Botox for Overactive Bladder

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

Study Summary

A variety of treatment options exist for patients with overactive bladder (OAB). These options include behavioral and pelvic floor physical therapy, pharmacologic treatment, neuromodulation (including both sacral and posterior tibial nerve stimulation), and surgery (eg, bladder augmentation). Multiple US Food and Drug Administration (FDA)-approved pharmacologic options are available to treat OAB, all of which fall into the anticholinergic class of medications. Unfortunately, this can be somewhat limiting either because of lack of efficacy or intolerable side effects such as dry mouth or constipation in patients who do not respond optimally.

Botulinum toxin was first evaluated for use in neurogenic bladder for patients who were refractory to treatment with anticholinergics (primarily oxybutynin plus trospium in the initial study) in 2000.[1] Since then, numerous publications have shown efficacy in treating both neurogenic and non-neurogenic (idiopathic) OAB. However, only a few studies have been properly conducted randomized, controlled trials. The study by Dmochowski and associates reports a phase 2 trial that evaluated the outcomes of onabotulinumtoxinA (BOTOX®, Allergan, Inc, Irvine, CA) for patients with idiopathic OAB.

This study evaluated the outcomes in 313 patients treated with intradetrusor injections of onabotulinumtoxinA. To qualify for study entry, patients had to have symptomatic, idiopathic OAB with urge urinary incontinence (UUI) for more than 6 months, a minimum of 8 or more UUI episodes weekly, an average of 8 or more micturitions daily, and inadequate previous treatment (defined as lack of efficacy or intolerable side effects) with anticholinergic medications. Random assignment was as follows:

•Placebo — 43 patients
•50 U onabotulinumtoxinA — 56 patients
•100 U onabotulinumtoxinA — 55 patients
•150 U onabotulinumtoxinA — 50 patients
•200 U onabotulinumtoxinA — 52 patients; and
•300 U onabotulinumtoxinA — 55 patients.
The procedure was performed cystoscopically, using a standard trigone- and dome-sparing template, with the medication evenly divided among 20 injection sites.

The primary endpoint was UUI at 12 weeks post-treatment. A marked improvement was noted in all treatment groups with a mean change from baseline of -17.4, -20.7, -18.4, -23.0, -19.6, and -19.4, respectively, for placebo and onabotulinumtoxinA 50, 100, 150, 200, and 300 U. A dose-response pattern was apparent with nonparametric analysis of the data; however, the investigators also noted minimal additional benefit with doses higher than 150 U. Evaluation of patients with 100% reduction in UUI revealed a significant improvement with doses of 100 U. No clear difference between doses from 100 U and 300 U was seen; moreover, a consistently lower response for all times was observed for a dose of 50 U. Similar findings with respect to sustained responses with doses of 100 U or more (but not at 50 U) were noted for other voiding diary parameters such as micturition frequency, urgency, nocturia, and voided volume. An increased risk for catheterization secondary to elevated residual was reported with higher doses of onabotulinumtoxinA: 0.6% at 50 U, 6.3% at 100 or 150 U, 60% at 200 or 300 U.

Viewpoint

This is an important study because this is the first large, randomized, placebo-controlled trial evaluating OAB for the treatment of UUI secondary to OAB. Although all doses of onabotulinumtoxinA were more effective than placebo, the lowest dose of 50 U appeared to consistently demonstrate less sustained efficacy. In addition, no significant advantage appeared to be associated with the use of doses higher than 150 U. These data, combined with the evidence that doses higher than 150 U appeared to place the patient at higher risk for urinary retention, have clearly influenced the phase 3 trial evaluating the use of onabotulinumtoxinA to treat idiopathic OAB. In the phase 3 trial patients will be injected with placebo or 100 U initially and, if a higher dose is requested with a second injection, a 150 U dose will be used; no doses higher than 150 U will be used.

The study does have some limitations, such as lack of strict definitions for urinary retention or when clean intermittent catheterization should be started and terminated; this was left to the individual investigator’s discretion. Future trials will have these defined in the protocol. In addition, this trial does not answer questions such as how will patients handle multiple injections over a prolonged time? Efficacy does appear to be similar with repeat injections but previous research has been limited to studies with smaller numbers of patients.[2,3] As of now, onabotulinumtoxinA for OAB is an “off-label” indication of the drug. However, use for this indication has become increasingly common with some insurance carriers covering the treatment for either idiopathic and/or neurogenic OAB. This may become less important as phase 3 trials are completed and data are presented to the FDA.

Source:  posted Jan 6, 2011 by David Ginsberg, MD, on study by Dmochowski R, Chapple C, Nitti VW, et al from J Urol. 2010;184: 2235-2236 at http://www.medscape.com/viewarticle/735129