OnabotulinumtoxinA Reduces UI from Neurogenic Detrusor Overactivity

Patients with spinal cord injury (SCI) or multiple sclerosis (MS) often experience neurogenic detrusor overactivity (NDO), which can lead to urodynamically measured increased bladder storage pressures and urinary incontinence (UI). Patients with UI experience a negative impact on their quality of life (QOL), according to researchers.

Treatment for NDO usually includes anticholinergics along with clean intermittent catheterization. However, adherence rates decrease over time due to lack of efficacy and adverse side effects, including dry mouth and constipation. Those side effects may pose significant baseline problems in patients with neurologic disease.

In early trials of onabotulinumtoxinA, patients with NDO were shown to develop fewer episodes of UI, and had improved urodynamic parameters and QOL. Researchers evaluated the safety and efficacy of onabotulinumtoxinA in patients with MS or SCI with UI as a result of NDO who were not adequately treated with anticholinergic therapy. They reported study results in the Journal of Urology^®[2012;187:2131-2139].

The researchers conducted this global, multicenter, randomized, double-blind, placebo-controlled, phase 3 trial as part of the DIGNITY (Double-Blind Investigation of Purified Neurotoxin Complex in Neurogenic Detrusor Overactivity) study. DIGNITY was conduced at 85 centers from September 2006, through May 2010; it included patients, 18 to 80 years of age with NDO ≥3 months in duration and ≥14 UI episodes per week, who were not adequately treated with anticholinergic therapy.

The primary efficacy end point was change from baseline in the number of weekly UI episodes following 6 weeks of treatment. Secondary end points at 6 weeks included maximum cystometric capacity (MCC), maximum detrusor pressure (MDP) during the first involuntary detrusor contraction, and Incontinence-QOL (I-QOL) total summary score.

Patients were randomized to receive 200 U or 300 U of onabotulinumtoxinA (Botox^®) or placebo (0.9% saline). Patients were evaluated at weeks 2, 6, and 12 with follow-up every 6 weeks until retreatment or exit from the study. Urodynamic analysis was done at baseline and at week 6 after each treatment.

The intent-to-treat population included 416 patients. Of those, 79% (n=329) completed the 52-week study and 21% (n=87) discontinued treatment early (including 13 patients who experienced an adverse event).

At 2, 6, and 12 weeks after treatment, each dose of onabotulinumtoxinA significantly decreased episodes of UI compared with placebo (P<.008). There were no clinically significant differences between the active dose groups.

Subanalysis of MS and SCI populations revealed similar results: at week 6, treatment resulted in a -30%, -67%, and -74% change from baseline in UI in the placebo and 200-U and 300-U onabotulinumtoxinA groups, respectively. Significantly more patients in both onabotulinumtoxinA groups attained the ≥50% responder threshold at week 6 for a reduction in weekly UI episodes compared with the placebo group (P≤.001). In addition, 36% and 41% of patients in the 200-U and 300-U groups, respectively, achieved dry status.

In both the 200-U and 300-U groups, MCC, MDP during the first involuntary detrusor contraction, and I-QOL total summary score were significantly improved over values in the placebo group (P<.001 for each dose group).

Median time to patient request for retreatment was longer for the onabotulinumtoxinA 200-U and 300-U groups, compared with placebo (256 and 254 days, respectively, vs 92); each treatment group versus placebo, P<.001.

In summary, the researchers stated, “OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms versus 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.”