OnabotulinumtoxinA Effective for Neurogenic Incontinence

Jill Stein

May 25, 2011

May 25, 2011 (Washington, DC) — OnabotulinumtoxinA significantly decreases episodes of urinary incontinence (UI) secondary to neurogenic detrusor overactivity (NDO) in patients with multiple sclerosis (MS) or spinal cord injury (SCI), according to the results of a phase 3 study released here at the American Urological Association 2011 Annual Scientific Meeting.

The data show that although there were no clinically relevant differences in efficacy or duration of effect between the 200 U and 300 U doses of onabotulinumtoxinA, the lower dose had a better safety profile.

"The main finding is that, essentially, the end points were [reached] in continence and urodynamic parameters, and there was really no significant difference in efficacy between the 200 U and 300 U [doses], . . . which is really what we wanted to see because we had always thought that the higher dose was what you need," David Ginsberg, MD, associate professor of clinical urology at the University of Southern California in Los Angeles and chief of the urology division at Rancho Los Amigos National Rehabilitation Center in Downey, California, told Medscape Medical News.

"It seems that as you go higher with the 300 U dose, you have a risk of leaving urine behind," he added. "The catheterization rates aren't any different, but there is a higher postvoid residual with the higher dose. The take-home message is that 200 U is the dosage we're probably going to be able to use."

He also noted that the study design and outcomes match a phase 3 study reported by Medscape Medical News at the 2011 annual meeting of the European Association of Urology.

"We had a similar study cohort of patients with a spinal injury at the thoracic level or lower or multiple sclerosis with an EDSS [Expanded Disability Status Scale] of 6.5 or less with the same primary end point and outcomes," he said. "What was different was the definition of requalification for treatment. In our study, we required a 50% return to baseline for voiding diary parameters, compared with a 30% return to baseline in the earlier study."

OnabotulinumtoxinA is not yet approved to treat UI secondary to NDO.

Dr. Ginsberg and his team randomized 416 patients to receive 30 intradetrusor injections (1 mL each) of onabotulinumtoxinA, 200 U or 300 U, or placebo, administered through a cystoscope (avoiding the trigone). Patients were followed for up to 64 weeks and could request retreatment once, starting at week 12.

Bladder dysfunction often occurs as a result of diseases or conditions that impair neuronal control of voluntary bladder functions, such as MS or SCI. The most frequent manifestation of neurogenic overactive bladder is NDO, which is characterized by phasic detrusor contractions during urodynamics, high bladder pressures, UI, and a significant decrease in quality of life.

Although anticholinergic agents are first-line therapy for NDO, they are associated with potentially bothersome effects, such as dry mouth and constipation, and might not provide sufficient efficacy. As a result, many patients discontinue treatment.

Phase 3 Study

Study participants had at least 14 UI episodes per week due to NDO, and were not adequately managed with anticholinergic agents.

Patients had the option of discontinuing anticholinergics before the study or remaining on therapy. For those continuing on anticholinergics, the same dose had to be maintained throughout the study.

Individuals using clean intermittent catheterization (CIC) at baseline were instructed to maintain their established frequency. Individuals not using CIC had to be willing to initiate it if necessary.

Treatment groups were similar with respect to baseline demographic and clinical characteristics.

The primary end point was the change from baseline to week 6 in the number of weekly UI episodes.

Significant Reduction in UI Episodes

Results showed that the median time to a request for retreatment was 92 days in the placebo group, 256 days in the 200 U group, and 254 days in the 300 U group.

OnabotulinumtoxinA 200 U decreased the number of weekly UI episodes (mean ± standard deviation) by 21.0 ± 23.8. OnabotulinumtoxinA 300 U reduced weekly UI episodes by a significantly greater number than placebo (22.7 ± 17.1 vs 8.8 ± 16.2 episodes; P < .001).

Also, 36% and 41% of patients in the 200 U and 300 U groups, respectively, were "dry." In other words, they reported a 100% reduction in UI episodes at week 6, compared with 10% of the placebo group (P < .001).

Results were similar irrespective of anticholinergic use.

Significant reductions in UI episodes were also observed in both the MS and SCI subgroups.

No clinically meaningful or statistical differences in efficacy were noted between the 2 onabotulinumtoxinA groups.

In both onabotulinumtoxinA groups, compared with placebo, maximum cystometric capacity was increased significantly (P < .001) and maximum detrusor pressure during the first involuntary detrusor contraction was decreased significantly (P < .001). Improvements in Incontinence Quality of Life questionnaire scores were observed in both onabotulinumtoxinA groups, compared with placebo (P < .001).

Overall, 34%, 49%, and 50% of patients in the placebo, 200 U, and 300 U dose groups, respectively, developed urinary tract infections, and 3%, 20%, and 17% experienced urinary retention. In patients not using CIC at baseline, 7%, 28%, and 40%, respectively, had initiated CIC at 6 weeks.

Need for New Treatments

Matthew O. Fraser, PhD, adjunct assistant professor of urology and research physiologist at Duke University and the Durham Veterans Affairs Medical Centers in North Carolina, told Medscape Medical News that urinary incontinence resulting from neurogenic detrusor overactivity is "fairly frequent" in the study subpopulations, and that current treatments have significant limitations.

"About 40% of patients with spinal cord impairment and multiple sclerosis have urinary incontinence due to neurogenic detrusor overactivity. Frontline treatment with anticholinergics may help in some cases, but not so much in others," he said. "When the antimuscarinic type of anticholinergic fails — either due to lack of efficacy or intolerable side effects — sacral neuromodulation may be an option, but the procedure requires invasive surgery and possibly additional permanent neurosurgery involving deafferentation in this population. Nonsurgical strategies include intravesical vanilloid treatment, but this approach had fallen out of favor for various reasons. Thus, new approaches, such as injection of the bladder submucosa and/or wall with [onabotulinumtoxinA], are being tested."

"The study results are, for the most part, impressive," he added. "It appears that [onabotulinumtoxinA] injections have dramatically reduced the neurogenic detrusor overactivity responsible for incontinence and increased bladder capacity, while at the same time inducing urinary retention resulting in increased urinary tract infection and clean intermittent catheterization rates," he said. "Thus, as is often the case, you take the good with the bad, and the reported increased score on the validated incontinence quality-of-life questionnaire supports this idea."

Dr. Fraser said that "the bottom line here is that these patients would prefer to have better control of when they void or manually withdraw urine than experience the socially debilitating condition of uncontrolled incontinence episodes."

Funding for the study was provided by Allergan. Dr. Ginsberg reports being a consultant and investigator for Allergan, which manufacturers Botox, and being a member of the company's speakers bureau. Dr. Fraser has disclosed no relevant financial relationships.

American Urological Association (AUA) 2011 Annual Scientific Meeting: Abstract 1515. Presented May 17, 2011.