cancer.

The General Practitioners (GPs) will phone the subject to report yes or no for 
probable benign prostatic hyperplasia (BPH) Part II (Visit 2). If the subject has 
probable BPH, the GP will schedules the subject for Visit 3 with a urologist. If the 
subject does not have probable BPH, then the subject has completed the study.

For those subjects that proceed to Part II (Visit 3) they will be scheduled for a 
urology assessment performed by a urologist. This assessment includes digital rectal 
examination (DRE) and a brief physical exam with review of the PSA test, for a 
confirmatory diagnosis of BPH and estimation of risk of progression of BPH.
 
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Rationale for the change: The phase of study is not applicable. Hence, phase IV has 
been deleted and DRE has been included to confirm the diagnosis and to rule out an 
abnormality suggesting prostate cancer by urologist.
2.1
Study Rationale
PREVIOUS TEXT
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to BPH is that it may help GPs identify patients 
who may have BPH for further tests and improve the speed of referrals to specialists 
when this is appropriate.
REVISED TEXT
The rationale for developing an instrument to screen populations of men for lower 
urinary tract symptoms (LUTS) due to BPH is that it may help a GPs to identify 
patients who may have BPH for further tests and improve the speed of referrals to 
specialists when this is appropriate.
Rationale for the change: The changes have been made to correct the typographical 
error.
4.
STUDY DESIGN
PREVIOUS TEXT
This non-randomized, interventional study utilizing a questionnaire-based assessment 
of men in General Practice. Validation of the tool was performed in a previous 
GlaxoSmithKline (GSK) study (FDC116700: Quick Question Tool Development and 
Linguistic Validation). Men who sign the informed consent form and meet the 
eligibility criteria will be enrolled and complete the Part I diagnostic tests at the GP 
clinic. If the GP determines that the subject has probable, the subject proceeds to Part 
II and is scheduled for a urologist assessment and diagnostic tests to confirm or refute 
a BPH diagnosis and to assess risk of progression of BPH.
REVISED TEXT
This non-randomized, interventional study utilizing a questionnaire-based assessment 
of men in General Practice. Validation of the tool was performed in a previous 
GlaxoSmithKline (GSK) study (FDC116700: Quick Question Tool Development and 
Linguistic Validation). Men who sign the informed consent form and meet the 
eligibility criteria will be enrolled and complete the Part I diagnostic tests at the GP 
clinic. If the GP determines that the subject has probable BPH (IPSS ≥8 and/or 
BPE/BPO questionnaire ≥3 with a PSA ≥2 ng/ml), the subject proceeds to Part II and 
is scheduled for a urologist assessment and diagnostic tests to confirm or refute a 
BPH diagnosis and to assess risk of progression of BPH.
 
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Rationale for the change: Included the probable BPH criteria for clarity and to 
maintain consistency with other sections of protocol.
4.1
Overall Design
PREVIOUS TEXT
First Paragraph:
To reproduce these circumstances of opportunistic screening, men will not be invited 
to attend their GPs but must attend spontaneously with for reasons that are not 
related to this study.
Third Paragraph:
After obtaining informed consent, GPs will initially assess all inclusion and exclusion 
criteria except for the questionnaire inclusion criterion.
All men with ‘probable BPH’ will proceed to Part II and will be scheduled for Visit 3 
with a urologist for confirmation of the GPs findings plus a brief physical exam and 
DRE.  Additional testing may be performed as per standard of care to assist with a 
confirmatory diagnosis; however this is not required by the protocol.
2) Estimate whether the patient is at risk of progression of BPH (PSA ≥2.0 ng/mL 
and/or other testing).
For the purposes of this study the diagnosis of the urologist (BPH yes/no) is the 
operational definition of confirmed BPH. Those men refusing referral to the 
urologist, but considered by the GPs to have BPH (after the tests specified above) 
will be classified as ‘probable BPH’.
Description of Visits:
VISIT 1 (primary care clinic)

Males ≥50 years visiting GP for reasons unrelated to the study

Patient provides informed consent

Inclusion/exclusion criteria confirmation

Medical history and demography

BPE/BPO and IPSS screening tools
Eligible to participate
 
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ENROLLED: Subject is enrolled and proceeds to Part I (GP Assessment) of the 
study.  If the GP diagnoses probable BPH, the subject will proceed to Part II 
(urologist assessment).
PART I: GP Assessment
After being enrolled, complete the following at Visit 1:

Urinalysis strip test.

If strip test is positive, send urine sample to local lab urinalysis.

PSA blood test
VISIT 2 (telephone call)

GP reviews urinalysis and PSA lab results.

Call subject: If lab results show NO probable BPH, then subject will not 
continue in the study.  If PSA lab results show PROBABLE BPH (≥2 ng/mL), 
subject proceeds to Part II and Visit 3 is scheduled for the urologist assessment.
If subject meets entry criteria, 
including a positive IPSS (score 
≥8) and/or BPE/BPO (score 
≥3).
 
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VISIT 3 (Part II – urologist clinic visit)

Urologist reviews medical history and symptoms

Brief physical examination

DRE

Review previous tests (BPE/BPO screening tool, IPSS screening tool, urinalysis, 
PSA)

NOTE: Urologist may need to perform additional diagnostic testing as per 
standard of care and as needed to assess the BPH diagnosis. This follow-
up is not prescribed by this protocol, however, any data collected that is 
used for the final diagnosis will be entered in the study case report form 
Urologist provides:

Confirmation of clinical diagnosis of BPH 
(or confirmation the subject does NOT 
have BPH).

Estimate whether the patient is at risk of 
progression of BPH (PSA≥2.0ng/mL 
and/or other tests).
 
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(CRF).  Advice or treatment post study will be discretion of the GP or 
Urologist. 
REVISED TEXT
First Paragraph:
To reproduce these circumstances of opportunistic screening, men will not be invited 
to attend their GPs but must attend spontaneously with for reasons that are not 
related to this study.
Third Paragraph:
After obtaining informed consent, the GPs will initially assess all inclusion and 
exclusion criteria except for the questionnaire inclusion criterion.
All men with ‘probable BPH’ will proceed to Part II and will be scheduled for Visit 3 
with a urologist for confirmation of the GP’s findings plus a brief physical exam and 
DRE.  Additional testing may be performed as per standard of care to assist with a 
confirmatory diagnosis;  such as a DRE, however this is not required by the protocol.
2) Estimate whether the patient is at risk of progression of BPH (PSA ≥2.0 ng/mL 
and/or other testing).
For the purposes of this study the diagnosis of the urologist (BPH yes/no) is the 
operational definition of confirmed BPH. Those men refusing referral to the urologist, 
but considered by the a GPs to have BPH (after the tests specified above) will be 
classified as ‘probable BPH’.
Description of Visits:
VISIT 1 (primary care clinic)

Males ≥50 years visiting GP for reasons unrelated to the study

Patient provides informed consent

Inclusion/exclusion criteria confirmation

Medical history and demography

BPE/BPO and IPSS screening tools
Eligible to participate
 
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ENROLLED: Subject is enrolled and proceeds to Part I (GP Assessment) of the 
study.  If the GP diagnoses probable BPH, the subject will proceed to Part II 
(urologist assessment).
PART I: GP Assessment
After being enrolled, complete the following at Visit 1:

Urinalysis strip test.

If strip test is positive, send urine sample to local lab urinalysis.

PSA blood test

Additional testing may be performed as per standard of care to assist with a 
confirmatory diagnosis such as a DRE, however this is not required.
VISIT 2 (telephone call)

GP reviews urinalysis and PSA lab results.

Call subject: If lab results show NO probable BPH, then subject will not 
continue in the study.  If PSA lab results show PROBABLE BPH (≥2 ng/mL), 
subject proceeds to Part II and Visit 3 is scheduled for the urologist assessment.
If subject meets entry criteria, 
including a positive IPSS (score 
≥8) and/or BPE/BPO (score 
≥3).
 
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VISIT 3 (Part II – urologist clinic visit)

Urologist reviews medical history and symptoms

Brief physical examination

DRE

Review previous tests (BPE/BPO screening tool, IPSS screening tool, urinalysis, 
PSA)

NOTE: Urologist may need to perform additional diagnostic testing as per 
standard of care and as needed to assess the BPH diagnosis. This follow-
up is not prescribed by this protocol, however, any data collected that is 
used for the final diagnosis will be entered in the study case report form 
Urologist provides:

Confirmation of clinical diagnosis of BPH 
(or confirmation the subject does NOT 
have BPH).

Estimate whether the patient is at risk of 
progression of BPH (PSA≥2.0ng/mL 
and/or other tests).
 
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(CRF).  Advice or treatment post study will be discretion of the GP or 
Urologist. 
Rationale for the change: Included the additional test such as a DRE to confirm the 
diagnosis and to maintain consistency with other sections of protocol.
5.2
Exclusion Criteria
PREVIOUS TEXT
CONCOMITANT MEDICATIONS
6. Current or prior use of the following: 
a.
5α-reductase inhibitors (finasteride or dutasteride), 
b. anti-cholinergics (e.g. oxybutynin, propantheline, tolerodine, solifenacin, 
darifenacin, miravegron) alpha-adrenoreceptor blockers (i.e., indoramin, 
prazosin, terazosin, tamsulosin, alfuzosin, doxazosin and silodosin). 
c.
Use of any investigational or marketed study drug within 30 days or 5 half-
lives of the drug in question, (whichever is longer), preceding the first study 
visit.
7. Use within previous 30 days at Visit 1 of:
a.
PDE-5 inhibitors for erectile dysfunction
b. anabolic steroids
REVISED TEXT
CONCOMITANT MEDICATIONS
6. Current or prior use of the following: 
a.
5α-reductase inhibitors (finasteride or dutasteride), 
b. anti-cholinergics (e.g. oxybutynin, propantheline, tolterodine, solifenacin, 
darifenacin, miravegronmirabegron) alpha-adrenoreceptor blockers (i.e., 
indoramin, prazosin, terazosin, tamsulosin, alfuzosin, doxazosin and 
silodosin), herbal products for urinary symptoms. 
c.
Use of any investigational or marketed study drug within 30 days or 5 half-
lives of the drug in question, (whichever is longer), preceding the first study 
visit.
7. Use within previous 30 days at Visit 1 of:
a.
PDE-5 inhibitors for erectile dysfunction
b. anabolic steroids
Rationale for the change: Herbal medications are used in several countries to treat 
BPH and therefore need to be excluded.
 
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5.6.2 Prohibited Medications and Non-Drug Therapies
PREVIOUS TEXT
Prohibited medications:

5α-reductase inhibitors (finasteride or dutasteride), 

anti-cholinergics (e.g. oxybutynin, propantheline, tolerodine, solifenacin, 
darifenacin, miravegron) alpha-adrenoreceptor blockers (i.e., indoramin, prazosin, 
terazosin, tamsulosin, alfuzosin, doxazosin and silodosin).

PDE-5 inhibitors for erectile dysfunction

anabolic steroids
REVISED TEXT
Prohibited medications:
•
5α-reductase inhibitors (finasteride or dutasteride), 
•
anti-cholinergics (e.g. oxybutynin, propantheline, tolterodine, solifenacin, 
darifenacin, miravegronmirabegron) alpha-adrenoreceptor blockers (i.e., indoramin, 
prazosin, terazosin, tamsulosin, alfuzosin, doxazosin and silodosin), herbal products 
for urinary symptoms. 
•
PDE-5 inhibitors for erectile dysfunction
•
anabolic steroids
Rationale for the change: Correction of spelling and rationale for the addition of 
herbal products to excluded products is that herbal products are commonly used to 
treat symptoms of BPH and therefore need to be excluded from the study. 
 
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6.1
Time and Events Table
PREVIOUS TEXT
Procedure
VISIT 1:
Screening/
Enrolment at GP Clinic
Study Period
(1 week 4 days to 6 weeks)
VISIT 2 (phone call): 
GP
VISIT 3: Urologist
(up to 6 weeks after V1)
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history
X
Concomitant medications (all ongoing and within 30 days prior to  
Visit 1)
X
IPSS screening tool
X
BPE/BPO screening tool
X
PROCEDURES AFTER SUBJECT IS ENROLLED1:
Urine strip test2
X
Urinalysis (only if urine strip test is positive)2
X
PSA blood test3
X
Results phone call to subject4
X
Digital rectal exam (DRE)5
X
Brief physical examination
X
Enter prostate-related results in the CRF from non-protocol required 
procedures
X
AE/SAE review (related to study procedures and/or participation)
==========================================
Concomitant medication review
==========================================
1.
Subject is enrolled after meeting eligibility requirements, which includes a positive BPE/BPO screening tool and/or positive IPSS screening tool.
2.
Urinalysis sent to local laboratory only if urine strip test is positive.
3.
PSA blood test sent to local lab.  Local lab results and reference ranges are entered in the CRF.
4.
For Visit 2, the GP calls the subject to report yes or no for probable BPH. If the subject has probable BPH, the GP schedules the subject for Visit 3 with the urologist.  If the 
subject does not have probable BPH, then the subject has completed the study.
5.
DRE is performed by the urologist.
 
 
 
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REVISED TEXT
Procedure
VISIT 1:
Screening/
Enrolment at GP Clinic
Study Period
(1 week 4 days to 6 weeks)
VISIT 2 (phone call): 
GP
VISIT 3: Urologist6
(up to 6 weeks after V1)
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Medical history
X
Concomitant medications (all ongoing and within 30 days prior to  
Visit 1)
X
IPSS screening tool
X
BPE/BPO screening tool
X
PROCEDURES AFTER SUBJECT IS ENROLLED1:
Urine strip test2
X
Urinalysis (only if urine strip test is positive)2
X
PSA blood test3
X
Results phone call to subject4
X
Digital rectal exam (DRE)5
X
X
Brief physical examination
X
Enter prostate-related results in the CRF from non-protocol required 
procedures
X
AE/SAE review (related to study procedures and/or participation)
==========================================
Concomitant medication review
==========================================
 
 
 
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1.
Subject is enrolled after meeting eligibility requirements, which includes a positive BPE/BPO screening tool and/or positive IPSS screening tool.
2.
Urinalysis sent to local laboratory only if urine strip test is positive.
3.
PSA blood test sent to local lab.  Local lab results and reference ranges are entered in the CRF.
4.
For Visit 2, the GP calls the subject to report yes or no for probable BPH. If the subject has probable BPH, the GP schedules the subject for Visit 3 with the urologist.  If the 
subject does not have probable BPH, then the subject has completed the study.
5.
DRE is performed by the urologist. The GP may conduct a DRE at visit 1 however the DRE will be repeated by the urologist to confirm the diagnosis and to rule out an 
abnormality suggesting prostate cancer.
6.
Information collected during visit 3 will be entered into the eCRF by the Principal Investigator.
 
 
 
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Rationale for the change: Clarified conduction of DRE exam diagnosis and to 
maintain consistency with other sections of protocol and to clarify data entry at visit 3
6.3.1.1
Time period and Frequency for collecting AE and SAE 
information
PREVIOUS TEXT

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 
REVISED TEXT

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.
Rationale for the change: Delete GSK product as there is no investigation of a 
product in this study. 
6.3.1.3
Regulatory Reporting Requirements for SAEs
PREVIOUS TEXT
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the 
safety of a product under clinical investigation are met.
REVISED TEXT
Prompt notification by the investigator to GSK or designee of SAEs related to study 
treatment (even for non- interventional post-marketing studies) or related to a GSK 
product is essential so that legal obligations and ethical responsibilities towards the 
safety of subjects and the safety of a product under clinical investigation are met.
Rationale for the change: Edited to for ease of reading and to delete “and the safety 
of a product under clinical investigation” as the study is not investigating a product. 
8.2
Sample Size Consideration
 
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PREVIOUS TEXT
Sufficient general practice centres (approximately 50 subjects per centre) in the top 5 
European markets will be recruited to administer the BPE/BPO screening tool to 1,500 
men using protocol defined criteria presenting to clinic. It is expected that 33% of the 
1,500 presenting (or approximately 500) will have a positive result on the BPE/BPO 
and/or IPSS screening tools and a probable BPH assessment by GP and thus will be 
assessed by a urologist.
REVISED TEXT
Sufficient general practice centres (approximately 50 subjects per centre) in the top 5 
European various markets will be recruited to administer the BPE/BPO screening tool to 
1,500 men using protocol defined criteria presenting to clinic. It is expected that 33% of 
the 1,500 presenting (or approximately 500) will have a positive result on the BPE/BPO 
and/or IPSS screening tools and a probable BPH assessment by GP and thus will be 
assessed by a urologist.
Rationale for change: The wordings have been edited to widen the scope for centre 
selection. 
 
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