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

Condition(s) targeted: Prostatic Hyperplasia

Intervention: Dutasteride plus tamsulosin (Drug); tamsulosin (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

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the subjects return to site at one month, then every 13 weeks until two years of treatment is complete or they are withdrawn.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.

Official title: Comparative Efficacy of Dutasteride Plus Tamulsoin With Lifestyle Advice Versus Watchful Waiting Plus Lifestyle Advice With Step-up Therapy to Tamsulosin in the Management of Treatment naïve Men With Moderately Symptomatic Benign Prostatic Hyperplasia and Prostate Enlargement.

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Change From Baseline in the Total International Prostate Symptom Score (IPSS) at Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the Last Observation Carried Forward (LOCF) Approach

Secondary outcome:

Number of Participants With Change From Baseline in the Indicated Improvement Categories in the IPSS at Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the LOCF Approach

Change From Baseline in the BPH Impact Index (BII) Score at Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the LOCF Approach

Change From Baseline in the BPH-related Health Status (BHS) Score at Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the LOCF Approach

Number of Events of Clinical Progression (CP) of BPH

Number of Participants With the Indicated First-occurring Component of Clinical Progression (CP) of BPH

Number of Participants Who Had Any BPH-related Surgery, Who Had the Indicated Type of Surgery, Who Had 2 BPH-related Surgeries, and Who Had >=3 BPH-related Surgeries

Number of Participants With the Indicated Responses to Question 1 of the Patient Perception of Study Treatment (PPST) Questionnaire at Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the LOCF Approach

Number of Participants With the Indicated Responses to Question 2 of the Patient Perception of Study Treatment (PPST) Questionnaire at Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 Using the LOCF Approach

Exposure to Study Drug

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Starting Post-randomization

Detailed description: 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.

Minimum age: 50 Years. Maximum age: N/A. Gender(s): Male.

Criteria:

- 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.

GSK Investigational Site, Aigrefeuille Sur Maine 44140, France

GSK Investigational Site, Angers 49000, France

GSK Investigational Site, Angers 49933, France

GSK Investigational Site, Corsept 44560, France

GSK Investigational Site, La Montagne 44620, France

GSK Investigational Site, La Rochelle 17000, France

GSK Investigational Site, Laval 53000, France

GSK Investigational Site, Le Temple De Bretagne 44360, France

GSK Investigational Site, Murs Erigne 49610, France

GSK Investigational Site, Nantes 44300, France

GSK Investigational Site, Nieul sur Mer 17137, France

GSK Investigational Site, Sautron 44880, France

GSK Investigational Site, Thouars 79100, France

GSK Investigational Site, Tierce 49125, France

GSK Investigational Site, Vihiers 49310, France

GSK Investigational Site, Berlin 10249, Germany

GSK Investigational Site, Eisleben 06295, Germany

GSK Investigational Site, Argos 21200, Greece

GSK Investigational Site, Athens 10552, Greece

GSK Investigational Site, Athens 115 22, Greece

GSK Investigational Site, Athens 11527, Greece

GSK Investigational Site, Athens 151 26, Greece

GSK Investigational Site, Larisa 41110, Greece

GSK Investigational Site, Patra 265 04, Greece

GSK Investigational Site, Rhodes 85100, Greece

GSK Investigational Site, Thessaloniki 564 29, Greece

GSK Investigational Site, Thessaloniki 546 42, Greece

GSK Investigational Site, Den Haag 2582 LJ, Netherlands

GSK Investigational Site, Doetinchem 7009 BL, Netherlands

GSK Investigational Site, Maarssen 3607 KN, Netherlands

GSK Investigational Site, Sneek 8601 ZK, Netherlands

GSK Investigational Site, Voerendaal 6367 ED, Netherlands

GSK Investigational Site, Wildervank 9648 BE, Netherlands

GSK Investigational Site, Winterswijk 7101 BN, Netherlands

GSK Investigational Site, Arad 310175, Romania

GSK Investigational Site, Bucharest, Romania

GSK Investigational Site, Alava 01004, Spain

GSK Investigational Site, Barcelona 8907, Spain

GSK Investigational Site, Cordoba 14004, Spain

GSK Investigational Site, Coslada 28822, Spain

GSK Investigational Site, Fuenlabrada (Madrid) 28942, Spain

GSK Investigational Site, Galdakano 48960, Spain

GSK Investigational Site, Getafe 28905, Spain

GSK Investigational Site, Malaga 29010, Spain

GSK Investigational Site, Marbella 29600, Spain

GSK Investigational Site, Mendaro, Guipuzcoa 20850, Spain

GSK Investigational Site, Murcia 30008, Spain

GSK Investigational Site, Pamplona 31008, Spain

GSK Investigational Site, San Sebastián 20014, Spain

GSK Investigational Site, Valencia 46010, Spain

GSK Investigational Site, Valladolid 47012, Spain

GSK Investigational Site, Bath BA1 3NG, United Kingdom

GSK Investigational Site, Bristol BS2 8HW, United Kingdom

GSK Investigational Site, Broadway, Fleetwood FY7 8GU, United Kingdom

GSK Investigational Site, Chadderton, Oldham OL9 0LH, United Kingdom

GSK Investigational Site, Glasgow G51 4TF, United Kingdom

GSK Investigational Site, High Heaton, Newcastle Upon Tyne NE7 7DN, United Kingdom

GSK Investigational Site, Vasto (CH), Abruzzo 66054, Italy

GSK Investigational Site, Aichach, Bayern 86551, Germany

GSK Investigational Site, Nuernberg, Bayern 90441, Germany

GSK Investigational Site, Hagenow, Brandenburg 19230, Germany

GSK Investigational Site, Oranienburg, Brandenburg 16515, Germany

GSK Investigational Site, Strausberg, Brandenburg 15344, Germany

GSK Investigational Site, Chalfont St Giles, Buckinghamshire HP8 4QG, United Kingdom

GSK Investigational Site, Avellino, Campania 83100, Italy

GSK Investigational Site, Napoli, Campania 80131, Italy

GSK Investigational Site, Sandbach, Cheshire CW11 1EQ, United Kingdom

GSK Investigational Site, Marburg, Hessen 35039, Germany

GSK Investigational Site, Roma, Lazio 00161, Italy

GSK Investigational Site, Milano, Lombardia 20132, Italy

GSK Investigational Site, San Fermo della Battaglia (CO), Lombardia 22020, Italy

GSK Investigational Site, Buchholz, Niedersachsen 21244, Germany

GSK Investigational Site, Essen, Nordrhein-Westfalen 45130, Germany

GSK Investigational Site, Torino, Piemonte 10126, Italy

GSK Investigational Site, Foggia, Puglia 71100, Italy

GSK Investigational Site, Leipzig, Sachsen 04109, Germany

GSK Investigational Site, Hettstedt, Sachsen-Anhalt 06333, Germany

GSK Investigational Site, Cagliari, Sardegna 09134, Italy

GSK Investigational Site, Kiel, Schleswig-Holstein 24143, Germany

GSK Investigational Site, Pisa, Toscana 56124, Italy

Starting date: December 2010
Last updated: July 17, 2014