Patient‐optimized doses of fesoterodine improve bladder symptoms in an open‐label,flexible‐dose study

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? We know that bladder‐relaxing agents antimuscrinics act on symptoms of overactive bladder and are the first treatment in such patients. We know that fesoterodine is a newer antimuscarinic with a good activity safety profile. This study adds to the experience that changing the dose of antimuscrinics as fesoterodine is often needed by patients, that the decision can be made by the patients, and the change in dose adds to the clinical result.

OBJECTIve

To assess changes in overactive bladder (OAB) symptoms and patient‐reported outcomes in a post hoc analysis in which subjects from a 12‐week, open‐label, flexible‐dose fesoterodine study were stratified according to whether they opted for dose escalation.

PATIENTS AND METHODS

Subjects with OAB (eight or more micturitions and three or more urgency episodes per 24 h) who reported dissatisfaction with tolterodine within 2 years of screening received fesoterodine 4 mg once daily for 4 weeks, with an optional dose increase to 8 mg after week 4 based on discussion of efficacy and tolerability between the subject and investigator. Subjects completed 5‐day diaries, the Patient Perception of Bladder Condition (PPBC) and Urgency Perception Scale (UPS) at baseline and weeks 4 and 12, and the Overactive Bladder Questionnaire (OAB‐q) at baseline and week 12. Subjects rated treatment satisfaction at week 12.

RESULTS

Dose escalation to 8 mg at week 4 was chosen by 255 (50%) of 513 subjects. At baseline, subjects who opted for dose escalation at week 4 (escalators) had significantly higher means for all diary variables except urgency urinary incontinence (UUI) episodes, significantly greater OAB‐q Symptom Bother scores and significantly lower OAB‐q health‐related quality of life (HRQL) scores (all P < 0.05) compared to subjects who did not opt for dose escalation (non‐escalators). There was no significant difference in the percentage of escalators (51%) and non‐escalators (48%) who reported at least one UUI episode on baseline diary. At week 4 (before the decision to escalate was made), all outcomes were significantly improved vs baseline among both groups (all P < 0.0001), although non‐escalators had significantly greater improvements in all diary variables and in PPBC and UPS scores than escalators (all P < 0.05), and the 5‐day diary‐dry rate (i.e. the percentage of subjects with at least one UUI episode on baseline diary and no UUI episodes on week 4 diary) was significantly higher (P= 0.0016) among non‐escalators (62%) than among escalators (42%). At week 12, all outcomes were again significantly improved vs baseline among both groups (all P < 0.0001). There were no significant differences between non‐escalators and escalators in week 12 improvements for most diary variables, UPS scores, OAB‐q Symptom Bother scores, the diary‐dry rate (68% vs 60%) or the percentage of subjects who reported treatment satisfaction (82% vs 78%). However, escalators still had significantly greater improvements from baseline in urgency episodes, PPBC scores and OAB‐q total HRQL and Coping domains (P < 0.05). Adverse event rates were similar between non‐escalators and escalators. Dry mouth was the most frequently reported adverse event; most cases were mild.

CONCLUSION

Flexible‐dose fesoterodine significantly improved OAB symptoms and patient‐reported outcomes in subjects who chose to remain on the initial 4‐mg dose, as well as in the 50% of subjects who escalated to the 8‐mg dose after 4 weeks. Non‐escalators had significantly fewer OAB symptoms at baseline and significantly greater improvements than escalators before dose escalation. Escalators showed increased symptom relief after dose escalation; improvements in most outcomes were similar among non‐escalators and escalators by week 12. Flexible‐dose fesoterodine was well tolerated, with similar adverse‐event profiles observed in the escalator and non‐escalator groups. These results may help clinicians to identify patients more likely to require fesoterodine 8 mg to achieve maximum relief of OAB symptoms and thus facilitate dose escalation in these patients.     

Comparison of fesoterodine and tolterodine in patients with overactive bladder

OBJECTIVE

To compare, in a post hoc analysis of a phase III trial, the maximum recommended doses of fesoterodine (8 mg) and tolterodine (4 mg) for improving overactive bladder (OAB) symptoms and health‐related quality of life (HRQoL), as fesoterodine effectively reduces OAB symptoms vs placebo.

PATIENTS AND METHODS

Eligible patients with frequency (≥eight voids/24 h) and either urgency (≥six episodes over 3 days) or urgency urinary incontinence (UUI; ≥three episodes over 3 days) were randomized to placebo, fesoterodine 4 or 8 mg, or tolterodine extended‐release (ER) 4 mg for 12 weeks; fesoterodine 4 mg data were published elsewhere. Patients completed a 3‐day bladder diary in which they recorded the time of each void, voided volume (VV), and the severity of urgency. A post hoc inferential analysis was conducted on the primary endpoint (voids/24 h), the two co‐primary endpoints (UUI episodes/24 h and treatment response), several secondary endpoints (severe urgency plus UUI per 24 h, mean VV (MVV)/void, and continent days/week), HRQoL, using the King’s Health Questionnaire (KHQ) and the International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF), and self‐reported bladder‐related problems. A subanalysis also assessed all endpoints for patients who were incontinent at baseline. Tolerability and safety were assessed by evaluating adverse events, residual urine volume, laboratory variables and treatment withdrawals.

RESULTS

By week 12, patients with OAB in both active‐treatment groups showed significant improvements in most bladder diary variables and treatment response rates compared with placebo. Fesoterodine 8 mg was statistically significantly better than tolterodine ER 4 mg for improving UUI episodes, severe urgency plus UUI, mean VV, and number of continent days/week. In addition, the fesoterodine and tolterodine ER groups showed significantly greater improvements in HRQoL than the placebo group, with positive changes in most domains of the KHQ and an improvement in ICIQ‐SF score. The fesoterodine 8‐mg group had statistically significant improvements over placebo in eight of nine KHQ domains. A major improvement in the severity of bladder‐related problems was reported by 39% of the fesoterodine 8 mg and 34% of the tolterodine ER groups vs 25% of those on placebo (P ≤ 0.01). Results for the subgroup of incontinent patients at baseline were similar to the overall results. Adverse events reported most commonly with active treatment included dry mouth, constipation, dry eye, dry throat, and nausea.

CONCLUSIONS

Both fesoterodine and tolterodine ER significantly improved OAB symptoms and HRQoL, with statistically significant advantages for fesoterodine 8 mg compared with tolterodine ER on several important endpoints.     

Early onset of fesoterodine efficacy in subjects with overactive bladder

Study Type – Therapy (cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? Fesoterodine is an effective treatment for overactive bladder. However, the length of time until the effects begin to be seen was not known. The study demonstrates that the effect of Fesoterodine 4 mg on overactive bladder symptoms can be seen at one week.

OBJECTIVE

To assess the onset of efficacy of fesoterodine 4 mg once daily on overactive bladder (OAB) symptoms after 1 week of treatment.

PATIENTS AND METHODS

This was a prespecified analysis of data collected during the first week of a 12‐week, open‐label, single‐arm, flexible‐dose study of fesoterodine. Eligible subjects were adult men and women (aged ≥ 18 years) who reported urinary frequency (eight or more micturitions per 24 h) and urgency (three or more episodes per 24 h) in 5‐day bladder diaries at baseline, and dissatisfaction with previous tolterodine or tolterodine extended‐release treatment received within 2 years of screening. All subjects received fesoterodine 4 mg once daily during the first 4 weeks of treatment (with an optional dose increase to fesoterodine 8 mg after week 4). Early onset of efficacy of fesoterodine 4 mg was assessed based on changes from baseline to week 1 in variables recorded in 5‐day bladder diaries, including total micturitions, urgency episodes, urgency urinary incontinence (UUI) episodes and nocturnal micturitions. Urgency and severe urgency episodes were defined as those rated ≥ 3 and ≥4, respectively, on the five‐point Urinary Sensation Scale (USS) (1 = no urgency, 5 = UUI); frequency‐urgency sum (a combined measure of micturition frequency and urgency) was defined as the sum of all USS ratings.

RESULTS

All bladder diary variables, including total and nocturnal micturitions, UUI episodes, urgency episodes, severe urgency episodes and frequency‐urgency sum per 24 h, were significantly improved (all P < 0.0001) after 1 week of treatment with fesoterodine 4 mg compared to baseline. The diary‐dry rate at week 1 (i.e. subjects with at least one UUI episode at baseline who subsequently reported no UUI episodes on week 1 diary) was 38%.

CONCLUSION

In this open‐label study of subjects with OAB who had been previously treated and dissatisfied with tolterodine, fesoterodine 4 mg showed a rapid onset of efficacy at 1 week.     

Sustained improvement in patient-reported outcomes during long-term fesoterodine treatment for overactive bladder symptoms: pooled analysis of two open-label extension studies

Study Type – Outcomes (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Short‐term (12‐week) trials have demonstrated that subjects with OAB who receive treatment with fesoterodine 4‐ and 8‐mg, either in fixed‐dose or flexible‐dose regimens, show significant improvements in measures of HRQL and other patient‐reported outcomes. The results of this long‐term, open‐label study show that treatment with fesoterodine for up to 24 months resulted in sustained improvement in measures of HRQL and severity of bladder‐related problems in subjects with OAB symptoms. Throughout the study, a high percentage of subjects reported satisfaction with fesoterodine treatment. The results were similar in men and women and across age groups (<45 years; 45–64 years; 65–74; ≥75 years). Long term treatment with fesoterodine is beneficial to patients with overactive bladder.

OBJECTIVES

• ? To evaluate the effects of long‐term fesoterodine treatment on health‐related quality of life (HRQL) and treatment satisfaction in subjects with overactive bladder (OAB) symptoms.
• ? To determine the impact of gender and age on these effects.

PATIENTS AND METHODS

• ? This is a post hoc analysis of data pooled from identically designed open‐label extensions of two randomized, double‐blind, 12‐week fesoterodine studies.
• ? Initial treatment was once‐daily fesoterodine 8 mg; subjects had the opportunity to receive open‐label fesoterodine for ≥24 months.
• ? After 1 month, subjects could elect dose reduction to 4 mg and subsequent re‐escalation to 8 mg; dose reduction and re‐escalation were each allowed once annually.
• ? Changes in scores on the King's Health Questionnaire (KHQ), International Consultation on Incontinence Questionnaire–Short Form (ICIQ‐SF) and a Likert scale evaluating severity of bladder‐related problems were assessed at open‐label baseline and months 12 and 24; treatment satisfaction was assessed at open‐label baseline and at months 4, 12 and 24.

RESULTS

• ? A total of 864 enrolled subjects were included (men, n= 182; women, n= 682; aged <45 years, n= 134; 45–64 years, n= 432; 65–74 years, n= 204; ≥75 years, n= 94); most subjects (77%) who continued treatment maintained the 8‐mg dose.
• ? Among subjects in the overall population, there were significant improvements in all KHQ domains, ICIQ‐SF scores, and bladder‐related problems at open‐label baseline vs double‐blind baseline (P < 0.05); additional significant improvements were observed at months 12 and 24 vs open‐label baseline in all outcomes (P < 0.05) except for the KHQ General Health Perception domain.
• ? When data were stratified by gender or age, significant improvements at open‐label baseline vs double‐blind baseline were further significantly enhanced or sustained at months 12 and 24 for most KHQ domains, and for ICIQ‐SF scores and bladder‐related problems for all groups. Women had significantly greater improvements than men in the KHQ Emotion (P= 0.0173) and Severity/Coping (P= 0.0112) domains and ICIQ‐SF scores (P= 0.0276) during open‐label treatment. Subjects aged <45 years had significantly greater improvement in the Personal Relationships domain compared with those aged 45–64 years (P= 0.0357) and in the Sleep/Energy domain compared with all other groups (all P < 0.02).
• ? Treatment satisfaction was high (≥92%) throughout open‐label treatment regardless of gender or age.

CONCLUSIONS

• ? Long‐term fesoterodine treatment was associated with sustained improvement in measures of health‐related quality of life and bladder‐related problems and with high treatment satisfaction in subjects with overactive bladder symptoms.
• ? Effects of gender and age were minimal.

     

Superior efficacy of fesoterodine over tolterodine extended release with rapid onset: a prospective,head‐to‐head,placebo‐controlled trial

Study Type – Therapy (RCT)
Level of Evidence 1b What’s known on the subject? and What does the study add? A previous trial found greater efficacy with the maximum available dose of fesoterodine 8 mg compared with the maximum available dose of tolterodine ER 4 mg and placebo for improving overactive bladder symptoms, and patient‐reported outcomes were demonstrated by a recent placebo‐controlled, head‐to‐head trial. The results of this trial, the largest to date to compare antimuscarinic efficacy, confirms the superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms, and further emphasize the clinical advantage of the availability of an additional 8‐mg dose over single‐dose tolterodine ER 4 mg.

OBJECTIVE

? To show the superior efficacy of fesoterodine over tolterodine extended release (ER) in a placebo‐controlled overactive bladder (OAB) trial with predefined treatment comparisons for both diary measures and patient‐reported outcomes.

MATERIALS AND METHODS

? In this 12‐week, double‐blind, double‐dummy trial, subjects reporting >1 urgency urinary incontinence (UUI) episode and ≥8 micturitions per 24 h at baseline were randomized to fesoterodine (4 mg for 1 week, 8 mg for 11 weeks), tolterodine ER 4 mg, or placebo. ? Subjects completed 3‐day bladder diaries, the Patient Perception of Bladder Condition (PPBC) and the Urgency Perception Scale (UPS) at baseline and weeks 1, 4 and 12 and the OAB Questionnaire at baseline and week 12.

RESULTS

? A total of 2417 subjects were randomized. At week 12, fesoterodine 8 mg showed superiority over tolterodine ER 4 mg and placebo on UUI episodes (primary endpoint), micturitions, urgency and most other diary endpoints, and on the PPBC, UPS and all OAB Questionnaire scales and domains (all P < 0.05). ? Superiority of fesoterodine 8 mg over tolterodine ER 4 mg was seen as early as week 4 (3 weeks after escalation to fesoterodine 8 mg). At week 1, fesoterodine 4 mg was superior to placebo on most diary variables, the PPBC and the UPS (all P < 0.05). Dry mouth and constipation rates were 28% and 4% with fesoterodine, 13% and 3% with tolterodine ER, and 5% and 2% with placebo. ? Discontinuation rates as a result of adverse events were 5%, 3% and 2% for fesoterodine, tolterodine ER and placebo, respectively.

CONCLUSIONS

? In this randomized study, which is the largest to compare antimuscarinic efficacy performed to date, fesoterodine 8 mg was superior to tolterodine ER 4 mg for UUI episodes, micturitions and urgency episodes, as well as for self‐reported patient assessments of bladder‐related problems, urgency, symptom bother and health‐related quality of life. ? The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was observed as early as 3 weeks after escalation from fesoterodine 4 mg for most outcomes. These data may have important implications for the clinical management of OAB patients previously treated with tolterodine ER.     

Efficacy of simplified bladder training in patients with overactive bladder receiving a solifenacin flexible‐dose regimen: results from a randomized study

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To compare the efficacy of flexible‐dose solifenacin 5/10 mg with and without simplified bladder training in patients with overactive bladder (OAB) syndrome.

PATIENTS AND METHODS

SOLAR (SOLifenacin Alone and with simplified bladder Re‐training) was a multicentre, prospective, randomized, parallel‐group, open‐label study in patients with OAB. After a 2‐week, single‐blind, placebo run‐in, 643 patients were randomized to treatment with either solifenacin 5 mg once daily (od) alone (323) or 5 mg od combined with simplified bladder training (320) for 8 weeks. At week 8, patients in both groups could request a dose increase to solifenacin 10 mg od for the remaining 8 weeks of the study. The primary efficacy endpoint was the change from baseline in the mean number of micturitions/24 h after 8 weeks. Secondary efficacy measures were the change in micturition frequency and other voiding diary variables at week 16. Patient‐reported outcomes were also assessed, including patient Perception of Bladder Condition, Incontinence Quality of Life, and Treatment Satisfaction using a visual analogue scale score; tolerability was also assessed.

RESULTS

Solifenacin given alone was effective in improving all measures of OAB evaluated in the study. When simplified bladder training was used combined with solifenacin there was a further significant improvement in micturition frequency at week 8, and this difference was maintained through to week 16. The use of simplified bladder training with solifenacin also significantly improved treatment satisfaction at week 16 over the responses to solifenacin given alone. There was no significant difference between the treatment groups at week 16 in urgency, incontinence or other secondary variables measured. The most common adverse event reported was dry mouth in both treatment groups; there was a low rate of discontinuation due to adverse events in the total study group.

CONCLUSION

Combined treatment with solifenacin and simplified bladder training was more effective than solifenacin alone in reducing micturition frequency at weeks 8 and 16, and improving treatment satisfaction at week 16 in patients with OAB. Simplified bladder training did not improve on the benefits of solifenacin alone in the symptoms of urgency or incontinence.     

Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head‐to‐head placebo‐controlled trial

Study Type – Therapy (RCT)
Level of Evidence 1b

OBJECTIVE

To compare the efficacy and tolerability of fesoterodine 8 mg with tolterodine extended‐release (ER) 4 mg and placebo in a randomized clinical trial of patients with an overactive bladder (OAB).

PATIENTS AND METHODS

In this 12‐week double‐blind, double‐dummy, placebo‐controlled, randomized clinical trial, eligible patients reported OAB symptoms for ≥3 months and recorded ≥8 voids and ≥1 urgency urinary incontinence (UUI) episode per 24 h in 3‐day bladder diaries at baseline. Patients were randomized in a 2:2:1 ratio to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks); tolterodine ER 4 mg; or placebo (with sham dose escalation for tolterodine ER and placebo). Endpoints were changes from baseline to week 12 in UUI episodes (primary endpoint), total and nocturnal voids, urgency episodes, severe urgency episodes, and frequency‐urgency sum per 24 h; mean voided volume per void (MVV); and the OAB questionnaire (OAB‐q), Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS). Safety and tolerability were assessed and summarized over the 12‐week study period.

RESULTS

Fesoterodine (636 patients) significantly improved UUI episodes at week 12 (primary endpoint) compared with tolterodine ER (641 patients; P = 0.017) and placebo (313 patients; P < 0.001). Fesoterodine also produced significantly greater improvements than tolterodine ER in MVV (P = 0.005). Fesoterodine significantly improved all diary endpoints compared with placebo (P < 0.001), except for nocturnal voids (P = 0.327). Tolterodine ER significantly improved all diary endpoints vs placebo (P < 0.001), except for nocturnal voids (P = 0.506) and MVV (P = 0.103). Diary dry rates (the proportion of patients reporting no UUI episodes at endpoint among those with one or more UUI episodes at baseline) were significantly higher with fesoterodine (64%) than with tolterodine ER (57%; P = 0.015) and placebo (45%; P < 0.001). Improvements in PPBC, UPS and OAB‐q scale and domain scores at week 12 were all significantly better with fesoterodine than placebo (all P < 0.001) and tolterodine ER (all P < 0.05) except for the OAB‐q Sleep domain vs tolterodine ER (P = 0.081). Dry mouth and constipation rates were 28% and 5% in the fesoterodine group, 16% and 4% in the tolterodine ER group, and 6% and 3% with placebo, respectively. Discontinuations due to treatment‐emergent adverse events were 6%, 4% and 2% in the fesoterodine, tolterodine ER, and placebo groups, respectively.

CONCLUSION

In patients with OAB, fesoterodine 8 mg showed superior efficacy over tolterodine ER 4 mg and placebo in reducing UUI episodes (primary endpoint) and in improving most patient‐reported outcome measures. Both active treatments were well tolerated.     

Listening to the patient: a flexible approach to the use of antimuscarinic agents in overactive bladder syndrome

Several studies with modern antimuscarinics have used a flexible‐dosing strategy. We reviewed data from several studies with solifenacin, darifenacin and oxybutynin extended‐release that evaluated the impact of dose flexibility on clinical management. A strategy based on patient‐requested dose increases was found to be consistently effective in improving the symptoms of overactive bladder. Patients requesting a dose increase often had more severe symptoms at baseline than those who did not request a dose increase, and these patients derived most benefit from the increased dose. Specialists and family doctors should encourage open discussion with their patients about requesting dose titration so as to meet patients' individual needs.     

Efficacy and tolerability of fesoterodine in women with overactive bladder

Introduction and hypothesis  We assessed fesoterodine efficacy and tolerability in women with overactive bladder (OAB). Methods  This post hoc analysis of pooled data from two clinical trials included 1,548 women with OAB randomized to placebo, fesoterodine 4 or 8 mg, or tolterodine extended release (ER) 4 mg (in 1 trial) for 12 weeks. Subjects completed 3-day bladder diaries at baseline and weeks 2 and 12 and rated Treatment Response at weeks 2 and 12. Results  By weeks 2 and 12, all active-treatment groups showed significant improvements in all five bladder diary variables assessed and greater Treatment Response rates vs placebo. Fesoterodine 8 mg was significantly more efficacious than fesoterodine 4 mg and tolterodine ER in improving urgency urinary incontinence episodes and continent days per week. The most common adverse events were dry mouth and constipation, which were predominately mild or moderate. Conclusions  Fesoterodine is efficacious and well tolerated in women with OAB.     

Modeling dose-response relationships of the effects of fesoterodine in patients with overactive bladder

Background

Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine.

Methods

Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models.

Results

The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively.

Conclusions

A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials.

Trial Registration

The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).