Tadalafil administered once daily for treatment of Korean men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: Results from a placebo-controlled pilot study using tamsulosin as an active control Proposed Authors

Background: This pilot study assessed the efficacy and safety of once-daily tadalafil or tamsulosin versus placebo during 12 weeks in Korean men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Methods: Following a 4-week placebo run-in period, 151 Korean men were randomly assigned to receive once-daily tadalafil 5 mg, tamsulosin 0.2 mg, or placebo for a 12-week treatment period. An analysis of covariance (ANCOVA) model was used to analyze the primary endpoint (International Prostate Symptom Score, IPSS) and secondary continuous efficacy variables. Safety parameters were tested with Fisher’s exact test, ANCOVA and analysis of variance (ANOVA) models. Results: The IPSS least squares mean changes from baseline to endpoint were numerically but not significantly improved in the tadalafil (-5.8) and tamsulosin (-5.4) groups compared with placebo (-4.2, P>0.05). Decreases in IPSS obstructive and irritative subscores, IPSS Quality of Life score, and BPH Impact Index (BII) from baseline to endpoint were largest in the tadalafil treatment group followed by tamsulosin, though none separated significantly from placebo. Increases in maximum urinary flow rate (Qmax) were small and not significantly different than placebo; the increase was largest in the tadalafil group (2.5 mL/s), followed by the placebo (2.3 mL/s) and tamsulosin (2.1 mL/s) groups. Subjects reporting at least 1 treatment-emergent adverse event (TEAE) were 26.5% in the tamsulosin group, 13.7% in the tadalafil group and 3.9% in the placebo group. The incidence of TEAEs was statistically significant for tamsulosin (p=.002) but not for tadalafil (p=0.16), compared with placebo. Conclusions: In this pilot study, men with BPH-LUTS treated with tadalafil 5 mg or tamsulosin 0.2 mg once daily experienced a reduction in BPH-LUTS, which was numerically, but not statistically significantly, better than placebo. Tadalafil was well tolerated, and very few subjects discontinued the study due to TEAEs. Larger studies in Asian men with BPH-LUTS treated with phosphodiesterase type 5 (PDE5) inhibitors are needed. Trial registration: ClinicalTrials.gov NCT00540124. BACKGROUND Men with benign prostatic hyperplasia (BPH) commonly experience lower urinary tract symptoms (LUTS) such as increased urinary frequency, urgency, intermittency, nocturia, straining, incomplete emptying, and weak urinary stream. The disorder is common in aging men, with estimates of men with BPH resulting in LUTS ranging from 30 to 35 million in the United States (US), Western Europe, and Japan [1]. One study in Korean and other Asian men found that the prevalence of symptomatic BPH (defined as International Prostate Symptom Score [IPSS] ≥8) ranged from 18% in men ages 40-49 years to 56% in men ages 70-79 years, suggesting that the prevalence in Asia is similar to that in Europe or the United States [2]. In 2 Korean studies conducted in community-dwelling men ≥50 years of age with a combined IPSS≥8, maximum urinary flow rate (Qmax) ≤15 mL/second, and prostate enlargement (per digital rectal exploration or transrectal ultrasound), the prevalence of BPH-LUTS prevalence was 11.1% and 20.2% [3,4]. The current standard-of-care medical therapy, globally as well as in Korea, for the treatment of bothersome moderate to severe BPH-LUTS is the use of alpha-1 adrenergic blockers (alpha blockers) [5], while 5-alpha reductase inhibitors (5-ARIs) are an acceptable alternative for men who also have an enlarged prostate. Although potentially effective at reducing urinary symptoms as monotherapy or in combination, both alpha blockers and 5-ARIs may produce unwanted side effects, including sexual dysfunction, which prompt some patients to avoid or discontinue therapy and which may be exacerbated with combination therapy. Additionally, alpha blockers may be associated with dizziness and hypotension [5,6]. Tamsulosin, a selective alpha blocker, is the most commonly prescribed treatment in men with BPHLUTS, both globally and in Korea [7]. In Korea, Japan, and many other Asian countries, the dose of tamsulosin approved for the treatment of men with urination disorder associated with prostatic hyperplasia is 0.2 mg, in contrast to 0.4 mg, which is the approved dose in the US and Europe [8]. Tadalafil (Cialis), a phosphodiesterase type 5 (PDE5) inhibitor, is currently approved in a number of Asian countries for on-demand treatment of erectile dysfunction (ED) and in the US and Europe for both on-demand and once-daily dosing for the treatment of ED. Because PDE5 is expressed and biologically active in the human bladder, urethra, prostatic tissue, and corpus cavernosum [9,10], it is postulated that a long-acting PDE5 inhibitor such as tadalafil may be efficacious not only in the treatment of men with ED, but also in the once-daily treatment of men with BPH-LUTS. In a recent 12-week global dose-finding study conducted in 1058 men with BPH-LUTS, tadalafil was associated with statistically significant and clinically meaningful improvements in multiple measures of LUTS, including quality of life, as well as ED improvement, compared to placebo [11]. The effects of tadalafil in the treatment of Korean men with BPH-LUTS have not been studied previously, and available data in Korean men treated with tamsulosin in double-blind placebo-controlled studies are limited. Furthermore, tadalafil and tamsulosin have not been assessed as medical therapies for BPHLUTS in the same placebo-controlled clinical trial utilizing the same criteria and study design. The aim of this pilot study was to assess the safety and efficacy of once-daily tadalafil 5 mg and tamsulosin 0.2 mg versus placebo during 12 weeks in Korean men with BPH-LUTS.