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Keywords:

  • fesoterodine;
  • tolterodine;
  • head-to-head;
  • patient-reported outcomes;
  • efficacy;
  • safety;
  • quality of life

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

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.


Abbreviations
OAB

overactive bladder

5-HMT

5-hydroxymethyl tolterodine

ER

extended-release

UUI

urgency urinary incontinence

HRQL

health-related quality of life

MVV

mean voided volume

(TE)AE

(treatment-emergent) adverse event

PPBC

Patient Perception of Bladder Condition

UPS

Urgency Perception Scale

OAB-q

OAB Questionnaire

USS

Urinary Sensation Scale

ancova

analysis of covariance.

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Antimuscarinic agents are the first-line pharmacological treatment for overactive bladder (OAB) [1]. Fesoterodine is a nonselective oral antimuscarinic agent for the treatment of OAB symptoms that is rapidly and extensively converted by ubiquitous esterases to its active metabolite, 5-hydroxymethyl tolterodine (5-HMT). As a result, fesoterodine is not detectable in plasma after oral dosing and its antimuscarinic effects are attributable to 5-HMT [2,3]. The pharmacokinetic profile of 5-HMT is dose-proportional at doses up to 12 mg [4]. Tolterodine is also converted to 5-HMT, although this occurs primarily in the liver via cytochrome P450 (CYP) 2D6. A significant fraction of unconverted tolterodine is found in plasma [3]. Thus, both tolterodine and 5-HMT contribute to antimuscarinic effects in patients who take tolterodine [5], and the ratio of tolterodine to 5-HMT varies depending on the CYP 2D6 metabolizer status of the patient.

By contrast with tolterodine extended-release (ER), for which 4 mg is the one approved dose for treatment in the general population of patients with OAB [6], fesoterodine is available in both 4- and 8-mg once-daily doses [7,8]. In two fixed-dose phase III studies, fesoterodine 4 and 8 mg significantly improved bladder diary variables, including micturition frequency, urgency episodes, and urgency urinary incontinence (UUI) episodes, compared with placebo [9,10]; a pooled analysis showed that fesoterodine 4 and 8 mg also significantly improved measures of health-related quality of life (HRQL) vs placebo [11]. One of the two phase III trials of fesoterodine included tolterodine ER as an active control [9]. A post hoc analysis showed statistically significant differences in favour of fesoterodine 8 mg over tolterodine ER 4 mg for UUI episodes as well as mean voided volume (MVV) per void [12]. However, there are currently no data from studies designed primarily to make a head-to-head comparison of fesoterodine vs tolterodine ER to assess whether the higher 8-mg dose of fesoterodine provides additional clinical benefit compared with the recommended 4-mg dose of tolterodine.

Thus the primary objective of the present study was to assess whether the efficacy of fesoterodine 8 mg is superior to that of tolterodine ER 4 mg and placebo in improving symptoms of OAB and patient-reported outcomes.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This was a 12-week, randomized, double-blind, double-dummy, placebo-controlled, parallel group, multicentre trial with a 2-week single-blind placebo run-in period. Upon completion of the placebo run-in, patients who met the entry criteria were randomized in a double-blind fashion to fesoterodine 8 mg, tolterodine ER 4 mg, or placebo, in a 2:2:1 ratio. A simple randomization schedule with a block size of five was implemented using a centralized system. The randomization schedule was generated, secured, distributed and stored by Pfizer Global Clinical Data Services; neither the investigator nor the patient was aware of which treatment was administered.

The USA and European fesoterodine product labels recommend a starting dose of fesoterodine of 4 mg once-daily, which can be increased to 8 mg once-daily based on individual response and tolerability [7,8]. In the present study, all patients in the fesoterodine group started on fesoterodine 4 mg for 1 week, followed by fesoterodine 8 mg for 11 weeks. All patients in the tolterodine ER group received tolterodine ER 4 mg capsules for all 12 weeks. A double-dummy design was used, with all patients receiving one tablet (fesoterodine 4 or 8 mg, or matching placebo) and one capsule (tolterodine ER 4 mg, or matching placebo) daily. Throughout the trial, including the placebo run-in and double-blind treatments, all medications were taken once daily in the morning.

The study was approved by the appropriate Institutional Review Boards and Independent Ethics Committees. All patients provided written informed consent, and the trial was conducted in accordance with the protocol, International Conference on Harmonization Good Clinical Practice guidelines, and applicable local regulatory requirements and laws.

Eligible patients were men and women aged ≥18 years, with symptoms of OAB (self-assessed) for ≥3 months before screening and a mean of one or more UUI episode/24 h and ≥8 voids/24 h reported in 3-day bladder diaries completed at baseline. Patients were excluded if they had: clinically significant hepatic or renal disease; lower genitourinary pathology or surgical treatment thereof responsible for voiding dysfunction; neurological conditions such as stroke, multiple sclerosis, spinal cord injury, or Parkinson’s disease; previous history of acute urinary retention requiring catheterization; symptoms of incontinence being predominately stress UI in the opinion of the investigator; treatment with antimuscarinic OAB medication within 2 weeks before screening; or use of any electrostimulation, bladder training, or pelvic floor exercises within 4 weeks of screening. Female patients of childbearing potential who were heterosexually active without using an adequate form of contraception, or who were pregnant, nursing, or with a positive urine pregnancy test were also excluded.

Patients completed 3-day bladder diaries at baseline and week 12. Efficacy endpoints corresponded to changes from baseline to week 12 in UUI episodes/24 h (primary endpoint); MVV/void; and voids, nocturnal voids, urgency episodes, severe urgency episodes, and frequency-urgency sum per 24 h. Patients rated the sensation associated with each void using the 5-point Urinary Sensation Scale (USS; 1, no urgency; 2, mild urgency; 3, moderate urgency; 4, severe urgency; 5, UUI) [13]. Urgency episodes and severe urgency episodes were defined by a rating of ≥3 and ≥4, respectively, on the USS. Frequency-urgency sum, defined as the sum of USS ratings associated with all voids over the course of 24 h averaged over the diary period, is an integrated, validated measure reflecting both voiding frequency and urgency [14,15] that has been used in several recent studies [16–19].

Patients also completed the Patient Perception of Bladder Condition (PPBC), Urgency Perception Scale (UPS), and OAB Questionnaire (OAB-q) at baseline and week 12. The PPBC is a validated single-item questionnaire that asks patients to rate their overall bladder condition; lower scores indicate less-severe bladder-related problems [20]. The validated UPS is a single-item instrument with a 3-point, ordered, categorical response scale to assess patients’ perception of urgency; higher scores indicate less urgency [21]. The validated OAB-q includes an eight-item Symptom Bother scale and a 25-item HRQL scale [22]. Symptom Bother items address the level of bother associated with the patient’s bladder condition; lower scores indicate less symptom bother. The HRQL scale comprises four domains (Concern, Coping, Sleep, and Social Interaction); higher scores indicate better HRQL. Each OAB-q scale or domain score is transformed so that scores range from 0 to 100 [22].

Sample size determination was based on the previously observed mean (sd) treatment difference of 0.44 (2.36) between fesoterodine 8 mg and tolterodine ER 4 mg groups for change in UUI episodes/24 h from baseline to week 12 [9]. A sample size of 606 patients per active treatment group was required to detect a difference between fesoterodine and tolterodine ER in the change in UUI episodes from baseline to week 12 using a two-sided t-test at the 5% significance level with 90% power. Based on the previously observed mean (sd) treatment differences of 1.07 (2.85) between fesoterodine 8 mg and placebo groups, and 0.63 (2.81) between tolterodine ER 4 mg and placebo groups [9], 303 patients were required in the placebo group for ≥88% power for each comparison. Thus, 1515 patients were required. Assuming that approximately 90% of the randomized patients would contribute to the full-analysis set, it was planned to randomize 1675 patients. Tolerability findings were analysed descriptively based on the safety-analysis set, which included all patients who were randomized and took one or more dose of double-blind study drug. Efficacy was analysed using the full-analysis set, which included randomized patients who took one or more dose of double-blind study drug and had one or more valid baseline or postbaseline efficacy assessment.

Treatment differences in changes in UUI episodes/24 h from baseline to week 12 (primary endpoint) were assessed using a closed testing procedure: the fesoterodine group was first compared with placebo, and then with the tolterodine ER group if the difference from placebo was significant. The tolterodine ER group was also compared with placebo. Numerical and percentage changes from baseline for each diary endpoint were considered in separate hierarchical order to preserve the α-level of 5% within each diary endpoint. Numerical changes were tested first, and percentage changes were tested only if the difference in numerical change was statistically significant.

The statistical analysis plan specified that all bladder diary data were to be tested for whether they met the normality assumptions, and the appropriate (parametric or nonparametric) analytical methods were to be used. This assessment, based on whether the residuals derived from analysis of covariance (ancova) were normally distributed [23], revealed that changes in UUI episodes/24 h did not meet normality assumptions, whereas other diary endpoints did (Fig. 1). Thus, baseline to week-12 differences in UUI episodes/24 h are presented as Winsorized means, which are less sensitive to outliers in the sample distribution tails, while still being a robust estimator of the sample mean. The Winsorized mean was calculated by replacing 5% of the sample distribution tails with values at the 5th and 95th percentiles, respectively. The significance of changes in UUI episodes were assessed using the nonparametric Van Elteren’s test, a stratified Wilcoxon-Mann–Whitney test [24,25].

image

Figure 1. Normality analyses for diary endpoints. Scatter plots of residuals yielded from fits of bladder diary data to an ancova model vs quantiles: UUI episodes/24 h (A), MVV/void (B), voids/24 h (C), and urgency episodes/24 h (D). Data represent the full-analysis set (placebo 313; tolterodine ER 641; fesoterodine 636).

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The statistical significance of baseline to week-12 changes in other diary endpoints, which met the normality assumptions, were determined based on an ancova model including baseline value as a covariate with treatment and country as factors. Percentage changes from baseline in bladder diary endpoints were analysed using ancova, except that a ranked score based on ranking of the percentage changes was used for the dependent variable and a ranked baseline value was used as a covariate. The Cochran-Mantel-Haenszel test stratified by country was used for PPBC and UPS data. An ancova model was used to assess treatment differences in OAB-q scale and domain scores that included baseline value as a covariate with treatment and country as factors. Statistical comparisons between the fesoterodine and tolterodine ER groups and between tolterodine ER and placebo groups for PPBC, UPS, and OAB-q data were not pre-specified and were conducted post hoc. Missing postbaseline data were imputed based on the last-observation-carried-forward principle using data from interim visits; baseline data were not carried forward. All tests were two-sided based on an α-level of 5%.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Of 1712 patients randomized, 1697 (fesoterodine 679; tolterodine ER 684; placebo 334) received one or more dose of study medication (Fig. 2). Among these patients, 91%, 92% and 88% in the placebo, tolterodine ER and fesoterodine groups, respectively, completed the study. Site audits conducted by an independent quality-assurance group revealed irregularities in bladder diary data obtained from two sites that were in violation of Good Clinical Practice guidelines; the patients from these two sites (107) were not included in the efficacy analyses. This decision was made before the database unblinding and was documented in the final statistical analysis plan. A sensitivity analysis showed that excluding these patients from the analysis of the primary endpoint did not affect the result.

image

Figure 2. Patient disposition. FAS = full analysis set; TEAEs (any cause). *Includes protocol violation, not meeting entrance criteria, and other reasons.

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Baseline demographic and clinical characteristics were similar among the placebo, tolterodine ER and fesoterodine groups (Table 1). Overall, approximately 80% were women, 78% were white, and the mean age of patients was approximately 58 years. The mean OAB symptom duration was approximately 7 years, and about half of the patients had previously used antimuscarinics. Of all patients, approximately 1% reported no UUI episodes during the 3-day diary period at baseline and were in violation of the study inclusion criterion. These patients were included in the safety and efficacy analyses with two relevant exceptions: they were excluded from the analyses of baseline to week 12 changes in UUI episodes/24 h and of the diary-dry rates (see below).

Table 1.  Baseline demographic and clinical characteristics*
Mean (sd), Mean (sd, range), or n (%) variablePlaceboTolterodine ERFesoterodine
  • *

    Demographic data represent the safety set; baseline diary variable data represent the full analysis set (placebo, 313; tolterodine ER, 641; fesoterodine, 636) for all patients reporting the symptom at baseline; patient-reported outcome data represent the full analysis set.

  • †1, Not able to hold urine. 2, Able to hold urine (without leaking) until I reach a toilet immediately. 3, Able to finish the ongoing work before going to the toilet (without leaking).

No. of patients334684679
Gender; women269 (81)564 (83)558 (82)
Age, years 58.4 (13.7, 20–95) 58.5 (13.2, 18–92) 57.8 (12.8, 19–88)
Race
 White261 (78)534 (78)539 (79)
 Asian 32 (10) 71 (10) 67 (10)
 Black 11 (3) 22 (3) 23 (3)
 Other 30 (9) 57 (8) 50 (7)
OAB duration, years  7.3 (0.3–62.2)  6.9 (0.2–60.8)  7.1 (0.3–66.2)
Patients with ≥1 UUI episode during the 3-day diary at baseline329 (99)672 (98)666 (98)
Bladder diary variables
 UUI episodes/24 h  2.6 (2.3)  2.5 (2.2)  2.4 (2.0)
 Total voids/24 h 11.9 (3.5) 11.7 (3.4) 11.7 (3.1)
 Nocturnal voids/24 h  2.3 (1.3)  2.2 (1.3)  2.2 (1.3)
 Urgency episodes/24 h  9.4 (4.2)  9.3 (3.7)  9.3 (3.9)
 Severe urgency episodes/24 h  5.7 (3.6)  5.9 (3.6)  5.9 (3.7)
 MV V/void, mL147.9 (58.3)154.1 (64.5)155.3 (61.8)
 Frequency-urgency sum/24 h 41.0 (14.3) 40.5 (13.8) 40.4 (13.4)
PPBC
 Not many problems at all (1)  2 (1)  5 (1)  2 (<1)
 Some very minor problems (2) 10 (3) 17 (3) 16 (3)
 Some minor problems (3) 21 (7) 38 (6) 52 (8)
 Some moderate problems (4) 97 (31)235 (37)228 (36)
 Severe problems (5)133 (43)243 (38)237 (38)
 Many severe problems (6) 50 (16) 94 (15) 95 (15)
UPS
 1131 (42)233 (37)227 (36)
 2169 (54)381 (60)371 (59)
 3 13 (4) 19 (3) 32 (5)
OAB-q
 Symptom Bother 58.9 (19.0) 58.6 (19.5) 57.5 (20.3)
 Total HRQL 56.0 (22.5) 55.6 (22.2) 58.4 (22.1)
  Concern 52.4 (25.0) 51.5 (25.7) 54.6 (25.3)
  Coping 48.2 (26.3) 48.0 (26.2) 52.2 (26.1)
  Sleep 55.0 (26.1) 54.4 (26.5) 55.5 (25.4)
  Social Interaction 74.4 (24.4) 74.6 (23.6) 76.6 (23.1)

The mean reduction in the number UUI episodes/24 h (primary endpoint) was significantly greater from baseline to week 12 in the fesoterodine group than with tolterodine ER (P = 0.017) or placebo (P < 0.001; Fig. 3A). Tolterodine ER also produced a significantly greater improvement in UUI episodes than placebo (P = 0.011).

image

Figure 3. Change from baseline to week 12 in UUI episodes/24 h (A), MVV/void (B), total voids/24 h (C), nocturnal voids/24 h (D), urgency episodes/24 h (E), severe urgency episodes/24 h (F), and frequency-urgency sum/24 h (G). Error bars represent the sem. Data represent the full-analysis set for patients reporting symptoms at baseline (except for voids/24 h and frequency-urgency sum). *P < 0.05 vs placebo; †P < 0.05 fesoterodine vs tolterodine ER.

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The median percentage reduction in UUI episodes in both the fesoterodine (100%) and tolterodine ER (100%) groups was significantly greater than the 82.1% reduction in the placebo group (both P < 0.001; Table 2). These data indicate that half or more of patients in the fesoterodine and tolterodine ER groups who had at least one UUI episode in the baseline diary reported no UUI episodes in bladder diaries at week 12; however, the statistically significant difference between these active treatment groups indicated that one group had a greater proportion of patients without UUI episodes at week 12 (P = 0.022). To assess the relative improvements in UUI episodes in the two active treatment groups, a post hoc analysis was used to determine the diary-dry rate, defined as the proportion of patients in each treatment group reporting one or more UUI episodes during the baseline diary period who reported no UUI episodes during the subsequent diary period; patients with no UUI episodes at baseline, constituting approximately 1% of study population, were not included in this analysis. The diary-dry rate at week 12 was significantly greater for patients receiving fesoterodine (64.0%, 396/619) than for those receiving tolterodine ER (57.2%, 358/626; P = 0.015) or placebo (45.0%, 138/307; P < 0.001). The difference between tolterodine ER and placebo in diary-dry rate at week 12 was also significant (P < 0.001).

Table 2.  Median percentage changes in bladder diary variables from baseline to week 12*
VariablePlaceboTolterodine ERFesoterodine
  • *

    Data represent the full analysis set.

  • P < 0.05 vs placebo;

  • P < 0.05 vs tolterodine ER.

  • ¶Inferential analysis was not done because the differences in the mean numerical change from baseline to week 12 were not statistically significant.

No. of patients313 641 636
UUI episodes/24 h−82.1−100−100
Total voids/24 h−12.1 −16.2 −18.9
Nocturnal voids/24 h−25.0 −27.9 −28.6
Urgency episodes/24 h−17.6 −30.8 −37.9
Severe urgency episodes/24 h−48.0 −63.4 −71.4

Fesoterodine produced a significantly greater increase in MVV/void from baseline to week 12 than tolterodine ER (P = 0.005) or placebo (P < 0.001; Fig. 3B). Compared with placebo, fesoterodine also significantly reduced voids (Fig. 3C), urgency episodes (Fig. 3E), severe urgency episodes (Fig. 3F), and frequency-urgency sum (Fig. 3G; all P < 0.001) per 24 h vs placebo, but not nocturnal voids/24 h (Fig. 3D; P = 0.327). The differences between fesoterodine and tolterodine ER on micturitions (P = 0.380), urgency episodes (P = 0.054), severe urgency episodes (P = 0.139), and frequency-urgency sum (P = 0.105) per 24 h were numerically in favour of fesoterodine but not statistically significant. Compared with placebo, tolterodine ER produced significantly greater baseline to week 12 improvements in voids (P < 0.001), urgency episodes (P < 0.001), severe urgency episodes (P < 0.001) and frequency-urgency sum (P < 0.001) per 24 h, but not MVV (P = 0.103) or nocturnal voids/24 h (P = 0.506). Median percentage changes in bladder diary variables are presented in Table 2.

The categorical change in PPBC score from baseline to week 12 (classified as a ≥2-point improvement, 1-point improvement, no change, or deterioration), was significantly more favourable in the fesoterodine group than in patients on placebo (P < 0.001) and tolterodine ER (P < 0.001, post hoc statistical comparison). Changes in the tolterodine ER group were also significantly more favourable than in the placebo group (P < 0.001, post hoc statistical comparison; Fig. 4). Consistent with this, the proportion of patients reporting ‘some minor problems’ or better on the PPBC at week 12 was higher in the fesoterodine group (55%) than in the tolterodine ER (45%, P < 0.001) and placebo (33%, P < 0.001) groups. The difference between the tolterodine ER and placebo groups was also statistically significant (P < 0.001).

image

Figure 4. Baseline to 12 week changes in PPBC. Data represent the full-analysis set. *P < 0.001 fesoterodine vs placebo; †P < 0.001 fesoterodine vs tolterodine ER (post hoc comparison); ‡P < 0.001 tolterodine vs placebo (post hoc comparison).

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The categorical change in UPS score from baseline to week 12 (classified as improvement, no change, or deterioration) was significantly more favourable for fesoterodine than placebo (P < 0.001) and tolterodine ER (P = 0.014, post hoc statistical comparison) groups (Fig. 5); the difference between the tolterodine ER and placebo groups was not statistically significant (P = 0.167, post hoc statistical comparison). The proportion of patients who reported ‘I am usually able to finish what I am doing before going to the toilet (without leaking)’ at week 12 was higher in the fesoterodine group (31%) than with tolterodine ER (23%, P = 0.002) or placebo (15%, P < 0.001) groups. The difference between the tolterodine ER and placebo groups was also statistically significant (P = 0.003).

image

Figure 5. Baseline to 12 week changes in UPS scores. Data represent the full-analysis set. *P < 0.001 fesoterodine vs placebo; †P = 0.014 fesoterodine vs tolterodine ER (post hoc comparison). The tolterodine ER vs placebo comparison was not significant (P = 0.167).

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Improvements in OAB-q scores from baseline to week 12 were significantly greater in the fesoterodine than the placebo group on the Symptom Bother scale, total HRQL scale, and all four HRQL domains (all P < 0.001). In a post hoc statistical comparison, improvements from baseline to week 12 in the fesoterodine group were also significantly greater than in the tolterodine ER group on the Symptom Bother (P < 0.001) and total HRQL (P = 0.006) scales and the Concern (P = 0.008), Coping (P = 0.002), and Social Interaction (P = 0.019) domains, but not on the Sleep domain (P = 0.081; Fig. 6). Also in a post hoc statistical comparison, improvements from baseline to week 12 in the tolterodine ER group were significantly greater than in the placebo group on the OAB-q Symptom Bother (P < 0.001) and total HRQL (P = 0.002) scales, and the Concern (P < 0.001), Coping (P = 0.004) and Social Interaction (P = 0.029) domains, but not on the Sleep domain (P = 0.052). For all treatment groups, least squares mean changes in all scale and domain scores from baseline to week 12 exceeded the minimally important difference of 10 points, which is the smallest change in score that is clinically meaningful [26], except for Social Interaction domain scores for the placebo (6.8 points) and tolterodine ER (9.4 points) groups.

image

Figure 6. Baseline to 12 week changes in OAB-q scores. Data represent the full-analysis set (placebo, 313; tolterodine ER, 641; fesoterodine 636). *P < 0.001 fesoterodine vs placebo; †P < 0.02 fesoterodine vs tolterodine ER (post hoc comparison); ‡P < 0.05 tolterodine ER vs placebo (post hoc comparison).

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Both fesoterodine and tolterodine ER were well tolerated with few patients discontinuing during the study due to adverse events (AEs). Among these patients, six (2%) receiving placebo, 28 (4%) receiving tolterodine ER, and 42 (6%) receiving fesoterodine, discontinued due to treatment-emergent AEs (TEAEs) of any cause. The most frequently reported TEAEs in the fesoterodine group were dry mouth (28%), headache (6%) and constipation (5%; Table 3). These were also the most frequently reported TEAEs in the tolterodine ER group, with rates of 16%, 3% and 4%, respectively. In the placebo group, the rates were 6%, 2% and 3%, respectively. The large majority of all AEs, including dry mouth, were mild or moderate in all treatment groups. Dry mouth was reported as severe by two (1%), seven (1%) and 14 (2%) patients in the placebo, tolterodine ER, and fesoterodine groups, respectively.

Table 3.  The most-commonly reported TEAEs (all cause), reported by ≥2% patients in the safety set in either active treatment group with higher incidence than placebo
VariablePlaceboTolterodine ERFesoterodine
No. of patients334684679
TEAEs, %
 Dry mouth  6.0 16.4 27.8
 Headache  2.4  3.4  5.6
 Constipation  3.0  4.1  5.4
 UTI  0.6  1.5  2.2
 Diarrhoea  1.2  2.2  2.1

There were four fatal serious AEs during the course of the study, including two in the placebo and two in the fesoterodine groups; these deaths were all reported as unrelated to study treatment. Non-fatal serious AEs occurring during treatment or within 30 days of the last dose were reported by six (2%), nine (1%) and 16 (2%) of patients in the placebo, tolterodine ER and fesoterodine groups, respectively. None of the serious AEs reported in the placebo or tolterodine ER groups were considered to be treatment-related. Two serious AEs reported in the fesoterodine group were considered to be treatment-related. One of these patients, a 70-year-old man with a history of benign prostatic enlargement and elevated PSA levels, developed urinary retention after 6 days of treatment with fesoterodine 4 mg and required catheterization.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This is the first head-to-head trial with the primary objective of assessing the superiority of fesoterodine over tolterodine ER for the treatment of OAB symptoms. Compared with tolterodine ER, fesoterodine showed significantly greater efficacy in reducing UUI episodes, the primary endpoint, and in increasing bladder capacity, as measured by MVV. The diary-dry rate at week 12 was also significantly greater among patients receiving fesoterodine than in those receiving tolterodine ER, and fesoterodine produced significantly greater improvements than tolterodine ER on the PPBC and UPS, and on the Symptom Bother and total HRQL scales, and the Concern, Coping, and Social Interaction domains of the OAB-q. These findings are consistent with a post hoc analysis of data from a phase III trial of fesoterodine that included tolterodine ER as an active control [9], which showed that fesoterodine 8 mg was significantly more effective than tolterodine ER 4 mg on several endpoints, including UUI episodes, MVV, and continent days/week. In the present study, improvements in voids, urgency episodes, severe urgency episodes, and frequency-urgency sum/24 h did not differ significantly between fesoterodine and tolterodine ER groups. However, improvements in all of these variables were numerically in favour of the fesoterodine group. A possible explanation for the lack of statistically significant differences in these diary variables might be that the study was powered to assess differences between treatment groups in baseline to week 12 changes in UUI episodes/24 h (the primary variable). As in the present study, the phase III trial that was used to calculate the sample size necessary to detect a treatment difference in UUI episodes also found that changes in frequency and urgency episodes were numerically in favour of fesoterodine 8 mg vs tolterodine ER 4 mg, but not statistically significant [9]. Also consistent with previous results [9,10,16,17,27–30], both tolterodine ER and fesoterodine were associated with significantly greater improvements in bladder diary variables and patient-reported outcomes than was placebo.

The patients’ perception of the impact of symptoms on their physical and emotional well-being is important in the management of OAB [31]. Measuring patient-reported outcomes has been aided by the development of several validated condition-specific instruments, such as those used in the present study [31]. Such instruments are important as they assess patients’ perception of bladder condition, urgency, symptom bother and HRQL, and thus yield information that is not captured by bladder diaries, in which patients only assess objective OAB symptoms. Moreover, correlations between scores on questionnaires and bladder diary variables, although small to moderate, have been shown to be statistically significant [20,21,32–34]. The present study shows that fesoterodine produced significantly greater improvements than tolterodine ER in symptom bother and HRQL, as measured by the OAB-q, and in patients’ overall assessments of bladder-related problems and urgency, as measured by the PPBC and UPS, respectively. These findings are notable because they suggest that the greater improvements in symptoms with fesoterodine than with tolterodine ER are meaningful to patients at the subjective level of perception of bladder-related problems, urgency, and emotional and physical aspects of HRQL.

Both fesoterodine and tolterodine ER were generally well tolerated, as reflected by the overall rates of discontinuation due to TEAEs in both treatment groups; the rates of TEAEs including, dry mouth, constipation, and headache, are generally consistent with those reported in previous trials of antimuscarinics [28]. The incidence of urinary retention was also low, although there was one case of urinary retention in the fesoterodine group reported as a serious AE related to study treatment.

While the study was designed to compare the higher recommended doses of fesoterodine and tolterodine ER, a potential limitation is that dose escalation was not optional for patients receiving fesoterodine in this study; this does not directly reflect clinical practice, where flexible dosing is used. With flexible dosing, patients who achieve acceptable efficacy with the 4 mg dose would not increase to 8 mg.

In conclusion, in the present patients with OAB symptoms, including UUI, fesoterodine 8 mg had superior efficacy over tolterodine ER 4 mg for reducing UUI episodes, the primary endpoint of this study, which was supported by a significantly greater diary-dry rate derived from a post hoc analysis. Fesoterodine 8 mg also had superior efficacy over tolterodine ER 4 mg in increasing MVV. Moreover, fesoterodine 8 mg produced significantly greater improvements than tolterodine ER 4 mg in patients’ assessments of bladder-related problems, urgency, symptom bother, and HRQL as measured by PPBC, UPS and OAB-q. Both active treatments were generally well tolerated. These results support the notion that the 8-mg dose of fesoterodine provides additional clinical benefit compared with tolterodine ER 4 mg.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

This study was sponsored by Pfizer Inc. Editorial assistance was provided by Simon J. Slater, PhD and Colin P. Mitchell, PhD from Complete Healthcare Communications, Inc. and was funded by Pfizer Inc.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Sender Herschorn is a Paid Consultant to the Sponsor and receives a Honorarium and Grant/Research support. Steven Swift is an Advisory Board member and a Patent Inventor for the clinical site and speakers bureau. Zhonghong Guan, Martin Carlsson, Jon D. Morrow, Marina Brodsky and Jason Gong are Employees of the Sponsor. Source of funding: Pfizer Inc.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES