Philip Van Kerrebroeck

A Phase III, Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicentre Study to Assess the Efficacy and Safety of the β3 Adrenoceptor Agonist, Mirabegron, in Patients With Symptoms of Overactive Bladder

OBJECTIVEnTo assess the efficacy and tolerability of mirabegron 25 mg and 50 mg once-daily vs placebo in patients with overactive bladder (OAB).nnnMATERIALS AND METHODSnPatients ≥18 years with OAB symptoms were recruited to a 2-week, single-blind, placebo run-in. Those with ≥8 micturitions per 24 hours and ≥3 urgency episodes were randomized 1:1:1 to once-daily mirabegron 25 mg or 50 mg, or placebo for 12 weeks. Primary endpoints were changes to final visit in mean number of incontinence episodes and micturitions per 24 hours. Key secondary endpoints were changes to final visit in mean volume voided or micturition, change to week 4 in mean number of incontinence episodes and micturitions per 24 hours, changes to final visit in mean level of urgency, number of urgency incontinence episodes, and urgency (grade 3 or 4) episodes per 24 hours. Patient-reported outcomes were assessed using the OAB-questionnaire, Patient Perception of Bladder Condition, and Treatment-Satisfaction-Visual Analog Scale.nnnRESULTSnBoth mirabegron groups demonstrated statistically significant improvements in coprimary endpoints vs placebo. Mirabegron 50 mg demonstrated significantly greater improvements vs placebo in the following: change to final visit in mean volume voided per micturition and change to week 4 in mean number of incontinence episodes per 24 hours. Statistically significant improvements vs placebo were demonstrated by mirabegron 50 mg in all patient-reported outcome scales with no increase in the incidence of treatment-emergent adverse events vs placebo.nnnCONCLUSIONnMirabegron 25 mg and 50 mg were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency. Mirabegron was well tolerated vs placebo.

Detrusor Underactivity and the Underactive Bladder: A New Clinical Entity? A Review of Current Terminology, Definitions, Epidemiology, Aetiology, and Diagnosis

CONTEXTnDetrusor underactivity (DU) is a common cause of lower urinary tract symptoms (LUTS) in both men and women, yet is poorly understood and underresearched.nnnOBJECTIVEnTo review the current terminology, definitions, and diagnostic criteria in use, along with the epidemiology and aetiology of DU, as a basis for building a consensus on the standardisation of current concepts.nnnEVIDENCE ACQUISITIONnThe Medline and Embase databases were searched for original articles and reviews in the English language pertaining to DU. Search terms included underactive bladder, detrusor underactivity, impaired detrusor contractility, acontractile detrusor, detrusor failure, detrusor areflexia, raised PVR [postvoid residual], and urinary retention. Selected studies were assessed for content relating to DU.nnnEVIDENCE SYNTHESISnA wide range of terminology is applied in contemporary usage. The only term defined by the standardisation document of the International Continence Society (ICS) in 2002 was the urodynamic term detrusor underactivity along with detrusor acontractility. The ICS definition provides a framework, considering the urodynamic abnormality of contraction and how this affects voiding; however, this is necessarily limited. DU is present in 9-48% of men and 12-45% of older women undergoing urodynamic evaluation for non-neurogenic LUTS. Multiple aetiologies are implicated, affecting myogenic function and neural control mechanisms, as well as the efferent and afferent innervations. Diagnostic criteria are based on urodynamic approximations relating to bladder contractility such as maximum flow rate and detrusor pressure at maximum flow. Other estimates rely on mathematical formulas to calculate isovolumetric contractility indexes or urodynamic stop tests. Most methods have major disadvantages or are as yet poorly validated. Contraction strength is only one aspect of bladder voiding function. The others are the speed and persistence of the contraction.nnnCONCLUSIONSnThe term detrusor underactivity and its associated symptoms and signs remain surrounded by ambiguity and confusion with a lack of accepted terminology, definition, and diagnostic methods and criteria. There is a need to reach a consensus on these aspects to allow standardisation of the literature and the development of optimal management approaches.

The evaluation and treatment of nocturia: a consensus statement

What’s known on the subject? and What does the study add?

A phase II dose-ranging study of mirabegron in patients with overactive bladder

Introduction and hypothesisMirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder.MethodsPatients completed a single-blinded, 2-week placebo run-in period followed by 12xa0weeks of randomized (nu2009=u2009928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200xa0mg once-daily (QD), placebo or tolterodine extended release (ER) 4xa0mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24xa0h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24xa0h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume.ResultsMirabegron 25, 50, 100, and 200xa0mg resulted in dose-dependent reductions (improvements) from baseline to end-of-treatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24xa0h respectively, versus 1.4 micturitions/24xa0h with placebo (pu2009≤u20090.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (pu2009<u20090.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events.ConclusionsThe favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program.

Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia.

PURPOSEnNocturnal polyuria is a common but often overlooked cause of nocturia. We investigated the proportion of adults with 2 or greater voids nightly who had nocturnal polyuria in 2 cohorts from the United States and Europe.nnnMATERIALS AND METHODSnData on nocturnal polyuria were obtained from 3 or 7-day frequency-volume charts completed by patients as part of screening for inclusion in subsequent trials of nocturia therapy. Patients recorded the time and volume of each void. Nocturnal polyuria was defined as nocturnal urine volume greater than 33% of 24-hour volume, including the first morning void.nnnRESULTSnIn the first cohort 1,003 patients were screened, of whom 846 provided evaluable diary data, including 641 (76%) with nocturnal polyuria. Of the total screened population of 1,003 patients 641 (64%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. In the second cohort 1,412 patients were screened, of whom 917 provided evaluable diary data, including 806 (88%) with nocturnal polyuria. Of the total screened population of 1,412 patients 806 (57%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. Of 158 patients receiving benign prostatic hyperplasia and/or overactive bladder medication 141 (89%) had nocturnal polyuria. In each cohort the nocturnal polyuria prevalence was high in all ethnic groups (63% or greater).nnnCONCLUSIONSnIn this large study nocturnal polyuria was present in most patients with nocturia regardless of gender, age, ethnicity, country and concomitant benign prostatic hyperplasia/overactive bladder therapy.

Combination Therapy with Solifenacin and Tamsulosin Oral Controlled Absorption System in a Single Tablet for Lower Urinary Tract Symptoms in Men: Efficacy and Safety Results from the Randomised Controlled NEPTUNE Trial

BACKGROUNDnStorage symptoms are particularly bothersome in men with lower urinary tract symptoms (LUTS) but may not be adequately treated by α-blocker monotherapy.nnnOBJECTIVEnTo assess the efficacy and safety of a fixed-dose combination (FDC) of solifenacin and an oral controlled absorption system (OCAS) formulation of tamsulosin compared with placebo and compared with tamsulosin OCAS (TOCAS) monotherapy in men with moderate to severe storage symptoms and voiding symptoms.nnnDESIGN, SETTING, AND PARTICIPANTSnA double-blind 12-wk phase 3 study in 1334 men with storage and voiding LUTS: total International Prostate Symptom Score (IPSS) ≥ 13, maximum urinary flow rate (Qmax) 4.0-12.0 ml/s, two or more urgency episodes per 24 h of Patient Perception of Intensity of Urgency Scale grade 3 or 4, and eight or more micturitions per 24h.nnnINTERVENTIONnPatients were randomised to placebo, TOCAS 0.4 mg, FDC solifenacin 6 mg plus TOCAS 0.4 mg, or FDC solifenacin 9 mg plus TOCAS 0.4 mg.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnPrimary efficacy end points were (1) total IPSS and (2) Total Urgency and Frequency Score (TUFS). An FDC met the success criteria if it demonstrated superiority compared with placebo and noninferiority compared with TOCAS for total IPSS, as well as superiority compared with TOCAS for TUFS.nnnRESULTS AND LIMITATIONSnReductions in total IPSS and TUFS were observed with both solifenacin 6 mg plus TOCAS (-7.0 and -8.1, respectively) and solifenacin 9 mg plus TOCAS (-6.5 and -7.6, respectively) compared with TOCAS (-6.2 and -6.7, respectively) and placebo (-5.4 and -4.4, respectively). Solifenacin 6 mg plus TOCAS met all prespecified success criteria for both primary end points, while solifenacin 9 mg plus TOCAS met success criteria compared with placebo but not compared with TOCAS. Both FDCs improved quality of life (QoL) measures and were well tolerated, with low incidences of acute urinary retention.nnnCONCLUSIONSnThe FDC of solifenacin 6 mg plus TOCAS significantly improved storage and voiding symptoms, as well as QoL parameters, compared with placebo. This FDC also improved storage symptoms and QoL compared with TOCAS alone in men with moderate to severe storage symptoms and voiding symptoms, and it was well tolerated.

Predictive factors for nocturia in elderly men: a cross-sectional study in 21 general practices

To measure the prevalence of nocturia in general practice and to determine which factors are associated with nocturia.

Artificial urinary sphincter (AMS 800) implantation for women with intrinsic sphincter deficiency: a technique for insiders?

Study Type – Therapy (case series) u2028Level of Evidenceu20034

Prostaglandin Receptor EP1 and EP2 Site in Guinea Pig Bladder Urothelium and Lamina Propria

PURPOSEnUrothelium has 2 main functions. It is a barrier to urine and has a sensory role. In response to stretch urothelium releases various substances that modulate afferent nerve activity. Recent data on the localization of cyclooxygenase type 1, the enzyme responsible for prostaglandin production, suggests that prostaglandin may have complex local action.nnnMATERIALS AND METHODSnThe bladders of 7 guinea pigs were stained for prostaglandin receptors type 1 and 2, and costained for vimentin and cyclooxygenase I.nnnRESULTSnProstaglandin receptor type 1 staining was seen in urothelial cells and in the suburothelium. Urothelial staining, which was often punctuate and weak, was detected in all urothelial cell layers, including suburothelial cells. In contrast, strong prostaglandin receptor type 2 staining was seen in the urothelium and in suburothelial cells. Cyclooxygenase I was absent in interstitial cells and umbrella cells with the highest concentration in the basal cell layer.nnnCONCLUSIONSnInterstitial cells express prostaglandin receptor types 1 and 2, indicating that they can respond to prostaglandin. Umbrella cells do not express cyclooxygenase I. Cyclooxygenase I was present in basal urothelial cells, making them a possible site of prostaglandin synthesis. Thus, prostaglandin produced by urothelium may target prostaglandin receptor types 1 and 2 in the urothelium and suburothelium. Therefore prostaglandin is hypothesized to have a role in signal regulation in the bladder wall.

Affective symptoms and the overactive bladder - A systematic review

BACKGROUNDnOveractive bladder syndrome (OAB) is characterised by urgency symptoms, with or without urgency incontinence, usually with frequency and nocturia. Although literature suggest an association between OAB, depression and anxiety, no systematic review has been presented.nnnOBJECTIVEnSystematically review the literature on the association of affective conditions with OAB.nnnMETHODSnSystematic review according to the PRISMA guidelines. This review is registered in the PROSPERO register (CRD4201400664).nnnRESULTSnForty-three articles were included, describing more than 80,000 subjects. Depression and OAB were positively associated in 26 studies, anxiety and OAB in 6 studies. Longitudinal studies reported: a) OAB subjects who developed depression/anxiety or b) depressed/anxious subjects developing OAB, or c) both. The quality of evidence in studies reporting an association between the co-occurrence of OAB and depression was rated level 3 in accordance with the GRADE framework. Evidence reporting on the co-occurrence of anxiety and OAB was rated GRADE level 2. Longitudinal associations between new onset of OAB in depressive subjects was GRADE level 2. Evidence reporting association of OAB with anxiety in longitudinal studies was of GRADE level 1.nnnCONCLUSIONnTo our knowledge, this systematic review is the first to give a comprehensive qualitative overview on the association between OAB and affective symptoms. Many evaluated studies failed to note longitudinal changes and lacked evidence of causality. Still, results revealed an association between OAB and affective symptoms and there is evidence for new onset of OAB in depressive subjects, but further research is necessary to examine the strength of the effect.