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- MATERIALS AND METHODS
- CONFLICT OF INTEREST
With the emergence of comparative effectiveness research as a driver of healthcare policy and reform, there is currently an emphasis on establishing the clinical value of one treatment over another . A number of randomized, double-blind, placebo-controlled trials have compared the efficacy of antimuscarinics for the treatment of overactive bladder (OAB) symptoms [2–9]. The International Conference on Harmonisation Good Clinical Practice guidelines recommend the superiority design for comparisons between active treatments and with placebo . However, most trials of antimuscarinic efficacy have been designed for comparison with placebo only; trials designed to compare the clinical efficacy of two antimuscarinics have either been based on a non-inferiority design or have lacked a placebo arm. Additionally, no placebo-controlled trials to date have reported predefined comparisons in both diary-based and patient-reported outcomes (PROs) measures.
Fesoterodine is an antimuscarinic agent that is rapidly and extensively converted by ubiquitous esterases to its active metabolite, 5-hydroxymethyl tolterodine (5-HMT); fesoterodine is not detectable in plasma after oral dosing, and all antimuscarinic effects are attributable to 5-HMT . Tolterodine is also converted to 5-HMT, although this occurs primarily in the liver via cytochrome P450 2D6. A significant fraction of unconverted tolterodine is found in plasma, and both tolterodine and 5-HMT contribute to antimuscarinic effects . After oral administration of tolterodine, there is considerable variability in the pharmacokinetic properties of 5-HMT and tolterodine between individuals with different cytochrome P450 2D6 phenotypes . There is much less variability in 5-HMT pharmacokinetics after oral administration of fesoterodine .
By contrast to tolterodine extended release (ER), for which 4 mg is the one approved dose for treatment in the general population of patients with OAB , fesoterodine is available in both 4 and 8 mg once-daily doses [15,16]. Notably, a post hoc analysis of a placebo-controlled phase III trial of fesoterodine that included tolterodine ER as an active control  showed significantly greater improvements in urgency urinary incontinence (UUI) episodes and mean voided volume (MVV) per micturition with fesoterodine 8 mg compared to tolterodine ER 4 mg . Consistent with these findings, a recent placebo-controlled, head-to-head trial showed that reductions in UUI episodes at 12 weeks (the primary endpoint) and increases in MVV per micturition and 3-day diary-dry rate (proportion of subjects with >0 UUI episodes on baseline bladder diaries who reported 0 UUI episodes at week 12; post hoc analysis) were significantly greater in subjects treated with fesoterodine 8 mg than in subjects treated with tolterodine ER 4 mg . Subjects receiving fesoterodine 8 mg also had significantly greater improvements on the Patient-Perception of Bladder Condition (PPBC), Urgency Perception Sale (UPS) and the Overactive Bladder questionnaire (OAB-q) compared to subjects receiving tolterodine ER 4 mg (all post hoc analyses) .
The present study, which is the largest placebo-controlled, randomized, head-to-head antimuscarinic study peformed to date, is the second study to prospectively assess the superiority of the maximum available dose of fesoterodine (8 mg) over the maximum available dose of tolterodine ER (4 mg). Notably, all comparisons of diary-based endpoints and PROs in the present study were predefined, and this is the first placebo-controlled study for which the time course of the superiority of one antimuscarinic over another has been reported.
- Top of page
- MATERIALS AND METHODS
- CONFLICT OF INTEREST
The present study is the largest double-blind, placebo-controlled, randomized study to compare antimuscarinic efficacy on OAB to date. It is also the first placebo-controlled, head-to-head superiority study of antimuscarinics designed to make predefined comparisons for both diary-based measures and PROs. The results show the superiority of fesoterodine 8 mg over tolterodine ER 4 mg for improving UUI episodes (the primary endpoint), micturitions, urgency episodes, severe urgency episodes and frequency–urgency sum, but not nocturnal micturitions or MVV. Fesoterodine 8 mg also produced significantly greater improvements compared to tolterodine ER 4 mg in assessments by subjects of their OAB symptoms, as measured by the PPBC, UPS and OAB-q. The superiority of fesoterodine 8 mg over tolterodine ER 4 mg was apparent at week 4 on all diary endpoints, except nocturnal micturitions, and also on the PPBC and UPS (OAB-q scores not captured at week 4).
These findings support those of a previous head-to-head trial designed to show the superiority of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms ; in that study, analyses comparing fesoterodine 8 mg and tolterodine ER 4 mg on 3-day diary-dry rates and PROs were not prespecified. Both studies found significantly greater improvements in UUI episodes, diary-dry rates and PPBC, UPS and OAB-q scores with fesoterodine 8 mg vs tolterodine ER 4 mg. In the present study, fesoterodine 8 mg was also associated with significantly greater improvements in micturitions, urgency episodes, severe urgency episodes and frequency–urgency sum compared to tolterodine ER 4 mg; treatment differences in these end points did not reach statistical significance in the previous head-to-head trial . The previous study found that fesoterodine 8 mg was associated with a significantly greater increase in MVV than tolterodine ER 4 mg. In the present study, the increase in MVV was significantly greater with fesoterodine 8 mg than tolterodine ER 4 mg at week 4, but not at week 12. The results of these two trials taken together strongly support the superiority of fesoterodine 8 mg over tolterodine ER 4 mg on these endpoints and show the clinical value of the 8-mg fesoterodine dose, whereby patients who opt to escalate to the highest approved dose of fesoterodine (8 mg) are likely to achieve better symptom improvement than patients treated with the highest approved dose of tolterodine ER. The present findings are also consistent with a post hoc analysis of a phase III trial of fesoterodine that included tolterodine ER as an active control , which showed significantly greater improvements in UUI episodes and MVV per micturition with fesoterodine 8 mg vs tolterodine ER 4 mg .
In the present study, fesoterodine 8 mg was superior to tolterodine ER 4 mg on all study endpoints, except nocturnal micturitions, as early as week 4, which is 3 weeks after dose escalation to fesoterodine 8 mg. There were no significant differences between fesoterodine 4 mg and tolterodine ER 4 mg at week 1. However, fesoterodine 4 mg was associated with statistically significant improvements on all study endpoints vs placebo at week 1, whereas tolterodine ER 4 mg was associated with statistically significant improvements in UUI episodes and PPBC and UPS scores vs placebo at week 1. The apparent early efficacy of fesoterodine 4 mg and tolterodine ER 4 mg on OAB symptoms is important because these symptoms are often bothersome and can negatively impact HRQL . Early efficacy at 1 week of treatment has been previously shown for tolterodine ER and other antimuscarinics [26–29].
Both the present study and the previous head-to-head study  showed that fesoterodine 8 mg produced significantly greater improvements than tolterodine ER 4 mg and placebo on several subjective, self-reported assessments of the severity of OAB symptoms and the impact of these symptoms on subjects’ lives, including measures of symptom bother, HRQL, urgency and global severity of bladder-related problems. Moreover, fesoterodine 8 mg was associated with significantly greater improvements than tolterodine ER 4 mg on PROs as early as week 4, which parallels the results of diary assessments in the present study. These findings are notable because they suggest that the superiority of fesoterodine 8 mg over tolterodine ER 4 mg in the improvement of bladder diary variables reflect differences in efficacy that are clinically meaningful to patients with OAB.
Both active treatments were generally well tolerated in the present study. The generally higher occurrence of treatment-emergent adverse events in the fesoterodine 8 mg group compared to the tolterodine ER 4 mg and placebo groups mainly consisted of an increased incidence of dry mouth, and may be attributed to the study design, where dose escalation was not optional; therefore, the dose of fesoterodine may have been escalated in patients for whom 4 mg is the optimal fesoterodine dose.
A potential limitation of the present study was that dose escalation was not optional for subjects receiving fesoterodine; however, this investigation was focused on the maximum available doses of each agent. Whereas the use of the higher available dose of each active treatment was appropriate in the present study to show superiority, this may not directly reflect clinical practice. With flexible dosing, patients who achieve sufficient efficacy with fesoterodine 4 mg or adverse events limiting dose escalation would not escalate to the 8-mg dose, and patients who have unacceptable tolerability with fesoterodine 8 mg would likely be treated with the 4-mg dose. Future research may assess whether fesoterodine 4 mg or flexible-dose fesoterodine are associated with greater efficacy than tolterodine ER 4 mg.
In conclusion, in subjects with OAB symptoms including UUI, superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg was observed in key diary endpoints, as well as in improving subjects’ assessments of bladder-related problems, urgency, symptom bother and HRQL. The present study also showed the superiority of fesoterodine 8 mg over tolterodine ER 4 mg and placebo on most endpoints as early as week 4. Both active treatments were generally well tolerated. These results, together with those of the previous head-to-head trial , offer substantial evidence supporting the superiority of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of OAB symptoms for several diary endpoints; the availability of an additional 8-mg dose provides fesoterodine with a clinical advantage over single-dose tolterodine ER 4 mg.