Herpes simplex virus gene therapy for dystrophic epidermolysis bullosa (DEB).

The FDA has recently approved Krystal biotech's beremagene geperpavec (B-VEC, Vyjuvek) to treat the wounds of dystrophic epidermolysis bullosa (DEB) patients. This represents a giant step, not only toward the treatment of this devastating disease, but also for the whole field of non-replicative (nr) recombinant HSV-1 vectors for gene therapy. To view this Bench to Bedside, open or download the PDF.

Treatment of neurogenic detrusor overactivity and overactive bladder with Botox (onabotulinumtoxinA): Development, insights, and impact.

Neurogenic detrusor overactivity (NDO) is a complication of multiple sclerosis, spinal cord injury (SCI), stroke, head injury, and other conditions characterized by damage to the upper motor neuronal system. NDO often leads to high bladder pressure that may cause upper urinary tract damage and urinary incontinence (UI). Prior to the use of onabotulinumtoxinA, oral anticholinergics and surgical augmentation cystoplasty were the treatment options. Overactive bladder (OAB) is non-neurogenic and affects a much larger population than NDO. Both NDO and OAB negatively impact patients' quality of life (QOL) and confer high health care utilization burdens. Early positive results from pioneering investigators who injected onabotulinumtoxinA into the detrusor of patients with SCI caught the interest of Allergan, which then initiated collaborative clinical trials that resulted in FDA approval of onabotulinumtoxinA 200U in 2011 for NDO and 100U in 2013 for patients with OAB who inadequately respond to or are intolerant of an anticholinergic. These randomized, double-blind, placebo-controlled trials for NDO showed significant improvements in UI episodes, urodynamic parameters, and QOL; the most frequent adverse events were urinary tract infection (UTI) and urinary retention. Similarly, randomized, double-blind, placebo-controlled trials of onabotulinumtoxinA 100U for OAB found significant improvements in UI episodes, treatment benefit, and QOL; UTI and dysuria were the most common adverse events. Long-term studies in NDO and OAB showed sustained effectiveness and safety with repeat injections of onabotulinumtoxinA, the use of which has profoundly improved the QOL of patients failing anticholinergic therapy and has expanded the utilization of onabotulinumtoxinA into smooth muscle.

Study design of a phase 4, real-world study (COMPOSUR) to evaluate vibegron in patients with overactive bladder.

BACKGROUND: Overactive bladder (OAB) is defined as urinary urgency accompanied by frequency and nocturia, with or without urge urinary incontinence (UUI). Vibegron, a selective ß3-adrenergic receptor agonist approved in the US in December 2020, demonstrated efficacy in reducing symptoms of OAB and was safe and well tolerated in the 12-week EMPOWUR trial and its 40-week, double-blind extension trial. The goal of the COMPOSUR study is to evaluate vibegron in a real-world setting to assess patient treatment satisfaction, tolerability, safety, duration of treatment, and persistence. METHODS: This is a 12-month, prospective, observational, real-world study, with an optional 12-month extension to 24 months, in the US assessing adults ≥ 18 years old starting a new course of vibegron. Patients must be previously diagnosed with OAB with or without UUI, symptomatic for ≥ 3 months before enrollment, and receive prior treatment with an anticholinergic, with mirabegron, or with a combination of an anticholinergic and mirabegron. Enrollment is performed by the investigator following exclusion and inclusion criteria guided by US product labeling, reinforcing a real-world approach. Patients complete the OAB Satisfaction with Treatment Questionnaire (OAB-SAT-q) monthly and the OAB Questionnaire short form (OAB-q-SF) and Work Productivity and Activity Impairment Questionnaire (WPAI:US) at baseline and monthly for 12 months. Patients are followed up via phone call, in-person visits, or telehealth (ie, virtual) visits. The primary endpoint is patient treatment satisfaction as determined by the OAB-SAT-q satisfaction domain score. Secondary endpoints include percent positive responses to individual OAB-SAT-q questions, additional OAB-SAT-q domain scores, and safety. Exploratory endpoints include adherence and persistence. DISCUSSION: OAB leads to a significant decrease in quality of life, as well as impairment of work activities and productivity. Persistence with OAB treatments can be challenging, often due to lack of efficacy and adverse effects. COMPOSUR is the first study to provide long-term, prospective, pragmatic treatment data for vibegron in the US and the resultant effect on quality of life among patients with OAB in a real-world clinical setting. Trial registration ClinicalTrials.gov identifier: NCT05067478; registered: October 5, 2021.

Efficacy and Safety of Vibegron for the Treatment of Overactive Bladder in Women: A Subgroup Analysis From the Double-Blind, Randomized, Controlled EMPOWUR Trial.

IMPORTANCE: The international phase 3 EMPOWUR trial demonstrated efficacy and safety of vibegron, a newer ß 3 -adrenergic receptor agonist, in adults with overactive bladder (OAB). Women are disproportionately affected by OAB, especially those with bothersome symptoms, such as urge urinary incontinence (UUI). OBJECTIVE: This subgroup analysis from EMPOWUR assessed efficacy and safety of vibegron in women. STUDY DESIGN: In EMPOWUR, patients with OAB were randomized 5:5:4 to 12 weeks of treatment with once-daily vibegron 75 mg, placebo, or tolterodine 4-mg extended release. Efficacy end points included change from baseline at week 12 in mean daily number of micturitions, UUI episodes, and urgency episodes. Safety was assessed through adverse events (AEs). RESULTS: Of the patients included in the analysis, 1286 (84.9%) were women (vibegron, n = 463; placebo, n = 459; tolterodine, n = 364). At week 12, women receiving vibegron showed significant reductions (95% confidence intervals of least squares mean differences does not include 0) from baseline versus placebo in mean daily micturitions, UUI episodes, and urgency episodes, with least squares mean differences (95% confidence intervals) of -0.5 (-0.8 to -0.2), -0.7 (-1.0 to -0.4), and -0.8 (-1.3 to -0.4), respectively. Treatment-emergent AE incidence was similar with vibegron (39%) and placebo (35%); the most common AE with incidence higher with vibegron (4.3%) than placebo (2.6%) was headache. CONCLUSIONS: In this subgroup analysis, women receiving vibegron showed significant reductions in key efficacy end points versus placebo and favorable safety profile, consistent with the overall results from EMPOWUR, suggesting that vibegron is efficacious and safe for the treatment of OAB in this patient population.

Pharmacokinetics and Safety of Vibegron 75 mg Administered as an Intact or Crushed Tablet in Healthy Adults.

Oral pharmacotherapy for overactive bladder, a condition that increases with age, includes anticholinergics and ß3 -adrenergic receptor agonists. Older adults, including those with dysphagia, may have difficulty swallowing tablets. In this phase 1 study in healthy adults, we assessed the pharmacokinetic profile of the ß3 -adrenergic receptor agonist vibegron administered as a single 75-mg dose as an intact tablet versus crushed and mixed with applesauce. Additional end points included safety (assessed by adverse events), perception of taste (assessed via questionnaire), and stability over 4 hours after crushing and mixing in applesauce (assessed by chromatography). Overall, 30 participants were randomized, and 29 were included in the pharmacokinetic analysis. Crushing a vibegron tablet and mixing with applesauce decreased vibegron maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 to infinity by ≈30% and ≈10%, respectively; however, these decreases were not considered clinically significant. Treatment-emergent adverse events were reported in 16 (53.3%) participants. Approximately half of participants reported the vibegron and applesauce mixture tasted as expected; of those reporting the taste was different than expected, 50% reported the taste as bitter. The mixture was stable for 4 hours in applesauce. The results of this study showed that crushing and administering vibegron with applesauce may be an appropriate option for patients with overactive bladder and swallowing difficulties.

Efficacy and safety of vibegron for the treatment of irritable bowel syndrome in women: Results of a randomized, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Preclinical and clinical studies suggest that ß3 -adrenergic receptor activation may be a novel target for treating abdominal pain and gastrointestinal motility dysfunction in patients with irritable bowel syndrome (IBS). This proof-of-concept study evaluated the efficacy and safety of the ß3 -adrenergic agonist vibegron in treating IBS-related pain. METHODS: Adult women with predominant-diarrhea IBS (IBS-D) or with mixed diarrhea/constipation (IBS-M), diagnosed using Rome IV criteria, were randomized 1:1 to receive once-daily vibegron 75 mg or placebo for 12 weeks. The primary endpoint was the percentage of patients with IBS-D considered abdominal pain intensity (API) weekly responders, defined as ≥30% reduction from baseline at week 12 in mean weekly worst abdominal pain over 24 hours using the API score. Patients completed a pain diary at baseline and at weeks 2, 4, 8, and 12. Safety was assessed by adverse events (AEs) in the overall IBS population. KEY RESULTS: Of the 222 patients with IBS randomized (vibegron, N = 111; placebo, N = 111), 85% completed the trial. There was no significant difference in the percentage of patients with IBS-D (vibegron, N = 66; placebo, N = 63) considered API weekly responders with vibegron vs. placebo (p = 0.8222) after 12 weeks. The incidence of AEs was comparable between treatment groups (33.3% each), with equal rates of worsening IBS symptoms (2.7% each). CONCLUSIONS AND INFERENCES: In women with IBS-D, vibegron was not associated with significant improvement in the percentage of API weekly responders. Vibegron was generally safe and well tolerated and, in particular, did not worsen IBS symptoms vs. placebo.

An Evaluation of the Efficacy and Safety of Vibegron in the Treatment of Overactive Bladder.

Pharmacologic treatment for overactive bladder (OAB), which is characterized by bothersome symptoms such as urgency and urge urinary incontinence (UUI), includes anticholinergics and ß3-adrenergic receptor agonists. Anticholinergics are associated with adverse effects including dry mouth, constipation, cognitive impairment, and increased risk of dementia. Therefore, the drug class of ß3-adrenergic receptor agonists may represent an effective, safe treatment option. Vibegron, a ß3-adrenergic receptor agonist, was approved for use in Japan (2018) and the United States (2020). Over the past 3 years, 2 phase 3 trials (EMPOWUR, EMPOWUR extension) have been conducted with once-daily vibegron 75 mg for the treatment of OAB, and additional secondary and subgroup analyses have detailed the efficacy and safety of vibegron. In the international phase 3 EMPOWUR trial, treatment with vibegron was associated with significant improvements compared with placebo in efficacy outcomes of micturition frequency, UUI episodes, urgency episodes, and volume voided as early as week 2 that were sustained throughout the 12-week trial. The 40-week EMPOWUR extension study, following the 12-week treatment period, demonstrated sustained efficacy in patients receiving vibegron for 52 weeks. Treatment with vibegron was also associated with improvements in patient-reported measures of quality of life. Across studies, vibegron was generally safe and well tolerated. A separate, dedicated ambulatory blood pressure monitoring study showed that treatment with vibegron was not associated with clinically meaningful effects on blood pressure or heart rate. Across all studies, vibegron was efficacious, safe, and well tolerated and thus represents a valuable treatment option for patients with OAB. Here, nearly 1 year after US approval, we review the published data on efficacy and safety of vibegron 75 mg for the treatment of OAB.

Effects of vibegron on ambulatory blood pressure in patients with overactive bladder: results from a double-blind, placebo-controlled trial.

OBJECTIVES: To characterize the blood pressure (BP) profile of the new ß3-adrenergic receptor agonist, vibegron, in patients with overactive bladder. METHODS: Patients were randomized to once-daily vibegron 75 mg or placebo for 28 days and underwent ambulatory BP monitoring. The primary endpoint was change from baseline (CFB) to day 28 in mean daytime ambulatory systolic BP (SBP). Secondary endpoints were CFB in mean 24-h SBP and in mean daytime and mean 24-h ambulatory diastolic BP (DBP) and heart rate (HR). Safety was assessed through adverse event reporting. RESULTS: Of 214 patients randomized, 96 receiving vibegron and 101 receiving placebo had evaluable baseline and day 28 measurements. Overall, 39.6 and 30.7% of patients receiving vibegron and placebo, respectively, had preexisting hypertension. The least squares mean difference (LSMD; 90% confidence interval) between vibegron and placebo in CFB in mean daytime SBP was 0.8 (-0.9, 2.5) mmHg. LSMD in CFB in mean daytime DBP and HR was 0.0 mmHg and 0.9 bpm, respectively. No significant differences between treatments were seen in CFB in mean 24-h SBP (LSMD, 0.6 mmHg), DBP (-0.2 mmHg) or HR (1.0 bpm). The most common treatment-emergent adverse event was hypertension, with rates comparable between groups [vibegron: n = 5 (4.7%); placebo: n = 4 (3.7%)]. One patient receiving vibegron took a prohibited medication (phentermine) known to increase BP. CONCLUSIONS: Once-daily vibegron had no statistically significant or clinically relevant effects on BP or HR.

OnabotulinumtoxinA for the Treatment of Patients with Overactive Bladder and Urinary Incontinence: Results of a Phase 3, Randomized, Placebo Controlled Trial.

PURPOSE: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. MATERIALS AND METHODS: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co-primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. RESULTS: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p ≤0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. CONCLUSIONS: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated.

A multicenter, randomized, double-blind, placebo controlled study of onabotulinumtoxinA 200 U to treat lower urinary tract symptoms in men with benign prostatic hyperplasia.

PURPOSE: We assessed the efficacy and tolerability of onabotulinumtoxinA 200 U vs placebo to treat lower urinary tract symptoms/benign prostatic hyperplasia in men previously treated with oral benign prostatic hyperplasia medication in a 24-week phase 2, multicenter, double-blind, randomized, placebo controlled, parallel group trial. MATERIALS AND METHODS: Patients with I-PSS (International Prostate Symptom Score) 14 or greater, peak urinary flow rate 4 to 15 ml per second and total prostate volume 30 to 80 ml were randomized 1:1 to a single intraprostatic treatment of onabotulinumtoxinA 200 U or placebo. A single-blind sham procedure followed by a 4-week run-in was included to attempt to minimize any potential placebo effect. Patients who still met eligibility criteria after the run-in entered the double-blind active treatment period. The primary end point was the change from baseline in total I-PSS at week 12. Other end points assessed at weeks 6, 12 and 24 included the change from baseline in total I-PSS, peak urinary flow rate, total prostate volume and post-void residual urine volume. RESULTS: Of 427 patients enrolled 315 were randomized and treated. Decreases from baseline in I-PSS were observed in the onabotulinumtoxinA and placebo groups (-6.3 vs -5.6 points, p <0.001) with no difference between the groups overall or in subgroups. Improvement was observed in the peak urinary flow rate, which was significant only at week 6 compared to placebo. Improvement was significant at all time points in a patient subgroup on stable concurrent α-blockers or 5α-reductase inhibitors during the study. Adverse events were similar in the 2 treatment groups. CONCLUSIONS: OnabotulinumtoxinA 200 U and placebo improved I-PSS and were well tolerated but no between group difference in efficacy was observed.

OnabotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity [corrected] regardless of concomitant anticholinergic use or neurologic etiology.

INTRODUCTION: To evaluate the efficacy and safety of onabotulinumtoxinA for the treatment of neurogenic detrusor overactivity (NDO) in subpopulations of etiology (multiple sclerosis [MS] or spinal cord injury [SCI]) and concomitant anticholinergics (use/non-use). METHODS: Data were pooled from two double-blind, placebo-controlled, pivotal, phase 3 studies including a total of 691 patients with ≥ 14 urinary incontinence (UI) episodes/week due to MS (n = 381) or SCI (n = 310). Patients received intradetrusor injections of onabotulinumtoxinA 200U (n = 227), 300U (n = 223), or placebo (n = 241). Change from baseline at week 6 in UI episodes/week (primary endpoint), urodynamics, quality of life (QOL), and adverse events (AEs) were assessed. RESULTS: Significant and similar reductions in UI episodes were observed regardless of etiology or anticholinergic use: at week 6, mean weekly decreases of -22.6 and -19.6 were seen in MS and SCI patients, respectively, and -20.3 and -22.5 in anticholinergic users and non-users, respectively, treated with onabotulinumtoxinA 200U. The 300U dose did not add to the clinical efficacy in any subpopulation. Similar proportions of patients achieved ≥ 50% or 100% reductions in UI episodes in all subgroups. Improvements in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and QOL were significant in both etiologies and were independent of anticholinergic use. The most common AEs in all groups were urinary tract infection and urinary retention. CONCLUSION: Regardless of concomitant anticholinergic use or etiology, onabotulinumtoxinA significantly improved UI symptoms, urodynamics, and QOL in patients with UI due to NDO. OnabotulinumtoxinA was well tolerated in all groups.

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 100U 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.

OnabotulinumtoxinA improves urodynamic outcomes in patients with neurogenic detrusor overactivity.

AIMS: To evaluate the effect of onabotulinumtoxinA on urodynamic outcomes in patients with urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO). METHODS: Results from two pivotal Phase III trials (n = 691) were pooled. MS or SCI patients with NDO, received intradetrusor onabotulinumtoxinA 200 U (n = 227), 300 U (n = 223), or placebo (n = 241). Change from baseline in UI episodes/week (Week 6), maximum cystometric capacity (MCC), maximum detrusor pressure at first involuntary detrusor contraction (IDC) (PdetmaxIDC), volume at first IDC (VpmaxIDC), and detrusor compliance (DC) were measured. RESULTS: OnabotulinumtoxinA significantly increased MCC overall (+153.6 ml with 200 U vs. +11.9 ml with placebo). Over 60% of onabotulinumtoxinA-treated patients had no IDC at Week 6; in patients with an IDC at Week 6, VpmaxIDC improved (+183.4 ml with 200 U vs. +17.5 ml with placebo), and PdetmaxIDC decreased (-32.4 cmH2O with 200 U vs. +1.1 cmH2O with placebo). OnabotulinumtoxinA-treated patients had a significant increase in DC (+59.8 ml/cmH2O with 200 U vs. -5.2 with placebo). Urodynamic improvements were comparable in patients regardless of baseline DC and corresponded with significant reductions in UI episodes/week for both onabotulinumtoxinA doses versus placebo, with no clinically relevant differences between 200 and 300 U groups. Most common adverse event was urinary tract infection (UTI); complicated UTIs were low across all treatment groups. In patients not catheterizing at baseline, a dose-dependent increase in post-void residual urine was observed at Week 2 following onabotulinumtoxinA treatment. CONCLUSIONS: OnabotulinumtoxinA significantly improved urodynamic outcomes in NDO patients, even in those with low baseline DC, and corresponded with improvements in UI episodes. Both doses of onabotulinumtoxinA were well tolerated.

Long-term efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: an interim analysis.

OBJECTIVE: To evaluate the long-term efficacy and safety of repeat onabotulinumtoxinA injections in patients inadequately managed by anticholinergics for urinary incontinence (UI) due to neurogenic detrusor overactivity. MATERIALS AND METHODS: Patients who completed either of 2 preceding phase III studies were offered entry into an extension study and received repeat onabotulinumtoxinA 200 U or 300 U. The data were integrated across the phase III and ongoing extension studies. The present interim analysis included all patients who received ≥ 1 onabotulinumtoxinA treatment. The data were analyzed by treatment cycle (cycles 1-5). The primary assessment was the change from baseline in UI episodes/wk at 6 weeks after each treatment. Additional assessments included ≥ 50% and 100% reductions in UI episodes, volume/void, Incontinence Quality of Life responses, and adverse events. RESULTS: A total of 387, 336, 241, 113, and 46 patients received 1, 2, 3, 4, and 5 onabotulinumtoxinA treatments, respectively. The UI episodes/wk were consistently reduced compared with baseline after repeated onabotulinumtoxinA treatment (-22.7, -23.3, -23.1, -25.3, and -31.9 for the 200-U onabotulinumtoxinA group in cycles 1-5). The proportion of patients reporting ≥ 50% and 100% ("dry") reductions from baseline in UI episodes at week 6 ranged from 73%-94% and 36%-55%, respectively. Increases in the mean volume/void (mean increase >130 mL) and improvements in quality of life were also observed after repeat treatment. The most common adverse events were urinary tract infections and urinary retention, with no change in the adverse event profile over time. CONCLUSION: The results of our study have shown that repeated onabotulinumtoxinA treatments provide sustained reductions in UI episodes and increases in the volume/void and quality of life in patients with neurogenic detrusor overactivity and UI who were inadequately managed by anticholinergics, with no new safety signals.

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) 30-100ml, 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.

OnabotulinumtoxinA for the treatment of patients with overactive bladder and urinary incontinence: results of a phase 3, randomized, placebo controlled trial.

PURPOSE: Overactive bladder affects 12% to 17% of the general population and almost a third experience urinary incontinence, which may severely impact health related quality of life. Oral anticholinergics are the mainstay of pharmacological treatment but they are limited by inadequate efficacy or side effects, leading to a high discontinuation rate. We report the results of the first large (557 patients), phase 3, placebo controlled trial of onabotulinumtoxinA in patients with overactive bladder and urinary incontinence inadequately managed with anticholinergics. MATERIALS AND METHODS: Eligible patients with overactive bladder, 3 or more urgency urinary incontinence episodes in 3 days and 8 or more micturitions per day were randomized 1:1 to receive intradetrusor injection of onabotulinumtoxinA 100 U or placebo. Co-primary end points were the change from baseline in the number of urinary incontinence episodes per day and the proportion of patients with a positive response on the treatment benefit scale at posttreatment week 12. Secondary end points included other overactive bladder symptoms and health related quality of life. Adverse events were assessed. RESULTS: OnabotulinumtoxinA significantly decreased the daily frequency of urinary incontinence episodes vs placebo (-2.65 vs -0.87, p <0.001) and 22.9% vs 6.5% of patients became completely continent. A larger proportion of onabotulinumtoxinA than placebo treated patients reported a positive response on the treatment benefit scale (60.8% vs 29.2%, p <0.001). All other overactive bladder symptoms improved vs placebo (p ≤ 0.05). OnabotulinumtoxinA improved patient health related quality of life across multiple measures (p <0.001). Uncomplicated urinary tract infection was the most common adverse event. A 5.4% rate of urinary retention was observed. CONCLUSIONS: OnabotulinumtoxinA 100 U showed significant, clinically relevant improvement in all overactive bladder symptoms and health related quality of life in patients inadequately treated with anticholinergics and was well tolerated.

Phase 3 efficacy and tolerability study of onabotulinumtoxinA for urinary incontinence from neurogenic detrusor overactivity.

PURPOSE: We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. MATERIALS AND METHODS: In this 52-week, international, multicenter, double-blind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. RESULTS: OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p<0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p<0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention. CONCLUSIONS: OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose.

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk. OBJECTIVE: To assess the effects of onabotulinumtoxinA (BOTOX(®), Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO. DESIGN, SETTING, AND PARTICIPANTS: This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n=154) or spinal cord injury (SCI; n=121) with UI due to NDO (≥14 UI episodes per week). INTERVENTION: Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n=92), 300 U (n=91), or placebo (n=92), avoiding the trigone. MEASUREMENTS: Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P(detmaxIDC)]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed. RESULTS AND LIMITATIONS: At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (-21.8 and -19.4, respectively) compared with placebo (-13.2; p<0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P(detmaxIDC), and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p<0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p<0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment. CONCLUSIONS: OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).

Urodynamic results and clinical outcomes with intradetrusor injections of onabotulinumtoxinA in a randomized, placebo-controlled dose-finding study in idiopathic overactive bladder.

AIMS: We assessed the effects of onabotulinumtoxinA (BOTOX®) on clinical and urodynamic variables in patients with idiopathic overactive bladder (OAB) and urinary urgency incontinence (UUI) with or without detrusor overactivity (DO), inadequately managed with anticholinergics. METHODS: Three hundred thirteen patients with OAB were randomized to double-blind intradetrusor injection with placebo (n = 44) or 1 of 5 onabotulinumtoxinA doses (50-300 U; n = 269). Primary efficacy variable was change from baseline in UUI episodes/week at week 12. Urodynamic assessments at baseline and weeks 12 and 36 included maximum cystometric capacity (MCC) and volume at first involuntary detrusor contraction (IDC). RESULTS: 76.0% of patients had baseline DO. Changes from baseline in MCC and volume at first IDC with onabotulinumtoxinA ≥100 U were superior to placebo at week 12, generally decreasing by week 36. Significant dose-dependent increases in MCC were observed for all onabotulinumtoxinA doses at week 12, and for 150, 200, and 300 U at week 36. Data suggested a dose-response relationship. At week 12 on diary, 15.9% of placebo and 29.8-57.1% of onabotulinumtoxinA 50-300 U recipients, respectively, did not demonstrate UUI. OnabotulinumtoxinA doses >150 U were more commonly associated with post-void residual urine volumes >200 ml. CONCLUSIONS: Improvements in urodynamic parameters and clinical outcomes generally trended together following onabotulinumtoxinA treatment. This therapy improved key urodynamic parameters in patients with idiopathic OAB and UUI, with no differences in outcomes between those with and those without baseline DO. Therefore, successful idiopathic OAB treatment with onabotulinumtoxinA does not appear to be related to pretreatment finding of DO.

Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database.

AIMS: To characterize the patient profile, medication utilization, and healthcare encounters of patients with neurogenic bladder dysfunction related to incontinence. METHODS: Medical and pharmacy claims were retrospectively analyzed from April 1, 2002 to March 31, 2007 to characterize neurogenic bladder patients. There were 46,271 patients in the Neurogenic bladder cohort, and 9,315 and 4,168 patients in Multiple Sclerosis (MS) and Spinal Cord Injury (SCI) subcohorts, respectively. Demographic data, concomitant diseases, use of overactive bladder (OAB) oral drug, and healthcare encounters were summarized using descriptive statistics. RESULTS: The mean age of neurogenic bladder patients was 62.5 (standard deviation 19.6) years. A high frequency of lower urinary tract infections (UTIs; 29%-36%), obstructive uropathies (6%-11%), and urinary retention (9%-14%), was observed. Overall, 33,100 (71.5%) patients were taking an OAB oral drug; 10,110 (30.5%) patients discontinued and did not restart. During the one-year follow-up period, 39.0% (8,034) of neurogenic bladder patients had a urology visit, 31.7% (14,679) had a neurology visit, 33.3% (15,415) were hospitalized, and 14.4% (6,646) were in a nursing home (highest rates observed in SCI subcohort). UTI diagnoses comprised over 20% of all hospitalizations one-year post-index. Annually, neurogenic bladder patients averaged 16 office and 0.5 emergency room visits. CONCLUSIONS: This is the largest observational study conducted to address the epidemiology of the neurogenic bladder population, including healthcare utilization. These data suggest that patients with neurogenic bladder may have suboptimal management, indicated by high incidences of urinary tract complications and hospitalizations.