Comparative Efficacy of Dutasteride Plus Tamulosin With Lifestyle Advice Versus Watchful Waiting Plus Lifestyle Advice in the Management of Treatment naïve Men With Moderately Symptomatic Benign Prostatic Hyperplasia and Prostate Enlargement

Comparative Efficacy of DuodartTM Versus Watchful Waiting With Step-up Therapy to Tamsulosin in the Management of Treatment naïve Men With Symptomatic BPH

Study FDC114615 is a two year, multi-centre, randomised, open-label trial to assess the efficacy of Dutasteride plus tamsulosin when compared to the standard practice of watchful waiting, with a defined escalation to tamsulosin in treatment naive men with symptomatic benign prostate hyperplasia (BPH).

Once consented, each subject will undergo screening procedures to ensure the prostate volume and post void residual are within eligible range. If all entry criteria are met, subjects will be randomised (1:1) to receive Dutasteride plus tamsulosin with lifestyle advice or watchful waiting, with lifestyle advice, with a defined escalation to tamsulosin. Escalation will be initiated when no improvement from baseline is scored using the International Prostate Symptom Score (version 2) (IPSS) questionnaire.

After randomisation, the subjects return to site at one month, then every 13 weeks until two years of treatment is complete or they are withdrawn. Key assessments, such as Adverse Events (AE's) and concomitant medication monitoring and completion of the quality of life questionnaires are performed at each visit and the data recorded.

This will be a European, multicentre, randomised, open-label, parallel group study. The aim of the study is to investigate whether Dutasteride plus Tamulson treatment with lifestyle advice is more effective than watchful waiting treatment plus lifestyle advice plus step-up therapy with tamsulosin for improvement of symptoms and Acte Urinary Retention (AUR) and BPH-related prostatic surgery, in older men (≥50 yrs), with moderate symptoms of BPH (IPSS 8-19), enlarged prostates (≥30cc) and Prostate Specific Antigen (PSA) ≥1.5ng/mL.

Data from all participating centres will be pooled prior to analysis. Investigative centres will be pooled a priori into clusters based on geographic location; these clusters may be used in analyses to adjust for site effects. Clusters will be defined once all investigative centres have been identified and randomisation has been completed.

Subjects will be screened for inclusion into the study and eligible subjects will be randomised by investigative centre. Subjects will be allocated to one of two treatment groups, according to a pre-determined randomisation schedule (in a 1:1 ratio):

• Dutasteride plus tamsulosin once daily plus lifestyle advice.
• Watchful waiting plus lifestyle advice. Escalation to tamsulosin 0.4 mg once daily at any visit from Week 4 if any IPSS measurement shows no improvement or worsening from baseline. At any study visit, if the IPSS is the same or greater than the baseline value for that subject, tamsulosin 0.4 mg once daily will be initiated. If tamsulosin is initiated, it will be continued for the remainder of the study unless the subject elects to withdraw from the study. Initiation of tamsulosin will be recorded in the electronic case report form (eCRF.) Subjects will self-administer study medication once daily for up to 104 weeks, (up to 100 weeks for those on tamsulosin). Subjects will return to the clinic at 4 weeks post-randomisation and then at 13-week intervals post-randomisation during the 2-year treatment period (i.e. at 4, 13, 26, 39, 52, 65, 78, 91 and 104 weeks) for the assessments listed as in Appendix 1 Time and Events Schedule.

Approximately 760, treatment naive men with symptomatic BPH will be randomised into the study in order to achieve at least 592 evaluable subjects. 380 into the Dutasteride plus tamsulosin with lifestyle advice arm and 380 into the watchful waiting plus lifestyle advice arm.

Treatment naïve is defined as a man that has recently been diagnoses with BPH whom has received no prescribed therapeutic treatment. For example, medicines such as 5 α-reductase inhibitors (5-ARIs) or invasive procedures such as transurethral resection of the prostate (TURP) prescribed to directly treat the BPH symptoms are considered therapeutic treatments. As per the entry criteria, phytotherapy is allowed unless it was performed less than two weeks prior to the screening visit.

The anticipated recruitment period will be approximately 6 months. The study will be conducted in approximately 8 countries within Europe.

• Males aged ≥50 years.
• A confirmed clinical diagnosis of BPH.
• International Prostate Symptom Score (IPSS) 8-19 at Visit 1 (screening).
• Prostate volume ≥30 cc (by transrectal ultrasonography; TRUS).
• Total serum prostate specific antigen (PSA) ≥1.5 ng/mL at Visit 1 (screening).
• Willing and able to give signed written informed consent and comply with study procedures.
• Fluent and literate in local language with the ability to read, comprehend and record information on the IPSS and BII questionnaires.
• Able to swallow and retain oral medication.
• Willing and able to participate in the study for the full 2 years.
• Men with a female partner of childbearing potential must either agree to use effective contraception or have had a prior vasectomy. Contraception must be used from 2 weeks prior to administration of the first dose of study treatment until at least 5 half-lives for the drug plus 3 months to allow clearance of any altered sperm after the last dose of study treatment.
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Note: If total serum PSA is >4 ng/mL and unless PSA value has been stable for at least the past 2 years, the investigator should make every appropriate effort to exclude the possibility of prostate cancer, e.g. further Digital rectal examination (DRE), review TRUS taken within previous month, consider 8-12 core prostate biopsy in accordance with routine clinical practice

Exclusion Criteria:

• Subjects meeting any of the following criteria must not be enrolled in the study:
• Total serum PSA >10.0 ng/mL at Visit 1 (screening).
• History or evidence of prostate cancer (e.g. positive biopsy or ultrasound within the previous 6 months, suspicious DRE and/or rising PSA).

Excluded medication and therapies Current or any prior use of the following prohibited medications

• a 5α-reductase inhibitor (finasteride or dutasteride),
• anti-cholinergics (e.g. oxybutynin, propantheline)
• an alpha-adrenoreceptor blocker (i.e. indoramin, prazosin, terazosin, tamsulosin, alfuzosin and doxazosin) for BPH or Lower urinary tract symptoms (LUTS)
• any drugs with anti-androgenic properties (e.g. spironolactone, flutamide, bicalutamide, cimetidine, ketoconazole, progestational agents) within the previous 6 months.
• any drugs noted for gynaecomastia effects, or could affect prostate volume, within 6 months of the Visit 1
• any investigational or marketed study drug within 30 days or 5 half-lives, (whichever is longer), preceding the first dose of study treatment.

Current use of:

• any alpha-adrenoreceptor blocker (i.e. indoramin, prazosin, terazosin, tamsulosin, alfuzosin and doxazosin)
• anabolic steroids.
• drugs known or thought to have an interaction with tamsulosin, e.g. cimetidine and warfarin.
• Use of phytotherapy for BPH within 2 weeks prior to Visit 1 (screening) and/or predicted to need phytotherapy during the study.

Have a known (immediate or delayed) hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study medication or excipients that, in the opinion of the Investigator or GlaxoSmithKline contraindicates their participation.

Recent Medical Procedures

• Previous prostatic surgery (including TURP, balloon dilatation, thermotherapy and stent replacement) or other invasive or minimally invasive procedures to treat BPH.
• History of flexible/rigid cystoscopy or other instrumentation of the urethra within 7 days prior to Visit 1 (screening). Catheterisation (<10F) is acceptable with no time restriction.

Medical history

• History of AUR within 3 months prior to Visit 1 (screening).
• Post-void residual volume >250 mL (suprapubic ultrasound) at Visit 1 (screening)..
• Any causes other than BPH, which may in the judgement of the investigator, result in urinary symptoms or changes in flow rate (e.g. neurogenic bladder, bladder neck contracture, urethral stricture, bladder malignancy, acute or chronic prostatitis, or acute or chronic urinary tract infections).
• History of 'first dose' hypotensive episode on initiation of alpha-1-adrenoreceptor antagonist therapy for hypertension.
• History of postural hypotension, dizziness, vertigo or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury.
• History of breast cancer or clinical breast examination finding of unclear origin or suggestive of malignancy.
• History of hepatic impairment or abnormal liver function tests at Visit 1 (screening). (defined as Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) or alkaline phosphatase >2 times the Upper limit of normal (ULN) , or total bilirubin >1.5 times the ULN, (unless associated with predominantly indirect bilirubin elevation or Gilbert's syndrome).
• History of renal insufficiency, or serum creatinine >1.5 times the upper limit of normal at Visit 1 (screening)..
• Prior history of malignancies (other than basal cell carcinoma or squamous cell carcinoma of the skin) within the past 5 years. Subjects who have had no evidence of the malignancy for ≥5 years are eligible.
• History of any illness (including psychiatric) that in the opinion of the investigator might confound the results of the study or poses additional risk to the subject.
• Any unstable, serious co-existing medical condition(s) including, but not limited to, myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident within 6 months prior to Screening visit; uncontrolled diabetes or peptic ulcer disease which is uncontrolled by medical management.
• History or current evidence of drug or alcohol abuse within the previous 12 months.
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator or GSK Medical Monitor.