MISCELLANEOUS Treatment Satisfaction with Flexible-dose Fesoterodine in Patients with Overactive Bladder who were Dissatisfied with Previous Anticholinergic Therapy: A Multicenter Single-Arm Clinical Study Jin Bong Choi1, Kang Jun Cho1, Won Hee Park2, Dong Hwan Lee3, Young-Ho Kim4, In Rae Cho5, Hana Yoon6, Young Sik Kim7, Joon Chul Kim1* Purpose: We investigated treatment satisfaction with flexible-dose fesoterodine in patients with overactive bladder (OAB) who were dissatisfied with previous anticholinergic therapy. Materials and Methods: The subjects were prescribed fesoterodine 4 mg for 4 weeks and fesoterodine 4 mg or 8 mg for another 8 weeks. The primary end point of this study was patients’ satisfaction after 12 weeks of fesoterodine treatment on a five-point Likert scale. Secondary end points included a change in the number of daytime micturition, urgency incontinence episodes, urgency episodes, and nocturnal micturition in a -24hour period from baseline to final assessment. Results: Overall, 84 patients were assigned to the treatment group in this study and 63 patients completed the -12week treatment course. A final fesoterodine dose of 4 mg and 8 mg was used by %71.4) 45) and %28.6) 18) patients, respectively. The satisfaction and dissatisfaction rates at 12 weeks were %69.9 and %14.2, respectively. Mean changes in the daytime micturitions (4.72 ± 9.73 vs. 2.86 ± 7.76), urgency episodes (5.68 ± 7.73 vs. ± 3.71 4.09), and nocturnal micturitions (1.36 ± 2.13 vs. 1.12 ± 1.68) in 24 hours improved significantly with flexible- dose fesoterodine treatment (P < .05). Most adverse events were mild and none were severe. Conclusion: The flexible dose fesoterodine represents an alternative treatment modality in patients with OAB who are dissatisfied with previous anticholinergic therapy in Korea. Keywords: fesoterodine; overactive bladder; patient satisfaction INTRODUCTION Overactive bladder (OAB) is defined as a syndrome that causes urgency (with or without urge incon- tinence), frequency, and nocturia.(1) The overall prev- alence of OAB is approximately 16% in the USA and six European countries (Sweden, France, Spain, Italy, Germany, and the United Kingdom). The prevalence of the syndrome does not differ by sex even though the severity and expressed symptoms do.(2,3) The overall prevalence of OAB in Korea has been reported to be approximately 12% and increases with age.(4) Although anticholinergics are considered the mainstay of treatment for OAB(5), their variable efficacy and poor compliance due to adverse effects such as dry mouth, constipation, and even cognitive impairment lead to low patient satisfaction.(6,7) As a result, physicians switch 1Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Republic of Korea. 2Department of Urology, Inha University College of Medicine, Incheon, Republic of Korea. 3Department of Urology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, Republic of Korea. 4Department of Urology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea. 5Department of Urology, Ilsanpaik Hospital, Inje University College of Medicine, Goyang, Republic of Korea. 6Department of Urology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea. 7Department of Urology, National Health Insurance Service, Ilsan Hospital, Goyang, Republic of Korea. *Correspondence: Department of Urology, Bucheon St. Mary’s Hospital, College of Medicine, Catholic University of Korea, 327 Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of Korea. Tel: +82-32-340-7071, Fax: +82-32-340-2124, E-mail: kjc@catholic.ac.kr. Received June 2018& Accepted February 2019 drugs or modify the dose when patients are dissatisfied with previous anticholinergic therapy. Previous studies have demonstrated that fesoterodine at dosages of 4 mg or 8 mg once daily significantly improved OAB symptoms.(8,9) Furthermore, the avail- ability of the flexible doses of fesoterodine provides an opportunity to maintain an optimal balance between benefits and risks in patients.(10) Recent data has shown that flexible-dose fesoterodine is associated with a high rate of patient treatment satisfaction, produced signifi- cant improvements in voiding diary variables and neg- ative symptoms, and resulted in a greater health-related quality of life.(11) Several studies also reported the effi- cacy of switching anticholinergic therapy, including to fesoterodine, when patients were dissatisfied with pre- vious anticholinergics.(11-13) However, there have been Urology Journal/Vol 17 No. 1/ January-February2020/ pp. 97-101. [DOI: 10.22037/uj.v0i0.4650] only a few study of flexible-dose fesoterodine in the Asian patients. Therefore, in this study, we examined treatment satis- faction with flexible-dose fesoterodine in adult subjects with OAB who were dissatisfied with previous anticholinergic treatment in the Korean population. MATERIALS AND METHODS Study design This prospective, multi-center, open-label, single-arm clinical study was conducted at seven different medical centers in Korea for 1 year. All seven centers are su- perior general hospitals under the college of medicine. Written informed consent was obtained from all sub- jects. The study was performed in accordance with the Good Clinical Practice guidelines of the International Conference on Harmonization and the ethical principles of the Declaration of Helsinki. The duration of the study was 12 weeks except for a washout period of 2 weeks and a 2 weeks baseline peri- od for screening. We recruited patients currently under- going treatment for OAB or through an IRB-approved subject recruitment announcement. After 4 weeks with fesoterodine 4 mg daily, the dosage was either main- tained at fesoterodine 4 mg daily or increased to 8 mg daily for the remaining 8 weeks of the study. Dose escalation was based on the subjects and physician assessments of efficacy and tolerability. If the symp- tom improvement was weak, the dose of fesoterodine was increased to 8mg, or if the side effects such as dry mouth were severe, 4mg of fesoterodine was main- tained. Adherence was measured by pill counts. Ethics This study was approved by the Institutional Review Board of The Catholic University of Korea (HC10MI- MI0094). Subjects The study included men or women aged ≥ 18 years with OAB (mean micturition frequency of > 8 per 24 hours and mean number of urgency episodes > 3 per 24 hours in a 3-day voiding diary) for > 3 months who were “somewhat dissatisfied” or “very dissatisfied” in the five-point Likert scale with other anticholinergic treatments (propiverine, oxybutynin, trospium, and so- lifenacin) for at least 1 month. Subjects with the fol- lowing conditions were excluded from the study: histo- ry of acute urinary retention requiring catheterization, neurogenic bladder, lower urinary tract surgery with- in 6 months, predominant stress urinary incontinence, significant pelvic organ prolapse, significant hepatic or renal function impairment, and any contraindications to fesoterodine usage. A sample size of 100 subjects was calculated to provide 10% level of margin for error and the 95% confidence interval for the percentage of treatment satisfaction rate at week 12. However, because the study was open label, the response to fesoterodine could be observed through- out the study. Therefore, the principal investigator de- cided to stop recruitment when obvious changes in sub- jects reporting treatment satisfaction were observed. Outcome measurements The primary end point of this study was patients’ sat- isfaction after 12 weeks of fesoterodine treatment on a five-point Likert scale as follows: very satisfied, some- what satisfied, neither satisfied nor dissatisfied, some- what dissatisfied, and very dissatisfied. Secondary end points included changes from baseline to week 12 in the number of daytime micturitions, urgency incontinence episodes, urgency episodes with urgency scale (five- point urinary sensation scale as follows: no urgency, mild urgency, moderate urgency, severe urgency, and urge incontinence), and nocturnal micturitions in 24 hours from the baseline to the final assessment through a 3-day voiding diary. Safety assessments included ad- verse events. Statistical methods SAS software version 9.4 (SAS Institute, Cary, NC, USA) was used for statistical analysis. The data is pre- sented as the mean ± standard deviation (SD). Com- parative analysis of change of variables in the voiding diaries was performed with a two-sided paired t-test. A P-value of < .05 was considered statistically significant. Safety analysis included all subjects who received at least one dose of the study drug. RESULTS Subjects Ninety-seven patients had been screened in 7 centers and 84 patients were enrolled and assigned to the treat- ment arm. The reasons for screening failure were that the inclusion criteria were not met or consent was with- drawn. Sixty-three patients completed the 12-week treatment period, while 21 did not. The reasons for dis- continuation were adverse events, protocol violation, loss to follow-up, and consent withdrawal (ure 1). Treatment Satisfaction with flexible-dose fesoterodine-Choi et al. Table 1. Demographic and baseline parameters Parameters Patients (n = 63) Age, years 59.1 ± 13.3 Range 26-82 Mean duration for suffering from OAB, months 42.6 ± 37.8 12 months or less 15 (23.8) 12 to 36 months 25 (39.7) Over 36 months 23 (36.5) Somewhat dissatisfied with prior anticholinergics 47 (74.6%) Very dissatisfied with prior anticholinergics 16 (25.4%) Data are presented in the format of mean ± standard deviation or n (%). Abbreviations: OAB, overactive bladder Miscellaneous 98 Vol 17 No 01 January-February 2020 99 The average age of the patients was 59.1 ± 13.3 years (range: 26 to 82 years) with the average age of fe- male patients being 58.3 ± 13.2 years (range: 26 to 82 years) and the average age of male patients being 64.4 ± 10.3 years (range: 45 to 76 years). The mean dura- tion for suffering from OAB was 42.6 ± 37.8 months with 12 months or less in 15 patients (23.8%), 12 to 36 months in 25 patients (39.7%), and over 36 months in 23 patients (36.5%). The number of subjects that were “somewhat dissatisfied” with prior anticholinergics were 47 (74.6%) with 16 (25.4%) being “very dissatis- fied” with prior anticholinergics (Table 1). Compliance on treatment after 12 weeks was 100% in 27 patients, 80-99% in 34 patients, and 60-79% in 2 patients. Primary outcome variable Sixty-three patients who conducted the evaluation of satisfaction and voiding diary on treatment for 12 weeks were available for efficacy evaluation. A final fesoterodine dose of 4 mg and 8 mg/day was used by 45 patients (71.4%) and 18 patients (28.6%), respectively. The satisfaction rate at 12 weeks of fesoterodine treat- ment was 69.9% (very satisfied at 19.1% and somewhat satisfied at 50.8%) and the dissatisfaction rate was at 14.2% (somewhat dissatisfied at 6.3% and very dissat- isfied at 7.9%). Secondary outcome variable Mean changes in the number of daytime micturitions (9.73 ± 4.72 vs. 7.76 ± 2.86, P = .001), urgency episodes (7.73 ± 5.68 vs. 3.71 ± 4.09, p = 0.005), and nocturnal micturitions (2.13 ± 1.36 vs. 1.68 ± 1.12, P < .001) in 24 hours improved significantly with the flexible dose fesoterodine treatments. There was no statistically sig- nificant improvement in the number of instances of ur- gency urinary incontinence (Table 2). Safety and tolerability Eighty-four patients who participated in this clinical study who took fesoterodine at least 1 time and under- went safety evaluations were available for tolerabili- ty evaluation. Adverse events occurred in 22 patients (26.2%) at 12 weeks. Dry mouth was the most com- monly reported adverse event and more commonly re- ported at 12 weeks compared to 4 weeks. There were no serious adverse events (Table 3). DISCUSSION The main findings of this multicenter, open-label, sin- gle-arm clinical study were: (1) The satisfaction rate af- ter 12 weeks of flexible-dose of fesoterodine treatment was approximately 70% with the dissatisfaction rate being around 14%. (2) Mean changes in the number of daytime micturitions, urgency episodes, and nocturnal micturitions in 24 hours improved significantly with flexible dose fesoterodine treatment. (3) Most of the adverse events that occurred were mild and none were severe. These findings are consistent with the results of oth- er previously published studies. The efficacy, safety, and tolerability of fixed dose fesoterodine (4 mg and 8 mg) for OAB were proven in two randomized clini- cal trials where the dose response effect of fesoterodine was defined.(14,15) In superiority trial, fesoterodine 8 mg showed statistically significantly superior efficacy than fesoterodine 4 mg or placebo.(8) Flexible-dose fesoterodine also significantly improved OAB symptoms and treatment satisfaction in sever- al randomized, double-blind, placebo-controlled tri- als(16-19) and open-label trials.(10,11,20) Recent systematic review of data from these clinical trials showed that flexible-dose fesoterodine provided clinical benefit to patients with OAB because of its dose-response effects. (21) These studies were designed to reflect clinical prac- tice better in that the patients decided the dose escala- tion according to their clinical response rather than to a defined study protocol. In previous open label, flex- ible-dose trials of fesoterodine, 50 to 59% of subjects who received fesoterodine 4 mg requested dose escala- tion to 8 mg.(10,11,20) However, a final fesoterodine dose of 8 mg/day was used by only 18 patients (28.6%) in our study, while approximately 70% of subjects who requested fesotero- dine 4 mg continuously or increase to 8 mg exhibited improvements in efficacy and tolerability as seen in other studies. Subjects who wanted to escalate their dose from fesoterodine 4 mg to 8 mg generally report- ed more severe baseline symptoms than subjects who wanted to continue the 4 mg dosage. The patients also exhibited lower improvements in efficacy and a higher incidence rate in adverse events during treatment with fesoterodine 4 mg. The patients’ baseline symptoms in our study were better than other studies and the rate of adverse events was low during treatment. As a result, patients who wanted to increase their dose of fesotero- dine were fewer in number. There was no statistically significant improvement in Table 2. Change of parameters of the voiding diary per 24 hours from baseline to fesoterodine treatment at 4 weeks and 12 weeks Baseline 4 weeks p-value 12 weeks p-value mean ± SD mean ± SD (baseline vs. 4 weeks ) mean ± SD (baseline vs. 12 weeks ) No. of daytime micturitions 9.73 ± 4.72 7.98 ± 2.66 <0.001 7.76 ± 2.86 0.001 No. of nocturnal micturitions 2.13 ± 1.36 1.69 ± 1.19 0.008 1.68 ± 1.12 0.005 No. of urgency episodes 7.73 ± 5.68 4.16 ± 4.40 <0.001 3.71 ± 4.09 < 0.001 No. of urgency urinary 0.25 ± 0..66 0.15 ± 0.58 0.132 0.26 ± 0.83 0.656 incontinence episodes Data are presented as the mean ± SD. Abbreviations: SD, standard deviation Adverse events 4 weeks No. (%) 12 weeks No. (%) Dry mouth 5 (5.9) 9 (10.7) Dry eye 0 (0) 1 (1.2) Constipation 1 (1.2) 1 (1.2) Gastrointestinal discomfort 0 (0) 1 (1.2) Voiding difficulty 2 (2.4) 2 (2.4) Others (headache, leg edema, 6 (7.1) 8 (9.5) cystitis, gum bleeding, sore throat, diabetes, cervicalgia, cholangitis) Table 3. Adverse events in response to fesoterodine treatment Treatment Satisfaction with flexible-dose fesoterodine-Choi et al. the number of instances of urgency urinary inconti- nence among the secondary outcome variables. While urgency urinary incontinence is considered a more notable symptom of OAB, continent OAB also has negative effects and decreases health-related quality of life. Coyne et al. reported that urinary urgency had a significant negative effect on health-related quality of life compared to incontinence urgency urinary in- continence in a national community survey using the National Overactive Bladder Evaluation Program.(22) Although urinary urgency can be quantifiable through counting urgency episodes in a voiding diary, this is in- sufficient to understand the patients’ overall symptoms. Therefore, patient-reported outcome data should be in- vestigated to measure the overall impact of treatment including adverse effects and tolerability. The current study has several limitations. The main lim- itation of the study was the relatively small sample size compared to other similar studies. Therefore, these find- ings cannot be generalized to the entire Korean popula- tion. There was also a lack of male patients with most of subjects being women (87.3%). As a result, a study in- volving a larger sample including more men should be performed in the future. Second, this study was an open label study and did not include a placebo group. How- ever, fesoterodine (4 mg and 8 mg) has been reported to be more efficacious for OAB symptoms than place- bos in previous randomized placebo-controlled clinical trials.(14,15) In addition, open-label studies are advanta- geous in that they reflect actual clinical practice and can determine an optimal balance between efficacy and tolerability. Third, we could not compare outcomes in subjects who received fesoterodine 4 mg for 12 weeks with subjects who escalated to the 8 mg dosage after 4 weeks. This is the limitation of an open-label, flexible dosing design because the baseline symptoms may vary between the two groups at the time of determination of dose escalation. Fourth, the satisfaction measurement was only dependent on the five-point Likert scale sur- vey, not on the objective measurements. So the reliabil- ity of the responses of the patients about their satisfac- tion of the medication was considered low. This should be supplemented in future studies. CONCLUSIONS Patients with OAB who were dissatisfied with previous anticholinergic therapy had a high satisfaction rate and tolerated the flexible dose fesoterodine well. Therefore, this treatment represents an alternative treatment mo- dality in patients with OAB who are dissatisfied with previous anticholinergic therapy in Korea. A study using a larger sample size including a number of male subjects should be performed in the future. ACKNOWLEDGEMENT The study was funded by Pfizer Pharmaceutical Korea Ltd. CONFLICT OF INTEREST The authors have no conflicts of interest to declare. REFERENCES 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61:37-49. 2. Stewart WF, Van Rooyen JB, Cundiff GW, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003;20:327-36. 3. Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int. 2001;87:760-6. 4. Lee YS, Lee KS, Jung JH, et al. Prevalence of overactive bladder, urinary incontinence, and lower urinary tract symptoms: results of Korean EPIC study. World J Urol. 2011;29:185-90. 5. Kim TH, Lee KS. Persistence and compliance with medication management in the treatment of overactive bladder. Investig Clin Urol. 2016;57:84-93. 6. Yoo ES, Kim BS, Kim DY, Oh SJ, Kim JC. The impact of overactive bladder on health-related quality of life, sexual life and psychological health in Korea. Int Neurourol J. 2011;15:143-51. 7. Ruxton K, Woodman RJ, Mangoni AA. Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta- analysis. Br J Clin Pharmacol. 2015;80:209- 20. 8. Chapple C, Schneider T, Haab F, et al. Superiority of fesoterodine 8 mg vs 4 mg in reducing urgency urinary incontinence episodes in patients with overactive bladder: results of the randomised, double-blind, placebo-controlled EIGHT trial. BJU Int. 2014;114:418-26. 9. Kelleher CJ, Tubaro A, Wang JT, Kopp Z. Impact of fesoterodine on quality of life: pooled data from two randomized trials. BJU Int. 2008;102:56-61. 10. Wyndaele JJ, Goldfischer ER, Morrow JD, Gong J, Tseng LJ, Choo MS. Patient- optimized doses of fesoterodine improve bladder symptoms in an open-label, flexible- dose study. BJU Int. 2011;107:603-11. 11. Wyndaele JJ, Goldfischer ER, Morrow JD, et al. Effects of flexible-dose fesoterodine on overactive bladder symptoms and treatment satisfaction: an open-label study. Int J Clin Pract. 2009;63:560-7. 12. Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders SW. Comparative efficacy and safety of transdermal oxybutynin and oral tolterodine versus placebo in previously treated patients with urge and mixed urinary incontinence. Urology. 2003;62:237-42. 13. Chancellor MB, Zinner N, Whitmore K, et al. Efficacy of solifenacin in patients previously Treatment Satisfaction with flexible-dose fesoterodine-Choi et al. Miscellaneous 100 Vol 17 No 01 January-February 2020 101 treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study. Clin Ther. 2008;30:1766- 81. 14. Nitti VW, Dmochowski R, Sand PK, et al. Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. J Urol. 2007;178:2488-94. 15. Chapple C, Van Kerrebroeck P, Tubaro A, et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol. 2007;52:1204- 12. 16. Dubeau CE, Kraus SR, Griebling TL, et al. Effect of fesoterodine in vulnerable elderly subjects with urgency incontinence: a double-blind, placebo controlled trial. J Urol. 2014;191:395-404. 17. Wagg A, Khullar V, Marschall-Kehrel D, et al. Flexible-dose fesoterodine in elderly adults with overactive bladder: results of the randomized, double-blind, placebo-controlled study of fesoterodine in an aging population trial. J Am Geriatr Soc. 2013;61:185-93. 18. Weiss JP, Jumadilova Z, Johnson TM, 2nd, et al. Efficacy and safety of flexible dose fesoterodine in men and women with overactive bladder symptoms including nocturnal urinary urgency. J Urol. 2013;189:1396-401. 19. Dmochowski RR, Peters KM, Morrow JD, et al. Randomized, double-blind, placebo- controlled trial of flexible-dose fesoterodine in subjects with overactive bladder. Urology. 2010;75:62-8. 20. Cardozo L, Hall T, Ryan J, et al. Safety and efficacy of flexible-dose fesoterodine in British subjects with overactive bladder: insights into factors associated with dose escalation. Int Urogynecol J. 2012;23:1581-90. 21. Wyndaele JJ, Schneider T, MacDiarmid S, Scholfield D, Arumi D. Flexible dosing with fesoterodine 4 and 8 mg: a systematic review of data from clinical trials. Int J Clin Pract. 2014;68:830-40. 22. Coyne KS, Payne C, Bhattacharyya SK, et al. The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey. Value Health. 2004;7:455-63. Treatment Satisfaction with flexible-dose fesoterodine-Choi et al.