Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder

Authors


Osamu Yamaguchi, Department of Urology, Fukushima Medical University School of Medicine, Hikarigaoka-1, Fukushima 960–1295, Japan. e-mail: yamaosa@cc.fmu.ac.jp

Abstract

OBJECTIVES

To compare solifenacin succinate (5 and 10 mg once-daily) to placebo and propiverine hydrochloride (20 mg once-daily), respectively, in Japanese patients with overactive bladder syndrome (OAB).

PATIENTS AND METHODS

A multicentre, 12-week, double-blind phase III trial randomized men and women aged ≥ 20 years with OAB to solifenacin 5 or 10 mg, propiverine 20 mg, or placebo. Changes at endpoint in number of voids/24 h, urgency, incontinence, urgency incontinence and nocturia episodes, volume voided/void, restoration of continence and quality of life (QoL) were examined.

RESULTS

Of 1593 patients randomized, 1584 were treated; at the endpoint there were greater reductions in mean (sd) voids/24 h with solifenacin 5 mg, at −1.93 (1.97), and 10 mg, at −2.19 (2.09), and propiverine 20 mg, at −1.87 (2.70), than with placebo, at −0.94 (2.29) (P < 0.001 for all). Solifenacin (5 and 10 mg) was superior to placebo, and no worse than propiverine 20 mg, for this variable. There were significantly fewer mean (sd) urgency, incontinence and urgency incontinence episodes with solifenacin and propiverine than with placebo, with respective changes on placebo of − 1.28 (2.90), − 0.72 (1.95) and − 0.69 (2.00); solifenacin 5 mg, − 2.41 (2.88), −1.59 (2.12) and −1.45 (1.89) (P < 0.001 for all), and 10 mg, −2.78 (2.82), − 1.60 (1.81) and − 1.52 (1.77) (P < 0.001 for all), and propiverine 20 mg, −2.30 (3.08), −1.25 (2.79) and − 1.19 (2.20) (P < 0.001, = 0.002 and = 0.002 respectively). All active treatments vs placebo improved the volume voided (P < 0.001 for all) and QoL; solifenacin 10 mg reduced nocturia episodes (P = 0.021) and significantly improved urgency episodes (P = 0.012) and volume voided (P = 0.009) vs propiverine 20 mg, and solifenacin 5 mg caused less dry mouth (P = 0.003). Solifenacin 10 mg caused more dry mouth (P = 0.012) and occurrences of constipation (P = 0.004) than propiverine 20 mg, but discontinuation rates between both treatment groups were similar. Continence was restored at endpoint in more than half of the patients on active treatment.

CONCLUSION

Solifenacin 5 and 10 mg once daily significantly improved the symptoms of OAB compared with placebo. Solifenacin therapy at 5 mg once daily is well-tolerated; 10 mg can be given if additional efficacy is required.

Abbreviations
OAB

overactive bladder

QoL

quality of life

ER

extended-release

STAR

‘Solifenacin and tolterodine (as an active comparator) in a randomized trial’

PVR

postvoid residual urine volume

ECG

electrocardiogram

KHQ

King’s Health Questionnaire

AE

adverse event.

INTRODUCTION

Overactive bladder syndrome (OAB) has a profound effect on the lifestyle of many individuals; in 2002, the ICS modified the definition of OAB to ‘urgency, with or without urgency incontinence, usually with frequency and nocturia’[1]. This definition of OAB not only clarified the symptoms required for a diagnosis of OAB [2] but also renewed interest in examining the epidemiology and prevalence of OAB in various countries [3–6]. The prevalence of OAB in Japan was recently reported in a nationwide study. It is estimated that 12.4%, or 8.1 million individuals, (aged ≥ 40 years) in Japan have OAB [7], and that few people are aware of the condition or simply do not seek their physician’s advice for other reasons, e.g. embarrassment or social stigma. In addition, the report concluded that, despite the use of the modified OAB definition and hence differences in prevalence results, findings were in line with previous European and USA studies [8,9], in that there are many people with OAB and adversely affected quality of life (QoL) [10]. The prevalence of OAB increases with age [8] (although importantly, it is not a normal part of the ageing process), and it is of interest that the percentage of the population classified as elderly (≥ 65 years) in Japan is estimated to increase from 17.4% in 2000 to 25% in 2014, and 36% in 2050.

The current mainstay of OAB pharmacotherapy are antimuscarinic agents, e.g. oxybutynin chloride (oxybutynin) and tolterodine tartrate extended-release (tolterodine ER), which are widely prescribed in Europe and the USA, and newer compounds such as solifenacin succinate (solifenacin) and darifenacin hydrobromide (darifenacin) that have recently been made available. In Japan, no new compounds have been launched for >10 years, and pharmacotherapeutic options for treating OAB symptoms have been limited to oxybutynin, flavoxate hydrochloride and propiverine hydrochloride (propiverine in Japan, 10–40 mg daily; in Europe, 15–45 mg daily). Propiverine is an antimuscarinic agent with mixed actions, including musculotropic (calcium antagonistic) activity, which are enhanced by its pharmacologically active metabolites [11,12]. Since its launch in 1993, propiverine has become the most widely prescribed agent for treating OAB in Japan; however, there are no quantitative urgency data available for propiverine therapy, or trials of its effectiveness compared with other antimuscarinic agents in Japanese patients, despite the importance of urgency (based on the ICS definition of OAB in 2002), and the recognized need for comparative trials.

Solifenacin is a novel muscarinic receptor antagonist recently launched for use in the treatment of OAB. Results of preclinical studies showed that solifenacin increased bladder capacity and volume voided without affecting residual volume or micturition pressure in a rat model of detrusor overactivity [13]. In in vitro and in vivo studies, solifenacin showed apparent functional selectivity for the bladder over salivary gland that was greater than that of tolterodine, oxybutynin and darifenacin [14–16]. This suggests that treatment with solifenacin might be associated with efficacy against OAB symptoms, with potentially less dry mouth than with other antimuscarinic drugs. Solifenacin is available in once-daily doses of 5 mg and 10 mg, with 5 mg recommended as the starting dose. Data on the efficacy (including reductions in urgency) and tolerability of solifenacin 5 mg and 10 mg were previously reported [17–19]. Recently, a direct comparison, ‘Solifenacin and tolterodine (as an active comparator) in a randomized trial’, or STAR, comparing solifenacin with tolterodine ER (4 mg once daily) was conducted in which solifenacin (in a flexible-dosing regimen) was shown to be no worse than tolterodine ER for the primary efficacy variable (the mean number of voids/24 h). In the same study, solifenacin was more effective than tolterodine ER in decreasing urgency episodes, urgency incontinence, pad usage and in increasing volume voided/void [20]. To date, no studies of any new antimuscarinic drugs, compared with propiverine as an active control, have been conducted in Japan to evaluate clinical outcomes for the treatment of OAB. Therefore, the present study was conducted to assess whether solifenacin 5 mg and 10 mg once daily was comparable with placebo and propiverine 20 mg once daily (the most commonly prescribed dose in Japan), respectively, in a large population of Japanese patients with OAB. In addition, the efficacy and safety of solifenacin 5 mg and 10 mg were also compared with placebo and propiverine 20 mg.

PATIENTS AND METHODS

Men and women aged ≥ 20 years and with symptoms of OAB reported for ≥6 months were eligible for screening and study enrolment. To be eligible for randomization after the 2-week placebo run-in period, patients had to report a mean number of voids/24 h of ≥ 8, ≥ 3 episodes of urgency and/or ≥ 3 episodes of urgency incontinence during a 3-day voiding-diary period.

Exclusion criteria at study entry included significant BOO, an assessment based on measuring the postvoid residual urine volume (PVR); patients with a PVR of ≥ 100 mL were excluded. In addition, the investigators (who were all urologists) assessed the presence of BOO symptoms, which were also grounds for exclusion. Other exclusion criteria included urinary retention, demonstrable stress incontinence, bladder stones, UTI, interstitial cystitis, previous or current malignant disease of the pelvic organs, and previous pelvic radiation. In addition, patients were excluded if they were taking concomitant anticholinergic medications, or had known or suspected hypersensitivity to anticholinergic medications or lactose.

The study was a multicentre, randomized, double-blind, double-dummy, placebo- and active-controlled phase III trial, conducted at 155 centres in Japan. The study design is shown in Fig. 1. At the initial screening visit (week − 2), a medical history was taken, with measurement of PVR, blood and urine laboratory analyses, 12-lead electrocardiogram (ECG) and physical examinations. Patients eligible for enrolment received placebo medication once daily during a 2-week run-in period. During the 3 days before the next visit (week 0), patients recorded episodes of voiding, urgency, incontinence and volume voided/void in a 3-day voiding diary. Patients were then randomized equally to 12-week, double-blind, once-daily treatment with either solifenacin 5 mg, solifenacin 10 mg, propiverine 20 mg or placebo.

Figure 1.

The study design.

The study was conducted in accordance with the International Conference on Harmonization and Good Clinical Practice guidelines, and the principles of the Declaration of Helsinki. The study protocol received Institutional Review Board approval at all sites. All patients were informed of the nature and purpose of the study, and written informed consent was obtained before screening.

The primary efficacy variable was the change from baseline to the endpoint visit in the mean number of voids/24 h. Efficacy data were measured at week 12, and the last-observation-carried-forward approach was used to determine endpoint values if week 12 data were not available. Secondary efficacy variables included the change from baseline in the mean number of urgency, incontinence and urgency incontinence episodes per 24 h, the mean number of nocturia episodes, and the mean volume voided/void. After randomization and the start of the 12-week treatment period, patients were evaluated for efficacy every 4 weeks. In addition to these variables, normalization rates for the mean number of voids/24 h (defined as the proportion of patients having <8 voids/24 h at endpoint vs patients with ≥ 8 voids/24 h at baseline), resolution of urgency episodes (defined as the number of patients with urgency at baseline vs the proportion of patients who became free of urgency at endpoint) and restoration of continence (defined as the number of patients with incontinence at baseline vs the proportion of patients becoming continent at endpoint) were evaluated. Data for these evaluations were collected by voiding diaries completed for 3 days before each visit.

Patient QoL was assessed using the King’s Health Questionnaire (KHQ) [21], a disease-specific instrument consisting of 21 questions in nine domains, designed to identify individual bladder problems and their effect on the patient. Each domain is scored individually, and while there is no overall score, reductions in domain scores represent improvements in QoL. Patients in the study were supplied with the questionnaire at week 0 and week 12, and changes in KHQ scores from baseline to study endpoint were evaluated.

Adverse events (AEs) were recorded and categorized by severity and likelihood of causal relationship to the study medication. Other safety assessments at weeks 4, 8 and 12 included physical examinations and AE recording. Laboratory test results and vital signs were assessed at weeks 0, 4 and 12, and a 12-lead ECG done during the run-in period and repeated at the end of the study.

The efficacy analysis population comprised all randomized patients with data available at baseline (visit 2) and for at least one visit thereafter, who received at least one dose of study medication. Patients whose domain score for at least one KHQ domain could be calculated and who received study drugs during the treatment period for ≥ 14 days comprised the QoL population. Safety analyses were conducted for all patients who received at least one dose of study medication.

The primary objective of the study was to assess the superiority of solifenacin to placebo and the non-inferiority of solifenacin to propiverine 20 mg in its effect on the reduction in the mean number of voids/24 h. The required enrolment was ≥ 350 patients per arm to detect superiority to placebo at a power of 90%, and the non-inferiority of solifenacin to propiverine 20 mg at a power of 80%, which were analysed by: a t-test with a one-sided significance level of 0.025 to verify the superiority of solifenacin 10 mg to placebo, followed by the superiority of solifenacin 5 mg to placebo. If the superiority of solifenacin 10 mg was verified, the 95% CI of the differences in the mean values between solifenacin 10 mg and propiverine 20 mg were calculated to verify the non-inferiority of solifenacin, which was confirmed when the upper limit of the CI was below 0.6. If the non-inferiority of solifenacin 10 mg to propiverine 20 mg, and the superiority of solifenacin 5 mg to placebo were verified, the 95% CI of the differences in the mean values between solifenacin 5 mg and propiverine 20 mg were calculated to verify the non-inferiority of solifenacin 5 mg to propiverine 20 mg, again confirmed when the upper limit of the CI was below 0.6.

For the analysis of the primary and secondary variables, treatment groups were compared using a one-sided t-test at a significance level of 0.025. QoL scores were analysed with summary statistics and the two-sided 95% CI calculated for the change from baseline in KHQ domain scores, compared between dosing arms at endpoint, using a t-test with a two-sided significance level of 0.05. For the analysis of AE, Fisher’s exact test was used to compare the placebo, solifenacin 5 mg, solifenacin 10 mg and propiverine 20 mg treatment arms, with a two-sided significance level of 0.05.

RESULTS

The study enrolled 2049 patients between June 2003 and January 2004, of whom 1593 were randomized (placebo, 406; solifenacin 5 mg, 400; solifenacin 10 mg, 385; propiverine 20 mg, 402) and 1584 were treated; in all, 136 (8.6%) discontinued before completing the study (Fig. 2). The baseline characteristics were comparable across all four treatment groups (Table 1).

Figure 2.


The disposition of the patients.

Table 1.  The baseline demographics, baseline symptom levels, final continence, and distribution of AEs
VariablePlaceboSolifenacin, mgPropiverine 20 mg
510
Subjects (full analysis set)395383371384
Men, n (%) 62 (15.7) 65 (17.0) 53 (14.3) 63 (16.4)
Women, n (%)333 (84.3)318 (83.0)318 (85.7)321 (83.6)
Mean (sd, range): Age, years 60.8 (12.5, 28.0–90.0) 60.4 (13.3, 20.0–89.0) 59.9 (13.0, 20.0–86.0) 59.6 (13.6, 23.0–94.0)
 <65, n (%)232 (58.7)222 (58.0)214 (57.7)218 (56.8)
 ≥65, n (%)163 (41.3) 161 (42.0)157 (42.3)166 (43.2)
Mean (sd, range) body weight, kg 56.2 (9.4, 36.0–90.0) 56.3 (9.7, 30.5–123.0) 57.1 (10.5, 35.0–117.4) 56.6 (10.0, 33.0–103.0)
Baseline OAB symptom level, mean (sd) {n}
Number of voids/24 h  11.25 (2.73) {395}  11.44 (2.94) {383}  11.15 (2.76) {371}  11.37 (2.71) {384}
Urgency episodes/24 h  4.04 (3.11) {395}  4.40 (3.38) {383}  4.47 (3.30) {371}  4.07 (3.19) {384}
Incontinence episodes/24 h  1.99 (2.11) {283}  2.35 (2.45) {274}  2.19 (2.04) {270}  2.15 (2.31) {295}
Urgency incontinence episodes/24 h  1.67 (1.95) {260}  1.95 (2.14) {235}  1.89 (1.91) {255}  1.82 (1.94) {262}
Nocturia episodes  1.84 (1.10) {361}  1.91 (1.22) {344}  1.78 (1.04) {334}  1.95 (1.29) {348}
Volume voided/void (mL)152.8 (44.28) {393}153.4 (52.91) {381}154.4 (50.21) {369} 151.2 (49.38) {383}
Years from start of symptoms, n (%)
 ≥0.5 to <1 39 (9.9) 46 (12.0) 36 (9.7) 38 (9.9)
 ≥1 to <3 81 (20.5) 89 (23.2) 97 (26.1) 85 (22.1)
 ≥3 to <5 40 (10.1) 34 (8.9) 45 (12.1) 38 (9.9)
 ≥5 to <10 37 (9.4) 24 (6.3) 23 (6.2) 22 (5.7)
 ≥10 24 (6.1) 23 (6.0) 14 (3.8) 20 (5.2)
 Unknown174 (44.1)167 (43.6)156 (42.0) 181 (47.1)
Type of incontinence presented at start of run-in, n (%)
 Urge244 (61.8)235 (61.4)213 (57.4)218 (56.8)
 Mixed135 (34.2)130 (33.9)143 (38.5)144 (37.5)
 None 16 (4.1) 18 (4.7) 15 (4.0) 22 (5.7)
Resolution/normalization rates, n (%) patients
Incontinent at baseline283274270295
Continent at endpoint105 (37.1)154 (56.2) 161 (59.6)165 (55.9)
With urgency episodes at baseline395383371384
Free of urgency at endpoint 82 (20.8)126 (32.9)138 (37.2)128 (33.3)
≥8 voids/24 h at baseline395383371384
≥8 voids/24 h at endpoint 83 (21.0)109 (28.5)137 (36.9) 101 (26.3)

In all, 1533 patients were eligible for the efficacy assessment, and efficacy results are summarized in Figs 3 and 4. There were statistically significant decreases from baseline to endpoint in the mean (sd) number of voids/24 h (the primary efficacy variable), in patients treated with solifenacin 5 mg and 10 mg, and propiverine 20 mg vs placebo (P < 0.001 for all active treatment groups vs placebo; Fig. 3). The superiority of both solifenacin 5 mg and 10 mg to placebo was confirmed (both P < 0.001, solifenacin vs placebo), as was the non-inferiority of solifenacin 5 mg and 10 mg to propiverine 20 mg (0.258, 0.003; upper limit of 95% CI for the difference between solifenacin 5 mg and 10 mg, respectively, and propiverine 20 mg). There was no statistically significant difference between the solifenacin 5 mg or 10 mg group and the propiverine 20 mg group for this variable. Both the solifenacin 5 mg and 10 mg treatment groups had statistically significant reductions from baseline to endpoint in urgency, incontinence and urgency incontinence episodes compared with the placebo group (Fig. 3; P < 0.001 for all active treatments vs placebo). Propiverine 20 mg also significantly reduced urgency (P < 0.001), incontinence (P = 0.002) and urgency incontinence (P = 0.002) from baseline to endpoint compared with placebo (Fig. 3). In all active treatment groups there was a statistically significant increase from baseline to endpoint in the mean volume voided/void vs the placebo group (all P < 0.001). Treatment with solifenacin 10 mg also resulted in statistically significant reductions from baseline to endpoint in the number of nocturia episodes vs placebo (P = 0.021).

Figure 3.

The mean change over 12 weeks in the number of voids/24 h, other urinary episodes and volume voided/void, with the results at endpoint given as the mean (sd). *P < 0.025 and †P < 0.001 vs placebo.

Figure 4.


The mean change in the number of voids/24 h, other urinary episodes and volume voided/void from baseline to endpoint (for patients with a full analysis). *P < 0.025 and †P < 0.001 vs placebo; ‡P < 0.025 vs propiverine 20 mg.

Compared with the propiverine 20 mg group, the solifenacin 10 mg group showed a statistically significant decrease in the number of urgency episodes/24 h (P = 0.012) and a statistically significant increase in the mean volume voided/void (P = 0.009; Fig. 4).

Normalization rates for OAB symptoms are also shown in Table 1. In the active treatment groups, more than half the patients who were incontinent at baseline had regained continence at endpoint, >30% had normalization of urgency episodes and >25% had normalized voiding frequency at the end of the study.

In assessing patient QoL using the KHQ, all active treatment groups had statistically significant improvements from baseline to endpoint in most domains compared with placebo (Fig. 5). There were no statistically significant differences between the improvements in the solifenacin 5 mg or 10 mg groups and the propiverine 20 mg group, except for the severity domain, where there was a significantly greater reduction with solifenacin 10 mg than with propiverine 20 mg (P < 0.05).

Figure 5.


The mean change from baseline to endpoint in QoL domain scores of the KHQ (for the QoL population). *P < 0.05 vs placebo; †P < 0.05 vs propiverine 20 mg.

Table 2 shows the incidences of major antimuscarinic treatment-emergent AEs. Among the active treatment groups, the incidence of dry mouth was lowest in patients treated with solifenacin 5 mg (16.9%), and most of these incidences (64/67 patients) were mild. The incidence of dry mouth with solifenacin 10 mg was 34.1%, but most of these cases (124/130) were classified as mild. The incidence of dry mouth was significantly lower in the solifenacin 5 mg group than that reported in the propiverine 20 mg group (25.8%; P = 0.003), while it was significantly higher in the solifenacin 10 mg group (P = 0.012 vs propiverine).

Table 2.  The distribution of major antimuscrinic AEs
Variable, n (%)PlaceboSolifenacin, mgPropiverine 20 mg
510
  • *

    P = 0.003,

  • P = 0.012,

  • P = 0.004 vs propiverine 20 mg.

N (safety population)405396381400
Discontinuation due to AEs  11 (2.7) 20 (5.1) 26 (6.8) 26 (6.5)
Dry mouth 23 (5.7) 67 (16.9)*130 (34.1)103 (25.8)
 Mild 23 (5.7) 64 (16.2)124 (32.5)100 (25.0)
 Moderate  0  3 (0.8)  6 (1.6)  3 (0.8)
 Severe  0  0  0  0
Constipation 16 (4.0) 42 (10.6) 72 (18.9) 45 (11.3)
 Mild 15 (3.7) 42 (10.6) 69 (18.1) 43 (10.8)
 Moderate  1 (0.2)  0  3 (0.8)  2 (0.5)
 Severe  0  0  0  0
Blurred vision  8 (2.0)  7 (1.8) 16 (4.2) 15 (3.8)
 Mild  8 (2.0)  7 (1.8) 14 (3.7) 14 (3.5)
 Moderate  0  0  2 (0.5)  1 (0.3)
 Severe  0  0  0  0

The incidence of constipation was similar in the solifenacin 5 mg and propiverine 20 mg groups (10.6% and 11.3%, respectively), and 18.9% in the solifenacin 10 mg group (P = 0.004 vs propiverine), and 4.0% in the placebo group. Blurred vision (mild in most cases) was reported in 1.8% and 4.2% of patients receiving solifenacin 5 mg and 10 mg, respectively, in 3.8% receiving propiverine 20 mg and in 2.0% receiving placebo. Other AEs which might be expected with antimuscarinic use, e.g. urinary retention and difficulty in voiding, were low in all treatment groups (urinary retention: solifenacin 5 mg, none; solifenacin 10 mg, none; propiverine 20 mg, one; placebo, none; difficulty in micturition: solifenacin 5 mg, 1.8%; solifenacin 10 mg, 3.9%; propiverine 20 mg, 3.3%; placebo, 1.0%, respectively). There were no clinically relevant changes in vital signs, physical examination findings, laboratory test values or 12-lead ECG.

Discontinuation rates were low and comparable within each treatment group; those due to AEs were also similar in the active treatment groups. The percentages of patients discontinuing treatment due to AEs were 2.7% in the placebo group, 5.1% and 6.8% in the solifenacin 5 mg and 10 mg groups, respectively, and 6.5% in the propiverine 20 mg group (Table 1).

DISCUSSION

Although the ICS definition of OAB places urgency at the centre of the OAB symptom complex [22], there is no universally accepted measure of this variable. Consequently, the present study was designed with a primary efficacy measure of reductions in voiding frequency, as measured by a voiding diary. Furthermore, this is the first report of a placebo- and active treatment-controlled trial in Japan comparing a new antimuscarinic agent with propiverine. There are two important facets of this study: first, it assessed the clinical efficacy and tolerability of solifenacin in a Japanese population, not only compared with placebo but also with propiverine, which has been widely prescribed over the last decade in Japan for treating OAB symptoms. Second, this study objectively measured and quantified the improvement of urgency episodes using voiding diaries. No studies have previously reported quantitative urgency improvements in a Japanese population. Although there is no consensus for measuring urgency, it would be more reliable to objectively measure this variable, rather than subjectively; voiding diaries could thus be rated as a reliable tool from the viewpoint of reproducibility [23]. A clear differentiation of sense of urge and urgency might be difficult to define using a subjective tool.

In the current study, solifenacin 5 mg significantly reduced voiding frequency, urgency episodes and incontinence episodes compared with placebo. In addition, 56.2% of patients treated with solifenacin 5 mg, who were incontinent at baseline, reported no episodes of incontinence at endpoint (compared with 37.1% of placebo-treated patients). These results were mirrored in the solifenacin 10 mg group, with significant reductions in urgency, incontinence, frequency and nocturia episodes compared with placebo. Of the patients in the solifenacin 10 mg group who reported incontinence at baseline, 59.6% regained continence at endpoint. In addition, solifenacin 10 mg was statistically better than propiverine 20 mg in reducing urgency episodes, and improving volume voided/void. Solifenacin 10 mg was also more effective than placebo in reducing nocturia episodes. These results are in agreement with European and USA data on the efficacy of solifenacin [17,19,24,25]. The present results also support the concept of beginning solifenacin therapy at 5 mg once daily, with the option of increasing the dose to 10 mg if additional efficacy is desired.

The effectiveness of solifenacin in treating urgency is notable, as the ICS deems urgency as central to OAB, due to its effect on frequency and urgency incontinence [22], and data from phase III European studies support the effect of solifenacin on urgency [17,19]. Interestingly, there was a similar effect in the present study with a Japanese population; these results suggest that solifenacin might be a good therapeutic option for treating urgency across different population types. In addition, solifenacin was significantly more effective than placebo in restoring continence, with over half the patients who reported incontinence episodes at baseline having regained continence at endpoint. The recent STAR study examined the efficacy of solifenacin compared with tolterodine ER, and found that in those patients who were incontinent at baseline, a significantly greater proportion treated with solifenacin regained continence at endpoint, compared with tolterodine ER (59% vs 49%; P = 0.006) [20]. Attaining continence is an important aim of therapy, as the social stigma and hygiene problems associated with this complaint are often the precipitating factor in a patient seeking treatment.

In the present study, solifenacin 10 mg significantly reduced the mean number of nocturia episodes (−0.46), vs placebo (−0.30; P = 0.021). A European phase III study ([19], noted above) reported that there were significant reductions in the mean number of nocturia episodes (−0.71) with solifenacin 10 mg, vs placebo (−0.52, P = 0.036). In addition, data pooled from four similar phase III studies showed that there was a greater reduction in the mean number of nocturia episodes with solifenacin 10 mg (−0.6), than with placebo (−0.4) [26]. Nocturia is an important symptom of OAB, as it increases with age and worsens QoL [27,28]. It has many causes and is associated with bladder storage disorder, polyuria and nocturnal polyuria; therefore, it is important to determine its cause [29,30]. Studies with muscarinic antagonists have only inconsistently shown statistically greater effects for nocturia than with placebo; these inconsistencies might relate to the multifactorial nature and aetiology of nocturia [31]. Although the current study has shown that solifenacin 10 mg is significantly effective for the OAB symptom of nocturia, further clinical investigations would be useful to fully determine the beneficial effects of solifenacin for this symptom.

Treatment with solifenacin and propiverine was well tolerated in this study. Solifenacin 5 mg had a similar efficacy to propiverine 20 mg, but notably the incidence of dry mouth (the most commonly occurring AE with antimuscarinic therapy [32], reported to be a main cause of reduced persistence with therapy [33]), was significantly lower with solifenacin 5 mg than with propiverine 20 mg (P = 0.003). The other typical antimuscarinic AEs, e.g. constipation and blurred vision, in the active treatment groups were mostly mild. Moreover, although dry mouth and constipation events were more common in patients treated with solifenacin 10 mg than in those treated with propiverine 20 mg (and the rate of dry mouth was significantly higher with solifenacin 10 mg than with propiverine 20 mg), most of these events were mild, and discontinuation rates due to AEs were similar in both the solifenacin 10 mg and propiverine 20 mg groups.

Difficulties in voiding, e.g. urinary retention, are additional potential risks associated with antimuscarinic use for OAB [34–36]. In the present study, no patients who were treated with solifenacin had urinary retention. In addition, the incidence of voiding difficulties was low and comparable between the treatment groups, further showing the good tolerability profiles of solifenacin in this study.

In addition to efficacy and tolerability considerations, it is important that patients are provided with tangible benefits in QoL to increase treatment adherence and persistence. In the present study, both solifenacin and propiverine were associated with significant improvements in patient QoL compared with placebo. Solifenacin treatment has already been reported to improve QoL, from the results of European clinical studies, which include a long-term extension study; patients treated with solifenacin, at both 5 and 10 mg, had significantly greater improvements from baseline to endpoint vs placebo in nine of the 10 domains of the KHQ (i.e. general health perception, incontinence impact, role limitations, physical limitations, social limitations, emotions, sleep/energy, severity measures and symptom severity) [37] during the 12-week European studies. In the present study, both solifenacin 5 and 10 mg had a similar beneficial effect in most domains of the KHQ, including the six domains that are considered to be the most clinically important in OAB, i.e. incontinence impact, severity measures, role limitations, physical limitations, social limitations and emotions.

In conclusion, solifenacin at both 5 and 10 mg once daily is an effective and well-tolerated therapy for treating symptomatic OAB, effectively reducing the principal OAB symptoms of urgency, frequency and incontinence. Solifenacin 5 mg is associated with a low incidence of dry mouth, combined with clinical efficacy in the treatment of OAB. If greater efficacy is required, the solifenacin dose can be increased to 10 mg; this availability of both 5 mg and 10 mg doses allows for greater flexibility in drug therapy. Solifenacin is thus an effective and well tolerated therapeutic option for treating OAB.

ACKNOWLEDGEMENTS

The study was funded and sponsored by Astellas Pharma Inc. (formerly Yamanouchi Pharmaceutical Co. Ltd), Tokyo, Japan. Editorial assistance was provided by Priya Venkatesan, Medicus International.

APPENDIX

Members of the Japanese Solifenacin Study Group in the study are as follows (in alphabetical order): T. Aika, Tokyo; K. Ameda, Hokkaido; M. Ando, Aichi; S. Ando, Fukuoka; R. Ara, Saitama; Y. Arai, Tokyo; S. Den, Osaka; A. Esa, Osaka; Y. Fujimoto, Kanagawa; S. Fujisawa, Kumamoto; T. Fujita, Fukui; T. Fujiwara, Kyoto; Y. Fukaya, Fukushima; T. Fukuda, Akita; K. Fukui, Aomori; K. Goji, Osaka; M. Gotoh, Aichi; Y. Hamada, Kumamoto; T. Hasegawa, Toyama; H. Hayami, Kanagawa; A. Hayashi, Tokyo; Y. Higashi, Kyoto; S. Hirabayashi, Aichi; S. Hirasawa, Tokyo; A. Hirayama, Nara; T. Hirose, Hokkaido; H. Horita, Hokkaido; M. Igarashi, Okinawa; M. Ikegami, Osaka; T. Ishida, Toyama; M. Ishigooka, Yamagata; Y. Ishii, Saitama; J. Ishikawa, Hyogo; T. Ishimatsu, Kumamoto; O. Ishizuka, Nagano; N. Itoh, Hokkaido; K. Ito, Fukushima; K. Ito, Osaka; A. Iwasa, Osaka; A. Iwasawa, Hokkaido; H. Kakizaki, Hokkaido; T. Kamijyo, Chiba; K. Kanbe, Miyagi; M. Kano, Fukuoka; N. Kataoka, Hyogo; Z. Kataumi, Chiba; Y. Katoh, Osaka; K. Kawahara, Kagoshima; S. Kawai, Fukuoka; M. Kawakita, Hyogo; H. Kawano, Fukuoka; H. Kikukawa, Kumamoto; T. Kinukawa, Aichi; S. Kobayashi, Hyogo; S. Kobakashi, Hokkaido; S. Kojima, Kanagawa; Y. Kondo, Osaka; Y. Kuma, Fukushima; A. Kumagai, Hokkaido; Y. Kurisu, Hokkaido; K. Kuroda, Tokyo; S. Lee, Chiba; E. Marui, Tokyo; M. Masuda, Kanagawa; O. Matsumoto, Hyogo; K. Matsumura, Hokkaido; S. Matsuo, Akita; H. Matsuoka, Fukuoka; T. Mayuzumi, Gunma; H. Mibu, Osaka; Y. Mihara, Fukuoka; H. Mimata, Oita; K. Miyakoda, Osaka; Y. Miyazaki, Fukuoka; S. Miyoshi, Osaka; O. Mochida, Fukuoka; H. Momose, Osaka; T. Mori, Hokkaido; R. Moriguchi, Tokyo; H. Morita, Hokkaido; O. Muraki, Fukushima; T. Murase, Aichi; K. Nagakura, Tokyo; T. Nagashima, Tokyo; H. Nakagawa, Miyagi; S. Nakagawa, Kyoto; C. Nakajima, Saitama; T. Nakamura, Chiba; N. Nakamura, Fukui; I. Nakamura, Hyogo; M. Nakanami, Fukuoka; N. Nakano, Miyagi; M. Namiki, Ishikawa; H. Narita, Aichi; M. Noguchi, Nagasaki; A. Nojiri, Kumamoto; M. Nonomura, Kyoto; H. Noto, Akita; S. Oba, Saitama; K. Obara, Niigata; H. Ogawa, Tokyo; B. Ogisu, Aichi; H. Okada, Tokyo; A. Ohmori, Fukuoka; T. Ohnuma, Miyagi; T. Otani, Aichi; M. Oya, Tokyo; S. Ozono, Shizuoka; K. Sakai, Ibaraki; T. Sakakibara, Aichi; S. Sakamoto, Oita; T. Sakata, Kumamoto; S. Sakuma, Fukuoka; S. Samma, Nara; Y. Satomi, Kanagawa; N. Seki, Fukuoka; N. Sekido, Ibaraki; M. Shimada, Kanagawa; T. Shirai, Kanagawa; M. Shiramizu, Kanagawa; A. Soeda, Hyogo; T. Sugiyama, Osaka; H. Sumiya, Saitama; S. Suto, Hokkaido; N. Suzuki, Hokkaido; K. Suzuki, Gunma; M. Tahara, Tokyo; H. Tahara, Fukuoka; M. Takada, Osaka; S. Takahashi, Tokyo; N. Takano, Fukuoka; K. Takatsuka, Hokkaido; N. Takayama, Hokkaido; M. Takei, Fukuoka; S. Tamaru, Fukuoka; N. Tanabe, Yamanashi; T. Tanaka, Tokyo; K. Tanaka, Aichi; M. Tokizane, Osaka; S. Torii, Kanagawa; M. Uchida, Osaka; T. Ueda, Shiga; S. Ueda, Fukuoka; T. Uemura, Osaka; S. Watanabe, Nagano; T. Yajima, Tokyo; M. Yajima, Kanagawa; S. Yamada, Aichi; Y. Yamada, Hyogo; O. Yamaguchi, Fukushima; T. Yamamoto, Kumamoto; N. Yamanaka, Hyogo; M. Yamashita, Hyogo; S. Yasuoka, Kanagawa; T. Yokota, Fukushima; H. Yokoyama, Tokyo; E. Yokoyama, Kanagawa; M. Yokoyama, Ehime; M. Yoshida, Tokyo; M. Yoshida, Kumamoto; T. Yoshida, Tokyo; H. Yoshinaga, Fukuoka.

CONFLICT OF INTEREST

Osamu Yamaguchi and Eiji Marui are consultants to Astellas Pharma.

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