David G. Wong

Tadalafil 2.5 or 5 mg administered once daily for 12 weeks in men with both erectile dysfunction and signs and symptoms of benign prostatic hyperplasia: results of a randomized, placebo-controlled, double-blind study.

INTRODUCTION Erectile dysfunction (ED) and lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) commonly coexist in aging men. Tadalafil, a phosphodiesterase type 5 inhibitor approved for treating ED, is currently being evaluated for treating BPH-LUTS. AIMS This multinational Phase 3 study assessed effects of tadalafil 2.5 or 5 mg once daily on ED and BPH-LUTS in men with both conditions during 12 weeks of double-blinded therapy. METHODS Men were ≥ 45 years old, sexually active, and experiencing ED for ≥ 3 months and BPH-LUTS for >6 months. Randomization (baseline) followed a 4-week placebo lead-in; changes from baseline were assessed via analysis of covariance and compared to placebo. A gatekeeping procedure controlled for multiple comparisons of co-primary and key secondary measures at end point (last post-baseline observation). MAIN OUTCOME MEASURES The co-primary measures were the International Index of Erectile Function-erectile function (IIEF-EF) domain and International Prostate Symptom Score (IPSS) score; key secondary measures were the Sexual Encounter Profile Question 3 (SEP Q3) and BPH Impact Index (BII). Treatment-emergent adverse events, serious adverse events, orthostatic vital signs, clinical laboratory and uroflowmetry parameters, and postvoid residual volume were assessed. RESULTS Tadalafil 2.5 mg (N = 198) and 5 mg (N = 208) significantly improved IIEF-EF domain scores (both P < 0.001) vs. placebo (N = 200) at end point. For IPSS, improvements were significant with tadalafil 5 mg (P < 0.001), but not 2.5 mg, for observations from 2 weeks through end point (least-squares mean ± standard error change from baseline at end point, placebo -3.8 ± 0.5, tadalafil 2.5 mg -4.6 ± 0.4, and 5 mg -6.1 ± 0.4). Tadalafil 5 mg significantly improved SEP Q3 and BII (P < 0.001). Overall, tadalafil was well tolerated with no clinically adverse changes in orthostatic vital signs or uroflowmetry parameters. CONCLUSIONS Tadalafil 5 mg significantly improved both ED and BPH-related outcomes through 12 weeks and was well tolerated.

Efficacy and Safety of the Coadministration of Tadalafil Once Daily with Finasteride for 6 Months in Men with Lower Urinary Tract Symptoms and Prostatic Enlargement Secondary to Benign Prostatic Hyperplasia

PURPOSE Medical treatment for men with lower urinary tract symptoms and prostatic enlargement secondary to benign prostatic hyperplasia is 5α-reductase inhibitor monotherapy or coadministration with an α-blocker. We assessed the effects of tadalafil 5 mg coadministered with finasteride 5 mg during 26 weeks on lower urinary tract symptoms and sexual symptoms. MATERIALS AND METHODS In an international, randomized, double-blind, parallel study of men 45 years old or older who were 5α-reductase inhibitor naïve and had an I-PSS (International Prostate Symptom Score) of 13 or greater and prostate volume 30 ml or greater, 350 were treated with placebo/finasteride and 345 received tadalafil/finasteride for 26 weeks. Changes in lower urinary tract symptoms secondary to benign prostatic hyperplasia were assessed with the I-PSS, erectile dysfunction improvements were assessed with the IIEF-EF (International Index of Erectile Function-Erectile Function) in sexually active men and safety was assessed by evaluating adverse events. RESULTS Least squares mean changes from baseline in I-PSS after 4, 12 and 26 weeks of tadalafil/finasteride coadministration were -4.0, -5.2 and -5.5, respectively. Corresponding values for placebo/finasteride coadministration were -2.3, -3.8 and -4.5 (p ≤ 0.022 at all visits favoring tadalafil/finasteride coadministration). I-PSS subscores (storage and voiding) and quality of life index were also numerically improved with tadalafil/finasteride coadministration. Least squares mean changes from baseline in IIEF-EF with tadalafil/finasteride coadministration were 3.7 after 4 weeks, and 4.7 after 12 and 26 weeks. Corresponding values for placebo/finasteride coadministration were -1.1, 0.6 and -0.0 (p <0.001 at all visits favoring tadalafil/finasteride coadministration). Tadalafil/finasteride coadministration was well tolerated and most adverse events were mild/moderate. CONCLUSIONS The coadministration of tadalafil/finasteride provides early improvement in lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement. Tadalafil/finasteride coadministration also improves erectile function in men who have comorbid erectile dysfunction.

Improvements in confidence, sexual relationship and satisfaction measures: results of a randomized trial of tadalafil 5 mg taken once daily.

An efficacy study of tadalafil (5 mg once daily) for treating erectile dysfunction included sexual satisfaction and psychosocial outcome measures such as Treatment satisfaction (THX) domain of Sexual Life Quality Questionnaire, Self-Esteem And Relationship (SEAR) questionnaire, Sexual Encounter Profile questions 4 (SEP4; hardness satisfaction) and 5 (SEP5; overall satisfaction), intercourse satisfaction (IS) and overall satisfaction (OS) domains of International Index of Erectile Function (IIEF), and partner SEP question 3 (pSEP3). After a 4-week run-in phase, participants were randomized to receive either tadalafil (N=264) or placebo (N=78) for 12 weeks. Participants and partners were more satisfied (THX) with tadalafil (75 and 73, respectively) than with placebo (51 and 55, respectively, P<0.001). Statistically significant improvements in sexual relationship, confidence, self-esteem and overall relationship (SEAR), in addition to IS, OS, SEP5 and pSEP3 for tadalafil compared with placebo (P<0.001) correlated with erectile function (EF) improvement (assessed by change from baseline in IIEF-EF score). Tadalafil significantly improved treatment and sexual satisfaction, while improving multiple outcomes measured by SEAR.

Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: Results from MOMENTUS: Multiple observations in men with erectile dysfunction in national tadalafil study in the US

INTRODUCTION Limited efficacy and safety data exist from open-label clinical trials of phosphodiesterase 5 inhibitors in men with erectile dysfunction (ED) and multiple comorbid (MCM) conditions, historically a difficult group to treat. AIM A multicenter study (Multiple Observations in Men with Erectile Dysfunction in National Tadalafil Study in the US) assessed efficacy and safety of tadalafil in men with ED and MCM conditions. MAIN OUTCOME MEASURES The primary end point was change from baseline in the erectile function (EF) domain of the International Index of Erectile Function. Secondary end points included the Sexual Encounter Profile, Global Assessment Questions, and Sexual Self-Confidence and Spontaneity Domains of the Psychological and Interpersonal Relationship Scales. METHODS This was an open-label, multicenter study in men with ED. Tadalafil 20 mg was administered as needed prior to sexual activity, up to once/day, for 12 weeks following a 4-week ED-treatment-free period. The MCM group was 155 of 1,911 men enrolled in this study. Men in the MCM group met eligibility criteria but could not be included in other predefined groups: (i) Caucasian; (ii) Black American; (iii) Hispanic (groups 1-3, < or =65 years, no diabetes or depression); (iv) depression, < or =65 years, no diabetes; (v) diabetes, < or =65 years, no depression; (vi) >65 years, no diabetes or depression; and (vii) ED subsequent to traumatic spinal cord injury. RESULTS Mean baseline EF domain score in MCM (mean age 65 +/- 9 years) was 12.2 +/- 6.5; 52% of subjects had severe ED; 72% diabetes mellitus; 67% cardiovascular disease (including hypertension); 49% hyperlipidemia; 38% depression; 84% had two or more comorbidities. At end point, there was a significant (P < 0.001) mean change of 7.6 from baseline in mean EF domain score. Among men with severe ED, 22% achieved an EF domain score > or =26. Most common adverse events were headache 5.2%; flushing 3.9% and nasal congestion 3.2%; 3% discontinued use because of an adverse event. CONCLUSIONS In this open-label clinical trial of older men with ED and MCMs, tadalafil 20 mg significantly increased all efficacy end points and was well-tolerated.

Efficacy and safety of tadalafil once daily : considerations for the practical application of a daily dosing option

ABSTRACT Objective: To provide clinically relevant information on tadalafil 2.5 or 5 mg once daily for the treatment of erectile dysfunction (ED), by reviewing safety and efficacy study findings. Findings from an integrated analysis of trials of tadalafil 10 and 20 mg as needed are presented to provide context for the daily dosing regime. Research design and methods: Of the three studies that included approved once-daily doses, two were conducted in the general ED population and one in a diabetic ED population. An integrated analysis was performed using 12-week efficacy and safety data from the studies conducted in the general ED population. Results: In the general ED population, the 12-week mean International Index of Erectile Function (IIEF) erectile function (EF) domain scores increased by 6.2 to an endpoint score of 19.2 and by 8.6 to 21.9 for 2.5 and 5 mg doses, respectively, versus an increase of 1.3 to 14.9 for placebo (p < 0.01). Mean successful intercourse attempts (SEP3) were 50% and 62% for tadalafil 2.5 and 5 mg once daily, respectively, versus 33% for placebo (p < 0.01). These findings were consistent with those for tadalafil as needed. In 1- and 2-year open label extensions of tadalafil 5 mg once daily, efficacy was maintained. In the diabetic ED population, 12-week mean IIEF EF scores increased by 4.8 to 18.3 and 4.5 to 17.2 with tadalafil 2.5 and 5 mg, respectively, versus an increase of 1.3 to 14.7 for placebo (p < 0.01). Mean successful intercourse attempts were more than 40% for each tadalafil dose, versus 28% for placebo (p < 0.01). The profile of treatment-emergent adverse events with tadalafil once daily was similar to that previously reported with as-needed treatment; the most common adverse events with tadalafil (dyspepsia, nasopharyngitis, headaches) were reported in ≤4% of participants. Conclusions: Findings from the three published studies support a favorable risk–benefit balance for tadalafil 2.5 or 5 mg once daily. Although no direct comparison studies were performed (no head-to-head trials), efficacy and safety findings were consistent with those with tadalafil as needed.

Direct Effects of Tadalafil on Lower Urinary Tract Symptoms versus Indirect Effects Mediated through Erectile Dysfunction Symptom Improvement: Integrated Data Analyses from 4 Placebo Controlled Clinical Studies

PURPOSE Tadalafil has regulatory approval for the treatment of men with signs/symptoms of benign prostatic hyperplasia with and without erectile dysfunction. We assessed whether the effects of treatment with tadalafil for lower urinary tract symptoms/benign prostatic hyperplasia are independent of improvements in erectile dysfunction. MATERIALS AND METHODS Four separate analyses used integrated data from 4 randomized, double-blind, placebo controlled studies in men with lower urinary tract symptoms/benign prostatic hyperplasia with and without erectile dysfunction to test whether total I-PSS (International Prostate Symptom Score) improvement was due to improvement in IIEF-EF (International Index of Erectile Function-Erectile Function domain score). Unidirectional and bidirectional path analysis models determined direct and indirect treatment effects mediated by improvements in lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction symptoms. RESULTS A total of 1,496 men, of whom 77% had erectile dysfunction, received at least 1 dose of tadalafil 5 mg once daily or placebo. The placebo adjusted treatment effect for men with erectile dysfunction was represented by a mean decrease of -2.3 (p <0.0001) in total I-PSS vs -2.2 (p = 0.0007) for men without erectile dysfunction. The correlation between change from baseline in total I-PSS and IIEF-EF was weak (r(2) = 0.08, p <0.0001). The unidirectional path analysis model suggested that the total treatment effect on total I-PSS score improvement (2.25) was derived from a direct treatment effect of 1.57 (70%, p <0.001) and an indirect treatment effect of 0.67 (30% via IIEF-EF improvement, p <0.001). Bidirectional path analysis showed that total I-PSS improvement was largely attributed to direct (92.5%, p <0.001) vs indirect (7.5%, p = 0.32) treatment effects via IIEF-EF improvement. CONCLUSIONS Regardless of the analytical approach, self-reported erectile dysfunction status did not appreciably influence tadalafil treatment response in men with lower urinary tract symptoms/benign prostatic hyperplasia, supporting the dual action of tadalafil on lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction.

Reliability of efficacy in men with erectile dysfunction treated with tadalafil once daily after initial success.

The reliability of response to treatment is an important component of erectile dysfunction (ED) treatment. This study examined the reliability of tadalafil once daily (that is, successful attempts/total attempts) following initial successful intercourse. Data pooled from two randomized, double-blind, placebo-controlled trials of men with ED who received tadalafil 2.5 mg (N=96), tadalafil 5 mg (N=206) or placebo (N=148) once daily were analyzed to determine the first-attempt success rate and subsequent reliability of response. The first-attempt success rate (Sexual Encounter Profile question 3 (SEP3)) was significantly higher among men taking tadalafil 2.5 mg (45.7%) and 5 mg (55.2%) compared to placebo (28.5%; P<0.05 and P<0.001, respectively). Furthermore, following initial success, men taking tadalafil 5 mg had a significantly greater proportion of successful intercourse (SEP3) on subsequent attempts (85.9%, P<0.001) compared to men taking placebo (70.2%). Overall, men with ED taking tadalafil once daily experienced a high rate of reliability of efficacy.

Treatment Patterns in Alpha-Blocker Therapy for Benign Prostatic Hyperplasia:

This study examined treatment patterns and patient characteristics of men initiating alpha adrenergic blocker therapy (alpha-blocker) for benign prostatic hyperplasia (BPH). The 2009 Thomson Reuters MarketScan® Database was used to identify the newly initiated alpha-blocker: men ≥40 years old with continuous medical and pharmacy coverage for 12 months before and after alpha-blocker initiation, with no alpha-blocker or 5-alpha-reductase inhibitors in the previous year, and with ≥1 BPH diagnosis within 1 month before and 6 months after alpha-blocker initiation. This study analyzed patient demographics, clinical characteristics, adherence (percentage of men achieving medication possession ratio [MPR] ≥ 0.8), restarting the same alpha-blocker after discontinuation, switching to another BPH medication, and type of alpha-blocker (alpha 1 type selective or alpha 1 subtype selective agents). T tests and chi-square tests compared differences at the .05 significance level. A total of 13,474 men met the study criteria (mean age of 63.1 years). Two thirds of the men discontinued alpha-blocker in the 12-month period, among which restarts or switches were statistically different (p = .036) but numerically similar across cohorts. Adherence for alpha 1 type selective agents versus alpha 1 subtype selective agents at 6 months was 43.3% versus 38.1% (p < .01); at 12 months, 34.4% versus 30.5% (p < .01). Alpha-blocker discontinuation rates were high, which confirms low medication adherence reported among medications for several other chronic conditions; therefore, it is necessary to understand the reasons for alpha-blocker discontinuation.

The Co-occurring Syndrome—Coexisting Erectile Dysfunction and Benign Prostatic Hyperplasia and Their Clinical Correlates in Aging Men: Results From the National Health and Nutrition Examination Survey

OBJECTIVE To establish a descriptive profile of men with coexistent erectile dysfunction (ED) and/or benign prostatic hyperplasia (BPH), ED only or BPH only compared to those with neither condition and to identify the determinants of coexisting disease. MATERIALS AND METHODS Self-report and/or medication use measures defining ED and BPH were assessed in men aged ≥40 years (N = 2142) between 2001 and 2004 using the National Health and Nutrition Examination Surveys. Descriptive analyses examined the ED and/or BPH covariate distribution. Logistic regressions calculated odds ratios (ORs, 95% confidence interval) comparing men with ED and/or BPH, BPH only, or ED only to men with neither condition. RESULTS Of 393 men with BPH, 57.8% had coexistent ED, confirming the moderately strong co-occurrence of the conditions (P <.0001). Coexisting ED and/or BPH occurred in 10.6% of participants, whereas 24.4% and 7.7% reported ED and BPH. After age 60, the odds of reporting ED, BPH, or ED/BPH vs neither almost tripled per decade of increasing age, corresponding to prevalence increases. The unadjusted odds of ED and/or BPH vs no disease increased 1.3 times per prostate-specific antigen unit (ng/mL) increase and 1.1 times per C-reactive protein unit (mg/dL) increase. Other predisposing factors for ED and/or BPH included higher body mass index (OR = 2.5), increased antidiabetic (OR = 2.9) or proton pump inhibitor use (OR = 2.3), increased healthcare visits (≥4; OR = 3.5), and more frequent urinary voiding difficulties (OR = 9.7). CONCLUSION Co-occurring ED and/or BPH is evident in ~10% of men ≥40 years old and is associated with significant clinical correlates. Clinicians need to pay greater attention to this clinically important syndrome in aging men.

Response to treatment with tadalafil in men with erectile dysfunction who reported no successful intercourse attempts at baseline

The purpose of this post hoc analysis was to evaluate response to tadalafil in patients with erectile dysfunction (ED) who reported failures in all sexual intercourse attempts before treatment. In a multicenter, open-label study, 1911 men received tadalafil 20 mg dosed as needed (up to once daily), for 12 weeks following a 4-week treatment-free run-in period. Efficacy measures included the sexual encounter profile (SEP) and the erectile function (EF) domain of the International Index of Erectile Function (IIEF-EF). Approximately, one-half (n=952, 49.9%) of the patients reported no successful intercourse attempts during the 4-week run-in period. Of these, 771 patients (81.0%) had at least one successful intercourse attempt during the treatment period. Furthermore, among responders, mean IIEF-EF scores at study end were similar regardless of success or no success at baseline. Patients who are unable to have successful intercourse should be encouraged to try oral phosphodiesterase type 5 inhibitor treatment for ED.