Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo-controlled clinical trial

Background

Acupuncture therapy has been used by many researchers in both male and female sexual dysfunction studies.

Objective

To determine whether acupuncture is effective as a premature ejaculation (PE) treatment compared with paroxetine and placebo.

Design, setting, and participants

The study was conducted with methodologic rigor based on Consolidated Standards of Reporting Trials (CONSORT) criteria. Ninety patients referred to the urology clinic at a tertiary training and research hospital with PE were included in this randomized controlled trial and randomly assigned into paroxetine, acupuncture, and placebo groups. Heterosexual, sexually active men aged between 28 and 50 yr were included. Men with other sexual disorders, including erectile dysfunction; with chronic psychiatric or systemic diseases; with alcohol or substance abuse; or who used any medications were excluded.

Intervention

The medicated group received paroxetine 20 mg/d; the acupuncture or sham-acupuncture (placebo) groups were treated twice a week for 4 wk.

Measurements

Intravaginal ejaculation latency times (IELTs) and the Premature Ejaculation Diagnostic Tool (PEDT) were used to assess PE. IELTs were calculated by using a partner-held stopwatch. Data were analyzed statistically.

Results and limitations

Median PEDT scores of paroxetine, acupuncture, and placebo groups were 17.0, 16.0, and 15.5 before treatment, and 10.5, 11.0, and 16.0 after treatment, respectively (p = 0.001, p = 0.001, and p = 0.314, respectively). Subscores after treatment were significantly lower than subscores before treatment in the paroxetine and acupuncture groups but remained the same in the placebo group. Significant differences were found between mean-rank IELTs of the paroxetine and placebo groups (p = 0.001) and the acupuncture and placebo groups (p = 0.001) after treatment. Increases of IELTs with paroxetine, acupuncture, and placebo acupuncture were 82.7, 65.7, and 33.1 s, respectively. Extent of ejaculation delay induced by paroxetine was significantly higher than that of acupuncture (p = 0.001). The most important limitation of the study was the lack of follow-up.

Conclusions

Although less effective than daily paroxetine, acupuncture had a significant stronger ejaculation-delaying effect than placebo.     

A Randomized Double-blind Placebo-controlled Phase 2 Dose-ranging Study of OnabotulinumtoxinA in Men with Benign Prostatic Hyperplasia

Background

Botulinum toxin treatment has been investigated as a minimally invasive alternative to oral medications in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH).

Objective

To explore the efficacy of onabotulinumtoxinA 100 U, 200 U, and 300 U versus placebo in men with LUTS/BPH in a phase 2 dose-ranging study.

Design, setting, and participants

A multicenter double-blind randomized, placebo-controlled 72-wk study enrolled men ≥50 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥12, total prostate volume (TPV) 30–100 ml, and maximum flow rate (Q_max) 5–15 ml/s.

Intervention

Single transperineal (n = 63) or transrectal (n = 311) administration of placebo (n = 94) or onabotulinumtoxinA 100 U (n = 95), 200 U (n = 94), or 300 U (n = 97) into the prostate transition zone.

Outcome measurements and statistical analysis

The primary efficacy end point was a change from baseline in IPSS at week 12. Secondary end points were Q_max, TPV, and transition zone volume (TZV). Analysis of covariance and the Cochran-Mantel-Haenszel method assessed the efficacy and proportion of IPSS responders. Adverse events (AEs) were assessed.

Results and limitations

Significant improvements from baseline in IPSS, Q_max, TPV, and TZV were observed for all groups, including placebo, at week 12 (p < 0.001), with no significant differences between onabotulinumtoxinA and placebo. However, in an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with onabotulinumtoxinA 200 U in prior α-blocker users (n = 180) at week 12. AEs were comparable across all groups.

Conclusions

Reductions in LUTS/BPH symptoms were seen in all groups, including placebo, with no significant between-group differences owing to a large placebo effect from the injectable therapy. The findings from the post hoc analysis in men previously treated with α-blockers will be further explored in an appropriately designed study.

Trial registration

http://www.Clinical Trials.gov; NCT00284518.     

Alvimopan Accelerates Gastrointestinal Recovery After Radical Cystectomy: A Multicenter Randomized Placebo-Controlled Trial

Background

Radical cystectomy (RC) for bladder cancer is frequently associated with delayed gastrointestinal (GI) recovery that prolongs hospital length of stay (LOS).

Objective

To assess the efficacy of alvimopan to accelerate GI recovery after RC.

Design, setting, and participants

We conducted a randomized double-blind placebo-controlled trial in patients undergoing RC and receiving postoperative intravenous patient-controlled opioid analgesics.

Intervention

Oral alvimopan 12 mg (maximum: 15 inpatient doses) versus placebo.

Outcome measurements and statistical analysis

The two-component primary end point was time to upper (first tolerance of solid food) and lower (first bowel movement) GI recovery (GI-2). Time to discharge order written, postoperative LOS, postoperative ileus (POI)-related morbidity, opioid consumption, and adverse events (AEs) were evaluated. An independent adjudication of cardiovascular AEs was performed.

Results and limitations

Patients were randomized to alvimopan (n = 143) or placebo (n = 137); 277 patients were included in the modified intention-to-treat population. The alvimopan cohort experienced quicker GI-2 recovery (5.5 vs 6.8 d; hazard ratio: 1.8; p < 0.0001), shorter mean LOS (7.4 vs 10.1 d; p = 0.0051), and fewer episodes of POI-related morbidity (8.4% vs 29.1%; p < 0.001). The incidence of opioid consumption and AEs or serious AEs (SAEs) was comparable except for POI, which was lower in the alvimopan group (AEs: 7% vs 26%; SAEs: 5% vs 20%, respectively). Cardiovascular AEs occurred in 8.4% (alvimopan) and 15.3% (placebo) of patients (p = 0.09). Generalizability may be limited due to the exclusion of epidural analgesia and the inclusion of mostly high-volume centers utilizing open laparotomy.

Conclusions

Alvimopan is a useful addition to a standardized care pathway in patients undergoing RC by accelerating GI recovery and shortening LOS, with a safety profile similar to placebo.

Patient summary

This study examined the effects of alvimopan on bowel recovery in patients undergoing radical cystectomy for bladder cancer. Patients receiving alvimopan experienced quicker bowel recovery and had a shorter hospital stay compared with those who received placebo, with comparable safety.

Trial registration

ClinicalTrials.gov identifier NCT00708201     

Dapoxetine and the treatment of premature ejaculation

Background

Premature ejaculation (PE) is the most common male sexual complaint. Off-label oral selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for the treatment of PE. Dapoxetine is a short-acting SSRI specifically designed for on-demand use. The objective of this communication is to summarize the clinical and physiological evidence regarding the role of the serotonergic pathway and specifically dapoxetine in the treatment of PE.

Methods

A PubMed search was conducted on articles reporting data on dapoxetine for the treatment of PE. Articles describing the pathophysiology and treatment options for PE were additionally included for review.

Results

The etiology of PE is multi-factorial in nature. There are many treatment options for PE such as psychological/behavioral therapy, topical anesthetic agents, phosphodiesterase type 5 (PDE-5) inhibitors, and tramadol hydrochloride. SSRIs play a major role in PE treatment. Animal and clinical studies in addition to its pharmacokinetic document dapoxetine’s clinical efficacy and safety for on-demand treatment of PE.

Conclusions

Dapoxetine demonstrates clinical efficacy and a favorable side effect profile. Dapoxetine is currently the oral drug of choice for on-demand treatment of PE.     

Perceived control over ejaculation is central to treatment benefit in men with premature ejaculation: results from phase III trials with dapoxetine

OBJECTIVES

To assess the utility of perceived control over ejaculation (‘control’) in the evaluation of treatment benefit in men with premature ejaculation (PE), and to compare effects associated with a two‐category or greater increase in this variable between men receiving dapoxetine and placebo.

PATIENTS AND METHODS

This subanalysis used combined data from all treatment groups in an integrated analysis of two identically designed, 12‐week, double‐blind, randomized, placebo‐controlled trials of dapoxetine. Men (2614) met the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision) criteria for PE, had a stopwatch‐measured intravaginal ejaculatory latency time (IELT) of ≤2 min in ≥75% of events in a 2‐week baseline period, and self‐reported moderate or severe PE. Men received placebo or dapoxetine 30 or 60 mg, 1–3 h before intercourse. The stopwatch‐measured IELT was recorded for each episode; the patient‐reported global impression of change (PGI; 7‐point scale, ‘much worse’ to ‘much better’), control and satisfaction with sexual intercourse (5‐point scales, ‘very poor’ to ‘very good’) were assessed monthly. The utility of a two‐category or greater increase in control was evaluated by examining the relationship of this variable with IELT and satisfaction with sexual intercourse.

RESULTS

Of 2341 men with baseline and endpoint assessments, 96.8% reported ‘very poor’ or ‘poor’ control at baseline, and 748 (32%) reported a two‐category or greater increase in control after treatment. More than 95% of those men rated their PE as ‘slightly better’, ‘better’, or ‘much better’ on the PGI; 67.1% gave ratings of ‘better’ or ‘much better.’ They also had greater improvements in IELT than men with less than a two‐category increase in control, with a mean (sd ) change from baseline of 3.7 (4.3) vs 0.77 (1.8) min, respectively, and a greater percentage reported good or very good satisfaction with sexual intercourse than men with less than a two‐category increase in control (74% vs 19%, respectively). Nausea, headache and upper respiratory tract infection were the most common adverse events reported by men with a two‐category or greater increase in control (15.8%, 7.4% and 6.6%, respectively) and those without (8.5%, 5.5% and 6.5%, respectively). The proportions of men with a two‐category or greater increase in control with dapoxetine 30 and 60 mg were 36.3% and 44.5%, respectively (vs 15% with placebo).

CONCLUSIONS

A two‐category or greater increase in control (5‐point scale) is useful for assessing the treatment benefit in men with PE; it corresponds with improvements in the man’s perception of his condition, substantially greater prolongation of IELT, and higher levels of satisfaction with sexual intercourse.     

A Multicenter,Double-blind,Randomized, Placebo-controlled Trial of the β3-Adrenoceptor Agonist Solabegron for Overactive Bladder

Background

β-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the β3 receptor subtype.

Objective

To evaluate the efficacy and tolerability of the highly selective and potent β3-adrenoceptor agonist solabegron in a clinical proof-of-concept study in incontinent women with overactive bladder (OAB).

Design, setting, and participants

This was a randomized, double-blind trial in adult women with OAB (one or more 24-h incontinence episodes and eight or more average 24-h micturitions).

Interventions

Solabegron 50 mg (n = 88), solabegron 125 mg (n = 85), or placebo (n = 85)—all twice daily—were administered.

Outcome measurements and statistical analysis

The primary efficacy end point was percentage change from baseline to week 8 in the number of incontinence episodes over 24 h. Secondary end points included actual change and percentage change from baseline to week 4 and week 8 in micturitions per 24 h, urgency episodes per 24 h, and volume voided per micturition. Adverse events (AEs) were assessed, as well.

Results and limitations

Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24 h when compared with placebo (p = 0.025). Solabegron 125 mg treatment also showed statistically significant reductions from baseline to weeks 4 and 8 in micturitions over 24 h and a statistically significant increase from baseline to week 8 in urine volume voided. Solabegron was well tolerated, with a similar incidence of AEs in each treatment group. There were no significant treatment differences for mean changes from baseline to week 8 in systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), or heart rate during the 24-h ambulatory measurement.

Conclusions

Solabegron significantly reduced the symptoms of OAB in women with moderate to severe OAB. Solabegron was safe, well tolerated, and did not demonstrate significant differences in AEs as compared to placebo. β3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.     

帕罗西汀与达帕西汀的对比，治疗早泄的新的选择性5-羟色胺再摄取抑制剂

达帕西汀氢氯化物是一种选择性5-羟色胺再摄取抑制剂,也是第一种被批准可以按需服用治疗早泄的药物。本文目的为研究按需服用达帕西汀（30mg和H60mg）和每日服用帕罗西汀（20mg）对早泄的疗效。研究募集了150名患者进行了长达1个月的研究。患者被分成3组,每组50人。第一组按需服用达帕西汀30mg。第二组按需服用达帕西汀60mg。第三组每日服用帕罗西汀20mg。治疗结束后,我们的结果检测值相对于基准阴道内射精潜伏期（IELT）延长了。与基准IELT相比,帕罗西汀组、30mg达帕西汀组和60mg达帕西汀组的治疗后IELT分别延长了117％（P〈0．01）,117％（P〈0．01）和170％（P〈0．01）。30mg达帕西汀组和帕罗西汀组的IELT增幅相同（P〉0．05）,而60mg达帕西汀组的IELT增幅明显高于30mg达帕西汀组（P〈0．05和帕罗西汀组P〈0．01）。性交前1～3小时服用达帕西汀60mg是针对早泄的非常有效的治疗方法。然而,与当前普遍使用的帕罗西汀相比,达帕西汀30mg疗效并不显著。     

Efficacy and Tolerability of Mirabegron,a β3-Adrenoceptor Agonist,in Patients with Overactive Bladder: Results from a Randomised European–Australian Phase 3 Trial

Background

Mirabegron, a β₃-adrenoceptor agonist, has been developed for the treatment of overactive bladder (OAB).

Objective

To assess the efficacy and tolerability of mirabegron versus placebo.

Design, setting, and participants

Multicenter randomised double-blind, parallel-group placebo- and tolterodine-controlled phase 3 trial conducted in 27 countries in Europe and Australia in patients ≥18 yr of age with symptoms of OAB for ≥3 mo.

Intervention

After a 2-wk single-blind placebo run-in period, patients were randomised to receive placebo, mirabegron 50 mg, mirabegron 100 mg, or tolterodine extended release 4 mg orally once daily for 12 wk.

Outcome measurements and statistical analysis

Patients completed a micturition diary and quality-of-life (QoL) assessments. Co–primary efficacy end points were change from baseline to final visit in the mean number of incontinence episodes and micturitions per 24 h. The primary comparison was between mirabegron and placebo with a secondary comparison between tolterodine and placebo. Safety parameters included adverse events (AEs), laboratory assessments, vital signs, electrocardiograms, and postvoid residual volume.

Results and limitations

A total of 1978 patients were randomised and received the study drug. Mirabegron 50-mg and 100-mg groups demonstrated statistically significant improvements (adjusted mean change from baseline [95% confidence intervals]) at the final visit in the number of incontinence episodes per 24 h (−1.57 [−1.79 to −1.35] and −1.46 [–1.68 to −1.23], respectively, vs placebo −1.17 [−1.39 to –0.95]) and number of micturitions per 24 h (−1.93 [−2.15 to −1.72] and −1.77 [−1.99 to −1.56], respectively, vs placebo −1.34 [−1.55 to −1.12]; p < 0.05 for all comparisons). Statistically significant improvements were also observed in other key efficacy end points and QoL outcomes. The incidence of treatment-emergent AEs was similar across treatment groups. The main limitation of this study was the short (12-wk) duration of treatment.

Conclusions

Mirabegron represents a new class of treatment for OAB with proven efficacy and good tolerability.

Trial identification

This study is registered at ClinicalTrials.gov, identifier NCT00689104.     

Safety and Efficacy of the Specific Endothelin-A Receptor Antagonist ZD4054 in Patients with Hormone-Resistant Prostate Cancer and Bone Metastases Who Were Pain Free or Mildly Symptomatic: A Double-Blind,Placebo-Controlled,Randomised, Phase 2 Trial

Background

The endothelin-A receptor (ETAR) has been implicated in the progression of prostate cancer.

Objectives

To investigate the safety and efficacy of the specific ETAR antagonist ZD4054 in patients with metastatic hormone-resistant prostate cancer (HRPC).

Design, setting, and participants

Double-blind, placebo-controlled, randomised, parallel-group, multicentre, phase 2 trial in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain.

Intervention

Patients were randomised to receive once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo.

Measurements

The primary end point was time to progression, defined as clinical progression, requirement for opiate analgesia, objective progression of soft-tissue metastases, or death in the absence of progression. Secondary end points included overall survival, time to prostate-specific antigen (PSA) progression, and safety. Statistical significance was preset at 20%.

Results and limitations

A total of 312 patients were randomised (ZD4054 10 mg, n = 107; ZD4054 15 mg, n = 98; placebo, n = 107). At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo (hazard ratio [HR] vs placebo for the ZD4054 10 mg group: 0.88 [80% CI: 0.71–1.09]; HR vs placebo for the ZD4054 15 mg group: 0.83 [80% CI: 0.66–1.03]). However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed (HR vs placebo for the ZD4054 10 mg group, 0.55 [80% CI: 0.41–0.73], p = 0.008; HR vs placebo for the ZD4054 15 mg group, 0.65 [80% CI: 0.49–0.86], p = 0.052) but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist.

Conclusions

The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated.

Trial registration

Clinicaltrials.gov NCT00090363.     

Dutasteride Treatment Over 2 Years Delays Prostate-specific Antigen Progression in Patients with Biochemical Failure After Radical Therapy for Prostate Cancer: Results from the Randomised,Placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS)

Background

Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial.

Objective

To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy.

Design, setting, and participants

Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries.

Intervention

The 5α-reductase inhibitor, dutasteride.

Outcome measurements and statistical analysis

The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression.

Results and limitations

Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p < 0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35–76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p < 0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53–75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study.

Conclusions

Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience.

Clinical trial registry

ClinicalTrials.gov, NCT00558363.     

OnabotulinumtoxinA 100 U Significantly Improves All Idiopathic Overactive Bladder Symptoms and Quality of Life in Patients with Overactive Bladder and Urinary Incontinence: A Randomised,Double-Blind,Placebo-Controlled Trial

Background

Overactive bladder (OAB) syndrome with urinary incontinence (UI) is prevalent in the population and impairs health-related quality of life (HRQOL).

Objective

To assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) treatment in patients with OAB with UI.

Design, setting, and participants

This pivotal, multicentre, double-blind, randomised, placebo-controlled, phase 3 study enrolled patients with idiopathic OAB with ≥3 urgency UI episodes over 3 d and ≥8 micturitions per day who were inadequately managed by anticholinergics.

Intervention

OnabotulinumtoxinA at a 100 U dose (n = 277) or placebo (n = 271), administered as 20 intradetrusor injections of 0.5 ml.

Outcome measurements and statistical analysis

Co–primary end points were change from baseline in the number of UI episodes per day and proportion of patients reporting positive treatment response on the treatment benefit scale (TBS) at week 12. Additional end points included other OAB symptoms (episodes of urinary urgency incontinence, micturition, urgency, and nocturia) and HRQOL (Incontinence Quality of Life [I-QOL], King's Health Questionnaire [KHQ]). Safety assessments included adverse events (AEs), postvoid residual (PVR) urine volume, and initiation of clean intermittent catheterisation (CIC).

Results and limitations

OnabotulinumtoxinA significantly decreased UI episodes per day at week 12 (−2.95 for onabotulinumtoxinA versus −1.03 for placebo; p < 0.001). Reductions from baseline in all other OAB symptoms were also significantly greater following onabotulinumtoxinA compared with placebo (p ≤ 0.01). Patients perceived a significant improvement in their condition, as measured by patients with a positive treatment response on the TBS (62.8% for onabotulinumtoxinA versus 26.8% for placebo; p < 0.001). Clinically meaningful improvements from baseline in all I-QOL and KHQ multi-item domains (p < 0.001 versus placebo) indicated positive impact on HRQOL. AEs were mainly localised to the urinary tract. Mean PVR was higher in the onabotulinumtoxinA group (46.9 ml versus 10.1 ml at week 2; p < 0.001); 6.9% of onabotulinumtoxinA patients versus 0.7% of placebo patients initiated CIC.

Conclusions

OnabotulinumtoxinA 100 U was well tolerated and demonstrated significant and clinically relevant improvements in all OAB symptoms, patient-reported benefit, and HRQOL in patients inadequately managed by anticholinergics.

Trial registration

ClinicalTrials.gov: NCT00910520.     

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)

Background

Storage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS).

Objective

To evaluate the combination of an antimuscarinic (solifenacin) with an α-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS.

Design, setting, and participants

A double-blind, 12-wk, phase 2 study in 937 men with LUTS (≥3 mo, total International Prostate Symptom Score [IPSS] ≥13, and maximum urinary flow rate 4.0–15.0 ml/s).

Intervention

Eight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or placebo.

Outcome measurements and statistical analysis

The primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups.

Results and limitations

Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24 h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone (p ≤ 0.05 for the dose–response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds.

Conclusions

Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated.

ClinicalTrials.gov identifier

NCT00510406     

Comparison of the clinical efficacy and safety of the on‐demand use of paroxetine,dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation: A randomised placebo‐controlled clinical trial

The aim of the study was to compare the clinical efficacy and safety of the on‐demand use of paroxetine, dapoxetine, sildenafil and combined dapoxetine with sildenafil in treatment of patients with premature ejaculation (PE). In a single‐blind placebo‐controlled clinical study, 150 PE patients without erectile dysfunction (ED) were included during the period of March 2015 to May 2016. Patients were randomly divided into five groups (30 patients each). On demand placebo, paroxetine (30 mg), dapoxetine (30 mg), sildenafil citrate (50 mg) and combined dapoxetine (30 mg) with sildenafil citrate (50 mg) were given for patients for 6 weeks in each group respectively. All patients were instructed to record intravaginal ejaculatory latency time (IELT) and evaluated with Premature Ejaculation Diagnostic Tool (PEDT) and the patient satisfaction score before and after treatment. The mean of IELT, satisfaction score and PEDT in all groups was significantly improved after treatment (p value = .001). Combined dapoxetine with sildenafil group had the best values of IELT, satisfaction scores and PEDT in comparison with other treatment groups (p value <.001). The combined dapoxetine with sildenafil therapy could significantly improve PE patients without ED as compared to paroxetine alone or dapoxetine alone or sildenafil alone with tolerated adverse effects.     

A Novel Treatment of Premature Ejaculation

The investigation of the etiology and treatment of premature ejaculation (PE), a common and significant problem for men and their partners, has been limited by the lack of defined outcomes and differences in clinical trial designs. Currently, no medication has been approved for the treatment for PE worldwide. Recognition of serotonin as a key mediator in ejaculatory signaling has raised interest in the utility of pharmacologic intervention for treating PE. Selective serotonin reuptake inhibitors (SSRIs) have been used off-label for PE, with varied results. However, treatment with currently available SSRIs typically requires chronic dosing that increases drug accumulation and the attendant risk of adverse events. Dapoxetine is an SSRI with a short half-life (1.2 h), developed specifically for the treatment of men with PE. This agent has a unique pharmacokinetic profile characterized by rapid absorption and elimination. Dapoxetine is metabolized by multiple pathways, and no clinically relevant drug–drug interactions have been identified. Furthermore, dapoxetine pharmacokinetics do not appear to be affected by food, age, alcohol, or phosphodiesterase type 5 (PDE5) inhibitors to a relevant degree. In two placebo-controlled phase 3 trials involving >2600 men with PE, dapoxetine 60 mg given as needed over 12 wk significantly prolonged the stopwatch-assessed intravaginal ejaculatory latency time (IELT) from 0.91 min at baseline to 3.32 min (p < 0.0001), increased control over ejaculation, and increased sexual satisfaction for men and their partners compared with placebo (both p < 0.0001). These results suggest that dapoxetine may meet the medical need for on-demand therapy for PE.     

Adverse Events of Intravesical Botulinum Toxin A Injections for Idiopathic Detrusor Overactivity: Risk Factors and Influence on Treatment Outcome

Background

Intravesical injection of botulinum toxin type A (BoNTA) provides effective treatment for detrusor overactivity and overactive bladder (OAB). However, the high rates of treatment-related adverse events (AEs) prevent its more widespread use.

Objective

To investigate the risk factors of increasing AEs after BoNTA injection for idiopathic detrusor overactivity (IDO).

Design, setting, and participants

This study included a total of 217 patients receiving their first intravesical BoNTA injection for refractory IDO in a tertiary university hospital from 2004 to 2009.

Measurements

AE incidence was analyzed according to gender, age, comorbidities, prostate condition in men, OAB subtype, BoNTA dose, injection site, and baseline urodynamic parameters. Successful outcome was determined based on patient perception of improvement of bladder condition at 3 mo.

Results and limitations

Successful outcomes were reported by 144 (66.3%) patients. By multivariable analysis, male gender (p = 0.013) and baseline postvoid residual (PVR) ≥100 ml (p = 0.003) were independent predictors of acute urinary retention (AUR). Baseline PVR ≥100 ml (p = 0.007) and receiving >100 U BoNTA (p = 0.029) were predictors of straining to void. The incidence of large PVR after treatment was associated with comorbidity (p = 0.011). Urinary tract infection occurred more frequently in women (p = 0.003) and in men with retaining prostate (p = 0.008). No AUR developed after bladder base/trigonal injection. Nevertheless, the occurrence of AUR or large PVR did not affect therapeutic outcome. This study is limited by nonconsecutive enrollment of patients.

Conclusions

Male gender, baseline PVR ≥100 ml, comorbidity, and BoNTA dose >100 U are risk factors for increasing incidence of AEs after intravesical BoNTA injection for IDO.     

Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

Background

Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB).

Objective

To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO).

Design, setting, and participants

Randomized, double-blind, parallel-group, placebo-controlled study in men aged >45 yr with LUTS and BOO for ≥3 mo, total International Prostate Symptom Score (IPSS) ≥8, BOO index ≥20, maximum urinary flow rate (Q_max) ≤12 ml/s, and voided volume ≥120 ml.

Interventions

Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk.

Outcome measurements and statistical analysis

Primary (safety) measurements: Q_max and detrusor pressure at Q_max (P_detQ_max). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo.

Results and limitations

Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P_detQ_max and Q_max. Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured.

Conclusions

TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P_detQ_max and Q_max in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention.     

Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation

Context

Erectile dysfunction (ED) and premature ejaculation (PE) are the two most prevalent male sexual dysfunctions.

Objective

To present the updated version of 2009 European Association of Urology (EAU) guidelines on ED and PE.

Evidence acquisition

A systematic review of the recent literature on the epidemiology, diagnosis, and treatment of ED and PE was performed. Levels of evidence and grades of recommendation were assigned.

Evidence synthesis

ED is highly prevalent, and 5–20% of men have moderate to severe ED. ED shares common risk factors with cardiovascular disease. Diagnosis is based on medical and sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to the patient's complaints and risk factors. Treatment is based on phosphodiesterase type 5 inhibitors (PDE5-Is), including sildenafil, tadalafil, and vardenafil. PDE5-Is have high efficacy and safety rates, even in difficult-to-treat populations such as patients with diabetes mellitus. Treatment options for patients who do not respond to PDE5-Is or for whom PDE5-Is are contraindicated include intracavernous injections, intraurethral alprostadil, vacuum constriction devices, or implantation of a penile prosthesis.PE has prevalence rates of 20–30%. PE may be classified as lifelong (primary) or acquired (secondary). Diagnosis is based on medical and sexual history assessing intravaginal ejaculatory latency time, perceived control, distress, and interpersonal difficulty related to the ejaculatory dysfunction. Physical examination and laboratory testing may be needed in selected patients only.Pharmacotherapy is the basis of treatment in lifelong PE, including daily dosing of selective serotonin reuptake inhibitors and topical anaesthetics. Dapoxetine is the only drug approved for the on-demand treatment of PE in Europe. Behavioural techniques may be efficacious as a monotherapy or in combination with pharmacotherapy. Recurrence is likely to occur after treatment withdrawal.

Conclusions

These EAU guidelines summarise the present information on ED and PE. The extended version of the guidelines is available at the EAU Web site (http://www.uroweb.org/nc/professional-resources/guidelines/online/).     

Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)

Background

The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear.

Objective

The primary objective was to compare the efficacy of tadalafil 5 mg once daily and tadalafil 20 mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length.

Design, setting, and participants

Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤68 yr of age with adenocarcinoma of the prostate (Gleason ≤7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada.

Interventions

1:1:1 randomisation to 9 mo of treatment with tadalafil 5 mg once daily, tadalafil 20 mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients).

Outcome measurements and statistical analysis

Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥22, SEP-3, and penile length.

Results and limitations

Four hundred twenty-three patients were randomised to tadalafil once daily (n = 139), on demand (n = 143), and placebo (n = 141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6–2.1; p = 0.675) and 0.9 (95% CI, 0.5–1.7; p = 0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p = 0.016; SEP-3: p = 0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1 mm; 95% CI, 0.4–7.8; p = 0.032).

Conclusions

Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo.

Trial registration

ClinicalTrials.gov identifier NCT01026818.     

Tolterodine Treatment Improves Storage Symptoms Suggestive of Overactive Bladder in Men Treated With α-Blockers

Background

Some men receiving α-blocker therapy for lower urinary tract symptoms report persistent storage symptoms suggestive of overactive bladder (OAB).

Objective

To evaluate the efficacy of tolterodine extended release (ER) in men on α-blocker therapy.

Design, setting, and participants

This double-blind trial included men aged ≥40 yr with frequency, urgency, and at least moderate problems reported on the Patient Perception of Bladder Condition (PPBC), despite being on a stable dose of α-blocker for ≥1 mo.

Interventions

Subjects were randomized to tolterodine ER 4 mg per day or placebo for 12 wk while continuing their prescribed α-blocker therapy.

Measurements

At baseline and week 12, subjects completed the PPBC, International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire (OAB-q), and 5-d bladder diaries using the five-point Urinary Sensation Scale (USS). Frequency–urgency sum was defined as the sum of USS ratings for all micturitions.

Results and limitations

PPBC improvement from baseline to week 12 was reported by 63.6% and 61.6% of subjects receiving tolterodine ER plus α-blocker and placebo plus α-blocker, respectively; this treatment difference, which was the primary end point, was not statistically significant (p > 0.6699). At week 12, subjects receiving tolterodine ER plus α-blocker had significantly greater improvements versus placebo plus α-blocker in 24-h micturitions (−1.8 vs −1.2; p = 0.0079) and daytime micturitions (−1.3 vs −0.8; p = 0.0123); 24-h urgency episodes (−2.9 vs −1.8; p = 0.0010), daytime urgency episodes (−2.2 vs −1.4; p = 0.0017), and nocturnal urgency episodes (−0.5 vs −0.3; p = 0.0378); frequency–urgency sum (−7.8 vs −5.1; p = 0.0065); IPSS storage subscale (−2.6 vs −2.1; p = 0.0370); and OAB-q symptom bother scale (−17.9 vs −14.4; p = 0.0086) and coping domain (15.4 vs 12.4; p = 0.0491). Acute urinary retention requiring catheterization occurred in <1% of either group. There were no clinically meaningful changes in postvoid residual volume or maximum urinary flow rate.

Conclusions

Men with bothersome OAB symptoms despite continued α-blocker therapy showed significantly greater improvements in diary variables, IPSS Storage scores, and symptom bother when receiving additional tolterodine ER versus placebo plus α-blocker.     

Treatment benefit of dapoxetine for premature ejaculation: results from a placebo‐controlled phase III trial

OBJECTIVE

To evaluate the overall treatment benefit of dapoxetine for premature ejaculation (PE), with specific emphasis on improvements in personal distress and interpersonal difficulty related to ejaculation. Although these factors are key elements of numerous sets of diagnostic criteria for PE, they have rarely been evaluated as outcome measures in clinical trials.

PATIENTS AND METHODS

In this randomized, double‐blind, placebo‐controlled, phase III trial we enrolled men aged ≥18 years, from the USA and Canada, who had a Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision, diagnosis of PE (1238 men). Men were randomized to receive placebo or dapoxetine 60 mg as needed or once daily for 9 weeks. The once‐daily treatment arm was included for analysis of withdrawal symptoms (primary endpoint; presented elsewhere). Patients completed the Premature Ejaculation Profile (PEP) on day 1 (before dosing), and on days 28 and 63 (or study endpoint), which comprised the outcome measures for perceived control over ejaculation, satisfaction with sexual intercourse, and personal distress and interpersonal difficulty related to ejaculation. The patient‐reported global impression of change in PE was reported on day 63 (or study endpoint). Treatment benefit measures included the composite criteria of at least a two‐category increase in perceived control over ejaculation and at least a one‐category decrease in personal distress related to ejaculation from baseline at study endpoint.

RESULTS

At baseline, ≈5% of patients in any treatment group reported ‘not at all’ or ‘a little bit’ of personal distress related to ejaculation, which increased to 54.3% of those receiving dapoxetine (vs 35.3% with placebo; P < 0.001). Similarly, 43.0% and 40.9% of men in the placebo and dapoxetine groups, respectively, reported ‘not at all’ or ‘a little bit’ of interpersonal difficulty related to ejaculation at baseline, which increased to 76.8% and 64.2% of those with dapoxetine and placebo, respectively (P < 0.001). The percentage of men who achieved the composite criteria with dapoxetine ‘as needed’ was 47.6%, vs 21.7% with placebo (difference from placebo, 25.9%; P < 0.001). The distribution of responses for the PEP among men who achieved the composite criteria was similar to that reported for men without PE in a previous observational study in the USA. The most common adverse events were nausea, dizziness, headache, diarrhoea and insomnia, which were more common with dapoxetine than with placebo.

CONCLUSION

Dapoxetine reduced the personal distress and interpersonal difficulty associated with PE, and was associated with patient‐reported improvements in their condition. The percentage of patients who achieved a composite of a two‐category or greater increase in perceived control over ejaculation and a one‐category or greater decrease in personal distress related to ejaculation was substantially greater than with placebo, as were all outcome measures.