Efficacy of TAC-302 for patients with detrusor underactivity and overactive bladder: a randomized, double-blind, placebo-controlled phase 2 study.

PURPOSE: This multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluated the efficacy and safety of TAC-302, a novel drug that restores neurite outgrowth, in patients with detrusor underactivity (DU) and overactive bladder (OAB). METHODS: After 2-4 weeks of observation, patients were randomized 2:1 to receive oral TAC-302 200 mg or placebo twice daily for 12 weeks. The primary endpoint was detrusor contraction strength, estimated by bladder contractility index (BCI) for males and projected isovolumetric pressure 1 (PIP1) for females. Secondary endpoints included changes in bladder voiding efficiency (BVE) and safety. RESULTS: Seventy-six patients were included (TAC-302, n = 52; placebo, n = 24). The mean (standard deviation [SD]) BCI for males was 64.6 (16.6) at baseline and 75.2 (21.1) at week 12 (p < 0.001) with TAC-302 (n = 27), and 61.3 (16.6) and 60.5 (16.7) (p = 0.82) with placebo (n = 11). The respective mean (SD) PIP1 for females was 18.8 (6.6) and 29.4 (9.4) (p < 0.001) with TAC-302 (n = 15), and 20.6 (7.5) and 25.5 (9.6) (p = 0.14) with placebo (n = 7). TAC-302 significantly increased BCI in males and BVE in both sexes. TAC-302 efficacy on OAB was not clearly shown. The incidences of adverse events (AEs), serious AEs, and AEs leading to dose interruption were similar between groups; no adverse drug reactions occurred. CONCLUSION: Considering the significant effects on BCI in males and BVE in both sexes, TAC-302 may benefit patients with DU. REGISTRATION: ClinicalTrials.gov Identifier NCT03175029 registered 6/5/2017.

Supervised machine learning algorithm identified KRT20, BATF and TP63 as biologically relevant biomarkers for bladder biopsy specimens from interstitial cystitis/bladder pain syndrome patients.

OBJECTIVES: This study was carried out to identify biomarkers that distinguish Hunner-type interstitial cystitis from non-Hunner-type interstitial cystitis patients. METHODS: Total ribonucleic acid was purified from 212 punch biopsy specimens of 89 individuals who were diagnosed as interstitial cystitis/bladder pain syndrome. To examine the expression profile of patients' bladder specimens, 68 urothelial master transcription factors and nine known markers (E-cadherin, cytokeratins, uroplakins and sonic hedgehog) were selected. To classify the biopsy samples, principal component analysis was carried out. A decision tree algorithm was adopted to identify critical determinants, in which 102 and 116 bladder specimens were used for learning and validation, respectively. RESULTS: Principal component analysis segregated tissues from Hunner-type and non-Hunner-type interstitial cystitis specimens in principal component axes 2 and 4. Principal components 2 and 4 contained urothelial stem/progenitor transcription factors and cytokeratins, respectively. A decision tree identified KRT20, BATF and TP63 to classify non-Hunner-type and Hunner-type interstitial cystitis specimens. KRT20 was lower in tissues from Hunner-type compared with non-Hunner-type interstitial cystitis specimens (P < 0.001). TP63 was lower in Hunner's lesions compared with adjacent mucosa from Hunner-type interstitial cystitis patients (P < 0.001). Blinded validation using additional biopsy specimens verified that the decision tree showed fairly precise concordance with cystoscopic diagnosis. CONCLUSION: KRT20, BATF and TP63 were identified as biologically relevant biomarkers to classify tissues from interstitial cystitis/bladder pain syndrome specimens. The biologically explainable determinants could contribute to defining the elusive interstitial cystitis/bladder pain syndrome pathogenesis.

Triple Therapy with Tamsulosin, Dutasteride, and Imidafenacin for Benign Prostatic Hyperplasia in Patients with Overactive Bladder Symptoms Refractory to Tamsulosin: Subgroup Analyses of the DIrecT Study.

AIM: To verify if the efficacy of the triple therapy with tamsulosin, dutasteride, and imidafenacin (TDI) is influenced by any background characteristics in patients with overactive bladder (OAB). METHODS: A subanalysis of data from the DIrecT study was conducted. Superiority of TDI over tamsulosin and dutasteride in terms of efficacy based on the Overactive Bladder Symptom Score (OABSS), total International Prostate Symptom Score (IPSS), IPSS quality of life index, and postvoid residual (PVR) was evaluated in binary subgroups. RESULTS: In the treatment groups, there was a significant interaction of total OABSS with testosterone level (≥4.8 vs. <4.8 ng/mL, p = 0.043) and PVR (≥20 vs. <20 mL, p = 0.018). For the total IPSS, no significant interaction was found except for the IPSS QOL index. For the IPSS QOL index, a significant interaction was found with testosterone level (≥4.8 vs. <4.8 ng/mL, p < 0.0001) as well as with total IPSS and total OABSS. For the PVR, no significant interaction was found except with total OABSS. CONCLUSIONS: Triple therapy with TDI is suggested to be a therapeutic option for benign prostatic hyperplasia in patients with residual OAB symptoms refractory to tamsulosin and in patients with various background characteristics regardless of severity of OAB symptoms. Trial Registry No. UMIN 000011980.

Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition).

The present article is an abridged English translation of the Japanese Clinical Guidelines for Female Lower Urinary Tract Symptoms (second edition), published in September 2019. These guidelines consist of a total of 212 pages and are unique worldwide in that they cover female lower urinary tract symptoms other than urinary incontinence. They contain two algorithms for "primary treatment" and "specialized treatment," respectively. These guidelines, consisting of six chapters, address a total of 26 clinical questions including: (i) treatment algorithms; (ii) what are female lower urinary tract symptoms?; (iii) epidemiology and quality of life; (iv) pathology and illness; (v) diagnosis; and (vi) treatment. When the patient's symptoms mainly involve voiding and post-micturition symptoms, specialized treatment should be considered. In the event of voiding symptoms concurrent with storage symptoms, residual urine should be measured; if the residual urine volume is <100 mL, then diagnosis and treatment for storage symptoms is prioritized, and if the volume is ≥100 mL, then specialized treatment should be considered. When storage symptoms are the primary condition, then the patient is subject to the primary treatment algorithm. Specialized treatment for refractory overactive bladder includes botulinum toxin injection and sacral nerve stimulation. For stress urinary incontinence, surgical treatment is indicated, such as urethral slings. The two causes of voiding symptoms and post-micturition symptoms are lower urinary tract obstruction and detrusor underactivity (underactive bladder). Mechanical lower urinary tract obstruction, such as pelvic organ prolapse, is expected to improve with surgery.

Efficacy and safety of intravesical instillation of KRP-116D (50% dimethyl sulfoxide solution) for interstitial cystitis/bladder pain syndrome in Japanese patients: A multicenter, randomized, double-blind, placebo-controlled, clinical study.

OBJECTIVE: To evaluate the efficacy and safety of intravesical KRP-116D, 50% dimethyl sulfoxide solution compared with placebo, in interstitial cystitis/bladder pain syndrome patients. METHODS: Japanese interstitial cystitis/bladder pain syndrome patients with an O'Leary-Sant Interstitial Cystitis Symptom Index score of ≥9, who exhibited the bladder-centric phenotype of interstitial cystitis/bladder pain syndrome diagnosed by cystoscopy and bladder-derived pain, were enrolled. Patients were allocated to receive either KRP-116D (n = 49) or placebo (n = 47). The study drug was intravesically administered every 2 weeks for 12 weeks. RESULTS: For the primary endpoint, the change in the mean O'Leary-Sant Interstitial Cystitis Symptom Index score from baseline to week 12 was -5.2 in the KRP-116D group and -3.4 in the placebo group. The estimated difference between the KRP-116D and placebo groups was -1.8 (95% confidence interval -3.3, -0.3; P = 0.0188). Statistically significant improvements for KRP-116D were also observed in the secondary endpoints including O'Leary-Sant Interstitial Cystitis Problem Index score, micturition episodes/24 h, voided volume/micturition, maximum voided volume/micturition, numerical rating scale score for bladder pain, and global response assessment score. The adverse drug reactions were mild to moderate, and manageable. CONCLUSIONS: This first randomized, double-blind, placebo-controlled trial shows that KRP-116D improves symptoms, voiding parameters, and global response assessment, compared with placebo, and has a well-tolerated safety profile in interstitial cystitis/bladder pain syndrome patients with the bladder-centric phenotype.

Bladder sensation evaluation of a carrageenan-induced chronic prostatitis model using a direct measurement of the bladder mechanosensitive single-unit afferent nerve activity.

AIMS: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) causes long-standing pain and/or storage symptoms. This study aimed to evaluate the likelihood of deterioration of bladder sensation in a carrageenan-induced CP/CPPS model by direct measurement of the bladder mechanosensitive single-unit afferent nerve activity. METHODS: In this study, male adult Sprague-Dawley rats were used. They were injected 50 µL of 3% λ-carrageenan or its vehicle (saline) into both lobes of the ventral prostate. Seven days following injection, the pain behavior at the pelvic-perineal area (using von Frey filaments), prostatic blood flow (using a laser blood flowmeter), and histology were examined along with cystometry (under conscious free-moving condition) and mechanosensitive single-unit afferent nerve activity (under urethane anesthesia). RESULTS: The prostate showed increased tissue weight and decreased blood flow and inflammatory cell infiltration in the carrageenan group compared to the control group. Consequently, the threshold of the pain behavior was decreased, and the basal and threshold pressures of the bladder were increased in the carrageenan group. In contrast, no significant differences of bladder histology and other cystometric parameters were found between the groups. Regarding Aδ- or C-fibers, the mechanosensitive afferent nerve activities revealed no differences in either group. CONCLUSIONS: The carrageenan-induced CP/CPPS rat model showed edema, ischemia, and inflammatory pain in the prostate, whereas a little change was detected in bladder sensation. These findings, which were evaluated using a direct measurement of the mechanosensitive single-unit afferent nerve activity, suggest that the bladder sensation is unlikely deteriorated in this model.

A randomized controlled study of the efficacy of tadalafil monotherapy versus combination of tadalafil and mirabegron for the treatment of persistent overactive bladder symptoms in men presenting with lower urinary tract symptoms (CONTACT Study).

AIM: To evaluate efficacy and safety of combination of tadalafil + mirabegron for overactive bladder/benign prostatic hyperplasia (OAB/BPH). METHODS: Male patients with lower urinary tract symptoms (50 to 89 years), with remaining OAB symptoms even after administering tadalafil for more than 8 weeks were randomly assigned to either tadalafil monotherapy group (5 mg/day) or tadalafil/mirabegron combination therapy group (5 mg/50 mg/day). The primary endpoint was change from baseline in total OAB symptom score (OABSS) at week 12. The secondary endpoints were changes in International Prostate Symptom Score (IPSS), NIH-chronic prostatitis symptom index (NIH-CPSI), and micturition chart parameters at weeks 4 and 12. RESULTS: A total of 176 patients were randomized to either monotherapy (87 patients) or combination therapy (89 patients). The baseline characteristics of patients in the two groups were similar. The total OABSS (95% confidence interval) of combination therapy was significantly decreased by 1.78 (1.05-2.50) points compared with that of monotherapy (P < .001). Changes from baseline in OABSS nighttime voiding score, urgency score, urgency incontinence score, IPSS storage subscores, NIH-CPSI total score, and numbers of voids, nighttime-voids, and urgency episodes/day in micturition chart were significantly reduced in combination therapy (all P < .001). Patient-reported outcome was significantly more satisfactory in combination therapy than in monotherapy (P < .001). One moderate adverse event (pain in hip joint) with hardly presumed causal relationship with therapy and seven mild adverse events were noted in monotherapy and combination therapy group, respectively. CONCLUSIONS: The effect of tadalafil/mirabegron combination therapy on relieving OAB symptoms appeared to be greater than that of tadalafil monotherapy and can be safely used.

Urodynamic efficacy of fesoterodine for the treatment of neurogenic detrusor overactivity and/or low compliance bladder.

OBJECTIVE: To examine the urodynamic effects of fesoterodine on neurogenic detrusor overactivity and/or low compliance bladder. METHODS: A total of 77 patients (52 men, 25 women; aged 61.6 ± 20.3 years) were given fesoterodine 4-8 mg/day and prospectively followed for 12 weeks. The primary end-point variable was change in the maximum cystometric capacity on urodynamic study. The secondary end-point was to assess the number of patients whose neurogenic detrusor overactivity disappeared, and the changes in the urodynamic parameters, lower urinary tract symptoms questionnaires and the 3-day frequency volume chart parameters after the treatment. RESULTS: A total of 13 patients (16.9%) withdrew because of adverse events (dry mouth or blurred vision), and four patients dropped out for unknown reasons. Finally, 60 patients completed the study. Bladder capacity at first desire to void, maximum cystometric capacity and bladder compliance increased by 29.2 mL, 79.9 mL and 22.2 mL/cm H2 O, respectively, showed statistical significance (P = 0.026, P < 0.001 and P < 0.001). Neurogenic detrusor overactivity disappeared in 12 of 51 patients (23.5%), and a significant increase was observed in bladder capacity at first involuntary contraction (P < 0.001), and a significant decrease was observed in maximum detrusor contraction (P < 0.001). In patients with low compliance bladder (with detrusor underactivity without neurogenic detrusor overactivity; n = 9), maximum cystometric capacity and bladder compliance increased significantly (P = 0.003 and P = 0.006, respectively). Overactive bladder symptom score, International Consultation on Incontinence Questionnaire-Short Form, most items of King's Health Questionnaire, and the number of urgency episodes and leaks in a day decreased significantly after treatment. CONCLUSIONS: Fesoterodine seems to be a valid treatment option for neurogenic detrusor overactivity and/or low compliance bladder in neurogenic bladder patients.

OnabotulinumtoxinA (botulinum toxin type A) for the treatment of Japanese patients with overactive bladder and urinary incontinence: Results of single-dose treatment from a phase III, randomized, double-blind, placebo-controlled trial (interim analysis).

OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA (botulinum toxin type A) 100 U in patients with overactive bladder and urinary incontinence. METHODS: This was a phase III, randomized, double-blind, placebo-controlled trial in Japanese patients who were inadequately managed with overactive bladder medications (anticholinergics and/or ß3 -adrenergic receptor agonists). Eligible patients were randomized 1:1 to receive a single dose of either onabotulinumtoxinA or placebo into the detrusor muscle (n = 124 each). The primary end-point was the change in the number of daily urinary incontinence episodes at week 12 from baseline. Secondary end-points included volume voided per micturition, other symptomatic measures (urinary urgency incontinence, micturition, urgency and nocturia) and patient-reported outcomes. RESULTS: In the onabotulinumtoxinA group, there was a significantly greater decrease from baseline in the mean number of daily urinary incontinence episodes compared with the placebo group (2.16; P < 0.001), and significantly greater improvement for all secondary end-points (P < 0.05). Urinary tract infection, dysuria, urinary retention and post-void residual urine volume increased represented adverse events occurring at a higher rate in the onabotulinumtoxinA group. The majority of these were mild or moderate in severity. CONCLUSIONS: Statistically significant and clinically relevant improvements in symptoms and patient-reported outcomes, and tolerability were seen in patients with overactive bladder and urinary incontinence who had been inadequately managed with overactive bladder medications after using onabotulinumtoxinA.

Regenerative treatment for male stress urinary incontinence by periurethral injection of adipose-derived regenerative cells: Outcome of the ADRESU study.

OBJECTIVES: To report the outcome of the ADRESU study, a multicenter, single-arm, investigator-initiated clinical trial to confirm the efficacy and safety of regenerative treatment for male patients with stress urinary incontinence. METHODS: The participants were male patients with mild-to-moderate stress urinary incontinence persisting for >1 year after prostatectomy. Autologous adipose-derived regenerative cells were isolated using the Celution system from adipose tissue obtained by liposuction. Adipose-derived regenerative cells and mixture of adipose-derived regenerative cells with adipose tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. The primary end-point was the proportion of patients with improvement of the urine leakage volume at 52 weeks (or last visit within 52 weeks). Improvement of leakage volume was defined as a decrease from baseline >50% by the 24-h pad test. A total of 10 secondary end-points were set. RESULTS: A total of 45 patients satisfying the eligibility criteria were enrolled. The primary end-point was met; the proportion of patients with improvement in leakage volume at 52 weeks was 37.2% (95% confidence interval 23.0-53.3%). No serious adverse events with causal relationships to the adipose-derived regenerative cells were encountered. There was a progressive improvement in secondary end-points. In the King's Health Questionnaire, improvement of quality of life scores showed greater improvement in responders, as compared with non-responders. CONCLUSIONS: Findings from the ADRESU study suggest the efficacy and safety of regenerative treatment for male patients with mild-to-moderate stress urinary incontinence.

Clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury.

The present article is an abridged English translation of the Japanese clinical guidelines for the diagnosis and treatment of lower urinary tract dysfunction in patients with spinal cord injury updated as of July 2019. The patients are adult spinal cord injured patients with lower urinary tract dysfunction; special consideration of pediatric and elderly populations is presented separately. The target audience is healthcare providers who are engaged in the medical care of patients with spinal cord injury. The mandatory assessment includes medical history, physical examination, frequency-volume chart, urinalysis, blood chemistry, transabdominal ultrasonography, measurement of post-void residual urine, uroflowmetry and video-urodynamic study. Optional assessments include questionnaires on the quality of life, renal scintigraphy and cystourethroscopy. The presence or absence of risk factors for renal damage and symptomatic urinary tract infection affects urinary management, as well as pharmacological treatments. Further treatment is recommended if the maximum conservative treatment fails to improve or prevent renal damage and symptomatic urinary tract infection. In addition, management of urinary incontinence should be considered individually in patients with risk factors for urinary incontinence and decreased quality of life.

Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease.

PURPOSE: To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. METHODS: We examined gastric emptying and colonic transit time in 19 dementia with Lewy bodies and 46 Parkinson disease patients. RESULTS: Gastric emptying was longer in dementia with Lewy bodies than in Parkinson disease (p = 0.014). Colonic transit time tended to be longer in dementia with Lewy bodies than in Parkinson disease. There was no relationship between gastric emptying and colonic transit time, nor between gastric emptying, colonic transit time and age. CONCLUSION: Gastric emptying was prolonged in dementia with Lewy bodies compared to Parkinson disease.

Comparison of the clinical effect of dutasteride therapy for benign prostatic hyperplasia when initiated at different time points: A multicentre, observational, retrospective chart review study.

AIM: To evaluate the effects of early (≤6 months after starting any medical treatment [baseline] for benign prostatic hyperplasia [BPH]), intermediate (between >6 months and 2 years from baseline) and late (2 years after baseline) initiation of add-on dutasteride therapy on the incidence of acute urinary retention (AUR) and BPH-related surgery in Japanese patients with moderate-to-severe BPH. METHODS: This multicentre, observational, retrospective chart review study used anonymised data from Japanese medical records. Eligible patients (≥50 years) were followed from baseline until first AUR, BPH-related surgery or Year 4. RESULTS: Overall, 1206 patients were included (early initiation: n = 793; intermediate: n = 233; late: n = 180). Early dutasteride initiation was not superior to late initiation in reducing the risk of first AUR or BPH-related surgery from baseline (hazard ratio [HR] 0.733; 95% confidence interval [CI] 0.468-1.150) but was superior in reducing the risk of first AUR alone (HR 3.449; 95% CI 1.796-6.623). One year after initiation, the cumulative incidence of first AUR rose rapidly in the late vs early and intermediate initiation groups. Incidences of all parameters (first AUR/BPH-related surgery, first AUR alone and BPH-related surgery alone) in patients undergoing BPH-related surgery in low incidence sites (ie clinical sites with ≤ 16% incidence of first AUR or BPH-related surgery) were significantly lower in the early vs late initiation groups. CONCLUSION: Early dutasteride initiation reduced the risk of AUR in a Japanese real-world setting. A randomised controlled trial is warranted to evaluate the benefit of early initiation in preventing BPH-related surgery in Japanese patients.

Molecular pathogenesis of interstitial cystitis based on microRNA expression signature: miR-320 family-regulated molecular pathways and targets.

Interstitial cystitis (IC), also known as bladder pain syndrome, is a chronic inflammatory disease that affects the bladder. The symptoms of IC vary, including feeling an urgent need for immediate urination and of needing to urinate often, as well as bladder or pelvic pain. Despite its high incidence, no molecular diagnostic methods are available for IC, and the molecular pathogenesis is unknown. microRNAs (miRNA) can regulate expression of RNA transcripts in cells and aberrant expression of miRNAs is associated with several human diseases. Here, we investigated the molecular pathogenesis of IC based on miRNA expression signatures. RNA sequencing of miRNA levels in IC tissues and comparison with levels in normal bladder tissue and bladder cancer revealed dysregulated expression of 366 miRNAs (203 and 163 down- and upregulated miRNAs, respectively). In particular, miR-320 family miRNAs(miR-320a, miR-320b, miR-320c, miR-320d and miR-320e) had downregulated expression in IC tissues. Genome-wide gene expression analyses and in silico database analyses showed that three transcription factors, E2F-1, E2F-2 and TUB, are regulated by miR-320 family miRNAs. Immunostaining of IC tissues confirmed that these transcription factors are overexpressed in IC tissues. Novel approaches that identify aberrantly expressed miRNA regulatory networks in IC could provide new prognostic markers and therapeutic targets for this disease.

Urological dysfunction in synucleinopathies: epidemiology, pathophysiology and management.

OBJECTIVE: Parkinson's disease (PD) and multiple system atrophy (MSA) are major neurogenerative diseases characterized pathologically by abnormal alpha-synuclein aggregation. PD and MSA are clinically characterized by motor disorder and bladder dysfunction (mainly urinary urgency and frequency, also called overactive bladder). However, few literatures are available concerning bladder dysfunction in PD or MSA. METHOD: A systematic review. RESULTS: The bladder dysfunction in MSA is more severe than that in PD for large post-void residual or urinary retention. These bladder dysfunctions presumably reflect the different nervous system pathologies. Overactive bladder in PD reflects lesions in the brain, e.g., in the prefrontal-nigrostriatal D1 dopaminergic bladder-inhibitory pathway. Overactive bladder in MSA reflects lesions similar to PD and the cerebellum (bladder-inhibitory), and the urinary retention in MSA presumably reflects lesions in the pontine micturition center and the sacral intermediolateral nucleus of the spinal cord (bladder-facilitatory). Bladder dysfunction not only impairs an individual's quality of life, it can also cause emergency hospitalizations due to acute retention and early institutionalization. Anticholinergics are the first-line treatment for bladder dysfunction in PD and MSA patients, but care should be taken for the management of bladder dysfunction-particularly in MSA patients due to the high prevalence of difficult emptying, which needs clean, intermittent catheterization. CONCLUSIONS: This review summarizes the epidemiology, pathophysiology, and management of bladder dysfunction in individuals with PD or MSA.

Lower Urinary Tract Function in Familial Spastic Paraplegia.

In order to investigate lower urinary tract function in hereditary spastic paraplegia (HSP), we recruited 12 HSP patients: 8 men, 4 women; mean age, 64.6 years; mean disease duration, 18.9 years; walk without cane, 2, walk with cane, 6, wheelchair bound, 3. We performed urinary symptom questionnaires and a urodynamic testing in all patients. As a result, urinary symptoms were observed in all but 3, including urinary urgency/frequency (also called overactive bladder) in 9 and hesitancy/poor stream in 6. Urodynamic abnormalities included detrusor overactivity during bladder filling in 10, underactive detrusor on voiding in 8 (detrusor hyperactivity with impaired contraction [DHIC] in 5), detrusor-sphincter dyssynergia (DSD) on voiding in 3, and post-void residual in 5. Sphincter electromyography showed neurogenic motor unit potential in 4. In conclusion, we observed high frequency of urinary symptoms in HSP. Urodynamics indicated that the main mechanism is DHIC with/without DSD for their urinary symptom, and sacral cord involvement in some cases. These findings facilitate patients' care including clean, intermittent catheterization.

Mirabegron or tolterodine for the treatment of overactive bladder in Japan: Which drug is more cost-effective as the first-line treatment?

OBJECTIVES: To assess the cost-effectiveness of mirabegron 50 mg relative to tolterodine extended release 4 mg for the treatment of overactive bladder if used as the first-line treatment in Japan. METHODS: A Markov model was developed to simulate the cost-effectiveness of the mirabegron first-line treatment (and tolterodine second-line) versus tolterodine first-line treatment (and mirabegron second-line) taken for 5 years from the randomized European-Australian study (SCORPIO trial) and single technology appraisal assessment report by the National Institute for Health and Care Excellence. The incremental cost-effectiveness ratio was calculated with utility value by quality-adjusted life year with cost using the medical fee and the drug price tariff in 2016. For the study of transition of treatment status, our analytical model was established. The transition probabilities of severity states were calculated based on the probabilities for the mean numbers of incontinence episodes/day and micturition episodes/day in mirabegron-treated and tolterodine-treated patients in the single technology appraisal assessment report. RESULTS: The 5-year expected effect per patient was 3.860 quality-adjusted life years for first-line mirabegron and 3.839 quality-adjusted life years for first-line tolterodine. The 5-year expected cost per patient was ¥526 191 for first-line mirabegron, and ¥472 390 for first-line tolterodine. The incremental cost-effectiveness ratio was ¥2 565 927/quality-adjusted life year. This value was below the willingness-to-pay threshold of ¥5 million/quality-adjusted life year. In more severe states, the incremental cost-effectiveness ratio exceeded ¥5 million. CONCLUSIONS: First-line mirabegron appears to be more cost-effective than first-line tolterodine. In patients with severe symptoms, first-line mirabegron is not economically preferable.

Therapeutic effect of propiverine hydrochloride on mixed-type urinary incontinence in women: The Female Urgency and Stress Urinary Incontinence Study of Propiverine Hydrochloride trial.

OBJECTIVES: To show the efficacy of propiverine hydrochloride in the management of symptoms of stress urinary incontinence in female patients with mixed-type urinary incontinence. METHODS: The study was carried out as a multicenter single-arm clinical trial at 64 institutions in Japan. The participants were female patients aged ≥20 years with mixed-type urinary incontinence. The frequency of stress urinary incontinence and urgency urinary incontinence was evaluated at baseline and 4, 8 and 12 weeks after treatment with propiverine hydrochloride. Subjective symptoms were evaluated using the Overactive Bladder Symptom Score and the International Consultation on Incontinence Questionnaire-Short Form. Functional urethral length and maximum urethral closing pressure were also measured at baseline and 12 weeks after treatment at the institutions where the urethral pressure profile was taken. RESULTS: In total, 49 mixed-type urinary incontinence patients were enrolled in the present study. The number of cases of urgency urinary incontinence was reduced time-dependently, which showed statistically significant differences between baseline and 4, 8 and 12 weeks after treatment. A similar statistically different reduction was also observed for stress urinary incontinence. The mean reduction rates of urgency urinary incontinence and stress urinary incontinence at 12 weeks after treatment were 63.9% and 44.3%, respectively. The total scores of International Consultation on Incontinence Questionnaire-Short Form and Overactive Bladder Symptom Score were gradually reduced, and the differences were statistically significant. Functional urethral length and maximum urethral closing pressure at 12 weeks after treatment did not show any statistical differences compared with those at baseline. CONCLUSIONS: Propiverine hydrochloride can be an effective therapeutic option for stress urinary incontinence in patients with mixed-type urinary incontinence.

Design of a single-arm clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells for male stress urinary incontinence in Japan: the ADRESU study protocol.

BACKGROUND: Male stress urinary incontinence is a prevalent condition after radical prostatectomy. While the standard recommendation for the management of urine leakage is pelvic floor muscle training, its efficacy is still unsatisfactory. Therefore, we have focused on regenerative therapy, which consists of administering a periurethral injection of autologous regenerative cells from adipose tissue, separated using the Celution® system. Based on an interim data analysis of our exploratory study, we confirmed the efficacy and acceptable safety profile of this treatment. Accordingly, we began discussions with Japanese regulatory authorities regarding the development of this therapy in Japan. The Ministry of Health, Labour and Welfare suggested that we implement a clinical trial of a new medical device based on the Pharmaceutical Affaires Act in Japan. Next, we discussed the design of this investigator-initiated clinical trial (the ADRESU study) aimed at evaluating the efficacy and safety of this therapy, in a consultation meeting with the Pharmaceuticals and Medical Device Agency. METHODS: The ADRESU study is an open-label, multi-center, single-arm study involving a total of 45 male stress urinary incontinence patients with mild-to-moderate urine leakage persisting more than 1 year after prostatectomy, in spite of behavioral and pharmacological therapies. The primary endpoint is the rate of patients at 52 weeks with improvement of urine leakage volume defined as a reduction from baseline greater than 50% by 24-h pad test. Our specific hypothesis is that the primary endpoint result will be higher than a pre-specified threshold of 10%. DISCUSSION: The ADRESU study is the first clinical trial of regenerative treatment for stress urinary incontinence by adipose-derived regenerative cells using the Celution® system based on the Japanese Pharmaceutical Affaires Act. We will evaluate the efficacy and safety in this trial to provide an adequate basis for marketing approval with the final objective of making this novel therapy widely available for Japanese patients. TRIAL REGISTRATION: This trial was registered at the University Hospital Medical information Network Clinical Trial Registry (UMIN-CTR Unique ID: UMIN000017901 ; Registered July 1, 2015) and at ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT02529865 ; Registered August 18, 2015).