Tomasz Rechberger

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 β(3)-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 50mg, mirabegron 100mg, 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 24h. 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 24h (-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 24h (-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.

Combination Treatment with Mirabegron and Solifenacin in Patients with Overactive Bladder: Efficacy and Safety Results from a Randomised, Double-blind, Dose-ranging, Phase 2 Study (Symphony)

BACKGROUND Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects. OBJECTIVE The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy. DESIGN, SETTING, AND PARTICIPANTS A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo. INTERVENTION A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters. RESULTS AND LIMITATIONS Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy. CONCLUSIONS Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo. PATIENT SUMMARY To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability. TRIAL REGISTRATION Clinical trials.gov: NCT01340027.

The Clinical Effectiveness of Retropubic (IVS-02) and Transobturator (IVS-04) Midurethral Slings: Randomized Trial

BACKGROUND Few series comparing the clinical efficacy of retropubic slings versus transobturator slings for the treatment of female stress urinary incontinence (SUI) are available. OBJECTIVE To compare clinical efficacy of retropubic tape operations and transobturator suburethral tape operations for the surgical treatment of female SUI. DESIGN, SETTING, AND PARTICIPANTS From January 2003 to December 2005, 611 patients underwent clinical and urodynamic evaluation before surgical treatment for SUI. Patients with advanced urogenital prolapse (pelvic organ prolapse-quantification scale [POP-Q] scale grade >1) were excluded, and 537 patients were included in this study. After 18 mo, 398 women were available for follow-up efficacy evaluation at a tertiary academic center. INTERVENTION All patients underwent either a retropubic sling procedure or a transobturator sling procedure. Patients were randomly allocated into two study groups at a ratio of 1:1. MEASUREMENTS After 18 mo all enrolled patients were clinically checked for clinical efficacy of both procedures. RESULTS AND LIMITATIONS Demographic and urodynamic parameters of patients were similar in both groups. No bladder injury occurred in the transobturator sling group (IVS-04), whereas 13 intraoperational bladder perforations (6.5%) occurred in the retropubic sling group (IVS-02) (p<0.001). The tape erosion rate was <2.5% in both groups (p=0.7). After 18 mo, 398 patients (201 in the IVS-02 group and 197 in the IVS-04 group) were evaluated in terms of clinical efficacy of the procedures. We found out that there was no statistically significant difference in clinical efficacy between these two procedures (chi(2)=1.88, p=0.39). In the IVS-02 group, 75.1% of patients (n=151) remained dry (cured), 16.9% of patients (n=34) reported significant improvement, and 8.0% of patients (n=16) were considered as failures. In the IVS-04 group, 74.1% of patients (n=146) remained dry, 14.2% of patients (n=28) reported significant improvement, and 11.7% (n=23) were considered as failures. CONCLUSIONS Based on an 18-mo follow-up, the efficacies of both techniques are comparable; however, the retropubic route appears to be more efficient in the intrinsic sphincter deficiency (ISD) group.

High-resolution three-dimensional endovaginal ultrasonography in the assessment of pelvic floor anatomy: a preliminary study

Introduction and hypothesisOur aim was to evaluate the morphological characteristics of the female pelvic floor that may be further elucidated with three-dimensional endovaginal ultrasonography (3D-EVUS).MethodsA consecutive series of 20 nulliparous females underwent 3D-EVUS. Measurements were determined according to pre-established criteria. Descriptive statistics and Spearman’s correlation test were performed.ResultsThe levator hiatus (LH) was measured in the oblique plane parallel to the pubovisceral muscle. A positive correlation was found between LH area and age (p = 0.03). The anteroposterior diameter of the urogenital hiatus, measured in the axial plane tilted from the symphysis pubis to the ischiopubic rami, correlated with LH area (p = 0.008). No urethral rotations were observed in the coronal plane. Significant correlations were found among urethral parameters. Mean anal sphincter measurements were comparable to previously reported magnetic resonance imaging and ultrasound measurements.Conclusions3D-EVUS allows measurements of key pelvic floor structures in planes that cannot be determined by conventional imaging modalities.

A randomized comparison between monofilament and multifilament tapes for stress incontinence surgery

Our objective was to compare monofilament and multifilament tapes positioned without tension at the midurethra for postoperative complications and cure rate. One hundred patients with stress urinary incontinence were randomly allocated into two study groups. Using identical surgical methodology, 50 patients had a monofilament tape inserted at the midurethra using the TVT delivery instrument, and another 50 a multifilament tape using the IVS delivery instrument. The only significant difference between the groups was in the incidence of postoperative urinary retention (p=0.023). Ten patients from the monofilament group required longer than normal (‘normal’ means to the morning of the next day) catheterization, in contrast to only two from the multifilament group. The clinical efficacy of both procedures was equally high. Conclusions were that both tapes appear to be equally effective in the surgical treatment of SUI. The higher incidence of postoperative urinary retention in the monofilament group was most likely caused by the elastic feature of this tape.

Female urinary stress incontinence in terms of connective tissue biochemistry

The role of connective tissue in the aetiology of female stress incontinence has been investigated. Collagen content and extractability as well as estrogen receptor concentration in vesico-vaginal fascia were measured after small tissue biopsies had been obtained during vaginal repair surgery in cases of urinary incontinence. The mean concentration of estrogen receptor in vesico-vaginal fascia among incontinent women was 49.4 +/- 14.8 fmol/mg of protein as compared to 29.6 +/- 13.1 in continent control group (P < 0.03; t-test). The mean hydroxyproline concentration in vesico-vaginal fascia of incontinent women was 13.8 +/- 2.6 micrograms/mg wet weight, whereas in the control group it was significantly higher 20.6 +/- 2.4 (P < 0.001). The role of connective tissue components in the aetiology of female stress incontinence is discussed.

OnabotulinumtoxinA Improves Health-Related Quality of Life in Patients With Urinary Incontinence Due to Idiopathic Overactive Bladder: A 36-Week, Double-Blind, Placebo-Controlled, Randomized, Dose-Ranging Trial

BACKGROUND Patients with urgency urinary incontinence (UUI) due to overactive bladder (OAB) refractory to oral antimuscarinics have limited therapeutic options. OnabotulinumtoxinA appears to be an effective new treatment. OBJECTIVE Assess disease-specific quality-of-life outcomes and general health-related quality-of-life (HRQOL) outcomes following treatment with onabotulinumtoxinA in patients with idiopathic OAB and UUI inadequately managed with antimuscarinics. DESIGN, SETTING, AND PARTICIPANTS A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted at 40 sites from July 2005 to June 2008 with 313 patients (288 females) with idiopathic OAB experiencing eight or more UUI episodes per week and eight or more micturitions per day at baseline, with follow-up of 36 wk. INTERVENTION Intradetrusor onabotulinumtoxinA (50 U, 100 U, 150 U, 200 U, or 300 U) or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HRQOL was assessed using the urinary Incontinence-Specific Quality-of-Life Instrument (I-QOL), the Kings Health Questionnaire (KHQ) symptom component, and the Medical Outcomes Study 36-Item Short-Form Health Survey. Descriptive statistics were used for absolute scores/changes from baseline. Within-group changes from baseline were assessed using paired t tests. Change from baseline for each onabotulinumtoxinA group compared with placebo was analyzed using an analysis of covariance model. RESULTS AND LIMITATIONS OnabotulinumtoxinA treatment at doses≥100 U produced significantly greater improvements than placebo in the I-QOL total and subscale scores at all follow-up visits from week 2 through week 24 (p<0.05). OnabotulinumtoxinA doses≥100 U produced significantly greater improvements than placebo in the KHQ symptom score at a majority of follow-up visits. HRQOL instruments demonstrated low to moderate correlations (Spearman correlation range: 0.01-0.51) with the symptoms of UUI recorded using daily diary data, with I-QOL demonstrating the highest correlations. A study limitation was that certain quality-of-life measures were exploratory and not validated. CONCLUSIONS A single onabotulinumtoxinA treatment with doses≥100 U resulted in statistically significant and clinically meaningful improvement in HRQOL by week 2 compared with placebo, and this improvement was sustained for ≤36 wk in patients with idiopathic OAB and UUI who were inadequately managed by oral antimuscarinics. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00168454.

The Efficacy and Safety of the Tension-Free Vaginal Tape Procedure Do Not Depend on the Method of Analgesia

OBJECTIVE The original tension-free vaginal tape (TVT) method, described by Ulmsten et al., routinely uses local anaesthesia during the procedure. Since the anaesthetic effect after local application of lidocaine hydrochloride was not always satisfactory we decided to introduce the spinal anaesthesia during this operation. The aim of the present study was to compare local and spinal anaesthesia with respect to their efficacy and safety in the TVT procedure. METHODS 103 women, with objectively confirmed stress urinary incontinence, were randomised into the study. Sixty-seven women were anaesthetised locally and 36 patients spinally. All TVT procedures were performed as originally described. Objective assessment of the influence of anaesthesia on intra-abdominal pressure at rest and during the cough test was done using a rectal catheter and a central venous pressure manometer. The efficacy of the TVT procedure was based on a gynaecological examination with a cough test and a three-degree subjective scale: complete cure, improvement or failure. RESULTS The success of the TVT procedure performed under local anaesthesia is comparable with that achieved under spinal analgesia (p=0.42). The number of complications that occurred in the two groups does not differ significantly (p=0.57). CONCLUSIONS Spinal anaesthesia impairs the ability to cough effectively during the TVT procedure. However, the efficacy and safety of the operations performed under this type of anaesthesia are comparable with the efficacy and safety of operations done under local anaesthesia.

3-D high-frequency endovaginal ultrasound of female urethral complex and assessment of inter-observer reliability

OBJECTIVES Assessment of the urethral complex and defining its morphological characteristics with 3-dimensional endovaginal ultrasonography with the use of high frequency rotational 360° transducer. Defining inter-observer reliability of the performed measurements. MATERIALS AND METHODS Twenty-four asymptomatic, nulliparous females (aged 18-55, mean 32 years) underwent high-frequency (12MHz) endovaginal ultrasound with rotational 360° and automated 3D data acquisition (type 2050, B-K Medical, Herlev, Denmark). Measurements of the urethral thickness, width and length, bladder neck-symphysis distance, intramural part of the urethra as well as rhabdosphincter thickness, width and length were taken by three investigators. Descriptive statistics for continuous data was performed. The results were given as mean values with standard deviation. The relationships among different variables were assessed with ANOVA for repeated measures factors, as well as T-test for dependent samples. Intraclass correlation (ICC) was calculated for each parameter. Intra- and interobserver reliability was assessed. Statistical significance was assigned to a P value of <0.05 (two-tailed). RESULTS Excellent reliability was observed for urethral measurements (length, width, thickness and volume) (ICC>0.8) and good reliability for rhabdosphincter measurements (ICC>0.6) between all three investigators. CONCLUSIONS Advanced EVUS provides detailed information on anatomy and morphology of the female urethral complex. Our results show that 360° rotational transducer with automated 3D acquisition, currently routinely used for proctological scanning is suitable for the reliable assessment of the urethral complex and can be applied in a routine diagnostics of pelvic floor disturbances in females.

The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial

Objective: To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. Patients and methods: This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > −0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance. Results: For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was −0.18 (−0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron. Conclusions: Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.