Could Reduced Fluid Intake Cause the Placebo Effect Seen in Overactive Bladder Clinical Trials? Analysis of a Large Solifenacin Integrated Database

Objective To assess the hypothesis that patients receiving placebo in overactive bladder (OAB) trials who experience less benefit from “treatment” continue with behavioral modifications such as fluid restriction, whereas those on active treatment adopt more normal drinking patterns. This may manifest itself as a reduction in micturition frequency (MF). Materials and Methods We interrogated a large integrated database containing pooled patient data from 4 randomized, placebo-controlled phase III OAB solifenacin studies. A statistical correction was applied to MF to remove the influence of fluid intake. Results Pooled analysis using patient-level data from 3011 patients and accounting for the studies within the models showed that all patients voided progressively less total urine per 24 hours during treatment than at baseline. However, reduction in total urine volume voided per 24 hours was larger in patients receiving placebo vs those on solifenacin; with a substantial decrease in 24-hour urine output in the placebo group from baseline to week 4, which was not the case in active groups. After correcting MF for volume voided for each patient using the statistical correction and averaging the corrected MF per treatment arm, the placebo effect almost disappeared. Patients on solifenacin voided less often, with a statistically significant increase in volume voided each time they voided, vs placebo. Conclusion Assuming volume voided is a good surrogate measure for fluid intake, this analysis shows that fluid restriction almost completely explains the reduction in MF in the placebo group. In contrast, patients receiving active treatment adopt more normal drinking patterns once they start to perceive improvement in their OAB symptoms

OnabotulinumtoxinA 100U provides significant improvements in overactive bladder symptoms in patients with urinary incontinence regardless of the number of anticholinergic therapies used or reason for inadequate management of overactive bladder

INTRODUCTION: A prespecified pooled analysis of two placebo-controlled, phase 3 trials evaluated whether the number of prior anticholinergics used or reason for their discontinuation affected the treatment response to onabotulinumtoxinA 100U in overactive bladder (OAB) patients with urinary incontinence (UI). METHODS: Patients with symptoms of OAB received intradetrusor injections of onabotulinumtoxinA 100U or placebo, sparing the trigone. Change from baseline at week 12 in UI episodes/day, proportion of patients reporting a positive response (‘greatly improved’ or ‘improved’) on the treatment benefit scale (TBS), micturition and urgency were evaluated by number of prior anticholinergics (1, 2 or ≥ 3) and reason for their discontinuation (insufficient efficacy or side effects). Adverse events (AE) were assessed. RESULTS: Patients had taken an average of 2.4 anticholinergics before study enrolment. OnabotulinumtoxinA reduced UI episodes/day from baseline vs. placebo, regardless of the number of prior anticholinergics (−2.82 vs. −1.52 for one prior anticholinergic; −2.58 vs. −0.58 for two prior anticholinergics; and −2.92 vs. −0.73 for three or more prior anticholinergics; all p < 0.001). The proportion of TBS responders was higher with onabotulinumtoxinA vs. placebo (69.0% vs. 37.2% for one prior anticholinergic; 58.8% vs. 24.8% for two prior anticholinergics and 56.4% vs. 22.5% for three or more prior anticholinergics; all p < 0.001). Similar results were observed regardless of the reason for discontinuation. OnabotulinumtoxinA reduced the episodes of urgency and frequency of micturition vs. placebo in all groups. AEs were well tolerated, with a comparable incidence in all groups. CONCLUSION: In patients with symptoms of OAB who were inadequately managed by one or more anticholinergics, onabotulinumtoxinA 100U provided significant and similar treatment benefit and safety profile regardless of the number of prior anticholinergics used or reason for inadequate management of OAB. ClinicalTrials.gov: NCT00910845, NCT00910520

Onset of action of the beta 3-adrenoceptor agonist, mirabegron, in Phase II and III clinical trials in patients with overactive bladder

Purpose Long-term persistence with pharmacotherapy for overactive bladder (OAB) requires a drug with an early onset of action and good efficacy and tolerability profile. Although antimuscarinics improve OAB symptoms within 1–2 weeks of initiating treatment, adherence after 3 months is relatively poor due to bothersome side effects (e.g., dry mouth and constipation). Mirabegron, a b3-adrenoceptor agonist, has demonstrated significant improvements in key symptoms of OAB and good tolerability after 12 weeks in Phase III studies. Methods This was a prespecified pooled analysis of three randomized, double-blind, placebo-controlled, 12-week studies, and a Phase II study, to evaluate efficacy and tolerability of mirabegron 25 and 50 mg versus placebo. The main efficacy endpoints were change from baseline to week 1 (Phase II only), week 4, and final visit in mean number of incontinence episodes/24 h, micturitions/24 h, and mean volume voided/micturition (MVV). Results A significant benefit for mirabegron 25 and 50 mg versus placebo was evident at the first assessment point, 4 weeks after initiation of therapy, in Phase III studies for incontinence, micturitions, and MVV. The earliest measured benefit was after 1 week, in the Phase II study. Quality-of-life parameters also significantly improved with mirabegron 25 and 50 mg as early as week 4. Significant benefits continued throughout the studies. Mirabegron was well tolerated. Conclusions The early onset of action and good overall efficacy and tolerability balance that mirabegron offers may lead to high rates of persistence with mirabegron in the long-term treatment of OAB

Etiology of nocturia response in men with diminished bladder capacity

Aims: To test the hypothesis that patients with nocturia owing to diminished global or nocturnal bladder capacity improve via increased bladder capacity. Methods: This is a retrospective analysis of voiding diaries completed at a VA urology clinic between 2008-2017. Inclusion required patients aged at least 18 years, male, undergoing treatment for nocturia, and having completed at least two 24-hour voiding diaries >= 1 month apart. Patients were divided into two cohorts: responders (any decline in nocturia) and non-responders (no change or any increase in nocturia). Patients were further sub-stratified as having low global bladder capacity (maximum voided volume [MVV] = 200 mL). Wilcoxon rank-sum was applied with a Bonferroni correction to test significance. Results: Forty pre- and post-treatment diaries from 27 patients, and 19 pre- and post-treatment diaries from 17 patients were identified as having low global and low nocturnal bladder capacity, respectively. Nocturia responders with low global bladder capacity demonstrated significant decline compared to non-responders in nocturnal urine volume (NUV) (-140 vs +75, P < 0.01) and nocturnal bladder capacity index (NBCi) (-0.59 vs +0.23, P < 0.01). Patients with low nocturnal bladder capacity similarly demonstrated decreased NUV (-30 vs +160, P = 0.04) and NBCi (-1.4 vs +0.33, P < 0.01). There was no significant change in MVV or NMVV for either group. Conclusions: Treatment directed at lowering nocturnal urine production and enabling patients to consistently void at capacity is a rational strategy to treat nocturia in patients with low bladder capacity

Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis

AbstractContextTo date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer.ObjectiveTo conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer.Evidence acquisitionWe searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale.Evidence synthesisNineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54–1.73, p<0.00001; I2=0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76–2.47, p < 0.00001; I2=48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results.ConclusionsRadiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making.Patient summaryWe reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery

Implantation of Autologous Bone-Marrow-Derived Cells Reconstructs Functional Urethral Sphincters in Rabbits

The purpose of this study was to determine if implantation of autologous bone-marrow-derived cells has the potential to treat stress urinary incontinence caused by intrinsic sphincter deficiency. Bone marrow cells harvested from femurs of New Zealand White rabbits were cultured for 10 days. Seven days before implantation, the urethral sphincters located at the internal urethral orifice were cryo-injured by spraying liquid nitrogen for 15 s. The cultured autologous bone-marrow-derived cells were implanted 7 days after cryo-injury. For controls, cell-free solutions were injected. At 7 and 14 days after implantation, leak point pressures were determined and the urethral sphincters were examined by immunohistochemistry. At 7 and 14 days, the cell-implanted regions contained numerous striated and smooth muscle-like cells expressing myoglobin and smooth muscle actin, respectively. The proportions of myoglobin- and smooth muscle actin-expressing areas in both the 7- and 14-day cell-implanted regions were significantly higher than in controls. By 14 days, these differentiated cells formed contacts with similar cells, creating layered muscle structures. At that time, the leak point pressure of the cell-implanted rabbits was significantly higher than that of the controls. In conclusion, autologous bone-marrow-derived cells can reconstruct functional urethral sphincters.ArticleTISSUE ENGINEERING PART A. 17(41098):1069-1081 (2011)journal articl

Cardiovascular safety in refractory incontinent patients with overactive bladder receiving add-on mirabegron therapy to solifenacin (BESIDE)

© 2017 John Wiley & Sons Ltd.Summary : Aims/objectives: : In the BESIDE study, combination therapy (antimuscarinic [solifenacin] and β3-adrenoceptor agonist [mirabegron]) improved efficacy over solifenacin monotherapy without exacerbating anticholinergic side effects in overactive bladder (OAB) patients; however, a potential synergistic effect on the cardiovascular (CV) system requires investigation. Methods: OAB patients remaining incontinent despite daily solifenacin 5 mg during 4-week single-blind run-in, were randomised 1:1:1 to double-blind daily combination (solifenacin 5 mg/mirabegron 25 mg, increasing to 50 mg after week 4), solifenacin 5 or 10 mg for 12 weeks. CV safety assessments included frequency of CV-related treatment-emergent adverse events (TEAEs), change from baseline in vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse rate) and electrocardiogram (ECG) parameters. Results: The frequency of hypertension, tachycardia and ECG QT prolongation, respectively, was low and comparable across combination (1.1%, 0.3%, 0.1%), solifenacin 5 mg (0.7%, 0.1%, 0.1%), and solifenacin 10 mg groups (0.8%, 0%, 0.1%). Adjusted mean (SE) change from baseline to end of treatment (EoT) in SBP, DBP, and pulse rate with combination (0.07 mm Hg [0.38], -0.35 mm Hg [0.26], 0.47 bpm [0.28]), solifenacin 5 mg (-0.93 mm Hg [0.38], -0.45 mm Hg [0.26], 0.43 bpm [0.28]) and solifenacin 10 mg (-1.28 mm Hg [0.38], -0.48 mm Hg [0.26], 0.27 bpm [0.28]) was generally comparable, with the exception of a mean treatment difference of ~1 mm Hg in SBP between combination and solifenacin monotherapy; SBP was unchanged with combination and decreased with solifenacin monotherapy. Mean changes from baseline to EoT in ECG parameters were generally similar across treatment groups, except for QT interval corrected using Fridericia's formula, which was higher with solifenacin 10 mg (3.30 mseconds) vs. combination (0.49 mseconds) and solifenacin 5 mg (0.77 mseconds). Conclusion: The comparable frequency of CV-related TEAEs, changes in vital signs and ECG parameters indicates no synergistic effect on CV safety outcomes when mirabegron and solifenacin are combined

Efficacy and Safety of Mirabegron Add-on Therapy to Solifenacin in Incontinent Overactive Bladder Patients with an Inadequate Response to Initial 4-Week Solifenacin Monotherapy: A Randomised Double-blind Multicentre Phase 3B Study (BESIDE)

AbstractBackgroundIncontinence has a greater detrimental effect on quality of life than other symptoms of overactive bladder (OAB) and is often difficult to treat with antimuscarinic monotherapy.ObjectiveTo evaluate the efficacy and the safety and tolerability of combination (solifenacin 5mg and mirabegron 50mg) versus solifenacin 5 or 10mg in OAB patients remaining incontinent after 4 wk of solifenacin 5mg.Design, setting, and participantsOAB patients remaining incontinent despite daily solifenacin 5mg during 4-wk single-blind run-in were randomised 1:1:1 to double-blind daily combination or solifenacin 5 or 10mg for 12 wk. Patients receiving the combination were initiated on mirabegron 25mg increasing to 50mg after week 4.Outcome measurements and statistical analysisThe primary end point was a change from baseline to end of treatment (EOT) in the mean number of incontinence episodes per 24h (stratified rank analysis of covariance [ANCOVA]). Key secondary end points were a change from baseline to EOT in the mean number of micturitions per 24h (ANCOVA) and number of incontinence episodes noted in a 3-d diary at EOT (mixed-effects Poisson regression). A trial (BESIDE) comparing combination treatment (solifenacin plus mirabegron) with one treatment alone (solifenacin) tested the superiority of combination versus solifenacin 5mg, noninferiority (and potential superiority) of combination versus solifenacin 10mg (key secondary end points), and the safety and tolerability of combination therapy versus solifenacin monotherapy.Results and limitationsA total of 2174 patients were randomised to combination (n=727), solifenacin 5mg (n=728), or solifenacin 10mg (n=719). At EOT, combination was superior to solifenacin 5mg, with significant improvements in daily incontinence (p=0.001), daily micturitions (p<0.001), and incontinence noted in a 3-d diary (p=0.014). Combination was noninferior to solifenacin 10mg for key secondary end points and superior to solifenacin 10mg for improving daily micturitions. All treatments were well tolerated.ConclusionsAdding mirabegron 50mg to solifenacin 5mg further improved OAB symptoms versus solifenacin 5 or 10mg, and it was well tolerated in OAB patients remaining incontinent after initial solifenacin 5mg.Patient summaryIn this 12-wk study, overactive bladder patients who remained incontinent despite initial solifenacin 5mg treatment received additional treatment with mirabegron 50mg. Combining mirabegron 50mg with solifenacin 5mg was superior to solifenacin 5mg alone in improving symptoms of incontinence and frequent urination, and it was well tolerated.Trial registrationClinicalTrials.gov NCT01908829

EFFICACY, SAFETY, AND TOLERABILITY OF MIRABEGRON IN PATIENTS AGED ≥65 YR WITH OVERACTIVE BLADDER WET: A PHASE IV, DOUBLE-BLIND, RANDOMISED, PLACEBOCONTROLLED STUDY (PILLAR)

Pozadina: Većina bolesnika s prekomjerno aktivnim mokraćnim mjehurom (PAMM) starija je od 65 godina. Dosad nije bilo prospektivnih ispitivanja kojima bi se ocijenila djelotvornost liječenja agonistom β3-adrenoreceptora mirabegronom u ovoj specifi čnoj dobnoj skupini. Cilj: Ispitivanje faze IV u kojem se uspoređuju mirabegron u fl eksibilnoj dozi i placebo u starijih bolesnika s PAMM om i urgentnom inkontinencijom. Dizajn, uvjeti i sudionici: Bolesnici iz lokalne zajednice koji imaju ≥ 65 godina i PAMM u trajanju od ≥ 3 mjeseca. Intervencija: Nakon 2 tjednog uvodnog razdoblja tijekom kojeg se primjenjivao placebo bolesnici s jednom ili više epizoda inkontinencije, tri ili više epizoda urgencije i prosječno osam ili više mokrenja tijekom 24 h bili su randomizirani u omjeru 1:1 za dvostruko zaslijepljenu primjenu 25 mg mirabegrona ili odgovarajuće formulacije placeba na dan tijekom 12 tjedana. Nakon 4. ili 8. tjedna doza se prema odluci bolesnika i ispitivača mogla povećati na 50 mg mirabegrona/odgovarajuće formulacije placeba na dan. Mjere ishoda i statistička analiza: Primarne mjere ishoda: promjena srednjeg broja mokrenja tijekom 24 h i srednjeg broja epizoda inkontinencije tijekom 24 h od početka ispitivanja do završetka liječenja. Sekundarne mjere ishoda: promjena srednjeg izmokrenog volumena nakon mokrenja, srednjeg broja epizoda urgencije tijekom 24 h i srednjeg broja epizoda urgentne inkontinencije tijekom 24 h od početka ispitivanja do završetka liječenja. Za ocjenu srednjeg broja mokrenja tijekom 24 h, srednjeg izmokrenog volumena nakon mokrenju i srednjeg broja epizoda urgencije tijekom 24 h koristila se analiza kovarijance (ANCOVA). Za ocjenu srednjeg broja epizoda inkontinencije tijekom 24 h i srednjeg broja epizoda urgentne inkontinencije tijekom 24 h koristila se stratifi cirana rang ANCOVA. Rezultati i ograničenja: Uz mirabegron su opažena statistički značajna poboljšanja u odnosu na placebo s obzirom na promjenu srednjeg broja mokrenja tijekom 24 h, srednjeg broja epizoda inkontinencije tijekom 24 h, srednjeg izmokrenog volumena nakon mokrenja, srednjeg broja epizoda urgencije tijekom 24 h i srednjeg broja epizoda urgentne inkontinencije tijekom 24 h od početka ispitivanja do završetka liječenja. Sigurnost i podnošljivost odgovarale su poznatom sigurnosnom profi lu mirabegrona. Zaključci: Potvrđene su djelotvornost, sigurnost i podnošljivost mirabegrona tijekom 12 tjedana u bolesnika s PAMM om i inkontinencijom u dobi od ≥ 65 godina. Sažetak za bolesnike: Ispitivali smo učinak mirabegrona u usporedbi s placebom u osoba u dobi od 65 ili više godina s prekomjerno aktivnim mokraćnim mjehurom i inkontinencijom. Mirabegron je ublažio simptome prekomjerno aktivnog mokraćnog mjehura u usporedbi s placebom. Opažene nuspojave bile su slične poznatim nuspojavama mirabegrona.Background: The majority of patients with overactive bladder (OAB) are aged >65 yr. There has been no prospectively designed study assessing treatment effi cacy with the b3-adrenoreceptor agonist, mirabegron, specifi cally in this age group. Objective: A phase IV study comparing fl exibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence. Design, setting, and participants: Community-dwelling patients aged ≥65 yr with OAB for ≥3 mo. Intervention: Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/ 24 h were randomised 1:1 to double-blind 25 mg/d mirabegron or matched placebo, for 12 wk. After week 4 or 8, the dose could be increased to 50 mg/d mirabegron/matched placebo based on patient and investigator discretion. Outcome measurements and statistical analysis: Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h. Stratifi ed rank ANCOVA was used for the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h. Results and limitations: Statistically signifi cant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Safety and tolerability were consistent with the known mirabegron safety profi le. Conclusions: Mirabegron effi cacy, safety, and tolerability over 12 wk were confi rmed in patients aged ≥65 yr with OAB and incontinence