OnabotulinumtoxinA Reduces Urinary Incontinence

Decrease Seen in Patients With MS and Spinal Cord Injury

Becky McCall

March 22, 2011

March 22, 2011 (Vienna, Austria) — Urinary incontinence caused by neurogenic detrusor overactivity in patients with either spinal cord injury (SCI) or multiple sclerosis (MS) has shown a significant reduction in the number of episodes, improvement in quality of life, and a decrease in bladder pressure with onabotulinumtoxinA (Botox, Allergan).

After presenting his results here at the European Association of Urology 26th Annual Congress, Francisco Cruz, MD, from the Department of Urology, Hospital de São João, Porto, Portugal, told Medscape Medical News that this is the largest study of its kind and was conducted to meet regulatory agency requirements for the treatment of patients with urinary incontinence resulting from neurogenic detrusor overactivity.

In this phase 3 study, patients received onabotulinumtoxinA, either 200 or 300 U, or placebo. "The results were highly positive, with the number of episodes of urinary incontinence significantly reduced, over placebo, with both doses," Dr. Cruz reported.

He added that there were important implications for dosing. "In fact, there was no clear, relevant difference between the 2 doses, which means 200 U might be the new optimum dose. For a long time, we have used 300 U, but given these results, we will probably change to 200 U. In terms of efficacy, there was no difference, but in terms of safety, 200 U was safer than 300 U," he pointed out.

Of the 275 patients enrolled in the double-blind, randomized, placebo-controlled, parallel-group study, 56% had MS and 46% had SCI, but all were severely incontinent. Ninety-two patients were randomly assigned to receive onabotulinumtoxinA 200 U, 91 patients were randomly assigned to receive onabotulinumtoxinA 300 U, and 92 patients were randomly assigned to receive placebo. Patients receiving the active compound received 30 intradetrusor injections of 1 mL each.

There were no differences between the groups at baseline in terms of disease characteristics and demographics. If patients had used anticholinergic drugs before the trial, they were allowed to continue at the same dose throughout the study.

The primary study end point comprised change from baseline in the number of weekly episodes of urinary incontinence, measured with 7-day patient diaries, with the primary time point at 6 weeks. Secondary end points included change from baseline in maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction, and incontinence quality of life.

Results showed that the number of episodes of urinary incontinence was reduced in both onabotulinumtoxinA groups (= .002 for both), with no clinically relevant differences between the 2 doses. In the 200 U group, 38.0% of the patients were "dry" (100% reduction in episodes), as were 39.6% in the 300 U group. Bladder capacity increased significantly (< .001) and bladder pressure during the first involuntary detrusor contraction decreased significantly (P < .001) at week 6 with both doses. Mean maximum detrusor pressure during first involuntary detrusor contraction at week 6 after treatment was 37.1 and 30.4 cm H2O in the 200 U and 300 U groups, respectively, and 50.1 cm H2O in the placebo group (P < .001).

Adverse events were reported in 74.4%, 86.8%, and 88.8% of the patients in the placebo, 200 U, and 300 U groups, respectively. "There were no severe side effects; most were mild to moderate. The most frequent adverse events were urinary tract infections, which were slightly more frequent in the 300 U group, and urinary retention, which was less of a problem in SCI patients who used clean intermittent catheterization (CIC), but in the MS patients this was a new method for them," explained Dr. Cruz.

He reported that in patients who did not use CIC at the study start, CIC was required in 12% of patients in the placebo group, in 20% of patients in the 200 U group, and in 42% of patients in the 300 U group during the first cycle of treatment. Only 1 serious adverse event was considered to be related to the study, because of muscular weakness; it was in a patient with SCI receiving 300 U onabotulinumtoxinA.

Quality of life was an important secondary end point, and the use of CIC might have had an effect on this. "One would imagine that CIC would confer poor quality of life, but we were extremely surprised because we couldn't see a difference in quality of life in patients voiding spontaneously and with CIC. Once dry, they had good quality of life — the important thing was to be dry. Incontinence is a major social inconvenience," said Dr. Cruz.

Victor Nitti, MD, from the Langone Medical Center at New York University, New York City, told Medscape Medical News that he believes these studies on botulinum toxin in neurogenic detrusor overactivity are truly a breakthrough.

"These are conditions that not only affect patients' lives, but in certain circumstances can also be threatening to kidney function — and can be life-threatening in some situations. If patients fail oral medication, the next step is major reconstructive surgery. Many of these patients really have to be treated — it is not elective — so to have something that treats them without major reconstructive surgery is important."

He added that "if we look at these results, they are impressive and dramatic, showing real significant differences in a refractory group of patients. Overall efficacy and reduction in incontinence, bladder pressure, and bladder capacity is very eye-opening. This will be a very significant treatment for these patients moving forward."

Dr. Cruz reports being a consultant to Allergan, which sponsored the study. Dr. Nitti reports being a consultant to several companies, including Astellas, Allergan, Pfizer, Medtronic, and Uroplasty.

European Association of Urology (EAU) 26th Annual Congress. Presented March 20, 2011.

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