Jihao Zhou

Efficacy and Safety of OnabotulinumtoxinA for Idiopathic Overactive Bladder: A Double-Blind, Placebo Controlled, Randomized, Dose Ranging Trial

PURPOSE Treatment options for patients with overactive bladder refractory to anticholinergics are limited. We assessed the dose response across a range of doses of onabotulinumtoxinA (BOTOX®) in patients with idiopathic overactive bladder and urinary urgency incontinence whose symptoms were not adequately managed with anticholinergics. MATERIALS AND METHODS In a phase 2, multicenter, randomized, double-blind study, 313 patients with idiopathic overactive bladder and urinary urgency incontinence experiencing 8 or more urinary urgency incontinence episodes a week and 8 or more micturitions daily at baseline received 50, 100, 150, 200 or 300 U intradetrusor onabotulinumtoxinA, or placebo. Symptoms were recorded using a 7-day bladder diary. The primary efficacy variable was weekly urinary urgency incontinence episodes and the primary end point was week 12. RESULTS Demographics and baseline characteristics were balanced across the treatment groups. Durable efficacy was observed for all onabotulinumtoxinA dose groups of 100 U or greater for primary and secondary efficacy measures, including the proportion of incontinence-free patients. When the dose response curves were analyzed, doses greater than 150 U contributed minimal additional or clinically relevant improvement in symptoms. This finding was also reflected in health related quality of life assessments. Dose dependent changes in post-void residual urine volume were observed and the use of clean intermittent catheterization was also dose dependent. The only adverse events significantly greater with onabotulinumtoxinA than with placebo were urinary tract infection and urinary retention. CONCLUSIONS OnabotulinumtoxinA at doses of 100 U or greater demonstrated durable efficacy in the management of idiopathic overactive bladder and urinary urgency incontinence. A dose of 100 U may be the dose that appropriately balances the symptom benefits with the post-void residual urine volume related safety profile.

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], Kings 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.

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

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.

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

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

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

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).

Treatment satisfaction and goal attainment with onabotulinumtoxinA in patients with incontinence due to idiopathic OAB

Introduction and hypothesisClinically meaningful overactive bladder syndrome (OAB) symptom relief is associated with patient satisfaction. This study evaluated the effects of onabotulinumtoxinA on patient satisfaction and goal attainment.MethodsIn a 36-week, multicenter, double-blind study, 313 participants with idiopathic OAB and urinary urgency incontinence inadequately managed with anticholinergics were randomized to placebo or one of five onabotulinumtoxinA doses. Assessment included a modified OAB-Patient Satisfaction with Treatment Questionnaire (PSTQ) and four Patient Global Assessment questions assessed changes in symptoms, quality of life, activity limitations, and emotions.ResultsMean changes from baseline in OAB-PSTQ scores for the main module (Q2–Q13) at week 12 were greater for each onabotulinumtoxinA group (range, −31.5% to −48.9%) versus placebo (−17.6%). Greater proportions of patients in onabotulinumtoxinA groups attained their primary goal (range, 34.5% to 65.3%) versus placebo (23.7%).ConclusionsPatients with OAB are more likely to be satisfied and/or achieve their primary treatment goal with onabotulinumtoxinA treatment than with placebo, consistent with symptom improvements.