OnabotulinumtoxinA 100U has been demonstrated to reduce urinary incontinence (UI) and significantly improve quality of life (QOL) in patients with idiopathic overactive bladder (OAB) in 2 large, randomized, placebo-controlled, phase 3 trials [1,2]. However, the time to onset of response, as well as efficacy and safety following repeat treatment, requires further characterization. This randomized, multicenter, placebo-controlled, phase 4 study evaluates the efficacy and safety of onabotulinumtoxinA as early as within 1 week post-treatment and also after retreatment.

This phase 4 study enrolled patients with OAB who had experienced ≥3 urgency UI episodes in a 3-day bladder diary and ≥8 micturitions per day. All patients were inadequately managed by an anticholinergic. Patients were randomized 1:1 to receive onabotulinumtoxinA 100U or placebo. Three-day bladder diaries were completed prior to each visit (ie, for week 1, diary entries would have commenced as early as the first 4 days post-treatment). Patients could request and receive retreatment with open-label onabotulinumtoxinA ≥12 weeks after the previous treatment if they met the following criteria: ≥2 urgency UI episodes and ≤1 urgency UI–free day according to a 3-day bladder diary in the week prior to qualification and a post-void residual urine volume <200 mL. Post-treatment assessments following the first treatment at weeks 1 and 12 (primary timepoint) and following the second treatment at week 12 in patients who requested and received retreatment with onabotulinumtoxinA included mean change from baseline in UI episodes/day (co-primary endpoint); proportion of patients who achieved UI reductions of 100% (co-primary endpoint); proportion of patients who achieved UI reductions of ≥50%; and mean changes from baseline in micturition frequency, nocturia, Incontinence-QOL (I-QOL) score, King’s Health Questionnaire (KHQ) role and social limitations domains, and International Consultation on Incontinence Questionnaire-UI (ICIQ-UI) score. Adverse events (AEs) and the incidence of clean intermittent catheterization (CIC) were recorded. Efficacy and QOL outcomes were analyzed in the intent-to-treat population (all randomized patients), and the incidence of AEs and CIC use was analyzed in the safety population (all patients who received treatment).

Significant reductions from baseline were seen with onabotulinumtoxinA (n=129) vs placebo (n=125) in UI episodes/day as early as within week 1 post-treatment (least squares [LS] mean: -2.9 vs -2.0, respectively; P=.005) and continued to week 12 (LS mean: -3.5 vs -1.6, respectively; P<.001). Significantly higher proportions of onabotulinumtoxinA-treated patients achieved a 100% reduction in UI episodes/day vs placebo after treatment 1 at weeks 1 (24.2% vs 4.8%; P<.001) and 12 (32.0% vs 7.2%; P<.001). Similarly, more onabotulinumtoxinA-treated patients achieved a ≥50% reduction in UI episodes/day vs placebo after treatment 1 at weeks 1 (59.4% vs 36.0%; P<.001) and 12 (67.2% vs 37.6%; P<.001). Decreases in micturition frequency and nocturia were also seen within 1 week following the first treatment with onabotulinumtoxinA vs placebo that continued to, and were significant at, week 12. The proportions of patients in the onabotulinumtoxinA and placebo groups using no incontinence pads in the past 24 hours at baseline were 23.4% and 19.2%, respectively, and the proportions using no pads post-treatment were 35.2% and 26.2% at week 1 and 46.7% and 31.9% at week 12. Improvements in total I-QOL score with onabotulinumtoxinA were consistently higher than the minimally important difference (10 points) and significantly higher than placebo following treatment 1 at weeks 1 and 12 (14.3 vs 5.6 and 27.1 vs 9.8, respectively; P<.001 for both). Significant improvements were also observed within 1 week following treatment 1 for the other QOL measures (KHQ role and social limitations domains and ICIQ-UI) and were sustained to week 12. 
Improvements in urinary symptoms and QOL seen 12 weeks following retreatment with open-label onabotulinumtoxinA were consistent with those seen with onabotulinumtoxinA following treatment 1. The mean reduction in UI episodes/day observed 12 weeks following retreatment in patients receiving onabotulinumtoxinA for the first time and who had received placebo at treatment 1 (n=107) was -4.1, and was -4.0 in those administered onabotulinumtoxinA for a second time (n=88). Following treatment 2, proportions of patients who achieved a 100% reduction in UI episodes/day were similar between those receiving onabotulinumtoxinA for a first or second time (37.4% vs 33.0%, respectively). Following retreatment, the proportions of patients who achieved a ≥50% reduction in UI episodes/day were also similar between patients receiving onabotulinumtoxinA for a first or second time (79.4% vs 69.3%). In addition, improvements observed in micturition frequency and nocturia 12 weeks following retreatment were consistent with those observed following treatment 1 with onabotulinumtoxinA. The proportion of patients using no incontinence pads 12 weeks following retreatment was 55.7% and 48.8% in those receiving onabotulinumtoxinA for the first and second times, respectively. Total I-QOL scores were 35.4 and 33.8 twelve weeks after the second treatment in patients receiving onabotulinumtoxinA for a first and second time, respectively. There were no unexpected safety signals in the first 12 weeks of either treatment cycle, and urinary tract infection was the most common AE reported. CIC rates for urinary retention only were 6.3% and 0% in onabotulinumtoxinA- and placebo-treated patients, respectively, in the 12 weeks following the first treatment. In the 12 weeks following the second treatment, CIC rates were 10.3% in patients receiving onabotulinumtoxinA for a first time (11/107) and 3.4% in those receiving onabotulinumtoxinA for a second time (3/88).

In patients with OAB who were inadequately managed by an anticholinergic, a robust early treatment response was observed with onabotulinumtoxinA treatment within 1 week that continued to at least week 12 and was consistent following a second treatment. Improvements were similar to those reported in prior phase 3 randomized controlled clinical trials. In addition, onabotulinumtoxinA-treated patients reported early and sustained decreases in the use of incontinence products and significant improvements on a number of disease-specific QOL measures. There were no new safety signals observed.

OnabotulinumtoxinA was well tolerated, and improvements in urinary symptoms and QOL observed with onabotulinumtoxinA were seen as early as within 1 week of treatment. Early improvements were sustained for at least 12 weeks and for at least an additional 12 weeks following retreatment.

Nitti VW, et al. J Urol. 2013;189(6):2186–2193.
Chapple C, et al. Eur Urol. 2013;64(2):249–256.