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Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α-reductase, the dominant form of 5α-reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half-life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double-blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one-year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α-reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long-term, progressive nature of BPH, the one-year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment. OBJECTIVE • To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months. PATIENTS AND METHODS • The Enlarged Prostate International Comparator Study was a multicentre, randomized, double-blind, 12-month, parallel-group study. • Men aged ≥50 years with a clinical diagnosis of BPH received once-daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4-week placebo run-in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24-month, open-label phase, during which patients received dutasteride 0.5 mg once daily. • The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA-SI) scores, improvement in maximum urinary flow rate (Qmax) and long-term safety in the 24-month open-label phase. RESULTS • Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study. • Similar reductions in mean AUA-SI scores and Qmax were also observed for men in both treatment groups. • A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open-label phase. CONCLUSION • Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Qmax and urinary symptoms associated with BPH in men with an enlarged prostate.

Summary Objective: To investigate the effect of combination therapy with dutasteride plus tamsulosin compared with each monotherapy on patient-reported health outcomes over 4 years in men with moderate-to-severe lower urinary tract symptoms (LUTS) because of benign prostatic hyperplasia (BPH). Methods: CombAT was a 4-year international, double-blind, randomised, parallel-group trial in men (n = 4844) with moderate-to-severe symptoms of BPH and at increased risk of disease progression [age ≥ 50 years, International Prostate Symptom Score (IPSS) ≥ 12, prostate volume ≥ 30 cc, serum prostate-specific antigen ≥ 1.5 ng/ml to ≤ 10 ng/ml and maximum urinary flow rate 5–15 ml/s with minimum voided volume ≥ 125 ml]. Subjects were randomised to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. The primary endpoint at 4 years was the time to event and proportion of subjects with acute urinary retention or undergoing BPH-related prostate surgery. Secondary endpoints included the health-outcomes measures, BPH Impact Index (BII), IPSS question 8 (IPSS Q8) and the Patient Perception of Study Medication (PPSM) questionnaire. Results: At 4 years, combination therapy resulted in significantly superior improvements from baseline in BII and IPSS Q8 than either monotherapy; these benefits were observed from 3 months onwards compared with dutasteride and from 9 months (BII) or 12 months (IPSS Q8) onwards compared with tamsulosin. Also at 4 years, the PPSM questionnaire showed that a significantly higher proportion of patients was satisfied with, and would request treatment with, combination therapy compared with either monotherapy. Conclusions: Combination therapy (dutasteride plus tamsulosin) provides significantly superior improvements in patient-reported quality of life and treatment satisfaction than either monotherapy at 4 years in men with moderate-to-severe BPH symptoms.

Benign prostatic hyperplasia (BPH) is a highly prevalent condition in aging men, which can be progressive and lead to acute urinary retention (AUR) and the need for surgery. It is commonly treated with alpha-blockers and 5alpha-reductase inhibitors (5ARIs), both of which improve the symptoms of BPH. Long-term treatment with 5ARIs can also reduce the risk of developing AUR and the need for surgery. The landmark Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated that over 4 years the combination of the type 2-specific 5ARI, finasteride and the alpha-blocker doxazosin was more effective than either agent alone in reducing overall clinical progression. Since the initiation of MTOPS, it has been shown that patients with larger prostates and higher prostate-specific antigen (PSA) levels are at greater risk of BPH progression, and are therefore arguably more likely to benefit from combination therapy. The Combination of Avodart and Tamsulosin (CombAT) trial is a 4-year, global, multicenter, randomized, double-blind, parallel-group study designed to investigate the benefits of combination therapy with the dual 5ARI dutasteride and the alpha-blocker tamsulosin compared with each monotherapy in improving symptoms and long-term outcomes in men with moderate-to-severe symptoms of BPH and prostate enlargement. Symptoms and long-term outcomes (AUR and surgery) will be assessed as separate primary endpoints at 2 and 4 years, respectively. Eligible patients were at least 50 years old with prostate volume > or =30 cm(3) and PSA level > or =1.5 ng/mL. A total of 4838 subjects have been enrolled. This paper describes the rationale, design and baseline data of the CombAT study.

Objectives To assess the long-term safety and efficacy of dutasteride, a dual type 1 and type 2 5-α-reductase inhibitor, in the treatment of symptomatic benign prostatic hyperplasia and associated lower urinary tract symptoms. Methods Data from two Phase IIIa multicenter, randomized, placebo-controlled trials of 2-year duration plus a 2-year open-label extension were pooled and analyzed. The entry criteria included age 50 years old or older, clinical diagnosis of benign prostatic hyperplasia, prostate volume of 30 cm 3 or greater, American Urological Association symptom score of 12 or greater, peak urinary flow rate of 15 mL/s or less, and prostate-specific antigen level of 1.5 ng/mL or greater but less than 10 ng/mL. Results A total of 2802 men were randomized into the double-blind phase of the two studies with 1908 patients (68%) completing the study. Of these, 1570 subjects were enrolled in the open-label phase, and 569 subjects received dutasteride for 48 months. Changes at the 48-month visit for dutasteride/dutasteride-treated subjects included improvement in prostate volume (−26.2%), American Urological Association Symptom Index (−6.1 points), and peak urinary flow rate (+2.8 mL/s). Changes for the placebo/dutasteride group included prostate volume (−20.7%), American Urological Association Symptom Index (−5.3 points), and peak urinary flow rate (+1.8 mL/s). Acute urinary retention and surgery occurred in a small percentage of subjects (less than 2% and less than 1%) in the open-label extension phase. Dutasteride was well tolerated with no statistically significant increase in drug-related adverse events during the open-label extension and no adverse laboratory trends. Conclusions Dual inhibition of 5-α-reductase with dutasteride provided sustained efficacy in subjects with symptomatic benign prostatic hyperplasia treated for 48 months. Near-complete, long-term suppression of dihydrotestosterone (93% at 48 months) with dutasteride did not lead to an increase in adverse events compared with that reported in the 2-year period.

BACKGROUND: Ranitidine 150 mg q.d.s. is the currently recommended dosage in the United States for the treatment of erosive oesophagitis. To determine whether a higher dose of ranitidine administered less frequently would also be effective in healing erosive oesophagitis, we compared ranitidine 300 mg b.d. with ranitidine 150 mg q.d.s. in the treatment of erosive oesophagitis. METHODS: This multicentre, double- blind, randomized, placebo-controlled study conducted in the United States compared two dosages of ranitidine in 772 patients with endoscopically diagnosed erosive oesophagitis. Patients were treated with ranitidine 300 mg b.d., ranitidine 150 mg q.d.s. or placebo for up to 12 weeks. Endoscopies were repeated after 4, 8 and 12 weeks of treatment. RESULTS: Ranitidine 300 mg b.d. was significantly more effective than placebo in healing erosive oesophagitis at weeks 8 and 12 (51 vs. 36% and 66 vs. 52%, respectively; P < or = 0.004). Significantly higher healing rates were also achieved with ranitidine 150 mg q.d.s. compared with placebo at 4, 8 and 12 weeks (37 vs. 21%, 62 vs. 36% and 77 vs. 52%, respectively; P < 0.001). Healing rates were significantly higher with ranitidine 150 mg q.d.s. than with ranitidine 300 mg b.d. at all scheduled endoscopies (P < or = 0.041). CONCLUSIONS: Ranitidine 300 mg b.d. is effective in healing erosive oesophagitis and may be appropriate as an alternative dosage regimen to ranitidine 150 mg q.d.s. in some patients with erosive oesophagitis.

• To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months.• The Enlarged Prostate International Comparator Study was a multicentre, randomized, double-blind, 12-month, parallel-group study. • Men aged ≥ 50 years with a clinical diagnosis of BPH received once-daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4-week placebo run-in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24-month, open-label phase, during which patients received dutasteride 0.5 mg once daily. • The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA-SI) scores, improvement in maximum urinary flow rate (Q(max)) and long-term safety in the 24-month open-label phase.• Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study. • Similar reductions in mean AUA-SI scores and Q(max) were also observed for men in both treatment groups. • A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open-label phase.• Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Q(max) and urinary symptoms associated with BPH in men with an enlarged prostate.

What’s known on the subject? and What does the study add? Treatment of benign prostatic hyperplasia (BPH) centres on two drug classes, 5α-reductase inhibitors and α-blockers. The 4-year Combination of Avodart® and Tamsulosin (CombAT) study investigated whether the combination of dutasteride and tamsulosin was more effective than either monotherapy in reducing the relative risk of AUR, BPH-related surgery, and BPH clinical progression in men with moderate-to-severe LUTS who were at increased risk of disease progression. Data from the 2- and 4-year, pre-planned primary and secondary endpoint analyses for the CombAT study have been reported previously. This study reports the outcomes of post hoc analyses of the influence of baseline parameters on the incidence of AUR, BPH-related surgery, and overall clinical progression in patients treated with tamsulosin, dutasteride, or combination therapy with both agents. OBJECTIVE • To investigate the influence of baseline variables on the 4-year incidence of acute urinary retention (AUR), benign prostatic hyperplasia (BPH)-related surgery and overall clinical progression in men treated with tamsulosin, dutasteride, or a combination of both. PATIENTS AND METHODS • The 4-year Combination of Avodart® and Tamsulosin (CombAT) study was a multicenter, randomized, double-blind, parallel-group study of clinical outcomes in men aged ≥50 years with symptomatic (International Prostate Symptom Score [IPSS]≥12) BPH, with prostate-specific antigen (PSA) levels of ≥1.5 ng/mL and ≤10 ng/mL, and a prostate volume (PV) of ≥30 mL. • Eligible patients received tamsulosin 0.4 mg, dutasteride 0.5 mg, or a combination of both. • The primary endpoint was time to first AUR or BPH-related surgery. Secondary endpoints included clinical progression of BPH and symptoms. Posthoc analyses of the influence of baseline variables (including age, IPSS health-related quality of life [HRQL], PV, PSA, IPSS, peak urinary flow rate [Qmax] and body-mass index [BMI]) on the incidence of AUR or BPH-related surgery, clinical progression of BPH, and symptoms were performed. RESULTS • There were 4844 men in the intent-to-treat population. Overall baseline characteristics were similar across all patient groups. • Regardless of baseline subgroup, the incidence of AUR or BPH-related surgery was higher in men treated with tamsulosin than in those treated with dutasteride or combined therapy. • Combined therapy was statistically better than tamsulosin in reducing the risk of AUR or BPH-related surgery in subgroups of baseline PV > 42.0 mL, in all subgroups of baseline PSA level, and all other baseline subgroups (P≤ 0.001). • Across treatment groups, the incidence of clinical progression was highest in men with a baseline IPSS of

Background: Combination therapy with dutasteride and tamsulosin provides significantly greater benefit than either monotherapy for various patient-reported outcomes in men with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and prostatic enlargement. Objective: To investigate whether combination therapy is more effective than either monotherapy in reducing the relative risk for acute urinary retention (AUR), BPH-related surgery, and BPH clinical progression over 4 yr in men at increased risk of progression. Design, setting, and participants: The Combination of Avodart (R) and Tamsulosin (CombAT) study was a 4-yr, multicenter, randomised, double-blind, parallel-group study in 4844 men >= 50 yr of age with a clinical diagnosis of BPH, International Prostate Symptom Score >= 12, prostate volume >= 30 cm(3), prostate-specific antigen 1.5-10 ng/ml, and maximum urinary flow rate (Q(max)) >5 and = 125 ml. Intervention: Oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Measurements: The 4-yr primary end point was time to first AUR or BPH-related surgery. Secondary end points included BPH clinical progression, symptoms, Q(max), prostate volume, safety, and tolerability. Results and limitations: Combination therapy was significantly superior to tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression. Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr. Safety and tolerability of combination therapy was consistent with previous experience with dutasteride and tamsulosin monotherapies, with the exception of an imbalance in the composite term of cardiac failure among the three study arms. The lack of placebo control is a study limitation. Conclusions: The 4-yr CombAT data provide support for the long-term use of dutasteride and tamsulosin combination therapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement. Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103). (C) 2009 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Background The purpose of the current study was to validate the US English Patient Perception of Study Medication (PPSM) questionnaire, which measures patient satisfaction with Benign Prostatic Hyperplasia (BPH) treatment and was administered to men with BPH lower urinary tract symptoms (LUTS) enrolled in a multi-national clinical trial. Methods Patients with moderate to severe BPH symptoms completed three disease-specific measures: The International Prostate Symptom Score (IPSS), the BPH Impact Index (BII) and the PPSM, at baseline (after completion of the placebo run-in period) and at every 13-week clinic visit thereafter for the duration of the study treatment period. The PPSM was analysed to assess its variability, reliability and validity. Results There were 879 patients included in the analyses, with a mean age of 66.7 years. The PPSM was found to comprise two factors – PPSM-Global and PPSM-Pain, with a Total Score ranging from 7 to 49. It demonstrated good internal consistency (Cronbach's alpha ranged from .95 to .97) and also demonstrated convergent validity through significant correlations with the IPSS (.48 to .58), IPSS Quality of Life (QoL) item (.41 to .63) and BII (.31 to .45) and known-groups validity against the IPSS, IPSS QoL item and BII. Conclusion Results support the use of the PPSM as a measure of satisfaction in BPH patient groups.

OBJECTIVE To investigate the effect of dutasteride and tamsulosin as combined therapy compared with each monotherapy for improving patient-reported health outcomes in men with moderate-to-severe urinary symptoms and prostate enlargement, reporting the pre-planned 2-year analyses from the CombAT trial. PATIENTS AND METHODS The CombAT study is an ongoing, international, double-blind, randomized, parallel-group trial. Men aged ≥50 years with a clinical diagnosis of benign prostatic hyperplasia (BPH), an International Prostate Symptom Score (IPSS) of ≥12 units, a prostate volume of ≥30 mL, a total serum prostate-specific antigen level of 1.5–10 ng/mL and a peak urinary flow of >5 and ≤15 mL/s, with a minimum voided volume of ≥125 mL, were randomized to receive 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months. The primary endpoint at 2 years was the change in IPSS from baseline. Secondary endpoints included various measures of health outcomes, which included the BPH Impact Index (BII), IPSS Question 8 (Q8), and the Patient Perception of Study Medication (PPSM) questionnaire. RESULTS Combined therapy resulted in significantly greater improvements in BII and IPSS Q8 from baseline than did dutasteride from 3 months and compared with tamsulosin from 9 months (BII) or 12 months (IPSS Q8). Assessments using the PPSM questionnaire showed that a significantly higher proportion of patients were satisfied with and would request dutasteride and tamsulosin combined therapy than with each monotherapy at 24 months. CONCLUSIONS Dutasteride and tamsulosin combined therapy provides significantly greater improvements in patient-reported quality of life and treatment satisfaction than both monotherapies at 2 years, following the trends for clinical improvements in symptom scores and peak urinary flow rates, in men with moderate-to-severe BPH symptoms.

Although ethnicity-based differences in prostate size and physiology have been reported, results of benign prostatic hyperplasia (BPH) treatment trials in predominantly Caucasian patients are assumed to be applicable to non-Caucasian populations. This post hoc analysis investigated whether an Asian subpopulation of men with moderate-to-severe BPH in the CombAT study achieves treatment responses in line with those of the overall study population. In this double-blind, randomized, parallel-group trial, 325 Asian men were assigned to treatment with 0.5mg dutasteride once daily, 0.4mg tamsulosin once daily or the combination. Decrease in international prostate symptom score (IPSS) at month 24 from baseline (the primary endpoint) was significantly greater with combination treatment compared with tamsulosin (P

Purpose: We investigated whether combination therapy with dutasteride and tamsulosin is more effective than either monotherapy alone for improving symptoms and long-term outcomes in men with moderate to severe lower urinary tract symptoms and prostatic enlargement (30 cc or greater). We report preplanned 2-year analyses. Materials and Methods: The CombAT study is an ongoing, multicenter, randomized, double-blind, parallel group study. Men 50 years or older with a clinical diagnosis of benign prostatic hyperplasia, International Prostate Symptom Score 12 points or greater, prostate volume 30 cc or greater, total serum prostate specific antigen 1.5 ng/ml or greater to 10 ng/ml or less and peak urinary flow greater than 5 to 15 ml per second or less with a minimum voided volume of 125 ml or greater were randomized to 0.5 mg dutasteride, 0.4 mg tamsulosin or the combination once daily for 4 years. Symptoms were assessed every 3 months and peak urinary flow was assessed every 6 months. The primary end point at 2 years was the change in International Prostate Symptom Score from baseline. Results: Combination therapy resulted in significantly greater improvements in symptoms vs dutasteride from month 3 and tamsulosin from month 9, and in benign prostatic hyperplasia related health status from months 3 and 12, respectively. There was a significantly greater improvement from baseline in peak urinary flow for combination therapy vs dutasteride and tamsulosin monotherapies from month 6. There was a significant increase in drug related adverse events with combination therapy vs monotherapies, although most did not result in the cessation of therapy. Conclusions: In men with moderate to severe lower urinary tract symptoms and prostate enlargement (30 cc or greater) combination therapy provides a significantly greater degree of benefit than tamsulosin or dutasteride monotherapy.

The relationship between 5α-reductase inhibitors and blood loss from the prostate has been well described and investigated previously. In a well-conducted study, authors from Sweden show that dutasteride, despite significantly lowering the tissue dihydrotestosterone levels, did not lower blood loss or transfusion rates after TURP. OBJECTIVE To determine whether pretreatment with dutasteride, a dual 5α-reductase inhibitor (5ARI), reduces surgical blood loss or postoperative complications in patients with benign prostatic hyperplasia (BPH) who undergo transurethral resection of the prostate (TURP). PATIENTS AND METHODS This double-blind, randomized, placebo-controlled, multicentre study comprised 214 patients with BPH. Placebo was compared with dutasteride 0.5 mg/day 2 weeks before and after TURP, or 4 weeks before and 2 weeks after TURP. Surgical blood loss was measured using a haemoglobin photometer (HemoCue AB, Angelholm, Sweden) and postoperative adverse events were recorded. Microvessel density (MVD) was calculated by immunostaining and light microscopy of the prostatic chips. RESULTS Although dutasteride reduced serum dihydrotestosterone (DHT) by 86–89% in 2–4 weeks, and intraprostatic DHT was ≈ 10 times lower than in the placebo group, the (adjusted) mean haemoglobin (Hb) loss during surgery was 2.15–2.55 g Hb/g resectate with no significant difference in blood loss between the groups either during or after TURP. Clot retention occurred in 6–11% and urinary incontinence in 14–15% of patients during the 14 weeks after TURP, with no difference between the groups. The MVD at TURP was also similar for all groups. CONCLUSION There were no significant reductions in blood loss during or after TURP or complications afterward with dutasteride compared with placebo, despite significant suppression of intraprostatic DHT. Blood loss and transfusion rates in the placebo group were lower than those previously reported in studies where there was a beneficial effect of a 5ARI, relative to placebo, on bleeding during TURP.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Ranitidine 150 mg twice daily (BID) is an approved therapeutic approach for relieving the symptoms of gastroesophageal reflux disease. Ranitidine 150 mg four times daily (QID) and cimetidine 800 mg BID are indicated for endoscopically diagnosed erosive esophagitis. This 12-week, randomized, multicenter trial involving 696 patients compared ranitidine 150 mg BID and ranitidine 150 mg QID with cimetidine 800 mg BID in healing erosive esophagitis. Healing rates, as determined by endoscopy, at 4, 8, and 12 weeks were comparable with ranitidine 150 mg BID (38%, 56%, and 71%, respectively) and cimetidine 800 mg BID (37%, 52%, and 68%, respectively), as were reductions in heartburn frequency and antacid consumption. However, ranitidine 150 mg QID produced significantly higher healing rates (49%, 67%, and 77%, respectively) and greater reductions in heartburn frequency and antacid consumption than cimetidine 800 mg BID. All treatment regimens were well tolerated. Thus ranitidine 150 mg BID is as effective as cimetidine 800 mg BID, and ranitidine 150 mg QID is more effective than cimetidine 800 mg BID in healing erosive esophagitis and reducing heartburn frequency and antacid consumption.

Department of Urology, UT Southwestern Medical Center, Dallas, Texas, USA Deaconess Clinic, Evansville, Indiana, USA Department of Urology, University of Toronto, Toronto, Ontario, Canada Urology Department, State University of Rio de Janeiro, Rio de Janeiro, Brazil Research and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA Department of Urology, Universita Vita Salute San Raffaele, Milan, Italy