Pharmacological treatment of women awaiting surgery for stress urinary incontinence. Duloxetine versus placebo in the treatment of stress urinary incontinence. Duloxetine versus placebo in the treatment of European and Canadian women with stress urinary incontinence. Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. Impact of duloxetine on quality of life for women with symptoms of urinary incontinence. A randomized controlled trial of duloxetine alone, pelvic floor muscle training alone, combined treatment and no active treatment in women with stress urinary incontinence.
Duloxetine, a serotonin/norepinephrine reuptake inhibitor, has been effective in the treatment of mild and moderate stress urinary incontinence. The aim of this trial was to assess its efficacy for women with severe stress urinary incontinence.
                One hundred nine women, aged 33-75 years, enrolled into this double-blind, randomized, placebo-controlled study. Subjects had to have a predominant symptom of stress urinary incontinence with an incontinence episode frequency 14 per week or more, pure urodynamic stress urinary incontinence, and continence surgery already scheduled. Women were randomized to placebo (n = 54) or duloxetine 80 mg/d (n = 55) for 4 weeks, escalated to 120 mg/d for 4 weeks. Assessment variables included incontinence episode frequency, continence pad use, the Incontinence Quality of Life (I-QOL) questionnaire, and the Willingness to Consider Surgery rating. A responder was defined as a subject with an incontinence episode frequency reduction of 50% or more.
                There were significant improvements with duloxetine compared with placebo in incontinence episode frequency (-60% versus -27%, P <.001), I-QOL score (+10.6 versus +2.4, P =.003), and pad use (-34.5% versus -4.8%, P =.008). At the conclusion of the 8-week study, 10/49 (20%) duloxetine-treated women were no longer interested in surgery, compared with 0/45 placebo-treated women (P =.001). Duloxetine-treated subjects were significantly more likely to be classified as responders (relative risk 4.68, 95% confidence interval 2.27-9.66). The number of subjects-needed-to-treat to gain an additional incontinence episode frequency responder with duloxetine was 2.02. All duloxetine responses were observed within 2 weeks. Side effects and discontinuations because of side effects were significantly more common with duloxetine.
                The data support duloxetine's efficacy in women with severe stress urinary incontinence and suggest that some women responding to duloxetine may reconsider their willingness to undergo surgery. The purpose of this study was to assess the efficacy and safety of duloxetine, a selective inhibitor of serotonin and norepinephrine reuptake, in the treatment of stress urinary incontinence.
                A double-blind, randomized, placebo-controlled study was conducted in 553 women aged 18 to 65 years with a predominant symptom of stress urinary incontinence. Subjects were randomized to placebo (n = 138 women) or duloxetine at one of three doses (20 mg/d, n = 138 women; 40 mg/d, n = 137 women; or 80 mg/d, n = 140 women). Outcome variables that were assessed after 12 weeks of treatment included incontinence episode frequency recorded in a real-time diary and answers provided to the Patient Global Impression of Improvement scale and the Incontinence Quality of Life questionnaire.
                Duloxetine was associated with significant and dose-dependent decreases in incontinence episode frequency that paralleled improvements that were observed in the Patient Global Impression of Improvement scale and the Incontinence Quality of Life questionnaire. The median incontinence episode frequency decrease with the use of the pooled diary analysis with placebo was 41% compared with 54% for duloxetine 20 mg per day (P =.06), 59% for duloxetine 40 mg per day (P =.002), and 64% for duloxetine 80 mg per day (P <.001). One half of the subjects at the 80 mg per day dose had a > or = 64% reduction in incontinence episode frequency (P <.001 vs placebo); 67% had > or = 50% reduction (P =.001 vs placebo). These improvements were observed despite significant concurrent dose-dependent increases in the average voiding interval in the duloxetine groups compared with the placebo group. Similar statistically significant improvements were demonstrated in a subgroup of 163 subjects who had more severe stress urinary incontinence (> or = 14 incontinence episode frequency per week; 49%-64% reduction in incontinence episode frequency in the duloxetine groups compared with 30% in the placebo group). Discontinuation rates for adverse events were 5% for placebo and 9%, 12%, and 15% for duloxetine 20, 40, and 80 mg per day, respectively (P =.04). Nausea was the most common symptom that led to discontinuation. None of the adverse events that were reported were considered to be clinically severe.
                This trial provides evidence for the efficacy and safety of duloxetine as a pharmacologic agent for the treatment of stress urinary incontinence. To assess the efficacy and safety of duloxetine in women with stress urinary incontinence.
                Randomised double-blind, placebo-controlled clinical trial.
                Fort-six centres in seven European countries and Canada.
                Four hundred and ninety-four women aged 24-83 years identified as having predominant symptoms of stress urinary incontinence using a clinical algorithm that was 100% predictive of urodynamic stress urinary incontinence in a subgroup of 34 women.
                The case definition included a predominant symptom of stress urinary incontinence with a weekly incontinence episode frequency > or =7, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequencies, a bladder capacity > or =400 mL and both a positive cough stress test and positive stress pad test. Subjects completed two urinary diaries prior to randomisation and three diaries during the active treatment phase of the study, each completed during the week prior to monthly visits. Subjects also completed quality of life questionnaires at each visit. Safety was assessed by the evaluation of treatment-emergent adverse events, discontinuation of treatment because of adverse events, serious adverse events, vital sign measurements, electrocardiograms (ECG) and clinical laboratory tests.
                After a two-week placebo lead-in, women received placebo or duloxetine 40 mg BD for 12 weeks.
                The percentage decrease in incontinence episode frequency and the change in the Incontinence Quality of Life (I-QOL) questionnaire total score were prespecified as co-primary outcome variables in the protocol.
                Incontinence episode frequency decreased significantly with duloxetine compared with placebo (median decrease of 50%vs 29%; P= 0.002) with comparable improvements in the more severely incontinent subgroup (those experiencing at least 14 incontinence episodes per week at baseline; 56%vs 27% decreases; P < 0.001). The primary analysis of I-QOL scores did not reveal a significant difference between treatment groups, due primarily to the carrying forward of low scores from patients who discontinued treatment very early due to duloxetine-associated adverse events. The increase in I-QOL scores was significantly greater for duloxetine than for placebo at each of the three postrandomisation visits after 4, 8, and 12 weeks of treatment. Discontinuation rates for adverse events were higher for duloxetine (22%vs 5%; P < 0.001) with nausea being the most common reason for discontinuation (5.3%). Nausea tended to be mild to moderate, not progressive, and transient.
                The findings support duloxetine as a potential treatment for women with stress urinary incontinence. To further assess, in a phase 3 study, treatment with duloxetine for women with stress urinary incontinence (SUI) in other geographical regions, including Argentina, Australia, Brazil, Finland, Poland, South Africa and Spain, as previous trials in North America and Europe provided evidence for the safety and efficacy of duloxetine as a pharmacological treatment for SUI in women.
                The study included 458 women aged 27-79 years enrolled in a double-blind, placebo-controlled trial. The patients with predominantly SUI were identified using a validated clinical algorithm. They were randomly assigned to receive placebo (231) or duloxetine 40 mg twice daily (227) for 12 weeks. The primary outcome variables included the incontinence episode frequency (IEF) and the Incontinence Quality of Life (I-QOL) questionnaire. Van Elteren's test was used to analyse the percentage changes in IEF where the stratification variable was weekly baseline IEF (IEF < 14 and > or = 14). Analysis of covariance was used to analyse I-QOL scores.
                The mean baseline IEF was 18.4/week; 55% of patients had a baseline IEF of > or = 14. There was a significantly greater median decrease in IEF with duloxetine with placebo (54% vs 40%, P = 0.05), with comparable significant improvements in quality of life (I-QOL score increases of 10.3 vs 6.4, P = 0.007). The improvements with duloxetine were associated with significantly greater increases in voiding intervals than with placebo (20.4 vs 8.5 min, P < 0.001). The placebo response was 10.7% and 12.5% higher than those reported in two European and North American phase 3 trials. This may have been related to more patients being naïve for incontinence management in the current trial. Discontinuation rates for adverse events were 1.7% for placebo and 17.2% for duloxetine (P < 0.001), with nausea being the most common reason for discontinuation (3.1%); it was the most common adverse event with duloxetine, but was mild or moderate in most (81%), did not worsen in any patient and resolved within 7 days in 60% and within 1 month in 86% of continuing patients; 88% of women who experienced nausea while taking duloxetine completed the trial.
                These results show improvements in incontinence and quality of life with duloxetine 40 mg twice daily for 12 weeks that are in keeping with those reported in two other recently completed phase 3 trials in Europe and North America. Duloxetine, a selective serotonin and norepinephrine reuptake inhibitor, increases rhabdosphincter contractility via the stimulation of pudendal motor neuron alpha-1 adrenergic and 5-hydroxytryptamine-2 receptors. In this first phase 3 study we assessed the efficacy and safety of duloxetine in women with stress urinary incontinence (SUI).
                A total of 683 North American women 22 to 84 years old were enrolled in this double-blind, placebo controlled study. The case definition included a predominant symptom of SUI with a weekly incontinence episode frequency (IEF) of 7 or greater, the absence of predominant symptoms of urge incontinence, normal diurnal and nocturnal frequency, a bladder capacity of 400 ml or greater, and a positive cough stress test and stress pad test. After a 2-week placebo lead-in period subjects were randomly assigned to receive placebo (339) or 80 mg duloxetine daily (344) as 40 mg twice daily for 12 weeks. Primary outcome variables included IEF and an incontinence quality of life questionnaire. Van Elteren's test was used to analyze percent changes in IEF with a stratification variable of weekly baseline IEF (less than 14 and 14 or greater). ANCOVA was used to analyze incontinence quality of life scores.
                Mean baseline IEF was 18 weekly and 436 subjects (64%) had a baseline IEF of 14 or greater. There was a significant decrease in IEF with duloxetine compared with placebo (50% vs 27%, p <0.001) with comparably significant improvements in quality of life (11.0 vs 6.8, p <0.001). Of subjects on duloxetine 51% had a 50% to 100% decrease in IEF compared with 34% of those on placebo (p <0.001). These improvements with duloxetine were associated with a significant increases in the voiding interval compared with placebo (20 vs 2 minutes, p <0.001) and they were observed across the spectrum of incontinence severity. The discontinuation rate for adverse events was 4% for placebo and 24% for duloxetine (p <0.001) with nausea the most common reason for discontinuation (6.4%). Nausea, which was also the most common side effect, tended to be mild to moderate and transient, usually resolving after 1 week to 1 month. Of the 78 women who experienced treatment emergent nausea while taking duloxetine 58 (74%) completed the trial.
                These phase 3 data are consistent with phase 2 data and they provide further evidence for the safety and efficacy of duloxetine as a pharmacological agent for the treatment of women with SUI. The objective of this study was to evaluate the effectiveness of duloxetine in improving quality of life among women with stress and mixed urinary incontinence. The study included 451 women with self-reported stress incontinence episodes (>or=1/week) who were randomized to duloxetine (40 mg BID) or placebo in a double-blind, usual care design. Patients and physicians were allowed to titrate, augment, and/or discontinue treatment. Concomitant treatments were permitted. The primary outcome was the Incontinence Quality of Life Questionnaire (I-QOL) score, with assessments at 3, 6, and 9 months. Other measures included the Patient Global Impression of Improvement (PGI-I) and adverse events. The adjusted mean change in I-QOL total score was greater in the duloxetine group than in the placebo group and at a level comparable to that found in previous clinical trials, but the difference between placebo and duloxetine was not statistically significant in the intent-to-treat, last observation carried forward (LOCF) analysis. The difference approached statistical significance in favor of duloxetine at 3 months (p=0.07). PGI-I ratings did not demonstrate significant superiority for duloxetine in LOCF analysis; however, study completers taking duloxetine were significantly more likely to rate themselves as "better" (70.2%) than completers taking placebo (50.8%, p<0.05). Women utilized a variety of treatment methods including pelvic floor muscle training, estrogen, anticholinergic medication, weight reduction, and smoking cessation. In this study, while mean I-QOL change scores were numerically higher for the duloxetine group than mean change scores for the placebo group, this difference was not statistically significant. Among women who completed the study on study drug, a significantly greater proportion of duloxetine women versus placebo women rated their condition to be better. We primarily compared the effectiveness of combined pelvic floor muscle training (PFMT) and duloxetine with imitation PFMT and placebo for 12 weeks in women with stress urinary incontinence (SUI). In addition, we compared the effectiveness of combined treatment with single treatments, single treatments with each other and single treatments with no treatment.
                This blinded, doubly controlled, randomized trial enrolled 201 women 18 to 75 years old with SUI at 17 incontinence centers in the Netherlands, United Kingdom and United States. Women averaged 2 or more incontinence episodes daily and were randomized to 1 of 4 combinations of 80 mg duloxetine daily, placebo, PFMT and imitation PFMT, including combined treatment (in 52), no active treatment (in 47), PFMT only (in 50) and duloxetine only (in 52). The primary efficacy measure was incontinence episode frequency. Other efficacy variables included the number of continence pads used and the Incontinence Quality of Life questionnaire score.
                The intent to treat population incontinence episode frequency analysis demonstrated the superiority of duloxetine with or without PFMT compared with no treatment or with PFMT alone. However, pad and Incontinence Quality of Life analyses suggested greater improvement with combined treatment than single treatment. A completer population analysis demonstrated the efficacy of duloxetine with or without PFMT and suggested combined treatment was more effective than either treatment alone.
                The data support significant efficacy of combined PFMT and duloxetine in the treatment of women with SUI. We hypothesize that complementary modes of action of duloxetine and PFMT may result in an additive effect of combined treatment.
The available evidence suggests that duloxetine treatment can significantly improve the quality of life of patients with stress urinary incontinence, but it is unclear whether or not benefits are sustainable. Adverse effects are common but not serious. About one in three participants allocated duloxetine reported adverse effects (most commonly nausea) related to treatment, and about one in eight allocated duloxetine stopped treatment as a consequence.