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

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the subjects return to site at one month, then every 13 weeks until two years of treatment is complete or they are withdrawn.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

Detailed Description
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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.

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

Conditions
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Prostatic Hyperplasia

Intervention / Treatment
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* Drug: Dutasteride plus tamsulosin
* Drug: tamsulosin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dutasteride plus tamsulosin<br>Dutasteride plus tamsulosin arm + lifestyle advice | Drug: Dutasteride plus tamsulosin<br>* Take 1 capsule daily<br>|
| Experimental: Watchful waiting with escalation to tamsulosin<br>Watchful waiting with escalation to tamsulosin | Drug: tamsulosin<br>* Take 1 capsule daily when escalation criteria met<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | The IPSS questionnaire is a 7-item self-administered questionnaire designed to quantify the following urinary symptoms: Question 1 (Q1), incomplete emptying; Q2, frequency; Q3, intermittency; Q4, urgency; Q5, weak stream; Q6, straining; Q7, nocturia. It has an additional, independent eighth question to assess change in BPH-related health status (BHS) and quality of life. BHS scores range from 0 to 6, where 0 indicates delighted and 6 indicates terrible. The 7 items in the IPSS questionnaire quantitatively measure the level of urinary symptoms reported as a total IPSS. The total IPSS (sum of the first 7 items) can range from 0 to 35: mild (0 to 7), moderate (8 to 19), or severe (20 to 35). Change from Baseline in IPSS total score was calculated as the Month 24 value minus the Baseline value. LOCF analysis involves bringing forward the last non-missing post-Baseline assessment for a participant with missing data and/or for a participant who discontinued from the study. | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Symptom improvement was assessed using IPSS categorical changes from Baseline. Change from Baseline categories were summarized by treatment group using five improvement levels: >=1 point through >=5 points. IPSS percent change from Baseline was summarized using seven improvement levels: >0 percent, >=10 percent, >=20 percent, >=25 percent, >=30 percent, >=40 percent, and >=50 percent. Change in IPSS from Baseline was analysed using the LOCF method and is summarized for the following categories: >=2 points, >=3 points, and percent change >=25. The 7 items in the IPSS questionnaire quantitatively measure the level of urinary symptoms reported as a total IPSS. The total IPSS (sum of the first 7 items) can range from 0 to 35: mild (0 to 7), moderate (8 to 19), or severe (20 to 35). | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 
| 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 | The BII is a 4-item questionnaire covering physical discomfort, worry, bother, and impact on usual activities, with a minimum score of 0 (best) and a maximum score (worst) of 13 points. Individual missing questionnaire responses were imputed, as applicable. Change from Baseline in the BII score was summarized by treatment group using the LOCF approach at each scheduled post-Baseline assessment. LOCF analysis involves bringing forward the last non-missing post-Baseline assessment for a participant with missing data and/or for a participant who discontinued from the study. Estimates are based on the adjusted means from the general linear model: Change from Baseline =Treatment + Cluster + Baseline Value. Baseline is defined as the Visit 2 value if it exists; otherwise, it is the latest of all Screening values. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 
| 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 | Each participant was asked the following question If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that?. This response was rated from 0 (delighted) to 6 (terrible). Change from Baseline in the BHS score was summarized by treatment group using the LOCF approach at each scheduled post-Baseline assessment. LOCF analysis involves bringing forward the last non-missing post-Baseline assessment for a participant with missing data and/or for a participant who discontinued from the study. Estimates are based on the adjusted means from the general linear model: Change from Baseline =Treatment + Cluster + Baseline Value. Baseline is defined as the Visit 2 value if it exists; otherwise, it is the latest of all Screening values. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 
| Number of Events of Clinical Progression (CP) of BPH | The number of participants with the first occurrence of clinical progression (CP) of BPH occurring on or after the randomization date are summarized by treatment and year. Time is based on the date of the first-occurring CP event, and is relative to the randomization date. CP of BPH is a composite of five endpoints assessed through the end of the study, including: symptom deterioration by IPSS >=3 points from Baseline (Visit 2); acute urinary retention related to BPH; incontinence (overflow or urge) related to BPH; recurrent urinary tract infection (UTI) or urosepsis related to BPH; renal insufficiency related to BPH (a single >=50% rise from Baseline serum creatinine and a total value >=1.5 milligrams/deciliter). For components that required multiple episodes, the first of the multiple episodes was utilized in terms of timing. | Up to 2 years | 
| Number of Participants With the Indicated First-occurring Component of Clinical Progression (CP) of BPH | CP of BPH is a composite of five endpoints assessed through the end of the study, including: symptom progression (symptom deterioration by IPSS >=3 points from Baseline [Visit 2]); acute urinary retention (AUR) related to BPH; incontinence (overflow or urge) related to BPH; recurrent urinary tract infection (UTI) or urosepsis related to BPH; renal insufficiency related to BPH (a single >=50% rise from Baseline serum creatinine and a total value >=1.5 milligrams/deciliter). The number of participants with CP of BPH, the number of participants with the indicated first-occurring component of CP of BPH, the number of participants with two simultaneously first-occurring components (Tied for first component), and the number of participants with multiple first-occurring components were summarized by treatment group. | Up to Month 24 | 
| 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 | BPH-related surgery was summarized for events occurring on or after the date of randomization. The number of participants who had any BPH-related surgery, the indicated type of surgery, and multiple surgeries was summarized by treatment. Type of surgery data (cystoscopy, transurethral resection of the prostate [TURP], and prostatectomy) are presented in terms of the first-occurring BPH-related surgery after randomization. It was possible for a single participant to have multiple surgeries. | Up to Month 24 | 
| 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 | The PPST questionnaire consists of two questions (asked to determine how satisfied participants are with the treatment received) and was administered at Baseline and all post-Baseline visits. Question 1 was: Overall, how satisfied are you with the treatment and its effect on your urinary problems? There were seven possible responses, including: very satisfied, satisfied, somewhat satisfied, neutral, somewhat dissatisfied, dissatisfied, and very dissatisfied. Response categories were created by grouping together very satisfied, satisfied, and somewhat satisfied responses into the category of Any Satisfaction (AS), and separately grouping neutral, somewhat dissatisfied, dissatisfied, and very dissatisfied responses into the category of Neutral or Any Dissatisfaction (N/AD). The LOCF method involves bringing forward the last non-missing post-Baseline assessment for a participant with missing data and/or for a participant who discontinued from the study. | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 
| 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 | The PPST questionnaire consists of two questions (asked to determine how satisfied participants are with the treatment received) and was administered at Baseline and all post-Baseline visits. Question 2 was: Would you ask your doctor for the treatment you received in this study? There were three possible responses, including: Yes, No, and Not sure. Response categories included Yes and No or Not Sure, created by grouping together No and Not sure. The LOCF method involves bringing forward the last non-missing post-Baseline assessment for a participant with missing data and/or for a participant who discontinued from the study. | Baseline and Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 | 
| Exposure to Study Drug | Study drug exposure (days) = treatment stop date - treatment start date + 1. Participants in the Watchful Waiting Escalated=Yes subgroup could have been escalated to study drug at any time during the study. Therefore, it is possible that participants were exposed to tamsulosin for a shorter length of time than participants in the dutasteride plus tamsulosin group. | Up to 2 years | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Starting Post-randomization | A post-randomization adverse event is defined as an event with an onset on or after the randomization date or with a missing onset date. An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment was exercised in deciding whether reporting was appropriate in other situations. Refer to the general non-serious AE/SAE module for a list of non-serious AEs (occurring at a frequency threshold of >=5%) and SAEs. | Up to 2 years |