Duloxetine vs Placebo in the Treatment of Stress Urinary Incontinence: A Four-Continent Randomized Clinical Trial
Millard RJ, Moore K, Rencken R, et al.
BJU Int. 2004;93:311-318
Duloxetine is the first new drug under evaluation for the treatment of stress urinary incontinence. This is a report on a US Food and Drug Administration phase III study of duloxetine treatment for women with stress urinary incontinence (SUI) from around the world. The study included a double-blind, placebo-controlled trial of 458 women age 27 to 79 years. Women with predominantly SUI were identified using a validated clinical algorithm and received placebo randomly (231) or duloxetine 40 mg 2 times per day (227) for a 12-week period.
The questionnaires for incontinence episode frequency (IEF) and the incontinence quality of life (I-QOL) were among the primary outcomes variables with mean baseline IEF at 18.4 per week. IEF with duloxetine showed a significantly greater median decrease than did placebo (54% vs 40%, P = .05) and showed significant improvements in quality of life than placebo (I-QOL score increases of 10.3 vs 6.4, P = .007). The improved duloxetine results were also associated with greater voiding intervals when compared with placebo (20.4 minutes vs 8.5 minutes, P < .001). Interestingly, the placebo responses were greater (10.7% and 12.5%) than in 2 other European and North American phase III trials, which may point to a greater number of patients who were naïve to incontinence management.
Rates for discontinuation due to side effects ranged from 1.7% for placebo to 17.2% for duloxetine (P < .001), with nausea being the most common reason for discontinuation (3.1%). Nausea was the most common side effect for duloxetine. However, nausea was reported to be mild to moderate for most patients (81%). Nausea did not worsen in any of the patients and in 60% of patients resolved within a 7-day period and in 86% of patients resolved within a month (for ongoing patients). Of the women who experienced some nausea with duloxetine, 88% of them completed the trial.
The safety and efficacy data from this study support duloxetine as the first oral agent for the indication of SUI. Duloxetine could fill an unmet medical need by providing a primary treatment for women who seek a pharmacotherapy treatment for their SUI, for those who are unable or unwilling to perform pelvic floor muscle training, or for those who wish to postpone or avoid continence surgery.
Randomized, Double-Blind Placebo- and Tolterodine-Controlled Trial of the Once-Daily Antimuscarinic Agent Solifenacin in Patients with Symptomatic Overactive Bladder
Chapple CR, Rechberger T, Al-Shukri S, et al.
BJU Int. 2004;93:303-310
An international, multicenter, randomized, double-blind trial, conducted at 98 centers, was presented comparing tolterodine and placebo with 2 doses of a new antimuscarinic drug, solifenacin, in patients with symptoms of overactive bladder (OAB), which include urgency, incontinence, and frequency. Adult patients with symptomatic OAB for 3 months were eligible. After a single-blind 2-week placebo run-in period, patients were randomized equally to a 12-week double-blind treatment with tolterodine 2 mg twice daily, placebo, or solifenacin 5 mg or 10 mg once daily. Efficacy variables included change from baseline in the mean number of urgency, incontinence, and urge incontinence episodes, and change from baseline in voids/24 h and mean volume voided/void.
A total of 1281 patients were enrolled; 1081 were randomized and 1077 treated and 1033 evaluated for efficacy. The change from baseline (−1.41, −32.7%) in the mean number of urgency episodes in a 24-hour period, when compared with placebo, was significantly lower with solifenacin 5 mg (−2.85, −51.9%) and 10 mg (−3.07, −54.7%; both P < .001), but not with tolterodine (−2.05, −37.9%; P = .0511). There was a statistically insignificant decrease in episodes of incontinence with tolterodine (−1.14; P = .1122) but a significant decrease in patients treated with solifenacin 5 mg (−1.42; P = .008) and 10 mg (−1.45; P = .0038). The mean number of voids per 24 hours was significantly lower in patients receiving tolterodine (−1.88, −15%; P = .0145), solifenacin 5 mg (−2.19, −17%) and 10 mg (−2.61, −20%; both P < .001) than with placebo (−1.20, −8.1%). With all 3 active treatments the mean volume voided/void was significantly higher (P < .001).
The use of solifenacin was well tolerated, with dry mouth, mostly mild, the most commonly reported side effect. This was reported in 18.6% of patients receiving tolterodine and in 4.9% receiving placebo, while also reported in 14.0% receiving 5 mg and 21.3% receiving 10 mg solifenacin.
At 5 mg and 10 mg once per day, solifenacin was effective and well tolerated for the treatment of OAB patients with acceptable anticholinergic side effects reported. As is true for all antimuscarinic agents, side-effect profiles with solifenacin should be balanced against efficacy. The low discontinuation rates should provide evidence for clinically meaningful efficacy and tolerability profile.