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Keywords:

  • efficacy;
  • overactive bladder;
  • safety;
  • tolerability;
  • tolterodine

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Abstract  Aim: To evaluate the long-term safety, tolerability and efficacy of extended-release (ER) tolterodine in Japanese patients completing 12-week treatment in a randomized, double-blind trial comparing tolterodine ER 4 mg once daily, oxybutynin 3 mg three times daily or placebo in patients with overactive bladder.

Methods: Of 293 Japanese patients completing the 12-week study, 188 continued in the open-label trial and received tolterodine ER 4 mg once daily for 12 months, irrespective of previous treatment. The primary objective was to assess the safety of tolterodine ER for up to 52 weeks of treatment and at post-treatment follow-up. Secondary endpoints included changes in micturition diary variables, patient perception of bladder condition and urgency and treatment benefit.

Results: Overall, 77% of patients completed 12 months of open-label treatment. Tolterodine ER was well tolerated and the most common adverse event was dry mouth (33.5%). In general, there was no increase in adverse event frequency with long-term treatment compared with short-term treatment. The efficacy of tolterodine ER was maintained over the 12-month period. The complete analysis showed a median reduction in incontinence  episodes/week (−92.9%; mean  reduction, −77.2%), a mean reduction in micturitions/24 h (−21.3%) and a mean increase in volume voided per micturition (19.6%). Of patients completing the 12-month study, 78.6% reported improvement in patient perception of bladder condition, 52.4% reported improvement in perception of urgency and 89.7% reported treatment benefit.

Conclusions: Favorable safety, tolerability and efficacy of once-daily tolterodine ER was maintained over 12 months in a Japanese overactive bladder patient population.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Overactive bladder (OAB) is a highly prevalent, chronic and often significantly debilitating disorder. Symptoms comprise urinary urgency with or without urge incontinence, often with urinary frequency and/or nocturia.1 According to the results of an epidemiological study performed in Japan, the prevalence of OAB (urination at least 8 times daily and urgency at least once a week) in men and women aged ≥40 years is 12.4% and the estimated number of patients with OAB is 8.1 million.2 Furthermore, the prevalence of OAB tends to increase with age.3,4 Global increases in life expectancy, particularly in countries such as Japan,5 are likely to be accompanied by increases in both OAB incidence and the number of patients receiving long-term therapy. Therefore, there is a need for effective and well-tolerated agents with good long-term compliance.

In Japan, pharmacotherapy of urinary incontinence or OAB has traditionally comprised agents such as propiverine6–8 or oxybutynin.9,10 However, the poor tolerability of traditional antimuscarinics like oxybutynin limits their usefulness and can lead to poor compliance or treatment discontinuation.11,12 Furthermore, Japanese patients have shown a low persistence with long-term propiverine therapy for OAB symptoms.13,14

Tolterodine, an antimuscarinic developed specifically for OAB, has equivalent efficacy to oxybutynin, but is significantly better tolerated, notably due to a lower frequency and intensity of dry mouth.15–18 Since 1997, tolterodine has been used widely and is now available in over 70 countries worldwide. To date, over 9 million patients have been treated with tolterodine and, outside Japan, it has become the mainstay of OAB therapy. A recently developed once-daily extended-release (ER) tolterodine formulation has shown improved efficacy and tolerability compared with its immediate-release counterpart in Caucasian OAB patients19 and was recently shown to be as effective, but better tolerated, than oxybutynin in a 12-week randomized, double-blind, placebo-controlled trial in Japanese and Korean patients with OAB.20

We investigated whether the favorable safety, tolerability and efficacy of tolterodine ER is maintained during long-term treatment in an open-label extension study in Japanese OAB patients.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

This 12-month, open-label, uncontrolled, extension study was conducted at 52 centers in Japan. The study was approved by the Independent Ethics Committees/Institutional Review Boards of the participating centers and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent.

Patients

Eligible Japanese patients completing 12 weeks’ treatment in a randomized, double-blind trial20 continued with 12 months’ open-label treatment with tolterodine ER 4 mg once daily, irrespective of (and without unblinding) the treatment received during the double-blind study (tolterodine ER 4 mg capsules once daily [Detrol capsule, Detrusitol, Pharmacia Corporation, Peapack, NJ], oxybutynin 3 mg tablets three times daily [Pollakisu, Aventis Pharma Ltd, Tokyo, Japan] or placebo).

The 12-week randomized study enrolled men and women aged ≥20 years with OAB symptoms including urinary urgency, urinary frequency (≥8 micturitions/24 h) and urge incontinence (≥5 episodes/week) for ≥6 months. Patients were recruited based solely on OAB symptoms, irrespective of prior antimuscarinic treatment or their response to such therapy. Exclusion criteria included demonstrable stress incontinence, total daily urine volume >3 L, average volume voided/micturition >200 mL, significant hepatic or renal disease, any contraindication for anticholinergic treatment, symptomatic or recurrent urinary tract infection, interstitial cystitis, hematuria or bladder outlet obstruction, indwelling catheter or intermittent self-catheterization, electrostimulation or bladder training within 14 days before randomization or expected to commence during the study. Concomitant treatment with other anticholinergic drugs or unstable dosages of drugs with anticholinergic side-effects, any other drug for OAB (except for estrogen started > 2 months before inclusion), potent CYP3A4 inhibitors or any investigational drug was not permitted during the study or the 14 days before randomization. Patients who were poorly compliant (missed >25% of prescribed medication), had an ongoing serious adverse event and pregnant or nursing women and women of childbearing potential not using reliable contraception were also excluded.

Study design

Figure 1 shows a schematic representation of the study protocol. After completing the 12-week double-blind study, eligible patients entered a 7- to 21-day washout period, followed by 12 months of open-label tolterodine ER and a 1- to 2-week post-treatment follow-up. Dose reduction to 2 mg once daily was permitted during the first 4 weeks of open-label therapy in the case of intolerance to therapy and only as an alternative to treatment withdrawal. Concomitant treatments not permitted during the double-blind study were also prohibited during the continuation study. Compliance was assessed by counting returned study medication (and patient recording of doses taken during the 7-day micturition chart-recording period); patients taking ≥75% of their medication were considered compliant.

image

Figure 1. A schematic representation of the 12-week randomized and 12-month, open-label treatment protocols. ER, extended-release.

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Safety and tolerability analysis

The primary study objective was to assess the safety of tolterodine ER over a 12-month period in Japanese OAB patients. Primary endpoints were the occurrence of adverse events, withdrawals over the 12-month treatment period and changes in laboratory variables and 12-lead electrocardiograms (ECG) over the 15-month period. Safety was assessed at weeks 4, 12, 24, 36 and 52 of the continuation study and at post-treatment follow-up. Adverse events and concomitant medication were recorded at each visit, clinical laboratory assessments (serum chemistry, hematology and urinalysis) assessed at weeks 12, 24 and 52, and ECG at baseline and weeks 12 and 52 or on withdrawal.

Efficacy analysis

The secondary objective was to evaluate the efficacy of tolterodine ER over a 15-month period (3 months of randomized treatment and 12 months of open-label treatment) in Japanese OAB patients. Secondary endpoints were changes in micturition variables (incontinence episodes per week, micturitions/24 h and volume voided/micturition) and patient perception variables (patient perception of bladder condition [PPBC] and urgency) over the 15-month treatment period. Treatment benefit was assessed at the end of treatment.

Baseline was defined as the start of the 12-week randomized study. Micturition charts were completed during the 7 days before the week 24 and 52 visits; volume voided/micturition was recorded for at least two complete days during this period. Perception variables were assessed at weeks 24 and 52 (or on withdrawal).

Patient perception of bladder condition was assessed on a 6-point ordered categorical scale: 0 = no problems; 1 = very minor problems; 2 = minor problems; 3 = moderate problems; 4 = severe problems; and 5 = many severe problems. Urgency was assessed on a 3-point scale: (i) not able to hold urine; (ii) able to hold urine until reaching toilet if went immediately; and (iii) able to finish tasks before going to the toilet. Treatment benefit was assessed on a 3-point scale: (i) no benefit; (ii) a little benefit; and (iii) much benefit.

Statistical analysis

All patients entering the 12-month open-label study who received at least one dose of tolterodine ER were evaluated for safety. Adverse events were summarized by system organ class and preferred term using frequency tables. Changes in laboratory variables were summarized descriptively and shift tables and scatter plots constructed.

Two efficacy analysis populations were defined: (i) intent-to-treat (ITT) population comprising all randomized patients who received at least one dose of study drug, using the last-observation-carried-forward for any missing 12-week values; and (ii) completer population comprising all patients completing the 12-month study (missing values not included). When estimating an effect in a single-arm study, analysis of the completer population is considered more appropriate than ITT analysis, as the latter requires adjustments for early dropouts; bringing forward patient data may introduce inaccuracies into the data. For micturition variables, changes from baseline (and relative change in incontinence episodes/week) were summarized descriptively, including 95% confidence intervals (CI). Micturition data are presented as means; however, the variable number of incontinence episodes has a positively skewed distribution and median values are therefore presented along with means for this parameter to facilitate the interpretation of results. P-values for changes from baseline were calculated using the non-parametric Wilcoxon signed rank test. Patient perception variables were summarized using frequency counts and proportions.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Patient characteristics

Of the 293 Japanese patients completing the 12-week study, 188 participated in the open-label trial (ITT/safety population). These 188 patients had previously received tolterodine ER (n = 80), oxybutynin (n = 74) or placebo (n = 34). Baseline characteristics of the safety population are summarized in Table 1. Approximately two-thirds of patients were female and the mean age was 63.6 years. Only around one-fifth of patients had received previous treatment for OAB and of these, most (75%) had experienced poor efficacy. Overall, 145 (77%) patients completed all 12 months of open-label treatment. Baseline demographic and micturition values were similar in the completer population.

Table 1.  Baseline demographic and clinical characteristics of Japanese patients with overactive bladder (OAB) at baseline of 12-month open-label study (safety population)
VariableSafety population (n = 188)
  1. With the exception of age, data were collected at the time of inclusion in the previous 12-week controlled study (Kawabe et al. in preparation); †% of those who previously received treatment for OAB.

Mean ± SD age, years (range)63.6 ± 11.9 (26.2–88.4)
Gender, male : female (%)65 : 123 (34.6 : 65.4)
Medical history, n (%)
Previous treatment for OAB 36 (19.1)
 With poor efficacy 27 (75)
 With good efficacy  9 (25)
Micturition chart variables,n (%)
≥8 micturitions/24 h188 (100)
≥5 incontinence episodes/week187 (99.5)
≤200 mL mean volume voided  per micturition186 (98.9)

In total, 43 patients withdrew prematurely due to adverse events (n = 19), lack of efficacy (n = 15), consent withdrawal (n = 7), lost to follow-up (n = 1) and protocol violation (n = 1). As an alternative to withdrawal, dosage reduction (to tolterodine 2 mg once daily) occurred in 10 patients during the first 28 days of open-label treatment. Of these patients, seven continued on the lower dosage, while three were later withdrawn (due to lack of efficacy [n = 2] or treatment-unrelated adverse event [n = 1]). The remaining 178 patients received tolterodine ER 4 mg daily throughout the trial (except for a temporary interruption in 14 patients due to adverse events). Treatment compliance was good, with 95.7% (n = 180) of all patients taking ≥75% of their study medication.

Safety and tolerability

Tolterodine ER was well tolerated during long-term treatment in this Japanese population. The incidence of the most commonly reported adverse events is summarized in Table 2 and compared with data from the 12-week randomized study. The most common event was dry mouth (total incidence, 33.5%) which was mild in all but one case. In the 12-week study, 36.8% of tolterodine ER recipients reported dry mouth, most of which was also mild (Fig. 2). Notably, the incidence of dry mouth diminished during the course of the current trial, occurring in 46 patients (24.5%) during the first 3 months, but in only nine (4.8%) and eight (4.3%) patients during the 3–6 and 6–12-month periods, respectively.

Table 2.  Most frequent adverse events reported by Japanese patients (safety population) during 12 weeks of randomized (Kawabe et al. in preparation) and 12 months of open-label treatment with extended-release tolterodine 4 mg once daily
Adverse event n (%)12-week study (n = 114)12-month open- label study (n = 188)
Dry mouth42 (36.8)63 (33.5)
Nasopharyngitis6 (5.3)50 (26.6)
Constipation12 (10.5)16 (8.5)
Diarrhoea6 (5.3)12 (6.4)
Arthralgia1 (0.9)11 (5.9)
Back pain3 (2.6)11 (5.9)
Headache6 (5.3)10 (5.3)
image

Figure 2. Comparison of percentage of tolterodine extended-release patients reporting dry mouth, and the severity of dry mouth, during 12 weeks of randomized (Kawabe et al. in preparation) and 12 months of open-label therapy in Japanese patients with overactive bladder.

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Nasopharyngitis (26.6%) was also frequently reported in the open-label study, but was always considered unrelated to treatment. Similarly, neither arthralgia nor back pain was considered treatment-related. Additionally, adverse events that might be expected with antimuscarinic therapy, such as thirst, blurred vision, dry eyes and difficulty in micturition, occurred in few patients. Urinary retention was not reported in any patient.

There were 19 withdrawals due to adverse events. The most frequent adverse events in these patients (alone or in combination with other events) included nasopharyngitis (n = 4), upper abdominal pain (n = 3), dry mouth (n = 3), dyspepsia (n = 3), abnormal ECG (n = 3) and headache (n = 3). Other events in these patients associated with antimuscarinic therapy included constipation (n = 2), difficulty in micturition (n = 2), blurred vision (n = 1) and dry eyes (n = 1).

Serious adverse events were experienced by 16 patients of whom five withdrew from treatment. Except for hyperglycemia in one patient who subsequently recovered at follow-up, none of these events were considered treatment-related. There was one death during the study (recurrent myocardial infarction resulting from concurrent diseases) but this was not considered to be related to treatment. Mean changes in clinical laboratory variables were small and few patients had shifts to abnormal values (in those that did, the shifts did not increase with continued treatment over 12 months), suggesting no treatment effect on these variables. Overall, few patients had changes in ECG evaluation, whether from normal baseline to abnormal (seven and 12 patients after 3 and 12 months, respectively) or baseline abnormal to normal (15 and 13 patients after 3 and 12 months, respectively) indicating minor ECG variability of no clinical significance during the 12 month treatment. Clearly, no drug-related ECG findings were seen after treatment for 3 or 12 months.

Efficacy

The efficacy of tolterodine ER was maintained during long-term treatment. Patients achieved improvements in all micturition chart variables after both 6 and 12 months of open-label therapy with tolterodine ER (Table 3). In the complete analysis, after 12 months of open-label therapy, the median reduction in the number of incontinence episodes/week was −92.9% (Fig. 3; mean reduction, −77.2%; Table 3), the mean reduction in the number of micturitions/24 h was −21.3% and the mean increase in volume voided per micturition was 19.6%. Similar, but slightly smaller changes in these micturition variables were noted in the ITT population (Table 3). In all cases, the changes from baseline in micturition variables were statistically significant (P < 0.0001). The percentage change in these micturition variables after 12 months of open-label tolterodine ER therapy was similar to that achieved during the 12-week study (Table 3).

Table 3.  Change from baseline in micturition diary variables after 12 weeks of randomized (Kawabe et al. in preparation) and 6 and 12 months of open-label treatment with extended-release tolterodine 4 mg once daily in Japanese patients with overactive bladder
Variable12-week randomized (n = 114)Open-label study
6 months12 months
ITT population (n = 188)Completer population (n = 145)ITT population (n = 188)Completer population (n = 145)
  • Data on file, Pfizer Corporation.

  • *

    12-month study: P < 0.0001 for change at 6 and 12 months versus baseline for intent-to-treat (ITT) and completer populations; 12-week study: P < 0.01 for change from baseline to week 12 versus placebo.

Number incontinence episodes/ week
 Baseline, median (range) 11.7 (4.0–168.0) 14.5 (4.0–168.0) 14.0 (4.7–168.0) 14.5 (4.0–168.0) 14.0 (4.7–168.0)
 Mean (SD) 19.3 (20.2) 20.6 (18.4) 19.5 (18.1) 20.6 (18.4) 19.5 (18.1)
 Median change (range) −8.0 (−67.8–18.0) −7.0 (−68.8–24.0) −9.0 (−57.0–24.0) −9.3 (−68.8–40.3)−10.3 (−52.3–17.0)
 Median percentage change (range)*−85.7% (−100–66.7)−64.2% (−100.0–71.4)−78.3% (−100.0–64.0)−84.7% (−100.0–94.4)−92.9% (−100.0–94.4)
 Mean change (SD)−11.3 (12.2) −9.9 (12.1)−11.4 (11.0)−11.6 (13.5)−13.7 (11.9)
 Mean percentage change (SD)−68.5% (39.8)−53.5% (44.0)−65.9% (37.9)−63.0% (46.1)−77.2% (36.0)
Number micturitions/24 h
 Baseline, mean (SD) 11.9 (3.0) 11.9 (3.1) 11.9 (3.1) 11.9 (3.1) 11.9 (3.1)
 Mean change (SD) −2.4 (2.4) −1.6 (2.3) −1.9 (2.4) −2.2 (2.6) −2.6 (2.6)
 Mean percentage change (SD)*−19.0% (16.9)−12.8% (17.0)−15.0% (17.2)−17.5% (19.7)−21.3 (19.4)
Volume voided/micturition (ml)
 Baseline, mean (SD)129.7 (38.0)122.4 (34.9)124.9 (35.2)122.4 (34.9)124.9 (35.2)
 Mean change (SD) 19.2 (31.4) 28.6 (32.8) 34.0 (34.4) 20.2 (33.5) 22.8 (36.5)
 Mean percentage change (SD)* 16.5% (26.8) 25.0% (29.1) 29.4% (30.4) 17.6% (27.8) 19.6% (29.8)
image

Figure 3. Median percentage change from baseline in incontinence episodes after 6 and 12 months of open-label treatment with tolterodine extended-release 4 mg once daily in Japanese patients with overactive bladder (completer population).

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In the completer population, improvement in PPBC was reported by 67.6% and 78.6% of patients after 6 and 12 months, respectively; improvement in perception of urgency was reported by 37.9% and 52.4% of patients, respectively, and treatment benefit was reported by 89.7% of patients. Once again, similar, but slightly smaller changes in these patient perception variables were noted in the ITT population.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

As OAB is a chronic condition, long-term therapy (and consequently satisfactory patient persistence with treatment) is usually required to maintain symptom relief.21 Persistence is influenced by many factors, including dosing frequency, tolerability and efficacy. The present study in Japanese OAB patients clearly shows a high degree of persistency with long-term tolterodine ER therapy together with durable efficacy and tolerability which was maintained over a 12-month period. This confirms the excellent long-term persistency, tolerability and efficacy of tolterodine ER recently reported in a Caucasian OAB population.22

Compliance improves with decreased dosing frequency.23 In the present study, over 95% of patients complied with their medication and this, together with favorable efficacy and tolerability, translated into a high proportion of patients (77%) completing 12 months of open-label therapy. This is comparable to the >70% completion rate observed with tolterodine ER over 12 months of treatment in Caucasian patients22 and is superior to the 62% rate noted with the immediate-release formulation of tolterodine,21 perhaps reflecting the superior efficacy and tolerability of tolterodine ER and the more convenient once-daily dosing regimen.19 In contrast, long-term studies of propiverine for OAB symptoms in Japanese patients have been associated with low persistence with therapy, with only a small proportion of patients (20–23.6%) continuing with propiverine treatment for longer than one year.13,14 The favorable persistency with tolterodine ER also contrasts markedly with the relatively poor long-term compliance observed with traditional antimuscarinics, such as oxybutynin. In a study of Caucasian women with detrusor instability and low bladder compliance, only 18% remained on treatment after 6 months of therapy with previously available anticholinergic therapies (>80% were on oxybutynin).24

The primary objective of the present study was to evaluate the long-term safety and tolerability of tolterodine ER. The results revealed a safety profile similar to that observed in previous studies, including the 12-month open-label trial in Caucasian patients,22 with no new safety concerns emerging. In general, there was no evidence of any increase in adverse event frequency with long-term exposure as seen by comparing the results with those from the 12-week study (Kawabe et al. in preparation20) in this Japanese patient population (Table 2). Thus, dry mouth was slightly less frequent and occurred with a generally lower intensity than in the short term study (Fig. 2). Notably, there were no instances of severe dry mouth with tolterodine ER in either the long- or short-term studies in Japanese patients. Furthermore, in the current study, the incidence of dry mouth decreased as the treatment duration increased, suggesting that tolerability improved over time and may explain the high compliance and completion rates observed. Other adverse events occurred with generally similar frequencies with the exception of nasopharyngitis and, to a lesser extent, arthralgia and back pain, which were more common in the long term trial. However, nasopharyngitis was seasonal, with most cases occurring during the colder months (October to February) and in no case was it considered treatment-related. The lower incidence in the 12-week study reflects the fact that most patients participated in that study from spring to autumn. Back pain and arthralgia were also in no case considered treatment-related. Events traditionally associated with antimuscarinic therapy (such as thirst, blurred vision or dry eyes) were reported by few patients in the present study. Additionally, no drug-related ECG findings were seen after 3 or 12 months of treatment. Notably, no patient in the present study receiving tolterodine ER experienced urinary retention. The lack of an increase in adverse event frequency in this Japanese population during long-term versus short-term tolterodine ER treatment mirrors the long-term use of this agent in Caucasian OAB patients.22

The proportion of patients (10%) discontinuing tolterodine ER therapy due to adverse events was the same as that reported with long-term treatment in Caucasian OAB patients.22 While slightly higher than in 12-week studies of tolterodine ER in both Japanese (Kawabe et al. in preparation) and Caucasian19 patients, it remains below the 16% rate reported with oxybutynin over 12 weeks of treatment in Japanese patients (Kawabe et al. in preparation). In clinical practice, poor tolerability can produce a lack of desire to continue treatment and consequently impair the overall clinical effectiveness of antimuscarinic therapy.

Maintenance of efficacy is also important in determining long-term clinical effectiveness. In the present study, improvements in micturition variables over 12 months were similar to those achieved during the 12-week study in Japanese patients (Table 3). Patients completing 12 months of open-label tolterodine ER therapy achieved median reductions in incontinence episodes/week of −92.9%, mean reductions in the number of micturitions/24 h of −21.3% and a mean increase in volume voided per micturition of 19.6%. This underlines the durable efficacy of tolterodine ER over the 12-month extension period and confirms the results previously observed in a Caucasian OAB population.22 Improvements in micturition variables were supported by improvements in patient perception variables. Of those patients completing the 12-month study, 78.6% reported improvement in PPBC, 52.4% reported improvement in perception of urgency and 89.7% reported treatment benefit. Once more, these results are consistent with those reported in Caucasian patients.22

Despite the high prevalence of OAB symptoms in Japan, many patients fail to seek therapy. For example, Ueda et al. reported that only 3% of Japanese women consulted a doctor for incontinence symptoms.2 In Japan, propiverine6–8 and oxybutynin9,10 have traditionally been indicated for the treatment of frequency or urinary incontinence associated with neurogenic and unstable bladder. However, the advent of tolterodine, an agent specifically developed to treat OAB, offers tolerability advantages over traditional anitimuscarinics which, together with the convenience of once-daily administration, translate into improved compliance and persistency, elements essential for effective long-term OAB therapy.

In conclusion, the present study shows that the favorable safety, tolerability and efficacy of once-daily tolterodine ER observed during a 12-week treatment period is maintained over 12 months in a Japanese OAB patient population and is comparable to that previously reported in Caucasian populations. The efficacy and tolerability profile of tolterodine ER, together with its relatively low discontinuation rate, is likely to result in improved clinical effectiveness and supports the use of this agent in the long term management of OAB.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

This study was sponsored by Pfizer Japan Inc, Tokyo Japan.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
  9. Appendix

Here follows a complete list of the members of the Japanese Tolterodine Study Group in alphabetical order:

Hironobu Akino, Yoshida-gun, Fukui; Shiro Baba, Sagamihara City, Kanagawa; Atsunobu Esa, Tennoji-ku, Osaka; Takuji Fujinaga, Koya, Wakayama; Junnosuke Fukui, Chuo-ku, Tokyo; Eitetsu Gon, Shizuoka; Momokazu Gotoh, Showa-ku, Nogoya; Takahiro Haginaka, Toyama; Yukio Homma, Tokyo; Kiyotaka Hoshinaga, Toyoake City, Aichi; Takahito Ikeuchi, Nagoya Mizuho-ku, Aichi; Hirohide Iriguchi, Kochi; Toshiya Ishida, Yokote City, Akita; Yoshio Ishida, Nakahara-ku, Kawasaki; Yasunori Ishii, Urawa, Saitama; Osamu Ishiko, Abeno-ku, Osaka; Shinji Kageyama, Hamamatsu City, Shizuoka; Hiroshi Kajikawa, Izumiohtsu City, Osaka; Yoshiyuki Kakehi, Kida-gun Kagawa; Tetsuo Katsumi, Kanazawa City, Ishikawa; Kazuki Kawabe, Tokyo; Mutsushi Kawakita, Moriguchi, Osaka; Takeshi Kawamura, Sumida-ku Tokyo; Kazuo Kitami, Fujisawa City, Kanagawa; Shinya Kobayashi, Sapporo City, Hokkaido; Kenjiro Kohri, Mizuho-ku, Nagoya; Hideki Komatsu, Minato-ku, Tokyo; Hitoshi Masuda, Bunkyo-ku, Tokyo; Shigeki Matsuo, Akita City, Akita; Hisashi Matsushima, Chiyoda-ku, Tokyo; Shigeyoshi Morimoto, Kishiwada City, Osaka; Hajime Morita, Bibai City, Hokkaido; Kouei Muguruma, Moriguchi, Osaka; Haruo Nakagawa, Sendai City, Miyagi; Yosuke Nakajima, Kanagawa-ku, Yokohama; Mikio Namiki, Kanazawa City, Ishikawa; Takashige Namima, Sendai City, Miyagi; Osamu Nishizawa, Matsumoto, Nagano; Kazumi Noguchi, Yokohama City, Kanagawa; Ryosuke Noguchi, Mito City, Ibaraki; Hiroya Oka, Kobe City, Hyogo; Yasutada Onodera, Aoba-ku, Yokohama; Seiichirou Ozono, Kashihara, Nara; Masafumi Sahashi, Shizuoka; Shigeo Sakashita, Obihiro City, Hokkaido; Shoji Samma, Nara City, Nara; Masayoshi Shimamura, Kanazawa City, Ishikawa; Naotake Shimoda, Akita; Atsushi Sone, Kurashiki; Takahide Sugiyama, Osaka Sayama City, Osaka; Kouji Suzuki, Uchinada, Ishikawa; Yasushi Suzuki, Morioka City, Iwate; Masashi Takaiwa, Yonezawa City, Yamagata; Hitoshi Takamoto, Kurashiki City, Okayama; Masayuki Takeda, Tamaho, Yamanashi; Mineo Takei, Hakata-ku, Fukuoka; Ikumasa Takenaka, Kida-gun, Kagawa; Shigeo Taketa, Kida-gun, Kagawa; Hideo Takeuchi, Kobe City, Hyogo; Toshiro Terachi, Tenri Nara; Takashi Tominaga, Chiyoda-ku, Tokyo; Keiichi Tozawa, Mizuho-ku, Nagoya; Sadamu Tsukamoto, Tuskuba-shi, Ibaraki; Osamu Ueki, Nanao City, Ishikawa; Toyoko Yamato, Okayama; Kousaku Yasuda, Koshigaya-city, Saitama; Teruhiko Yokoyama, Shikata-cho, Okayama; Masaki Yoshida, Kumamoto.