2015N231088_00 CONFIDENTIALGlaxoSmithKline group of companies 201897

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TITLE PAGE

Division: Worldwide Development

Information Type: Clinical Protocol

Title: An Open-label, Randomized, Single Dose, Two-way Crossover study to Determine the Bioavailability of one Fixed Dose Combination Capsule Formulation of Dutasteride and Tamsulosin Hydrochloride (0.5mg/0.2mg) Relative to Co-administration of one Dutasteride 0.5mg capsule and one Tamsulosin Hydrochloride 0.2mg tablet in Healthy Male Subjects in the Fed and Fasted States.

Compound Number: GI198745+GI138525

Development Phase I

Effective Date: 24-JUN-2015

Author(s):

(DMPK); (RD Platform Technology & Science); (CPSSO); (ADD); (RD Platform

Technology & Science); (CS); (CPMS).

Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

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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/Cell/Pager Number

Fax Number Site Address

Primary Medical Monitor

(US Pharmacovigilance)

5 Moore Drive/ PO Box 13398, RTP, NC 27709-3398, United States

Secondary Medical Monitor

980 Great West Road, Brentford, Middlesex, TW8 9GS, United Kingdom

SAE contact information

Medical monitor(s) as above

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK

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.

Regulatory Agency Identifying Number(s): Investigational New Drug (IND) 047838

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 Signature Date

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TABLE OF CONTENTS

PAGE

1. PROTOCOL SYNOPSIS FOR STUDY 201897........................................................8

2. INTRODUCTION....................................................................................................102.1. Study Rationale ..........................................................................................102.2. Brief Background ........................................................................................10

3. OBJECTIVE(S) AND ENDPOINT(S) ......................................................................11

4. STUDY DESIGN ....................................................................................................124.1. Overall Design ............................................................................................124.2. Treatment Arms and Duration.....................................................................134.3. Type and Number of Subjects.....................................................................134.4. Design Justification.....................................................................................134.5. Dose Justification........................................................................................144.6. Benefit:Risk Assessment ............................................................................14

4.6.1. Risk Assessment .........................................................................154.6.2. Benefit Assessment .....................................................................204.6.3. Overall Benefit:Risk Conclusion...................................................20

5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............205.1. Inclusion Criteria .........................................................................................205.2. Exclusion Criteria........................................................................................215.3. Screening/Baseline/Run-in Failures ............................................................225.4. Withdrawal/Stopping Criteria.......................................................................235.5. Subject and Study Completion....................................................................23

6. STUDY TREATMENT ............................................................................................246.1. Investigational Product and Other Study Treatment....................................246.2. Treatment Assignment................................................................................256.3. Blinding.......................................................................................................256.4. Packaging and Labeling..............................................................................256.5. Preparation/Handling/Storage/Accountability ..............................................266.6. Compliance with Study Treatment Administration .......................................266.7. Treatment of Study Treatment Overdose....................................................276.8. Treatment after the End of the Study ..........................................................276.9. Lifestyle and/or Dietary Restrictions............................................................27

6.9.1. Meals and Dietary Restrictions ....................................................276.9.2. Caffeine, Alcohol and Tobacco ....................................................286.9.3. Activity .........................................................................................28

6.10. Concomitant Medications and Non-Drug Therapies....................................286.10.1. Permitted Medications and Non-Drug Therapies..........................286.10.2. Prohibited Medications and Non-Drug Therapies.........................28

7. STUDY ASSESSMENTS AND PROCEDURES .....................................................297.1. Time and Events Table ...............................................................................307.2. Screening and Critical Baseline Assessments ............................................317.3. Safety .........................................................................................................31

7.3.1. Adverse Events (AE) and Serious Adverse Events (SAEs)..........31

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7.3.1.1. Time period and Frequency for collecting AE and SAE information...................................................31

7.3.1.2. Method of Detecting AEs and SAEs ...........................327.3.1.3. Follow-up of AEs and SAEs........................................327.3.1.4. Regulatory Reporting Requirements for SAEs............32

7.3.2. Pregnancy ...................................................................................337.3.3. Physical Exams ...........................................................................337.3.4. Vital Signs....................................................................................337.3.5. Orthostatic Vital Signs..................................................................337.3.6. Electrocardiogram (ECG).............................................................347.3.7. Clinical Safety Laboratory Assessments ......................................34

7.4. Pharmacokinetics .......................................................................................357.4.1. Blood Sample Collection..............................................................357.4.2. Sample Analysis ..........................................................................36

8. DATA MANAGEMENT ...........................................................................................36

9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................379.1. Sample Size Considerations.......................................................................37

9.1.1. Sample Size Assumptions ...........................................................379.1.2. Sample Size Sensitivity................................................................379.1.3. Sample Size Re-estimation or Adjustment ...................................38

9.2. Data Analysis Considerations .....................................................................389.2.1. Interim Analysis ...........................................................................38

9.3. Key Elements of Analysis Plan ...................................................................389.3.1. Final Analyses .............................................................................38

9.3.1.1. Pharmacokinetic Analyses..........................................389.3.1.2. Safety Analyses..........................................................39

10. STUDY GOVERNANCE CONSIDERATIONS........................................................3910.1. Posting of Information on Publicly Available Clinical Trial Registers............3910.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................4010.3. Quality Control (Study Monitoring) ..............................................................4010.4. Quality Assurance.......................................................................................4110.5. Study and Site Closure ...............................................................................4110.6. Records Retention ......................................................................................4210.7. Provision of Study Results to Investigators, Posting of Information

on Publically Available Clinical Trials Registers and Publication .................42

11. REFERENCES.......................................................................................................44

12. APPENDICES ........................................................................................................4512.1. Appendix 1: Abbreviations and Trademarks................................................4512.2. Appendix 2: Definition of and Procedures for Recording, Evaluating,

Follow-Up and Reporting of Adverse Events...............................................4912.2.1. Definition of Adverse Events........................................................4912.2.2. Definition of Serious Adverse Events ...........................................5012.2.3. Definition of Cardiovascular Events .............................................5112.2.4. Recording of AEs and SAEs ........................................................5212.2.5. Evaluating AEs and SAEs............................................................5212.2.6. Reporting of SAEs to GSK...........................................................54

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12.3. Appendix 3: Collection of Pregnancy Information........................................5512.4. Appendix 4: Country Specific Requirements ...............................................56

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1. PROTOCOL SYNOPSIS FOR STUDY 201897

Rationale

This study is required to assess the suitability of one fixed dose combination (FDC) capsule formulation of dutasteride/tamsulosin (0.5 mg/0.2 mg) compared to separate co-administration of the reference products (dutasteride 0.5 mg and tamsulosin (0.2 mg) for further development.

The candidate test formulation will be assessed on the basis of the Test/Reference ratios, confidence intervals (CIs) and variability for Cmax (rate of absorption) and Area Under Concentration-time curve (AUC) (extent of absorption).

Objective(s)/Endpoint(s)

Objectives Endpoints

Primary

To determine the bioavailability of a FDC capsule formulation of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of one dutasteride 0.5 mg capsule and one tamsulosin hydrochloride 0.2 mg tablet in healthy male subjects in fed and fasted states.

Tamsulosin AUC(0-t) and AUC(0-∞) [defaulting to AUC(0-t) if AUC(0-∞) cannot be consistently determined] and Cmax.

Dutasteride AUC(0-t) and Cmax.

Secondary

To characterize the pharmacokinetics of dutasteride and tamsulosin.

Time to Cmax (tmax) and t1/2 (tamsulosin only) as data permit.

To monitor the safety and tolerability following administration of the dutasteride in healthy adult male subjects in fed and fasted states.

Safety and tolerability of all treatments as assessed by vital signs (blood pressure and pulse rate), ECG measurements and review of adverse events.

Overall Design

This is an open-label, randomized, single dose, two-way crossover study enrolling healthy male subjects, split into fed and fasted cohorts.

In both cohorts, one FDC capsule formulation of dutasteride 0.5 mg/tamsulosin 0.2 mg will be administered as well as, in a different treatment period, the co-administration of the reference products (AVODART™ and Harnal D).

Each subject enrolled will be allowed to participate in only one cohort (i.e., will receive treatment under fasted or fed conditions) and will participate in both treatment periods. The treatment periods will be separated by a washout period of at least 28 days between dosing. The two cohorts differ only between the administrations of treatments in the absence or presence of food; the remainder of the study assessments and procedures are identical for both cohorts.

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Treatment Arms and Duration

The total duration in the study for each subject will be approximately 2.5 months from screening to the final follow-up visit.

In either the fed or fasted state, subjects in cohorts 1 and 2 will receive:

A: 1 x FDC capsule of dutasteride 0.5 mg/tamsulosin 0.2 mg.B: 1 x dutasteride 0.5 mg capsule and 1x tamsulosin 0.2 mg tablet.

Type and Number of Subjects

Up to 56 healthy male subjects will be enrolled such that approximately 48 subjects complete dosing and critical assessments (24 per cohort).

Analysis

This study is designed to estimate the bioavailability of the FDC capsule formulation of dutasteride 0.5 mg/tamsulosin 0.2 mg under fed and fasted states relative to concomitant dosing of commercial formulations of the two components, and;

For each primary pharmacokinetic (PK) endpoint, point estimates and corresponding 90% confidence intervals will be constructed for the ratio of the geometric mean of the test treatment to the geometric mean of the reference treatment.

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2. INTRODUCTION

2.1. Study Rationale

GlaxoSmithKline (GSK) proposes the development of a fixed dose combination (FDC) of dutasteride 0.5 mg and tamsulosin 0.2mg for once daily oral administration for the treatment of signs and symptoms of benign prostatic hyperplasia (BPH) in men. The doses included in the FDC are the approved daily dosages of AVODART™ (dutasteride) and Harnal D (tamsulosin) for the treatment of signs and symptoms BPH in Asia. To support the development of the FDC, in healthy male subjects this study will investigate the relative bioavailability of the FDC in the fed and fasted states, compared to AVODART™ and Harnal D.

2.2. Brief Background

Benign prostatic hyperplasia is a common condition in the aging male. In the general population, symptoms are reported in nearly 50% of men aged 50 years and pathological changes are found in 88% of men in their ninth decade. BPH manifests as lower urinary tract symptoms (LUTS), including storage symptoms (e.g., urgency, frequency, nocturia) and voiding symptoms (e.g., hesitancy, a weak urine stream, and terminal dribbling). These symptoms can have a severe impact on a patient’s quality of life, leading to worry, discomfort, and a negative impact on the extent to which patients can carry out their normal activities [Barry, 1995]. BPH is a slowly progressive condition characterized by increased prostatic volume. Associated life-long consequences may include reduced urinary flow and acute urinary retention (AUR), exacerbation of LUTS, urosepsis, frequent urinary tract infections, pyelonephritis, and the need for catheterization and surgical intervention (primarily transurethral resection of the prostate [TURP]).

Commonly used and recommended treatment options include pharmacotherapeutic agents such as alpha blockers and 5α-reductase inhibitors (5ARIs). They have different modes of action. Alpha blockers have a rapid onset of action and are believed to act by reducing prostate tone and bladder outlet obstruction. 5ARIs, on the other hand, reduce prostate volume through lowering dihydroxytestosterone (DHT).

GlaxoSmithKline (GSK) completed a 4 year global study: Combination of Dutasterideand Tamsulosin (CombAT) in which dutasteride 0.5 mg and tamsulosin 0.4 mg were co-administered once daily for 4 years. This study demonstrated that the co-administrationof dutasteride and tamsulosin provided superior symptom improvement compared to themonotherapies alone (Roehrborn, 2010). The data supported the approval of co-administration in the USA and Europe in 2008 and also supported the approval of a Fixed Dose Combination (FDC) product in the USA and Europe in 2010. The lower dose of tamsulosin in this study (0.2 mg) is approved and preferred in Asia, considering a key complication associated with the higher dose: postural hypotension.

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3. OBJECTIVE(S) AND ENDPOINT(S)

Objectives Endpoints

Primary

To determine the bioavailability of a FDC capsule formulation of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of one dutasteride 0.5 mg capsule and one tamsulosin hydrochloride 0.2 mg tablet in healthy male subjects in fed and fasted states.

Tamsulosin AUC(0-t) and AUC(0-∞) [defaulting to AUC(0-t) if AUC(0-∞) cannot be consistently determined] and Cmax.

Dutasteride AUC(0-t) and Cmax.

Secondary

To characterize the pharmacokinetics of dutasteride and tamsulosin.

Time to Cmax (tmax) and t1/2 (tamsulosin only) as data permit.

To monitor the safety and tolerability following administration of the dutasteride in healthy adult male subjects in fed and fasted states.

Safety and tolerability of all treatments as assessed by vital signs (blood pressure and pulse rate), ECG measurements and review of adverse events.

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4. STUDY DESIGN

4.1. Overall Design

Figure 1 Study Schematic

This is an open-label, randomized, single dose, two-way crossover study enrolling healthy male subjects, split into two cohorts:

- Cohort 1: subjects will receive study treatment in the fasted state. - Cohort 2: subjects will receive study treatment in the fed state.

In both cohorts, one FDC capsule formulation of dutasteride 0.5 mg/tamsulosin 0.2 mg will be administered as well as, in a different treatment period, the co-administration of the reference products (AVODART™ and Harnal D).

Each subject enrolled will be allowed to participate in only one cohort (i.e., will receive treatment under fasted or fed conditions) and will participate in both treatment periods.

All subjects will:

- Attend a screening visit within 30 days of treatment period 1.

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- Present to the site day -1 of each treatment period for the collection of baseline clinical lab safety samples (such that results are available prior to dosing on day 1).

- Be admitted to the clinical unit on day -1 of each treatment period.

- Administer the study treatment in the morning of day 1 of each treatment period, in either the fed or fasted state as per the randomization schedule.

- Remain in the clinical unit until completion of all assessments, up until the collection of the 72 hour post dose pharmacokinetic (PK) sample.

The two treatment periods will be separated by a minimum washout period of 28 days to ensure that dutasteride is effectively eliminated from the subject between dosing occasions; the washout period will be calculated from day of dosing to the subsequent day of dosing (day 1) in the following Treatment Period.

Upon completion of the second treatment period, or early withdrawal, subjects will return to the clinical unit within 10-14 days for a follow up visit. LSLV will be declared when the final subject has completed this follow-up visit.

4.2. Treatment Arms and Duration

The total duration in the study for each subject will be approximately 2.5 months from screening to the final follow-up visit.

In either the fed or fasted state, subjects in cohorts 1 and 2 will receive:

- A: 1 x FDC capsule of dutasteride 0.5 mg/tamsulosin 0.2mg;- B: 1 x dutasteride 0.5 mg capsule and 1x tamsulosin 0.2mg tablet.

4.3. Type and Number of Subjects

A maximum of 56 subjects will be randomized such that approximately 48 evaluable subjects complete the study (24 per cohort).

4.4. Design Justification

This study is required to confirm the suitability of a FDC capsule formulation of dutasteride/tamsulosin (0.5 mg/0.2 mg).

This study design allows the evaluation of the pharmacokinetics of the FDC after a single dose under both fed and fasted states. The two-way crossover design is well-established and conforms to standard guidelines of a bioavailability and a bioequivalence study.

The candidate test formulation will be assessed on the basis of the Test/Reference ratios, confidence intervals (CIs) and variability for Cmax (rate of absorption) and Area Under Concentration-time curve (AUC) (extent of absorption).

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4.5. Dose Justification

The oral doses proposed for the two drugs within FDC, dutasteride/tamsulosin (0.5 mg/0.2 mg), are the approved daily dosages at which these drugs are marketed for BPH in Asia.

4.6. Benefit:Risk Assessment

Summaries of findings from both clinical and non-clinical studies conducted with GSKGI198745+GI138525 can be found in the Investigator’s Brochure and product information sheets. The following section outlines the risk assessment and mitigation strategy for this protocol.

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4.6.1. Risk Assessment

Please refer to the table below for a comprehensive list of risk factors. While this is a single dose study the information below is provided for completeness for the investigator.

Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

Dutasteride

Male Breast Cancer There have been three cases of male breast cancer reported in dutasteride clinical trials, one of which was in the placebo group. GSK has received post marketing reports of male breast cancer.

Subjects with current or history of breast cancer or clinical breast examination finding suggestive of breast malignancy are excluded from the study.

Information regarding male breast cancer will be communicated through the protocol, ICF, dutasteride label and the IB.

High-grade prostate cancer In a 4-year study of over 8,000 men aged 50 to 75, with a prior negative biopsy for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), 1,517 men were diagnosed with prostate cancer. There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). There was no increased incidence in Gleason 5-6 or 7-10 prostate cancers. No causal relationship between dutasteride and high grade prostate cancer has been established. The clinical significance of the numerical imbalance is unknown. The observation is relevant to subjects with increased PSA levels who were on study drug for a prolonged period.

Patients with prior medical history or evidence of prostate cancer will be excluded from the study.

Information regarding prostate cancer will be communicated through the protocol, ICF, dutasteride label and the IB.

As with most drug-related adverse events, it would be anticipated that the frequency of AEs would not generally be the same given the lower exposures and shorter duration achieved in a single dose study.

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Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

Cardiovascular events, including, cardiac failure REDUCE and CombAT each showed an imbalance in percentages of subjects with ‘cardiac failure’ composite event term. In REDUCE, the percentages of subjects with a composite cardiac failure event were 0.7% (30/4105) in the dutasteride group and 0.4% (16/4126) in the placebo group. In CombAT, the percentages of subjects with a composite cardiac failure event were 0.9% (14/1610) in the dutasteride+tamsulosin group, 0.2% (4/1623) in the dutasteride group, and 0.6% (10/1611) in the tamsulosin group.

Only healthy subjects will be enrolled in this study.

Information regarding possible cardiac failure will be communicated through the protocol, ICF, dutasteride label and the IB.

Interference with PSA test, potentially leading to undiagnosed prostate cancer.

Dutasteride causes a decrease in mean serum PSA levels by approximately 50% after six months of treatment Effect on PSA has been known only after repeat dosing and reversible after discontinuation. This effect will likely be insignificant as the study recruits healthy subjects, who receive only three doses of dutasteride.

Per exclusion criteria (Section 5.2), investigator needs to make every appropriate effort to exclude the possibility of prostate cancer.

Given the duration of dutasteride exposure is quite limited in this study design, it would not be anticipated that a meaningful effect on PSA would occur.

Potential for decreased male fertility due to effects on sperm/semen characteristics

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in normal volunteers aged 18 to 52 (n=27 dutasteride, n=23 placebo) throughout 52 weeks of treatment and 24 weeks of post treatment follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, in the dutasteride group when adjusted for changes from baseline in the placebo group. The clinical significance of dutasteride's effect on semen characteristics for an individual patient’s

Information regarding possible effects on fertility will be communicated through the protocol, ICF, dutasteride label and the IB.

As with most drug-related adverse events, it would be anticipated that the frequency of AEs would not generally be the same given the lower exposures and shorter duration achieved in a single dose study.

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Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

fertility is not known.

Interference with formation of external genitalia in the male fetus if a woman carrying a male fetus is exposed to dutasteride

Feminization of the external genitalia was noted in male fetuses of female rats and rabbits orally dosed with dutasteride. However, i.v. administration of dutasteride to pregnant Rhesus monkeys during embryofetal development at doses of up to 2010 nanograms/animal/day did not produce adverse maternal or fetal toxicity. This dose represents a multiple of at least 186-fold (nanograms/kg basis) the potential maximum daily dose in a 50 kg woman, resulting from exposure to 5 mL semen (assuming 100% absorption) from a dutasteride-treated man.

In consideration of supportive data presented here, and consistent with product labeling in the U.S., contraception is not specifically required as the risk related to exposure is considered negligible.

Details of all pregnancies in female partners who are pregnant or become pregnant of male subjects should be self reported to the site after the start of dosing and until 50 days post-last dose.

Sexual adverse events including the potential for the persistence of sexual adverse events

Impotence, decreased libido and ejaculation disorder were reported more frequently in patients on dutasteride than on comparators in clinical trials. Some of these events persisted after stopping dutasteride.

Information regarding possible effects on sexual function, including persistence after drug withdrawal, will be communicated through the protocol, ICF, dutasteride label and the IB.

As with most drug-related adverse events, it would be anticipated that the frequency of AEs would not generally be the same given the lower exposures and shorter duration achieved in a single dose study.

Investigator may withdraw patient(s) from the study due to adverse event, as per their clinical judgment.

Depressed mood In animal models, there is a theoretical basis for alteration in mood with 5ARI treatment based on known effects on neurosteroid metabolism and/or transient effects on hippocampal neurogenesis, and evidence that dutasteride crosses the blood-brain

Information regarding possible effects of depressed mood will be communicated through the protocol, ICF, dutasteride label and the IB.

As with most drug-related adverse events, it would be

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Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

barrier.

A review of data from large clinical trial programs for BPH and prostate cancer risk reduction and data from a smaller study for alopecia found no evidence of an imbalance of reported depression associated with dutasteride compared to placebo or active comparator.

Post marketing reports indicate some patients experience a rapid onset of depressed mood after starting dutasteride, and resolution on cessation of treatment.

anticipated that the frequency of AEs would not generally be the same given the lower exposures and shorter duration achieved in a single dose study.

Allergic reactions The incidences of allergic reactions observed in placebo-controlled trials of dutasteride are low and similar between treatment groups. GSK has received post-marketing spontaneous reports of allergic reactions with dutasteride that led to inclusion of allergic reactions in the Adverse Reactions section of the Global Prescribing Information.

Subjects with known hypersensitivity to either product are excluded from the study.

Information regarding allergic reactions will be communicated through the protocol, ICF, dutasteride label and the IB.

Tamsulosin

Hypotension As with other alpha-1 adrenergic blockers, orthostatic hypotension can occur in patients treated with tamsulosin, which in rare cases can result in syncope.

Exclusion of subjects with a history of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal reactions or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury.

Administration will be done under medical supervision

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Potential Risk of Clinical Significance Summary of Data/Rationale for Risk Mitigation Strategy

in a hospitalized setting.

Orthostatic vital signs are measured during the first day of dosing. Subjects who experience orthostatic hypotension are required to remain recumbent until orthostasis has resolved and should be treated at the discretion of the Investigator.

Study Procedures

Exposure to women. Dutasteride is absorbed through the skin. Administration will be done under medical supervision in a hospitalized setting. Female site staff must avoid contact with leaking capsules.

This risk will be communicated to female site staff through the Product Information section of the Study Reference Manual and will be instructed to use gloves when administering dutasteride.

Blood Sampling An intravenous cannula will be inserted into subjects to obtain blood samples for testing. This may cause some pain, discomfort, bruising and redness/irritation at the site of injection.

Subjects will be monitored closely by site staff during the visits. The cannula will be removed if this is causing pain and discomfort.

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4.6.2. Benefit Assessment

Subjects enrolled into this study will be healthy volunteers. There will not be a direct benefit to the subject for taking part in this study.

4.6.3. Overall Benefit:Risk Conclusion

Taking into account the measures taken to minimized risk to subjects participating in this study, the potential risks identified in association with the FDC and with both components administered separately are justified by the anticipated benefits that may be afforded to patients for the management of BPH in adult males.

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 IB/IB supplement(s), product label, add other pertinent documents.

Deviations from inclusion and exclusion criteria are not allowed because they can potentially jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

5.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

AGE

1. Male subjects aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.

TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY

2. Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring.

3. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor if required agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.

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WEIGHT

4. Body weight 50 kg and body mass index (BMI) within the range 18 – 30 kg/m2

(inclusive).

INFORMED CONSENT

5. Capable of giving signed informed consent as described in Section 10.2 which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

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. ALT and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

3. History of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal reactions or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject atrisk of injury.

4. History of diabetes or peptic ulcer disease which is uncontrolled by medical management.

5. Current or history of:- Breast cancer or clinical breast examination finding suggestive of breast

malignancy.- Malignancy within the past five years, except for basal cell carcinoma of the

skin. Subjects with a prior malignancy who have had no evidence of disease for at least the past 5 years are eligible.

6. Prior medical history or evidence of prostate cancer (e.g., positive biopsy, or suspicious ultrasound, or suspicious digital rectal examination [DRE]). Patients with suspicious ultrasound or DRE who have had a negative biopsy within the preceding 6 months and stable prostate specific antigen (PSA) are eligible for the study.

Note: The investigator should make every appropriate effort to exclude the possibility of prostate cancer, including consideration of prostate biopsy in any subject with a known abnormal PSA.

7. Based on averaged QTc values of triplicate ECGs obtained over a brief recording period:

- QTcF > 450 msec

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CONCOMITANT MEDICATIONS

8. Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study (See Section 6.10).

RELEVANT HABITS

9. History of regular alcohol consumption within 6 months of the study defined as:

For US sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof distilled spirits.

CONTRAINDICATIONS

10. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA

11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. .

12. A positive pre-study drug/alcohol screen.

13. A positive test for HIV antibody.

14. Where participation in the study would result in donation of blood or blood products in excess of 500 mL over the duration of the study.

15. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 50 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

16. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

17. Unable to swallow and retain oral medication.

5.3. Screening/Baseline/Run-in Failures

Screen failures are defined as subjects who consent to participate in the clinical trial but are never subsequently randomized. In order to ensure transparent reporting of screen failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, and respond to queries from Regulatory authorities, a minimal

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set of screen failure information is required including Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events.

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/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”.

A subject may withdraw from study treatment at any time at his own request, or may be withdrawn at any time at the discretion of the investigator for safety, behavioral 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.

For an individual study participant, stopping criteria include, but are not limited to:

Severe signs or symptoms, or significant changes in any of the safety assessments, that put the safety of the individual at risk (e.g., ECG, vital signs, laboratory tests, etc), as judged by the Principal Investigator in consultation with the Medical Monitor if necessary.

5.5. Subject and Study Completion

A completed subject is one who has completed all phases of the study including the in follow-up visit.

The end of the study is defined as the last subject’s last on site visit to the study centre; which is the in house follow-up visit (10-14 days post last dose).

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6. STUDY TREATMENT

6.1. Investigational Product and Other Study Treatment

The term ‘study treatment’ is used throughout the protocol to describe any combination of products received by the subject as per the protocol design. Study treatment may therefore refer to the individual study treatments or the combination of those study treatments.

Study Treatment

Product name:FDC

Dutasteride / Tamsulosin HCl

Combination

Harnal D Tablets (Tamsulosin HCl

Commercially available

AVODART Capsules(Dutasteride; Commercially

available)

Formulation description:

Each capsule contains a mixture

of dutasteride formulation CR

(equivalent to 0.5 mg) and coated tamsulosin DF

(equivalent to 0.2 mg tamsulosin)

N/A N/A

Dosage form:(Hard) Shell

CapsuleOral disintegrating

tabletSoft gelatin capsule

Unit dose strength(s)/Dosage level(s):

0.5 mg / 0.2 mg 0.2 mg 0.5 mg

Route of Administration Oral

Dosing instructions: Once

Physical description:Colored Size 1 hard

shell capsule

White, round standard convex

tablet print on face

Oblong, size 6, dull yellow capsules.

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6.2. Treatment Assignment

Subjects will be assigned to one of two treatment sequences (AB or BA) in accordance with the randomization schedule generated by Clinical Statistics, prior to the start of the study, using validated internal software.

A description of each regimen is provided in the table below:

Regimen Description

A FDC - Fixed dose combination capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg). Each capsule will contain a mixture of dutasteride (0.5 mg) and tamsulosin (0.2 mg).

B Co-administration of dutasteride 0.5 mg capsule and tamsulosin hydrochloride 0.2 mg tablet.

6.3. Blinding

This will be an open-label study.

6.4. Packaging and Labeling

The contents of the label will be in accordance with all applicable regulatory requirements.

The Harnal-D Tablets will be provided in the commercial packaging.

Commercially available AVODART (dutasteride) soft gelatin capsules will be purchased by the study site to be dosed along with Harnal-D Tablets will be supplied in induction sealed HDPE containers with CRC caps.

The FDC capsules containing mixture of dutasteride (0.5 mg) and tamsulosin HCl (0.2 mg) will be extemporaneously compounded at the clinical site prior to dosing.

The dutasteride pellets (0.5 mg) and tamsulosin (0.2 mg) to be used in the extemporaneously compounded FDC will be supplied to the clinic packed in HDPE bottles.

All study medication will be labelled with the study number, drug name and strength, quantity, and lot number.

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6.5. Preparation/Handling/Storage/Accountability

A description of the methods and materials required for extemporaneous compounding of the FDC capsule will be detailed in a Study Specific Technical Agreement/Memo (TTS) or Pharmacy Manual which will be accompanied by a Quality Agreement.

The compounding procedure for each capsule involves weighing out pellets equivalent to 0.2 mg of tamsulosin HCl and transferring into a hard shell capsule body. This is followed by weighing out hot melt extrudate pellets equivalent to 0.5 mg of dutasteride and transferring into the hard-shell capsule body and closing and locking the hard shell capsule.

The Harnal-D Tablet storage instructions state they must be stored in the original packaging at room temperature.

Dutasteride 0.5 mg capsules (AVODART) should be stored at or below 25°C.

Per the extemporaneous compounding materials, Tamsulosin HCl Pellets should be stored at or below 25°C and Dutasteride pellets (0.5 mg) should be stored at or below 25°C.

Only subjects enrolled in the study may receive study treatment and only authorized site staff may supply or administer study treatment. All study treatments must be stored in a secure environmentally controlled and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) is responsible for study treatment accountability, reconciliation, and record maintenance (i.e. receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment are provided in the SRM.

Dutasteride is absorbed through the skin. Female site staff must avoid contact with leaking capsules.

For males, under normal conditions of handling and administration, study treatment is not expected to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

6.6. Compliance with Study Treatment Administration

When the individual dose for a subject is prepared from a bulk supply, the preparation of the dose will be confirmed by a second member of the study site staff.

When subjects are dosed at the study site, they will receive study treatment directly from the investigator or designee, under medical supervision. The date and time of each dose administered in the clinic will be recorded in the source documents. The dose of study

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treatment and study participant identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study treatment. Study site personnel will examine each subject’s mouth to ensure that the study treatment was ingested.

6.7. Treatment of Study Treatment Overdose

GSK does not recommend specific treatment for an overdose. The investigator or physician in charge of the subject at the time will use clinical judgment to treat any overdose.

6.8. Treatment after the End of the Study

Subjects will not receive any additional treatment from GSK after completion of the study because only healthy volunteers are eligible for study participation.

6.9. Lifestyle and/or Dietary Restrictions

6.9.1. Meals and Dietary Restrictions

Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication until after the final dose.

Per the randomization schedule subjects will be administered the treatment in either the fed or fasted states as described in below.

COHORT 1 (fasted state) Day 1:

In each treatment period, subjects will be required to fast for approximately 10 hours prior to dosing with the exception of water, which will be allowed freely except for 1 hour before and 1 hour after dosing.

COHORT 2 (fed state) Day 1:

In each treatment period, subjects will be required to fast for approximately 9.5 hours prior to dosing. Subjects will be served breakfast 30 minutes prior to dosing and will be given approximately 25 minutes to complete and must finish within this period. Administration of study medication will occur approximately 30 minutes after the start of breakfast. Every effort must be made by the subject to consume the entire meal within 25 minutes. These subjects will receive the standard FDA ‘high fat’ breakfast (2 eggs fried in butter, 2 strips bacon, 4 oz. hash brown potatoes, 8 oz. whole milk, 2 slices of toast or biscuit with 2 tsp. butter). Following dosing, subjects will not be allowed food until 4 hours post dose.

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COHORTS 1 & 2 Days 1, 2, 3 and 4:

Following dosing on Day 1, subjects will not be allowed food until 4 hours post dose. All other meals will be served at the times outlined in the Time and Events Table (Section 7.1) in a seated position. Meals served will be standardized throughout the study i.e., the same meals will be served to all ethnic groups (if applicable). Snacks can be served at the discretion of the site but should be the same throughout the study.

6.9.2. Caffeine, Alcohol and Tobacco

During each dosing session, subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 24 hours prior to the start of dosing until collection of the final PK sample during each session.

During each dosing session, subjects will abstain from alcohol for 24 hours prior to the start of dosing until collection of the final PK sample during each session.

Subjects who use tobacco products will be instructed that use of nicotine-containing products (including nicotine patches) will not be permitted while they are in the Clinical Unit.

6.9.3. Activity

Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection for clinical laboratory tests. Subjects may participate in light recreational activities during studies (e.g., watch television, read).

6.10. Concomitant Medications and Non-Drug Therapies

6.10.1. Permitted Medications and Non-Drug Therapies

Acetaminophen (paracetamol), at doses of 2 grams/day is permitted for use any time during the study. Other concomitant medication may be considered on a case by case basis by the investigator in consultation with the GSK Medical Monitor if required.

6.10.2. Prohibited Medications and Non-Drug Therapies

Subjects must abstain from taking prescription or non-prescription drugs (including vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until completion of the follow-up visit, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study.

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7. STUDY ASSESSMENTS AND PROCEDURES

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table, are essential and required for study conduct.

This section lists the procedures and parameters of each planned study assessment. The exact timing of each assessment is listed in the Time and Events Table Section 7.1.

The following points must be noted:

If assessments are scheduled for the same nominal time, THEN the assessments should occur in the following order:

1. 12-lead ECG

2. vital signs

3. blood draws.

Note: The timing of the assessments should allow the blood draw to occur at the exact nominal time.

The timing and number of planned study assessments, including safety, and PK assessments may be altered during the course of the study based on newly available data (e.g., to obtain data closer to the time of peak serum concentrations) to ensure appropriate monitoring.

The change in timing or addition of time points for any planned study assessments must be documented in a Note to File which is approved by the relevant GSK study team member and then archived in the study sponsor and site study files, but this will not constitute a protocol amendment.

The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the Informed Consent Form.

No more than 500 mL of blood will be collected over the duration of the study, including any extra assessments that may be required.

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7.1. Time and Events Table

Procedure

Screening (up to 30 days prior to Day -1)

Treatment Periods 1 & 2Minimum 28 day washout between

day 1 of each treatment period

Follow-up10-14 days

(post-last dose)3

NotesDay -1

Day 1

Day 2

Day 3

Day 4

Informed consent XInclusion and exclusion criteria X X Refer to Section 5.1 and Section 5.2 for Inclusion and Exclusion Criteria.Demography XFull physical exam X Includes height, weight and BMI.Medical history X Includes substance usage, past and current medical conditions and medications.

HIV, Hep B and Hep C screen XLaboratory assessments X X1

12-lead ECG X X X XScreening Visit only: Triplicate ECG measurements to be collected.Day 1 & 2: Single ECG measurements to be collected at 4 h & 24 h post dose.

Vital signs X X1 X XDay -1: Duplicate measurement. Baseline is defined as the mean of two measurements.Day 2: Vital sign measurements to be collected at 24 h post dose.

Orthostatic Vital Signs X Day 1 at pre-dose and 4 hours post-dose.Urine Drug/ Alcohol test (serum) X XBrief physical exam X X A Brief Physical Exam may be collected at either Day -1 OR Day 1 pre-dose.

Study Treatment XTreatment to be administered in the morning per the randomization schedule. Subjects to remain in a sitting or semi-supine position for approximately 4 hours after dosing.

PK Sampling X X X XPK sampling times: Pre-dose, 15 min, 30 min, 45 min, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 36, 48 & 72 h post dose.

Meals X X X X X

Per the randomization schedule subjects to be dosed in either the fed or fasted states. Refer to Section 6.9.2 for further information. For both cohorts, following dosing, subjects will not be allowed food until 4 hours post dose. The meal can be given once all other assessments at the 4 h time point have been collected. The time will be recorded in the eCRF. The time of breakfast completion will also be captured on Day 1 for the fed cohort.

Admission to the unit X X X X X Subjects to remain at the clinical unit until the collection of the 72 hr PK sample.Outpatient Visit X XAdverse Event(s) 2 ============================================== Concomitant Medication ============================================== 1. All results must be reviewed by a physician prior to dosing on Day 1. 2. AEs/SAEs will be collected from the start of dosing up until the follow-up visit. Any SAEs related to study participation or concomitant medications will be recorded from the time a subject consents to

participate in the study and until the follow-up visit. 3. Subjects will present to the site for the follow-up visit 10-14 days post last dose for Vital Signs, ECG, AE & concomitant medication review. The final subject to complete this visit will determine formal

study end for study analysis (i.e., Last Subject Last Visit).

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7.2. Screening and Critical Baseline Assessments

The following demographic parameters will be captured: year of birth, sex, race and ethnicity.

Medical/medication/family history will be assessed as related to the inclusion/exclusion criteria listed in Section 5.

Procedures conducted as part of the subject’s routine clinical management (e.g., physical exam, blood counts) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided the procedure meets the protocol-defined criteria and has been performed in the timeframe of the study.

7.3. Safety

Planned time points for all safety assessments are listed in the Time and Events Table (Section 7.1). Additional time points for safety tests (such as vital signs, physical exams and laboratory safety tests) may be added during the course of the study based on newly available data to ensure appropriate safety monitoring.

7.3.1. Adverse Events (AE) and Serious Adverse Events (SAEs)

The definitions of an AE or SAE can be found in Appendix 2.

The investigator and their designees are responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

7.3.1.1. Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be continuously monitored and collected from the start of Study Treatment until the follow-up contact (see Section 7.3.1.3), per the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after obtaining informed consent may be recorded on the Medical History/Current Medical Conditions section of the CRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time a subject consents to participate in the study up to and including any follow-up contact.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in Appendix 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/she considers the event reasonably related to the study treatment or study participation, the investigator must promptly notify GSK.

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If an AE occurs which, in the investigator’s judgment, is possibly related to suicidality a suicide Possible Suicidality-related Adverse Event (PSRAE) form should be completed by investigators or their designated staff, of the circumstances surrounding possibly suicidality-related AEs (refer to the SRM for more information).

NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in Appendix 2.

7.3.1.2. Method of Detecting AEs and SAEs

Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?”

7.3.1.3. Follow-up of AEs and SAEs

After the initial AE/SAE report, the investigator is required to proactively follow each subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in Section 4.6.1) will be followed until resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up (as defined in Section 5.4). Further information on follow-up procedures is given in Appendix 2.

7.3.1.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to study treatment (even for non- interventional post-marketing studies) is essential so that legal obligations and ethical responsibilities towards the safety of subjects and the safety of a product under clinical investigation are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

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An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

7.3.2. Pregnancy

Details of all pregnancies in female partners who are pregnant or become pregnantof male subjects will be self reported to the site after the start of dosing and until 50 days post-last dose.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks of learning of the pregnancy and should follow the procedures outlined in Appendix 3.

7.3.3. Physical Exams

A complete physical examination will include, at a minimum, assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and weight will also be measured and recorded.

A DRE may also be performed, as per the investigator’s judgment, to confirm the patient does not meet exclusion criteria.

A brief physical examination will include, at a minimum assessments of the skin,lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious illnesses.

7.3.4. Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will include temperature, systolic and diastolic blood pressure and pulse rate.

- Day - 1: vital signs measurements will be performed in duplicate. The average of these measurements will be considered as the baseline. All measurements will be recorded into the CRF.

At all other time points, single vital sign measurements will be collected for the remainder of the study.

7.3.5. Orthostatic Vital Signs

In order to obtain orthostatic vital signs, both orthostatic blood pressure and pulse rate will be taken in a sequential order as follows:

Supine (1 measurement)- After the subject has been supine for at least 5 minutes.

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Sitting (1 measurement)- At 2 minutes after the subject has been sitting on edge of bed with feet on floor

(or dangling feet from bedside depending on height of bed).

Standing (2 measurements)- At 1 minute and 3 minutes after subject has been standing.

Subjects meeting the following criteria assessed during orthostatic testing will be required to remain recumbent until orthostasis has resolved:

a decrease in systolic blood pressure of > 20 mmHg, or a decrease in diastolic blood pressure > 10 mmHg, or an increase in pulse rate of > 20 beats per minute, or any symptoms of faintness, light headedness, dizziness, spinning sensation, or vertigo;

If orthostatic hypotension occurs, it should be treated at the discretion of the Investigator.

All readings will be recorded in the case report form (CRF).

7.3.6. Electrocardiogram (ECG)

12-lead ECGs will be obtained in semi-supine position after 5 minutes rest at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcF intervals.

- Screening Visit only: Triplicate ECGs will be collected at screening and averaged to determine QTcF eligibility.

- At all other time points, single ECG measurements will be collected. If measurements are out of range, investigator to repeat in triplicate to confirm.

7.3.7. Clinical Safety Laboratory Assessments

All protocol required laboratory assessments, as defined below must be conducted in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.Laboratory requisition forms (if applicable) must be completed and samples must be clearly labeled with the subject number, protocol number, site/centre number, and visit date. Details for the preparation and shipment of samples will be provided by the institution’s local laboratory and are detailed in the laboratory manual. Reference ranges for all safety parameters will be provided to the site by the laboratory responsible for the assessments.

If additional non-protocol specified laboratory assessments are performed at the institution’s local laboratory and result in a change in subject management or are considered clinically significant by the investigator (e.g., SAE or AE or dose modification) the results must be recorded in the CRF.

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Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed in Table below.

All laboratory tests with values that are considered clinically significantly abnormal during participation in the study or within 7 days after the last dose of study treatment should be repeated until the values return to normal or baseline. If such values do not return to normal within a period judged reasonable by the investigator, the etiology should be identified and the sponsor notified.

Table 1 Protocol Required Safety Laboratory Assessments

Laboratory Assessments

Parameters

Hematology Platelet Count RBC Indices: WBC count with Differential:RBC Count MCV NeutrophilsHemoglobin MCH LymphocytesHematocrit Monocytes

EosinophilsBasophils

Clinical Chemistry 1

BUN Potassium AST (SGOT) Total and direct bilirubin

Creatinine Sodium ALT (SGPT) Total ProteinGlucose Calcium Alkaline phosphatise Albumin

Routine Urinalysis

Specific gravity pH, glucose, protein, blood and ketones by dipstick Microscopic examination (if blood or protein is abnormal)

Other Screening Tests

HIV Hepatitis B (HBsAg) Hepatitis C (Hep C antibody) Alcohol and drug screen (to include at minimum: amphetamines,

barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)NOTES :1. Local urine testing will be standard for the protocol unless serum testing is required by local

regulation or ethics committee.

7.4. Pharmacokinetics

7.4.1. Blood Sample Collection

Blood samples for pharmacokinetic (PK) analysis of dutasteride and tamsulosin will be collected at the time points indicated in Section 7.1, Time and Events Table. The actual date and time of each blood sample collection will be recorded. The timing of PK samples may be altered and/or PK samples may be obtained at additional time points to ensure thorough PK monitoring.

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Blood samples (approximately 2 mL) for pharmacokinetic analysis of dutasteride and tamsulosin will be collected into 2 mL Clot Activator Blood Tubes. Immediately after the sample is drawn, gently invert the tube 5 times. Allow sample to stand at room temperature for at least 20 minutes (but no more than 40 minutes) to permit clot formation. Centrifuge the sample at room temperature or under refrigeration 2 ºC to 8 ºC at 2500 to 3000 rpm (approximately 650 to 1450 x g) for 10 to 15 minutes to achieve a clear serum layer over the red cells (the speed and time may be varied according to the make and model of centrifuge used). Immediately transfer the resulting serum into one appropriately labeled 1.8 mL Round Bottom Skirted Cryovia tube (Nunc #34904), cap and freeze samples at -20 C until shipment.

7.4.2. Sample Analysis

Serum analysis will be performed under the control of PTS-DMPK/Scinovo, GlaxoSmithKline, the details of which will be included in the Study Reference Manual (SRM). Concentrations of dutasteride and tamsulosin will be determined in serumsamples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).

Once the serum has been analyzed for dutasteride and tamsulosin any remaining serum may be analyzed for other compound-related metabolites and the results reported under a separate PTS-DMPK/Scinovo, GlaxoSmithKline protocol.

8. DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system. Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and an internal validated medication dictionary, GSKDrug.

CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy. Subject initials will not be collected or transmitted to GSK according to GSK policy.

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9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES

Bioavailability

This study is designed to estimate the relative bioavailability of the FDC formulations of dutasteride 0.5 mg/tamsulosin HCl 0.2 mg relative to concomitant dosing of commercial formulations of the two components under fed and fasted states.

No formal statistical hypotheses will be tested. An estimation approach will be used to evaluate the comparisons of interest, with point estimates and associated 90% confidence intervals presented to provide a range of plausible values for the comparisons.

9.1. Sample Size Considerations

9.1.1. Sample Size Assumptions

The table below summarizes the observed estimate of within subject CV for the primary endpoints AUC and Cmax of tamsulosin and dutasteride from study ARI117057.

PK Parameter CVw

Tamsulosin AUC(0-∞) 20.0%

Cmax 25.7%

Dutasteride AUC(0-t) 13.2%

Cmax 28.2%

The largest of the within subject CV estimates is 25.7% for Tamsulosin and 28.2% for Dutasteride, which translates to a standard deviation (SD) of 0.255 and 0.258, respectively on the natural log scale. Based on these SDs, the half width of the 90% confidence intervals for Tamsulosin and Dutasteride will be within 14% and 15% of the point estimate, respectively, i.e., if we assume a treatment ratio effect of 1 (no effect), the 90% CI is equivalent to (0.88, 1.14), and (0.87, 1.15), respectively, based on a sample size of 24 statistically evaluable subjects in each cohort.

9.1.2. Sample Size Sensitivity

Assuming the within subject CV for Tamsulosin or Dutasteride is higher than expected or the number of statistically evaluable subjects is different from 24, the table on the following page below shows the precision (the half width of the 90% confidence interval):

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Evaluable Subjects CVw Precision

20

26% 15%

28% 16%

32% 19%

24

26% 14%

28% 15%

32% 17%

28

26% 12%

28% 13%

32% 15%

9.1.3. Sample Size Re-estimation or Adjustment

No sample size re-estimation will be performed.

9.2. Data Analysis Considerations

9.2.1. Interim Analysis

A formal unblinded pharmacokinetic interim analysis would be conducted after all subjects have completed treatment period 2.

Unblinded Randomization codes will be used for the interim analysis.

9.3. Key Elements of Analysis Plan

9.3.1. Final Analyses

Each cohort will be analyzed separately; there will be no combination of data across cohorts. Each cohort will be analyzed with the same methods.

9.3.1.1. Pharmacokinetic Analyses

Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology Modeling & Simulation department within GlaxoSmithKline. Serum dutasteride and tamsulosin concentration-time data will be analyzed by non-compartmental methods with Phoenix 6.3 or greater. Calculations will be based on the actual sampling times recorded during the study. From the serum concentration-time data, the following pharmacokinetic parameters will be determined, as data permit: maximum observed serum concentration (Cmax), time to Cmax (tmax) and area under the serum concentration-time curve [AUC(0-t)]. For tamsulosin, half-life (t½) and AUC(0-∞) will also be computed, as permitted by the data.

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Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively. All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D.

Statistical analyses of the pharmacokinetic parameter data will be the responsibility of Clinical Statistics, GlaxoSmithKline.

Following loge-transformation, AUC(0-∞), AUC(0-t) and Cmax of tamsulosin and AUC(0-t)

and Cmax of dutasteride of cohort 1 (Fasted) and cohort 2 (Fed) will be separately analyzed using a mixed effects model with fixed effect terms for period and treatment. Subject will be treated as a random effect in the model. Point estimates and their associated 90% confidence intervals will be constructed for the differences, B-A. The point estimates and their associated 90% confidence interval will then be back-transformed to provide point estimates and 90% confidence intervals for the ratio, B:A in both the cohorts separately.

The within-subject coefficients of variation (CVw) for AUC(0-∞), AUC(0-t) and Cmax will be calculated based on the loge-normal distribution where:

CVw(%)= SQRT(exp(MSE) – 1) x 100

MSE is the residual mean squared error from the model. CVw represents a pooled measure of within-subject variability across regimens.

Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of the residual plots. Normality will be examined by normal probability plots, while homogeneity of variance will be assessed by plotting the residuals against the predicted values for the model.

Tmax of tamsulosin and dutasteride of cohort 1(Fasted) and cohort 2 (Fed) will be separately analyzed with the non-parametric Wilcoxon Matched Pairs Method [Steinijans, 1983] to compute point estimates and associated 90% confidence intervals for the median differences, B-A in both the cohorts separately.

Further details of the planned analyses will be provided in the RAP.

9.3.1.2. Safety Analyses

Safety data will be presented in tabular and/or graphical format and summarized descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.

10. STUDY GOVERNANCE CONSIDERATIONS

10.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrollment of subjects begins.

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10.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a site, GSK will obtain favorable 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.

Obtaining signed informed consent.

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to IRB/IEC).

GSK will provide full details of the above procedures, either verbally, in writing, or both.

Signed informed consent must be obtained for each subject prior to participation in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate informed consent) and the clinical protocol should be concurrently submitted for approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the clinical protocol where required by regulatory authorities. In this situation, written approval of the clinical protocol should state that approval of optional assessments is being deferred and the study, with the exception of the optional assessments, can be initiated.

10.3. Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK will monitor the study and site activity to verify that the:

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Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.

10.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study.

In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

10.5. Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations including GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking such action with the investigator or the head of the medical institution (where applicable). When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK willpromptly 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.

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10.6. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken.

The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, GSK standards/procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, archival at an off-site facility or transfer of ownership of the records in the event the investigator is no longer associated withthe site.

10.7. Provision of Study Results to Investigators, Posting of Information on Publically Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

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.

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A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

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11. REFERENCES

AVODART (dutasteride 0.5 mg) Product Information. NA, October, 2014

Barry MJ, O’Leary MP. Advances in benign prostatic hyperplasia. The development and clinical utility of symptom scores. Urol Clin North Am 1995;22:299-307.

FLOMAX (Tamsulosin hydrochloride 0.4 mg) Product Information. July, 2011

GlaxoSmithKline Document Number UM2008/00364/01. ARI40006. – A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy and Safety of Dutasteride 0.5mg Administered Orally Once Daily for Four Years to Reduce the Risk of Biopsy-Detectable Prostate Cancer. 23-FEB-2010

GlaxoSmithKline Document Number ZM2007/00022/00. ARI109882. An Open-Label, Randomized, Single Dose Three-Period Partial Crossover Study to Determine the Bioequivalence and Food Effect of a Combination Capsule Formulation of Dutasteride and Tamsulosin Hydrochloride (0.5mg/0.4mg) Compared to Concomitant Dosing of AVODART™ 0.5mg and Flomax 0.4mg Commercial Capsules in Healthy Male Subjects. August 2007.

HARNAL-D (Tamsulosin hydrochloride 0.2mg) Product Information. NA, 2012.

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

Napalkov P, Maisonneuve P, Boyle P. Worldwide patterns of prevalence and mortality from benign prostatic hyperplasia. Urology 1995 Sep;46(3 Suppl A):41-6.

Roehrborn, CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorosi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010 Nov;58(5):801.

Steinijans VW, Diletti, E. Statistical Analysis of Bioavailability Studies: Parametric and Nonparametric Confidence Intervals. Eur J Clin Pharmacol, 1983;24:127-136.

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12. APPENDICES

12.1. Appendix 1: Abbreviations and Trademarks

Abbreviations

AE Adverse EventALT Alanine aminotransferase (SGPT)ANOVA Analysis of VarianceAST Aspartate aminotransferase (SGOT)5AR 5α-reductase AUC Area under concentration-time curveBE BioequivalenceBMI Body mass indexBP Blood pressureBPH Benign prostatic hyperplasiaBPM Beat Per MinuteBQL Below the quantification limitBUN Blood urea nitrogenCBC Complete blood countCDMP Clinical Document Management and PublishingCI Confidence IntervalCIB Clinical Investigator’s BrochureCLr Renal clearanceCL Systemic clearance of parent drugCmax Maximum observed drug concentrationCmin Minimum observed concentrationCO2 Carbon dioxideCONSORT Consolidated Standards of Reporting TrialsCPK Creatine phosphokinaseCPMS Clinical Pharmacology Modelling & SimulationCPSR Clinical Pharmacology Study ReportCP-RAP Clinical Pharmacology Reporting and Analysis PlanCRF Case Report FormCRO Contract Research OrganizationCRU Clinical Research UnitCτ Pre-dose (trough) concentration at the end of the dosing

intervalCt Last observed quantifiable concentrationCS Clinical StatisticsCV Coefficient of varianceDBP Diastolic blood pressureDDI Drug-drug interactionDHT DihydrotestosteroneDDS Drug Development SciencesDILI Drug Induced Liver Injury

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DMPK Drug Metabolism and PharmacokineticsDNA Deoxyribonucleic acidDRE Digital rectal examinationECG ElectrocardiogramEDC Electronic data captureEISR Expedited Investigator Safety ReportFDA Food and drug administrationFTIH First time in humansGCP Good Clinical PracticeGGT Gamma glutamyltransferaseGSK GlaxoSmithKlineGSP Global Clinical Safety and PharmacovigilenceHBsAg Hepatitis B surface antigenHIV Human Immunodeficiency Virush/hr Hour(s)HR Heart rateHWE Hardy-Weinberg EquilibriumIB Investigator’s BrochureICH International Conference on Harmonization of Technical

Requirements for Registration of Pharmaceuticals for Human Use

IDMC Independent Data Monitoring CommitteeIDSL Integrated Data Standards LibraryIEC Independent Ethics CommitteeIND Investigational New DrugIP Investigational ProductIRB Institutional Review BoardIU International UnitIV IntravenousKg KilogramL LiterLFTs Liver function testsln Naperian (natural) logarithmLOQ Limit of quantificationLLQ Lower limit of quantificationμg MicrogramμL MicroliterMAT Mean absorption timeMCH Mean corpuscular hemoglobinMCHC Mean corpuscular hemoglobin concentrationMCV Mean corpuscular volumeMedDRA Medical Dictionary for Regulatory ActivitiesMg MilligramsmL MillilitermmHg Millimeters of mercuryMPHL Male pattern hair loss

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MRT Mean residence timeMSDS Material Safety Data Sheetmsec MillisecondsN Sample sizeNQ Non-quantifiable concentration measured as below LLQPD Pharmacodynamic(s)PK Pharmacokinetic(s)PSRI Periodic Safety Reports for InvestigatorsQC Quality controlQD Once dailyQTcB QT duration corrected for heart rate by Bazett’s formulaQTcF QT duration corrected for heart rate by Fridericia’s

formulaQSI Quantitative Sciences IndiaRAP Reporting and Analysis PlanRBA Relative BioavailabilityRBC Red blood cellsRNA Ribonucleic acidSAE Serious adverse event(s)SAS Statistical Analysis SoftwareSBP Systolic blood pressureSD Standard deviationSGOT Serum glutamic-oxaloacetic transaminaseSGPT Serum glutamic pyruvic transaminaseSOP Standard Operating ProcedureSRM Study reference manualSUSAR Suspected, Unexpected, Serious Adverse drug ReactionT Infusion durationt Time of last observed quantifiable concentrationt½ Terminal phase half-lifeτ Dosing intervaltlag Lag time before observation of drug concentrations in

sampled matrixtlast Time of last quantifiable concentrationtmax Time of occurrence of CmaxULN Upper limit of normalUK United KingdomUS United StatesVd/F Apparent volume of distribution after extravascular (e.g.,

oral) administrationWBC White blood cellsWHO World Health Organization

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Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

AVIDART Chiron RIBAAVODART Harnal DAVOLVE InFormCOMBODART WinNonlinDUAGENDUODARTFLODARTJALYNJUTEOZYFETOR

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12.2. Appendix 2: Definition of and Procedures for Recording, Evaluating, Follow-Up and Reporting of Adverse Events

12.2.1. Definition of Adverse EventsAdverse 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 judgment 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).

Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen.

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12.2.2. 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 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

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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any dose:

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.

12.2.3. Definition of Cardiovascular Events

Cardiovascular Events (CV) Definition:

Investigators will be required to fill out the specific CV event page of the CRF for the following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization

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12.2.4. Recording of AEs and SAEs

AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review alldocumentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by GSK. In this instance, all subject identifiers, with the exception of the subject number, will be blinded on the copies of the medical records prior to submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical information. In such cases, the diagnosis will be documented as the AE/SAE and not the individual signs/symptoms.

12.2.5. Evaluating AEs and SAEs

Assessment of Intensity

The investigator will make an assessment of intensity for each AE and SAE reported during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities

Severe: An event that prevents normal everyday activities. - an AE that is assessed as severe will not be confused with an SAE. Severity is a category utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as described in the definition of an SAE.

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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 out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to the study treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal information to include in the initial report to GSK. However, it is very important that the investigator always make an assessment of causality for every event prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting requirements.

Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as may be indicated or as requested by GSK to elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or investigations, histopathological examinations or consultation with other health care professionals.

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.

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12.2.6. Reporting of SAEs to GSK

SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper SAE data collection tool and fax it to GSKs Pharmacovigilance Department per the fax number in the Sponsor Contact Information page, beside the Primary Medical Monitor’s name.

Site will enter the serious adverse event data into the electronic system as soon as it becomes available.

The investigator will be required to confirm review of the SAE causality by ticking the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., InForm system) will be taken off-line to prevent the entry of new data or changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated data on a previously reported SAE after the electronic data collection tool has been taken off-line, the site can report this information on a paper SAE form or to the Medical Monitor or the study manager (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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12.3. Appendix 3: Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female partner of a male study subject who is pregnant or becomes pregnant while participating in this study. This applies only to subjects who are randomized to receive study medication.

Details of all pregnancies in female partners who are pregnant or become pregnant of male subjects will be self reported to the site after the start of dosing and until 50 days post-last dose.

After obtaining the necessary signed informed consent from the female partner directly, the investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK.

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or indication for procedure.

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12.4. Appendix 4: Country Specific Requirements

No country-specific requirements exist.

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