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Results Presented of Phase III Trial Involving Trospium, Overactive Bladder Treatment

CHICAGO, April 29 /PRNewswire/ -- Data presented today at the American Urological Association (AUA) annual meeting showed that trospium, a new developmental drug for overactive bladder (OAB), significantly reduced the symptoms of OAB while demonstrating a favorable tolerability and safety profile. In the recently completed Phase III clinical trial, which was conducted with researchers from Vanderbilt University, trospium met dual, pre-specified endpoints, including reduction in frequency of urination and reduction in the number of incontinent episodes, marking the first time any drug in the category has met both endpoints in a clinical trial. Trospium also reduced the severity of urgency, one of the three major components of OAB.

According to the AUA, approximately 17 million Americans, 85 percent of whom are women, suffer from OAB, defined as urge incontinence and urgency and frequency of urination. This population is expected to rise as the percentage of Americans over 60 years of age continues to increase. OAB can lead to urinary incontinence and is the leading cause of nursing home admissions, with an estimated 50 percent of nursing home residents suffering from this condition.

"Unfortunately, OAB is drastically undertreated in the U.S. for a number of reasons," said Roger R. Dmochowski, M.D., professor of urologic surgery in the Department of Urologic Surgery at Vanderbilt University Medical Center and one of the investigators in this trial. "OAB patients face stigma associated with their condition, and of the less than 20 percent who do receive pharmacological treatment, many stop taking their medication due to intolerable side effects. Cognitive side effects have also been observed in patients taking drugs to treat the symptoms of OAB. In trials, trospium not only proved highly effective in reducing the symptoms of OAB, but it did so with a relatively low incidence of dry mouth and constipation, side effects which often cause patients to discontinue drug therapy."

According to Dmochowski, trial results showed that treatment with trospium also reduced the severity of urgency, a hallmark symptom of OAB, and that overall symptom reduction was observed an average of one week after treatment initiation. "Patients with OAB shouldn't have to wait three to four weeks for relief, which is the average onset of action for currently available pharmacological treatments. We are excited about the potential for trospium to help patients faster, with fewer side effects."

Study design
The randomized, double-blind, placebo-controlled trial conducted by Indevus is believed to be the first study in the OAB category to pre-specify and to achieve dual primary endpoints, comparing the reduction in the frequency of urination and the reduction in urge urinary incontinence episodes among drug-treated patients versus placebo patients. The 12-week trial measured the effects of 20 milligrams of trospium chloride versus placebo, twice daily, on symptoms of OAB. The trial included 523 patients, 262 treated with trospium and 261 treated with placebo, at 51 clinical sites in the U.S.

Patient entry criteria included urinary frequency of ten or more toilet voids per day, symptoms of OAB (including urgency) lasting at least six months, and an average of one or more incontinence episodes per day. Patients were excluded if the major reason for their urinary frequency or urine loss was stress incontinence. The average age of patients in both the trospium and placebo groups was 62 years, and women comprised 71 percent of the trospium group and 78 percent of the placebo group. More than 400 of these patients are participating in an ongoing nine-month open label extension of the study.

Study findings
Patients treated with trospium experienced statistically significantly fewer toilet voids per day at the end of the 12-week trial than did patients on placebo. The improvement (decrease) in number of toilet voids for the trospium group compared with the placebo group was observed at each measurement date during the trial (weeks 1, 4 and 12). At week 12, trospium patients had 2.37 (p Trospium patients also experienced statistically significantly fewer episodes of urge urinary incontinence per day at the end of the 12-week trial than did placebo patients. This improvement (decrease) in incontinence episodes for the trospium group was observed beginning at week 1 and continued throughout the study. Trospium patients had 59 percent (p Trospium patients increased their volume voided per void beginning at week 1 and continuing through week 12 (p Trospium was well tolerated as evidenced by its adverse event profile that included the most common adverse events associated with the antimuscarinic class of drugs: dry mouth and constipation. The incidence of dry mouth observed in trospium patients was 21.8 percent, while constipation was observed in 9.5 percent of these patients.

About Trospium
Currently under development in the U.S., trospium belongs to a class of anticholinergic compounds known as muscarinic receptor antagonists. These compounds relax smooth muscle tissue found in the bladder, thus decreasing bladder contractions. Overactive or unstable detrusor muscle function is believed to be the cause of overactive bladder.

Trospium possesses a quarternary ammonium structure and thus does not appear to have the potential to cross the blood-brain barrier. At therapeutic concentrations in vitro, trospium does not interact with drugs metabolized by the Cytochrome P-450 system, a metabolic pathway commonly associated with drug-drug interactions, and it is excreted largely unchanged in the urine.

Trospium has been extensively studied and is currently marketed as a prescription drug product in Europe, where it is one of the leading products for overactive bladder/urinary incontinence. Indevus Pharmaceuticals, Inc. licensed exclusive U.S. rights to trospium from Madaus AG, a German pharmaceutical company, in late 1999.

Source: Vanderbilt University

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