Benign Prostatic Hyperplasia Trial With Dutasteride And Tamsulosin Combination Treatment

Phase 3

Completed

Conditions: Prostatic Hyperplasia

Interventions: Drug: dutasteride 0.5mg once daily for 4 years
Drug: tamsulosin 0.4mg once daily for 4 years

Registration Number: NCT00090103

Lead Sponsor: GlaxoSmithKline

Brief Summary: This study will investigate the efficacy and safety of treatment with dutasteride and tamsulosin, administered once daily for 4 years, alone and in combination, on the improvement of symptoms and clinical outcome in men with moderate to severe symptomatic Benign Prostatic Hyperplasia (BPH). Study visits are every 3 months for up to 4 years (18 clinic visits). Transrectal ultrasound (TRUS) is done annually.

Detailed Description: A randomised, double-blind, parallel group study to investigate the efficacy and safety of treatment with Dutasteride (0.5 mg) and Tamsulosin (0.4 mg), administered once daily for 4 years, alone and in combination, on the improvement of symptoms and clinical outcome in men with moderate to severe symptomatic benign prostatic hyperplasia.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 4844

Inclusion Criteria

Not provided

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

total serum PSA >10.0ng/mL at Screening
history or evidence of prostate cancer (e.g. positive biopsy or ultrasound, suspicious DRE). Patients with suspicious ultrasound or DRE who have had a negative biopsy within the preceding 6 months and stable PSA are eligible for the study.

Note: If total serum PSA is >4ng/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 DRE, review TRUS taken within previous month, consider 8-12 core prostate biopsy in accordance with routine clinical practice.

previous prostatic surgery (including TURP, balloon dilatation, thermotherapy and stent replacement) or other invasive procedures to treat BPH.
history of flexible/rigid cystoscopy or other instrumentation of the urethra within 7 days prior to the Screening Visit. Routine catheterisation is acceptable with no time restriction.
history of AUR within 3 months prior to Screening Visit.
post-void residual volume >250mL (suprapubic ultrasound) at 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 breast cancer or clinical breast examination finding of unclear origin or suggestive of malignancy.
use of any 5-alpha-reductase inhibitor (e.g. Proscar®, Propecia®, Avodart®), any drugs with antiandrogenic properties (e.g. spironolactone, flutamide, bicalutamide, cimetidine, ketoconazole, metronidazole, progestational agents), or other drugs which affect prostate volume, within past 6 months of the Screening Visit and throughout the study (other than as study medication).
concurrent use of anabolic steroids
use of phytotherapy for BPH within 2 weeks of Screening Visit and/or predicted to need phytotherapy during the study.
use of any alpha-adrenoreceptor blockers (i.e. indoramin, prazosin, terazosin, tamsulosin, alfuzosin and doxazosin) within 2 weeks of Screening Visit and/or predicted to need any alpha blockers other than tamsulosin during the study.

Note: the purpose of this criteria is to be able to standardise baseline symptom severity for all enrolled patients prior to randomisation and not to specifically exclude current alpha-adrenoreceptor blocker users from participation in the study.

use of any alpha-adrenoreceptor agonists (e.g. pseudoephedrine, phenylephrine, ephedrine) or anticholinergics (e.g. oxybutynin, propantheline) or cholinergics (e.g. bethanecol chloride) within 48 hours prior to all uroflowmetry assessments.
hypersensitivity to any alpha-/beta- adrenoreceptor blocker or 5-alpha-reductase inhibitor, or other chemically-related drugs.
concurrent use of drugs known or thought to have an interaction with tamsulosin, e.g. cimetidine and warfarin.
history of hepatic impairment or abnormal liver function tests at Screening defined as alanine aminotransferase (ALT), aspartate aminotranferase (AST), and/or alkaline phosphatase >2 times the upper limit of normal, or total bilirubin >1.5 times the upper limit of normal (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 or serum creatinine ≥1.5 mg/dL at Screening.
prior history of malignancies other than basal cell carcinoma or squamous cell carcinoma of the skin within the past 5 years. Subjects with a prior malignancy who have had no evidence of disease for at least the past 5 years are eligible.
history of any illness that in the opinion of the investigator might confound the results of the study or poses additional risk to the patient.
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 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 unsuccessful treatment with tamsulosin or 'first dose' hypotensive episode on initiation of alpha-1-adrenoreceptor antagonist therapy.
history of unsuccessful treatment with finasteride or dutasteride
history or current evidence of drug or alcohol abuse within the previous 12 months.
participation in any investigational or marketed drug trial within 30 days (or 5 half-lives whichever is the longer) preceding the Screening Visit and/or during the course of this study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Combo	dutasteride 0.5mg once daily for 4 years	Combination of dutasteride (0.5mg) and tamsulosin (0.4mg), once daily
Combo	tamsulosin 0.4mg once daily for 4 years	Combination of dutasteride (0.5mg) and tamsulosin (0.4mg), once daily
dutasteride	dutasteride 0.5mg once daily for 4 years	dutasteride 0.5mg once daily
tamsulosin	tamsulosin 0.4mg once daily for 4 years	tamsulosin 0.4mg once daily

Primary Outcome Measures

Name	Time	Method
Number of Participants With AUR or BPH-related Surgery	Baseline (Day 1) through Year 4	A participant was considered to have AUR when he was unable to urinate and required bladder catheterization. BPH is also known as an enlarged prostate. When symptoms of BPH become bothersome, surgery may be required. When events of AUR and BPH-related surgery were participant reported or identified, they were recorded in the participants' clinic record.
Number of Events of Acute Urinary Retention (AUR) or Benign Prostatic Hyperplasia (BPH)-Related Prostatic Surgery at the Indicated Time Periods.	Years 1, 2, 3, and 4	A participant was considered to have AUR when he was unable to urinate and required bladder catheterization. BPH is also known as an enlarged prostate. When symptoms of BPH become bothersome, surgery may be required. When events of AUR and BPH-related surgery were participant-reported or identified, they were recorded in the participants' clinic record.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With an Event of Post-baseline BPH-related Macroscopic Hematuria	Baseline (Day 1) through Year 4	A participant was considered to have macroscopic hematuria when there was presence of blood in the urine. The event of macroscopic hematuria was either participant-reported or identified by the investigator during a clinic visit. Overall Crude Rate is the number of participants from the total number analyzed that experience experienced an incident of post-baseline BPH or Non-BPH related macroscopic hematuria. Participants may appear in both categories.
Adjusted Mean Change From Baseline in International Prostate Symptom Score (IPSS) at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, and 48	The IPSS is a 7-item questionnaire that measures urinary symptoms. It measures the level of urinary symptoms (including incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia) reported as the total IPSS score. Each of the 7 questions has a 6-point response scale (0=none/not at all to 5=almost always) with a total score that can range from 0-35: mild (0-7), moderate (8-19), or severe (20-35). Estimates are based on adjusted (least squares) means from the general linear model: change from baseline IPSS = Treatment + Cluster + Baseline IPSS.
Adjusted Mean Change From Baseline in Urinary Flow Rate (Qmax) at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, and 48	Peak maximum urinary flow (Qmax) of urinary flow using a Medtronic (formerly Dantec) Uroflow Meter (Urodyn 1000 or Duet models) with a Thompson filter was measured. Estimates are based on adjusted (least squares) means from the general linear model: Change from baseline Qmax = treatment + cluster + baseline Qmax.
Number of Events of First BPH Clinical Progression at Years 1, 2, 3 and 4	Years 1, 2, 3, and 4	The time when the first symptom/event of BPH clinical progression has occurred (i.e. AUR, incontinence) was measured. Summaries are based on the first occuring event after treatment start. The time period is from treatment start to each participant's last treatment visit. The Year 4 events include all those that occur during the fourth year and beyond.
Adjusted Mean Percent Change From Baseline in Prostate Volume at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, and 48	Prostate volume measurements were conducted annually using Transurethral ultrasound (TRUS). The anteroposterior, cephalocaudal, and transverse diameters of the prostate obtained by TRUS calculate the total prostate volume centimeters (cc). Percent change from baseline = \[(post-baseline - baseline)/baseline value\] x 100. Estimates were based on the adjusted (least squares) means from the general linear model: log(post-baseline/baseline value) + treatment + cluster + log(baseline value) and are reported as percent change from baseline.
Number of Visits to GP/Urologist Regarding BPH-related Surgery Since the Last Study Visit	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with BPH-related surgery. Responses to the following question were recorded: "Has the participant needed to visit his general practitioner (GP)/Urologist regarding BPH-related surgery since the last study visit?". If the answer to the question was "yes," the number of visits was recorded.
The Number of Participants With Each of the Five Components of BPH Clinical Progression	Baseline (Day 1) to Year 4	The five components measured were symptom deterioration, BPH-related AUR, BPH-related incontinence, recurrent BPH-related Urinary Tract Infection (UTI), and BPH-related renal insufficiency.
Adjusted Mean Change From Baseline in Transition Zone (Portion of the Prostate That Surrounds the Proximal Urethra) Volume at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, and 48	Prostate volume (PV) measurements were conducted annually using Transurethral ultrasound (TRUS). The anteroposterior, cephalocaudal, and transverse diameters of the prostate obtained by TRUS calculate the total PV in centimeters (cc). Results are for the transition zone measurements of the prostate in a small subset of participants. Percent change from baseline (BL) = \[(post-BL - BL)/BL value\] x 100. Estimates are based on the adjusted (least squares) means for the general linear model: log(post-BL/BL value) = treatment + cluster + log(BL value) and are reported as percent change from BL.
Adjusted Mean Change From Baseline in BPH-Related Health Status (BHS) at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, 48	The effect of study treatment on BHS was assessed by using three self-administered questionnaires: the International Prostate Symptom Score (IPSS), the BPH Impact Index (BII), and Patient Perception of Study Medication (PPSM). The BHS score was collected on the IPPS questionnaire and ranged from 0 (best) to 6 (worst). Percent change from baseline = \[(post-baseline - baseline)/baseline value\] x 100. Estimates were based on the adjusted (least squares) means from the general linear model: change from baseline BPH-related health status = treatment + cluster + baseline BPH-Related health status.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 2 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "How satisfied are you with the effect of the study medication on control of your urinary problems?" Satisfact., satisfaction.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 3 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Since you began taking the study medication, how has the strength of your urinary stream changed?".
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 6 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "How satisfied are you with the effect the study medication has on your pain prior to urinating?". Satisfact., satisfaction.
Number of Events of Symptom Deterioration at the Indicated Time Periods	Years 1, 2, 3, and 4 (from treatment start until each participant's last treatment-phase visit)	The number of participants (par.) with symptom deterioration of International Prostate Symptom Score (IPSS) ≥4 points on two consecutive visits post-baseline are presented. Data are based on the first occurrence of an event after treatment start. The year-4 events include all that occured during the 4th year and beyond. The IPSS is a 7-item questionnaire measuring the level of urinary symptoms reported as the total score. Each question has a 6-point response scale (0=none/not at all to 5=almost always), with a total score ranging from 0-35: mild (0-7), moderate (8-19), or severe (20-35).
Number of Unscheduled Visits to GP/Urologist Regarding AUR Symptoms Since the Last Study Visit	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with an episode of AUR. Responses to the following question were recorded: "Has the participant needed to make any unscheduled visits to his general practitioner (GP)/Urologist regarding AUR symptoms since the last study visit?" If the answer to the question was "yes," the number of visits was recorded.
Number of "Yes" Responses to the Question: "Would the Participant Have Paid a Visit to His GP/Urologist Regarding AUR Symptoms if the Study Visit Had Not Been Planned"?.	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with an episode of AUR. Responses to the following question were recorded: "Would the participant have paid a visit to his GP/Urologist regarding AUR symptoms if this study visit had not been planned?". If the answer to the question was "yes," the number of Yes responses was recorded.
Number of "Yes" Responses to the Question: "Would the Participant Have Paid a Visit to His GP/Urologist Regarding BPH-related Surgery Since the Last Study Visit?"	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with BPH-related surgery. Responses to the following question were recorded: "Would the participant have paid a visit to his general practitioner (GP)/Urologist regarding BPH-related surgery since the last study visit?". If the answer to the question was "yes," the number of Yes responses was recorded.
Number of Unscheduled Visits to GP/Urologist (Outpatient) Planned, Not Relating to the Study (Including Visits Resulting From UTI, UI, Macroscopic Haematuria, Etc.)	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with unplanned visits to GP/Urologist. Responses to the following question were recorded: "Does the participant have any unscheduled GP/Urologist (outpatients) visits planned, not relating to the study (this can include visits resulting from UTI, UI, macroscopic haematuria, etc.?". If the answer to the question was "yes," the number of visits was recorded.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 1 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Since you began taking the study medication, how has control of your urinary problems changed?".
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 4 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "How satisfied are you with the effect of the study medication on the strength of your urinary stream?". Satisfact., satisfaction.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 5 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Since you began taking the study medication, how has your pain prior to urinating changed?".
Number of Participants With an Event of Post-baseline BPH-related Hematospermia	Baseline (Day 1) through Year 4	A participant was considered to have hematospermia when there was presence of blood in the semen. Hematospermia can occur from prostatitis (prostate infection), from cancer, or after a prostate biopsy. The event of hematospermia was either participant-reported or identified by the investigator during a clinic visit. Overall Crude Rate is the number of participants from the total number analyzed that experience experienced an incident of post-baseline BPH or Non-BPH related hematospermia. Participants may appear in both categories.
Adjusted Mean Change From Baseline in BPH Impact Index (BII) at Months 12, 24, 36, and 48	Baseline and Months 12, 24, 36, and 48	The BII is a 4-item questionnaire, score range of 0 (best) to 12 (worst) for questions 1-3, and 0 (best) to 13 (worst) for question 4, that assesses the overall impact of BPH on a participant's general sense of well being and measures aspects of physical discomfort, worry, and bother, all of which can be affected by BPH and its symptoms. BII score = sum of questions 1-4. Change from baseline = Post-Baseline Value. Estimates are based on the adjusted (least squares) means from the general linear model: change from baseline BII = treatment + cluster + baseline BII.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 11 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Overall, how satisfied are you with the study medication and it's effect on your urinary problems?". Satisfact., satisfaction.
Number of Unplanned Visits to GP/Urologist That Would Have Taken Place if a Scheduled Study Visit Had Not Been Planned (Including Visits Resulting From UTI, UI, Macroscopic Haematuria, Etc.)	Every 3 months from Month 3 to Month 48	At each scheduled 13-week clinic visit post-randomization, the investigator was to record details of any health care utilization associated with unplanned visits to GP/Urologist. Responses to the following question were recorded: "Has the participant had any unplanned GP/Urologist (outpatient) visits that would have taken place if a scheduled study visit had not been planned (this can include visits resulting from UTI, UI macroscopic haematuria, etc?". If the answer to the question was "yes," the number of visits was recorded.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 10 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "How satisfied are you with the effect the study medication has on your ability to go about your usual activities without interference from your urinary problems?". Satisfact., satisfaction.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 8 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "How satisfied are you with the effect the study medication has on your pain during urination?". Satisfact., satisfaction.
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 9 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Since you began taking the study medication, how has the way your urinary problems interfere with your ability to go about your usual activities changed?".
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 12 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Would you ask your doctor for the medication you received in this study?".
Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 7 (LOCF)	Baseline and Months 12, 24, 36, and 48	This 12-item questionnaire (PPSM) was developed by GlaxoSmithKline for use in this study and was designed to quantify the participant's perceptions and satisfaction with the effect of study treatment on control of their urinary symptoms at baseline and Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, and 48. Participants were asked to respond to the question of "Since you began taking the study medication, how has your pain during urination changed?".