ORIGINAL PAPER
A randomised, prospective double-blind, propiverinecontrolled trial of imidafenacin in patients with overactive bladder C. Park,1,* J. Park,2,* M.-S. Choo,3 J. C. Kim,4 J. G. Lee,5 J. Z. Lee,6 K.-S. Lee,7 D. Y. Kim,8 S.-J. Lee,9 J. T. Seo10
1
Department of Urology, Gangneung Asan Medical Center, University of Ulsan College of Medicine, Gangneung, Korea 2 Department of Urology, Eulji University Hospital, Daejeon, Korea 3 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 4 Department of Urology, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea 5 Department of Urology, Korea University Anam Hospital, Seoul, Korea 6 Department of Urology, Pusan National University Hospital, Pusan, Korea 7 Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Urology, Catholic University of Daegu School of Medicine, Daegu, Korea 9 Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea 10 Department of Urology, Cheil General Hospital, Kwandong University College of Medicine, Seoul, Korea Correspondence to: Prof. Myung-Soo Choo, MD, PhD, Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpagu, Seoul 138-736, Korea Tel.: +82 2 3010 3735 Fax: +82 2 477 8928 Email: [email protected] *Changmyon Park and Jinsung Park contributed equally to this study.
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ABSTRACT
What’s known
Aim: To assess the efficacy and safety of imidafenacin compared with propiverine for treatment of overactive bladder (OAB) in Korean patients. Materials and methods: Patients with OAB symptoms were randomised to double-blind treatment with 0.1 mg of imidafenacin twice daily (group A) or propiverine 20 mg once daily (group B) for 12-week regimen, and assessed for efficacy and safety. The primary efficacy outcome was per cent change of weekly urgency urinary incontinence (UUI) episodes at week 12. The secondary efficacy outcomes were changes in the micturitions per day, urine volume voided per micturition, urgency episodes per day, complete disappearance of incontinence episodes and severity of urgency from baseline to week 12. Quality of life and safety profiles were also compared. Results: Of 162 patients randomised, 140 completed the study protocol. The per cent change of weekly UUI episodes at week 12 was 69.1% in group A and 70.4% in group B (both p < 0.0001). The lower limit of 95% onesided confidence interval of the difference between the groups was above the non-inferiority margin ( 19.42%). Other voiding parameters and quality of life significantly improved at week 12 in both the groups. The discontinuation rates caused by adverse events were low in both the groups. While dry mouth was the most common adverse event (group A: 28.4% vs. B: 30.4%, p = 0.783), the severity of dry mouth was significantly less in the group A than B (p = 0.042) There were no significant differences in other safety profiles. Conclusions: After the 12-week treatment of imidafenacin 0.1 mg twice daily, all OAB symptoms and quality of life improved. Imidafenacin was not inferior to propiverine for the reduction of UUI episodes, and was better tolerated than propiverine in the safety profile. Our results indicate that imidafenacin is a safe and effective drug in Korean patients with OAB.
Introduction The prevalence of overactive bladder (OAB) syndrome defined as urgency with or without urge incontinence is 11.8% in Western countries and 12.2% in Korea, and increases with advancing age (1,2). OAB deteriorates a patient’s quality of life (QOL). It is associated with mental stress and depression, limiting patient social ability and daily life (3,4). Treatment of OAB consists of behavioural therapy such as bladder training and pharmacological therapy, with antimuscarinic receptor (MR) drugs mainly used. Anti-MR drugs block MRs, inhibiting
Imidafenacin is a novel antimuscarinic agent with M1 and M3 selectivity. Japanese placebo-controlled phase II and active-controlled phase III trials have already been performed for imidafenacin, and they showed that imidafenacin was superior to placebo and not inferior to propiverine or solifenacin in its efficacy and safety. However, no comparative studies have been published regarding the efficacy and safety of imidafenacin in other ethnicities except Japanese.
What’s new This study was a prospective, randomised, doubleblinded, double-dummy, propiverine-controlled, phase III multicentre trial in Korea. In this study, we first demonstrated that imidafenacin was effective for improving the overactive bladder symptoms of Korean patients for at least 3 months, and imidafenacin was not inferior to propiverine in efficacy outcomes. In addition, we found that severity of dry mouth was significantly lower in the imidafenacin group than the propiverine group.
the binding of acetylcholine. Symptoms such as urgency, urgency urinary incontinence (UUI) and frequency are improved by prohibiting the contraction of smooth muscles in the bladder. However, the anti-MR drugs are associated with adverse events (AEs) including dry mouth and constipation, which are the main reasons for drug discontinuation and compromised patient compliance to continuous treatment (5,6). To relieve the AEs of anti-MR drugs, new drugs with more selectivity for the bladder have been developed. Imidafenacin, a novel anti-MR drug, shows a high affinity for M3 and M1 receptors in rats ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196. doi: 10.1111/ijcp.12255
Efficacy and safety of imidafenacin in Korean OAB patients
and inhibits rhythmic bladder contractions with high selectivity to the bladder rather than the salivary glands (7–9). Several comparative studies of the efficacy and safety of imidafenacin and other anti-MR agents have been reported with Japanese OAB patients (10–13). No comparative studies have been published regarding the efficacy and safety of imidafenacin in other ethnicities except Japanese. In this study, we compared the efficacy and tolerability of imidafenacin 0.1 mg twice daily and propiverine 20 mg once daily in Korean patients with symptoms of OAB.
Materials and methods Patients and study design This study was a prospective, randomised, doubleblinded, double-dummy, phase III multicentre trial at eight hospitals in Korea. The study protocol was approved by the Institutional Review Board of each institution, was in conformity with the ethical principles of the Declaration of Helsinki, and followed the International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from each patient before screening. Eligible criteria were OAB patients aged ≥ 19 years who had five or more UUI episodes per week, eight or more micturitions per day and one or more urgency frequency per day for ≥ 3 months. Patients with clinically significant stress urinary incontinence, significant bladder outlet obstruction, urinary tract infections, interstitial cystitis, previous or current malignant disease in the pelvic organs, indwelling catheters or intermittent catheterisation, any medical condition contraindicating the use of antimuscarinic medication (including narrow angle glaucoma and urinary or gastric retention), > 100 ml in postvoid residual (PVR) volume, > 3,000 ml in daily voided volume according to the voiding diary during the observation period, > 3.0 mg/dl in total bilirubin levels, > 2.5 times (or > 100 IU/l) in AST or ALT and > 2.0 mg/dl in serum creatinine levels were excluded. Other exclusion criteria included patients who were treated with non-pharmacological treatment for OAB including electrostimulation therapy or a bladder training program within 3 months before the run-in period; propiverine HCl within 4 weeks; concomitant medication of contraindicated drugs within 2 weeks; genitourinary tract surgery within 6 months before the run-in period; pregnant and nursing women. The study design is shown in Figure S1. After initial screening, patients were examined for suitability for the trial, and those taking contraindicated drugs were enrolled following 2 weeks of washout period. ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
During the 2-week run-in period, patients were prescribed placebo twice a day, and a voiding diary was taken for 1 week before the next visit (baseline). During the run-in period, past medical history, physical examination, 12-lead electrocardiography, laboratory tests including liver and renal function test were examined. In accordance with a predefined randomisation sequence created by a computer random number generator, eligible patients were randomised with a 1 : 1 ratio to either imidafenacin (group A) or propiverine (group B). During the treatment period, the double-blind, double-dummy method was used. All study medication and placebos were similar in appearance and smell. Treatment allocations were blinded to patients, investigators and all study personnel directly involved in conduct of the study. Group A took 0.1 mg tablets of imidafenacin twice a day and a propiverine placebo once a day while group B took 20 mg of propiverine HCl once a day and an imidafenacin placebo twice a day. Test drugs not taken by the patient were returned to check the patient’s medication compliance. If the compliance rate was above 80%, the patient was regarded as compliant. Patients were seen at 4, 8 and 12 weeks after treatment.
Assessment of efficacy and tolerability Seven-day voiding diaries were taken at baseline and at week 4, 8 and 12 after treatment. UUI, micturition and urgency episodes during the 7-day periods were recorded. Urine volume voided per micturition was recorded for at least three complete days. The severity of urgency for the past 1 week was assessed by the investigator during interviews with the patients at baseline, 4, 8 and 12 weeks after treatment using the Indevus Urgency Severity Scale, a 4-grade validated scale (none: no urgency; mild: awareness of urgency, but is easily tolerated; moderate: enough urgency discomfort that it interferes with or shortens your usual activity or tasks; severe: extreme urgency discomfort that abruptly stops all activity or tasks). The proportions of patients who improved by one or more grade during the treatment period were calculated. The primary efficacy outcome was the per cent change in the number of UUI per week from the baseline. The secondary efficacy outcomes were the changes in the number of micturitions per day, the urine volume voided per micturition, complete disappearance of incontinence episodes and the severity of urgency, as well as the per cent change of urgency episodes per day. The patients’ QOL was assessed using the Korean version of King’s Health Questionnaire (KHQ) (14) at baseline and 12 weeks. The
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Disclosures All authors declare no competing financial interests.
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Efficacy and safety of imidafenacin in Korean OAB patients
change in KHQ domain scores from the baseline to the end of the study was also evaluated. Safety and tolerability were evaluated by AEs, blood pressure, pulse rate, 12-lead electrocardiography and PVR volumes as measured by bladder scans at the baseline and 12 weeks. Laboratory tests were performed at the baseline, 4 and 12 weeks. At each visit, any AEs were checked by an investigator or self-reported through a self-reported questionnaire. The severity of dry mouth and constipation was assessed using a mild, moderate or severe three-point scale. A cardiologist at each participating centre confirmed electrocardiography parameters.
Statistical analysis Using one-sided of a-level of 0.05 with 80% power and assuming that non-inferiority margin to per cent change of UUI per week was 19.42% from prior Japanese phase 3 study (11), 62 patients per group were required. Allowing for a possible 25% dropout rate, we aimed to enrol 83 patients per group (total 166 patients). Non-inferiority analysis of primary efficacy outcome was primarily based on the per-protocol set (PPS) population, and analysis for the full analysis set (FAS) population was also performed. Analyses of secondary efficacy outcomes were two-sided with null hypotheses of no difference rejected if p-values were less than 0.5. Non-inferiority analysis of secondary efficacy outcomes was not performed. The PPS was defined as the subjects who were eligible and were compliant with the protocol. The FAS was defined as subjects who were eligible, received at least one dose of the study drug, and was examined at least once for the efficacy end-points. Analyses of safety were carried out based on the randomised subjects who received at least one dose of the study drug.
For statistical analyses, Fisher’s exact or chi-square tests were used to compare categorical variables between groups. Within each treatment group, paired t-test or Wilcoxon’s signed rank test was used to make comparisons between the baseline and end of the treatment. Between-group comparison was performed using t-test or Wilcoxon’s rank sum test. Data are expressed as the mean SD. Statistical analyses were performed using SAS v.9.1 (SAS Institute, Cary, NC, USA).
Results From November 2006 to November 2007, 256 patients were screened, of whom 162 (group A: 82, group B: 80) were randomised. Patient disposition is summarised in Figure 1. While there was no significant difference in dropout rate between the two groups (A: 14.6% [12/82] and B: 12.5% [10/80], p = 0.820), at least 85% of patients in each group (70 per group) completed the study. The main reasons for dropouts were consent withdrawal and AEs in both groups. The FAS and the PPS included 75 and 67 of group A vs. 76 and 64 of group B, respectively. Baseline demographic and clinical characteristics of the PPS are summarised in Table 1. The two groups were well balanced in sex distribution, age (mean age: A, 58.3 years vs. B, 56.1 year) and various clinical characteristics except the severity of urgency (Table 1). Covariate-adjusted analyses demonstrated that the severity of urgency did not affect the results of the primary efficacy outcome.
Efficacy Table 2 shows the mean changes in all efficacy variables from baseline to week 12 in the two groups. After 12 weeks of treatment, UUI episodes per week
Figure 1 Patient disposition ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
Table 1 Demographic and clinical characteristics of patients for per-protocol set population
Demographic Sex, n (%) Age (years) Weight (kg) Clinical Duration from onset of symptom (month) Neurological aetiology, n (%) Medical history, n (%) Previous treatment for incontinence, n (%) Previous treatment with propiverine, n (%) Concomitant medications, n (%) Urgency urinary incontinence episodes per week Micturitions per day Urgency episodes per day Urine volume per micturition (ml) Severity of urgency, n (%)
Postvoid residual volume (ml)
Group A (N = 67)
Group B (N = 64)
p-value
Male Female Mean SD Mean SD
10 (14.93) 57 (85.07) 58.31 11.45 60.72 8.48
9 (14.06) 55 (85.94) 56.13 11.29 60.09 7.31
1.000*
Mean SD Neurogenic bladder Detrusor instability No Yes No Yes No Yes No Yes Mean SD Mean SD Mean SD Mean SD Mild Moderate Severe Mean SD
18.58 42.34 0 (0) 67 (100) 8 (11.94) 59 (88.06) 7 (10.45) 60 (89.55) 2 (2.99) 65 (97.01) 21 (31.34) 46 (68.66) 24.37 16.66 10.2 2.16 5.25 2.94 162.91 54.54 10 (14.93) 42 (62.69) 15 (22.39) 15.85 20.62
16.5 32.35 4 (6.25) 60 (93.75) 9 (14.06) 55 (85.94) 13 (20.31) 51 (79.69) 5 (7.81) 59 (92.19) 24 (37.50) 40 (62.50) 22.27 16.71 11.35 3.6 5.17 3.36 155.44 57.09 20 (31.25) 25 (39.06) 19 (29.69) 19.48 25.22
0.179† 0.963† 0.279† 0.054* 0.798* 0.147* 0.267* 0.469* 0.235† 0.111† 0.598† 0.332† 0.017*
0.661†
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. *Fisher’s exact test. †Wilcoxon’s rank sum test.
decreased from 24.37 16.66 to 8.73 15.53 in the group A and from 22.27 16.71 to 8.12 17.23 in the group B. The per cent change from baseline in UUI per week was 69.14 38.86% and 70.36 48.23% in the group A and B, respectively (all p < 0.0001). The lower limit of 95% one-sided confidence interval of the difference between the groups was 11.43 in the PPS analysis and 11.33 in the FAS analysis. Hence, the lower limits were above the non-inferiority margin ( 19.42%). In addition, the extent of decrease in UUI per week was similar between the two groups (Table 2, between-group comparison p > 0.05). Compared with baseline, after 12 weeks of treatment, secondary efficacy outcomes including micturitions per day, urine volume voided per micturition and urgency episodes per day significantly improved in both the groups (Table 2). Comparison of the extent of improvement in efficacy outcomes between the groups showed that improvement in the severity of urgency was significantly greater in the group A than group B at week 4 (62.69% vs. 40.63%, p = 0.015) and week 12 (82.09% vs. 64.06%, p = 0.029). Similar findings were observed in the analysis in the FAS analysis (Table 2). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Compared with baseline, patient QOL assessed by KHQ significantly improved in both groups at week 12 (Figure 2). Between-group comparison of each domain in the KHQ showed that improvement in the physical limitation domain was significantly greater in the group A than the group B (Figure 2D, p = 0.031).
Tolerability The proportions of patients discontinuing treatment owing to AEs were 4.94% (4/81) in group A and 6.33% (5/79) in B. The most frequently reported AEs resulting in discontinuation were dermatitis (n = 1), dyspepsia (n = 1), dry mouth (n = 1) and cystitis (n = 1) in the group A, and dry mouth (n = 3), headache (n = 1) and increased intraocular pressure (n = 1) in the group B. Adverse events were reported in 54.32% of the group A and 62.03% of group B (Table 3A, p = 0.323). Dry mouth, the most common AE, was reported in 28.40% of group A and 30.38% of group B (p = 0.783). As shown in Table 3B, severity of dry mouth was mild (23.46%) or moderate (4.94%) in the group A, whereas it was mild (15.19%),
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Table 2 Changes in efficacy outcomes
PPS population Group A (N = 67)
FAS population p-value† (A vs. B)
Group B (N = 64)
Primary efficacy outcome Urgency urinary incontinence episodes per week, Mean SD Baseline 24.37 16.66 22.27 Week 4 12.47 18.46 11.29 Week 8 9.31 13.46 9.42 Week 12 (End-point) 8.73 15.53 8.12 % change from baseline 69.14 38.86 70.36 95% CI of difference vs. Propiverine 11.43–13.87 p-value*,‡ < 0.0001 < 0.0001 Secondary efficacy outcomes Micturitions per day, Mean SD Baseline 10.20 2.16 11.35 Week 4 8.97 2.31 9.59 Week 8 8.72 2.06 9.55 Week 12 (End-point) 8.61 2.30 9.37 Change from baseline 1.59 1.82 1.99 p-value*,‡ < 0.0001 < 0.0001 Urine volume voided per micturition (ml), Mean SD Baseline 162.91 54.54 155.44 Week 4 178.42 60.85 179.66 Week 8 180.53 67.68 179.39 Week 12 (End-point) 184.43 66.88 180.69 Change from baseline 21.52 41.1 25.25 p-value*,‡ < 0.0001 < 0.0001 Urgency episodes per day, Mean SD Baseline 5.25 2.94 5.17 Week 4 3.07 3.06 3.60 Week 8 2.58 3.01 2.78 Week 12 (End-point) 2.29 3.26 2.39 % change from baseline 59.21 45.21 57.14 p-value*,‡ < 0.0001 < 0.0001 Complete disappearance of incontinence episodes (%) Baseline 0 0 Week 4 14.93 15.87 Week 8 19.4 28.13 Week 12 (End-point) 32.84 40.63 Severity of urgency (%, ≥ 1 grade improvement compared with baseline) Baseline – – Week 4 62.69 40.63 Week 8 77.61 64.06 Week 12 (End-point) 82.09 64.06
16.71 18.23 18.6 17.23 48.23
0.235§ 0.213§ 0.190§ 0.287§ 0.399§
Group A (N = 75)
p-value† (A vs. B)
Group B (N = 76)
24.80 18.63 13.41 20.98 10.23 17.24 9.71 18.80 69.17 38.80 11.33–12.38 < 0.0001
< 0.0001
23.63 12.19 10.49 9.34 69.70
18.19 22.09 21.20 20.08 46.98
0.441§ 0.130§ 0.299§ 0.462§ 0.528§
3.60 3.23 3.26 3.25 2.48
0.111§ 0.327§ 0.351§ 0.301§ 0.367§
10.41 9.14 8.73 8.64 1.69 < 0.0001
2.55 2.55 2.19 2.40 1.86
11.37 9.58 9.56 9.49 2.00 < 0.0001
3.58 3.26 3.21 3.19 2.47
0.160§ 0.502§ 0.287§ 0.147§ 0.495§
57.09 75.93 70.95 74.22 47.42
0.332§ 0.668§ 0.897§ 0.680§ 0.545§
161.84 178.34 180.76 184.36 22.92 < 0.0001
53.09 59.66 66.71 66.11 40.36
153.42 176.41 175.63 177.55 25.05 < 0.0001
55.80 71.87 69.75 71.42 45.90
0.260§ 0.480§ 0.605§ 0.478§ 0.732§
3.36 3.56 3.45 3.40 44.12
0.598§ 0.522§ 0.845§ 0.521§ 0.531§
5.24 3.15 2.64 2.38 59.57 < 0.0001
3.07 3.29 3.29 3.51 44.70
5.14 3.57 2.86 2.51 57.18 < 0.0001
3.40 3.88 3.68 3.62 43.36
0.580§ 0.788§ 0.804§ 0.433§ 0.462§
0 13.33 20.83 33.33
1.000¶ 0.305¶ 0.371¶
0.015¶ 0.123¶ 0.029¶
–
0 20 29.17 39.73
0.381¶ 0.336¶ 0.491¶
43.42 65.28 66.67
0.034¶ 0.199¶ 0.034¶
– 61.33 76.39 83.33
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. PPS, Per protocol set; FAS, full analysis set; CI, confidence interval; SD, standard deviation. *Comparison between baseline and end-point within each group. †Comparison between Group A and B. ‡Wilcoxon’s Signed Rank Test. §Wilcoxon’s Rank Sum Test. ¶Fisher’s Exact Test.
moderate (13.92%) and severe (1.27%) in the group B (p = 0.042). The incidence of constipation was lower in the group A than group B without statistical significance (4.94% vs. 12.66%, p = 0.084). There were no significant differences in the risk of blurred
vision (mild in all cases), dyspepsia (mild in most cases) and pyuria (mild in all cases) between the groups (Table 3A). Postvoid residual volumes of the safety populations at baseline were 14.96 19.45 ml in group A and ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
(A)
(B)
(D)
(G)
(C)
(E)
(F)
(H)
(I)
Figure 2 Change from baseline in the King’s Health Questionnaire during 12 weeks of treatment. Data are shown as the mean + SD at baseline and 12 weeks. Comparison between baseline and end-point (12 weeks) within each group was performed using Wilcoxon’s signed rank test or paired t-test, and between-group comparison was performed using Wilcoxon’s rank sum test. *p < 0.0001 vs. baseline; †p < 0.001 vs. baseline; ‡p < 0.05 vs. baseline; §p < 0.05 betweengroup comparison
20.28 25.19 ml in group B (p = 0.377). The PVR volumes at week 12 were 20.58 30.73 ml in group A and 24.84 44.87 ml in group B, respectively (p = 0.515). Compared with baseline, there were no significant increases in the PVR volumes at week 12 in both the groups. No patients underwent urinary retention or voiding difficulty in either group. There were no clinically relevant changes in physical examination, vital signs, electrocardiography including QT interval prolongation and arrhythmia, cognitive dysfunction and laboratory tests in both the groups. In the group B, there was statistically significant decrease (mean SD = 4.49 13.81) in the systolic blood pressure at week 12 compared with baseline (Wilcoxon’s signed rank p = 0.017). However, clinically significant hypotension was not observed in either group.
Discussion In this randomised propiverine-controlled clinical trial, 0.1 mg of imidafenacin twice daily was effective ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
for improving the OAB symptoms of Korean patients for at least 3 months. In addition, we confirmed that imidafenacin was not inferior to propiverine for the reduction of UUI episodes per week: overall per cent reduction in weekly UUI was about 70% in both drugs (mean reduction of UUI episodes: imidafenacin 15.64 per week vs. propiverine 14.15 per week). In the Japanese double-blind, placebo and propiverine-controlled phase 3 trial including large numbers of randomised patients (781 patients), per cent change from baseline in UUI per week was 68.54 36.58% and 73.08 43.15% in the imidafenacin and propiverine group (11), similar to our results. Regarding the primary efficacy outcome, in a US multicentre trial (15), changes in weekly UUI episodes of extended-release oxybutynin 10 mg and tolterodine 4 mg were 69.1% and 72.8%, respectively. In our previous study with other OAB drugs in Korean OAB patients (16), per cent decrease in mean daily (not weekly) UUI episode with 5 mg solifenacin was 59.4%, 10 mg solifenacin was 57.6% and 4 mg tolterodine was 52.3%. Thus, results from
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Efficacy and safety of imidafenacin in Korean OAB patients
Table 3 Adverse events (A) that occurred in more than 2% of patients and severity of major adverse events (B) in
both the groups
Adverse events
Group A (N = 81) n (%)
Group B (N = 79) n (%)
p-value
(A) Total Dry mouth Dyspepsia Pyuria Constipation Cystitis Vision blurred Nausea oedema peripheral Thirst Dry eye Pruritus Abdominal pain upper Abdominal discomfort Headache Urinary tract infection
44 (54.32) 23 (28.40) 5 (6.17) 5 (6.17) 4 (4.94) 3 (3.70) 2 (2.47) 2 (2.47) 2 (2.47) 1 (1.23) 1 (1.23) 1 (1.23) 0 (0) 0 (0) 0 (0) 0 (0)
49 (62.03) 24 (30.38) 2 (2.53) 4 (5.06) 10 (12.66) 2 (2.53) 4 (5.06) 2 (2.53) 0 (0) 3 (3.80) 2 (2.53) 2 (2.53) 3 (3.80) 2 (2.53) 2 (2.53) 2 (2.53)
0.323* 0.783* 0.443† 1.000† 0.084* 1.000† 0.440† 1.000† 0.497† 0.364† 0.618† 0.618† 0.118† 0.242† 0.242† 0.242†
Group A (N = 81), n (%)
Group B (N = 79), n (%)
Adverse events
Mild
Moderate
Severe
Mild
Moderate
Severe
(B) Dry mouth‡ Dyspepsia Pyuria Constipation Vision blurred Dry eye
19 (23.46) 3 (3.70) 5 (6.17) 3 (3.70) 2 (2.47) 1 (1.23)
4 1 0 1 0 0
0 1 0 0 0 0
12 (15.19) 2 (2.53) 4 (5.06) 7 (8.86) 4 (5.06) 2 (2.53)
11 (13.92) 0 (0) 0 (0) 4 (5.06) 0 (0) 0 (0)
1 0 0 0 0 0
(4.94) (1.23) (0) (1.23) (0) (0)
(0) (1.23) (0) (0) (0) (0)
(1.27) (0) (0) (0) (0) (0)
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. *v2 Test. †Fisher’s Exact Test. ‡Fisher’s exact p-value (between-group comparison) = 0.042.
our study and other clinical trials indicate that 0.1 mg of imidafenacin twice daily improves OAB symptoms like other anti-MR agents. The magnitudes of changes in the secondary efficacy outcomes including micturitions per day, the urine volume voided per micturition, urgency episodes per day and complete disappearance of incontinence episodes were similar at each evaluation period between the two groups. Interestingly, we found that while baseline severity of urgency was significantly worse in the imidafenacin group, imidafenacin was more effective than propiverine in improving the severity of urgency at week 4 and week 12. In addition to improvement in voiding parameters, the 12-week treatment of imidafenacin significantly decreased the KHQ scores in all domains from baseline, demonstrating statistically significant improvements of patient QOL. Of note, our finding that improvement in the physical limita-
tion domain was significantly greater in group A than group B (p = 0.031) may indicate superiority of imidafenacin in terms of QOL. This finding is different from the Japanese phase 3 trial (11) in which propiverine was associated with significantly greater improvement than imidafenacin in the domains of role limitation, emotions and symptom severity. Further studies are needed to understand the change in patient QOL after the treatment of imidafenacin. Imidafenacin was well tolerated by patients with only a few discontinuations caused by AEs, and most AEs were mild in severity. Although the incidence of dry mouth, the most common AE of anti-MR drugs, was not significantly different between the imidafenacin and propiverine group (group A: 28.40% vs. B: 30.38%, p = 0.783), severity of dry mouth was significantly lower in the imidafenacin group than the propiverine group (p = 0.042). This finding is in line with other studies in which imidafenacin is ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
preferable to other anti-MR agents including solifenacin (12,13), propiverine (11) in terms of safety profile. For example, in the Japanese phase 3 trial, dry mouth was reported in 31.5% and 39.9% of imidafenacin and propiverine group, significantly lower in the imidafenacin group (p = 0.03). Zaitsu et al. (13) found that although the incidence of dry mouth was 71.4% after 52 weeks of imidafenacin and 90% after 52 weeks of solifenacin treatment (p > 0.05), the severity of dry mouth was significantly lower in the imidafenacin group (p = 0.0092). The possible mechanisms of less dry mouth in our study and the aforementioned studies (11–13) are attributable to a higher selectivity of imidafenacin for the bladder over other organs. For example, in an in vivo rat model, the relative bladder selectivity of imidafenacin was reported to be 15-fold higher over salivary gland, 150-fold higher over colon and 50-fold higher over heart, respectively, than that of propiverine (17). In addition, imidafenacin has higher affinities for M3 and M1 receptors and higher selectivity for the urinary bladder than for the salivary gland (7,8). In our study, the risk of constipation was lower in the group A than group B (p = 0.084). In another study by Zaitsu et al. (13), the incidence and severity of constipation were significantly lower in the imidafenacin group than solifenacin group (p = 0.0013). Integrating these findings, we believe that imidafenacin has more favourable safety profile than propiverine. Consistent with other reports (10,11,13), after 12 weeks of treatment with 0.1 mg of imidafenacin twice daily, none of our patients experienced urinary retention requiring catheterisation, and there were no significant increases in the PVR volumes. We did not find any cardiac AEs and cognitive dysfunction, which are rare but possible AEs of anti-MR agents (18–20). Regarding cognitive dysfunction, a study of Yamamoto and colleagues using positron emission tomography scans in monkeys showed that in contrast to dose-dependent cognitive dysfunction caused by oxybutinin, imidafenacin did not induce discernible cognitive impairment (20). Although the M1
References 1 Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: 1306–14; discussion 14-5. 2 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. 3 Liberman JN, Hunt TL, Stewart WF et al. Healthrelated quality of life among adults with symptoms
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receptor is the most abundant in the cerebral cortex of brain, M2-M5 receptors are also differentially expressed between brain regions and the other MR subtypes, specifically M2 receptor, are involved in cognitive function (21). Taken together higher affinity of imidafenacin for M1 receptors in addition to higher selectivity for the bladder over other organs and the results of aforementioned study in which imidafenacin was not associated with more common cognitive impairment (20), further studies are needed to clarify the mechanism of cognitive dysfunction related to anticholinergics. Although several studies demonstrated long-term efficacy, safety and tolerability of imidafenacin up to 1 year in Japanese OAB patients (12,13), it has been unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese (22). From our results, we confirmed the efficacy and tolerability of imidafenacin in Korean patients with OAB for at least 3 months. To our knowledge, this study is the first report demonstrating the efficacy and safety of imidafenacin in ethnicities other than Japanese.
Conclusions After the 12-week treatment of imidafenacin 0.1 mg twice daily, all the OAB symptoms and QOL improved. Imidafenacin was not inferior to propiverine for the reduction of UUI episodes, and associated with significantly greater improvement in the physical limitation domain than propiverine. After imidafenacin medication, the discontinuation rates caused by AEs were low, and the severity of dry mouth was significantly lower than propiverine. Our results indicate that imidafenacin is a safe and effective drug for Korean patients with OAB.
Acknowledgements This study was supported by a grant from the LG Life Sciences Ltd., Seoul, Korea.
of overactive bladder: results from a U.S. community-based survey. Urology 2001; 57: 1044–50. 4 Gill SS, Mamdani M, Rochon PA. Management of overactive bladder. N Engl J Med 2004; 350: 2213. 5 Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000; 55: 33–46; discussion 50. 6 Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 1997; 104: 988–93.
7 Kobayashi F, Yageta Y, Segawa M, Matsuzawa S. Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittelforschung 2007; 57: 92–100. 8 Kobayashi F, Yageta Y, Yamazaki T et al. Pharmacological effects of imidafenacin (KRP-197/ ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung 2007; 57: 147–54.
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9 Yamada S, Seki M, Ogoda M, Fukata A, Nakamura M, Ito Y. Selective binding of bladder muscarinic receptors in relation to the pharmacokinetics of a novel antimuscarinic agent, imidafenacin, to treat overactive bladder. J Pharmacol Exp Ther 2011; 336: 365–71. 10 Homma Y, Yamaguchi T, Yamaguchi O. A randomized, double-blind, placebo-controlled phase II dose-finding study of the novel anti-muscarinic agent imidafenacin in Japanese patients with overactive bladder. Int J Urol 2008; 15: 809–15. 11 Homma Y, Yamaguchi O. A randomized, double-blind, placebo- and propiverine-controlled trial of the novel antimuscarinic agent imidafenacin in Japanese patients with overactive bladder. Int J Urol 2009; 16: 499–506. 12 Yokoyama T, Koide T, Hara R, Fukumoto K, Miyaji Y, Nagai A. Long-term safety and efficacy of two different antimuscarinics, imidafenacin and solifenacin, for treatment of overactive bladder: a prospective randomized controlled study. Urol Int 2013; 90: 161–7. 13 Zaitsu M, Mikami K, Ishida N, Takeuchi T. Comparative evaluation of the safety and efficacy of long-term use of imidafenacin and solifenacin in patients with overactive bladder: a prospective,
14
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18 19
open, randomized, parallel-group trial (the LIST study). Adv Urol 2011; 2011: 854697. Oh SJ, Park HG, Paick SH et al. Translation and linguistic validation of Korean version of the King’s Health Questionnaire instrument. Korean J Urol 2005; 46: 438–50. Diokno AC, Appell RA, Sand PK et al. Prospective, randomized, double-blind study of the efficacy and tolerability of the extended-release formulations of oxybutynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc 2003; 78: 687–95. Choo MS, Lee JZ, Lee JB et al. Efficacy and safety of solifenacin succinate in Korean patients with overactive bladder: a randomised, prospective, double-blind, multicentre study. Int J Clin Pract 2008; 62: 1675–83. Yamazaki T, Muraki Y, Anraku T. In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats. Naunyn Schmiedebergs Arch Pharmacol 2011; 384: 319–29. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013–22. Andersson KE. Antimuscarinics for treatment of overactive bladder. Lancet Neurol 2004; 3: 46–53.
20 Yamamoto S, Maruyama S, Ito Y et al. Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: a monkey PET study with [(11)C](+)3-MPB. Neuroimage 2011; 58: 1–9. 21 Seeger T, Fedorova I, Zheng F et al. M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 2004; 24: 10117–27. 22 Masumori N. Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature. Patient Prefer Adherence 2013; 7: 111–20.
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Study design. Paper received April 2013, accepted July 2013
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A randomised, prospective double-blind, propiverinecontrolled trial of imidafenacin in patients with overactive bladder C. Park,1,* J. Park,2,* M.-S. Choo,3 J. C. Kim,4 J. G. Lee,5 J. Z. Lee,6 K.-S. Lee,7 D. Y. Kim,8 S.-J. Lee,9 J. T. Seo10
1
Department of Urology, Gangneung Asan Medical Center, University of Ulsan College of Medicine, Gangneung, Korea 2 Department of Urology, Eulji University Hospital, Daejeon, Korea 3 Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 4 Department of Urology, Bucheon St. Mary’s Hospital, The Catholic University of Korea, Bucheon, Korea 5 Department of Urology, Korea University Anam Hospital, Seoul, Korea 6 Department of Urology, Pusan National University Hospital, Pusan, Korea 7 Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 8 Department of Urology, Catholic University of Daegu School of Medicine, Daegu, Korea 9 Department of Urology, Kyung Hee University School of Medicine, Seoul, Korea 10 Department of Urology, Cheil General Hospital, Kwandong University College of Medicine, Seoul, Korea Correspondence to: Prof. Myung-Soo Choo, MD, PhD, Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpagu, Seoul 138-736, Korea Tel.: +82 2 3010 3735 Fax: +82 2 477 8928 Email: [email protected] *Changmyon Park and Jinsung Park contributed equally to this study.
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ABSTRACT
What’s known
Aim: To assess the efficacy and safety of imidafenacin compared with propiverine for treatment of overactive bladder (OAB) in Korean patients. Materials and methods: Patients with OAB symptoms were randomised to double-blind treatment with 0.1 mg of imidafenacin twice daily (group A) or propiverine 20 mg once daily (group B) for 12-week regimen, and assessed for efficacy and safety. The primary efficacy outcome was per cent change of weekly urgency urinary incontinence (UUI) episodes at week 12. The secondary efficacy outcomes were changes in the micturitions per day, urine volume voided per micturition, urgency episodes per day, complete disappearance of incontinence episodes and severity of urgency from baseline to week 12. Quality of life and safety profiles were also compared. Results: Of 162 patients randomised, 140 completed the study protocol. The per cent change of weekly UUI episodes at week 12 was 69.1% in group A and 70.4% in group B (both p < 0.0001). The lower limit of 95% onesided confidence interval of the difference between the groups was above the non-inferiority margin ( 19.42%). Other voiding parameters and quality of life significantly improved at week 12 in both the groups. The discontinuation rates caused by adverse events were low in both the groups. While dry mouth was the most common adverse event (group A: 28.4% vs. B: 30.4%, p = 0.783), the severity of dry mouth was significantly less in the group A than B (p = 0.042) There were no significant differences in other safety profiles. Conclusions: After the 12-week treatment of imidafenacin 0.1 mg twice daily, all OAB symptoms and quality of life improved. Imidafenacin was not inferior to propiverine for the reduction of UUI episodes, and was better tolerated than propiverine in the safety profile. Our results indicate that imidafenacin is a safe and effective drug in Korean patients with OAB.
Introduction The prevalence of overactive bladder (OAB) syndrome defined as urgency with or without urge incontinence is 11.8% in Western countries and 12.2% in Korea, and increases with advancing age (1,2). OAB deteriorates a patient’s quality of life (QOL). It is associated with mental stress and depression, limiting patient social ability and daily life (3,4). Treatment of OAB consists of behavioural therapy such as bladder training and pharmacological therapy, with antimuscarinic receptor (MR) drugs mainly used. Anti-MR drugs block MRs, inhibiting
Imidafenacin is a novel antimuscarinic agent with M1 and M3 selectivity. Japanese placebo-controlled phase II and active-controlled phase III trials have already been performed for imidafenacin, and they showed that imidafenacin was superior to placebo and not inferior to propiverine or solifenacin in its efficacy and safety. However, no comparative studies have been published regarding the efficacy and safety of imidafenacin in other ethnicities except Japanese.
What’s new This study was a prospective, randomised, doubleblinded, double-dummy, propiverine-controlled, phase III multicentre trial in Korea. In this study, we first demonstrated that imidafenacin was effective for improving the overactive bladder symptoms of Korean patients for at least 3 months, and imidafenacin was not inferior to propiverine in efficacy outcomes. In addition, we found that severity of dry mouth was significantly lower in the imidafenacin group than the propiverine group.
the binding of acetylcholine. Symptoms such as urgency, urgency urinary incontinence (UUI) and frequency are improved by prohibiting the contraction of smooth muscles in the bladder. However, the anti-MR drugs are associated with adverse events (AEs) including dry mouth and constipation, which are the main reasons for drug discontinuation and compromised patient compliance to continuous treatment (5,6). To relieve the AEs of anti-MR drugs, new drugs with more selectivity for the bladder have been developed. Imidafenacin, a novel anti-MR drug, shows a high affinity for M3 and M1 receptors in rats ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196. doi: 10.1111/ijcp.12255
Efficacy and safety of imidafenacin in Korean OAB patients
and inhibits rhythmic bladder contractions with high selectivity to the bladder rather than the salivary glands (7–9). Several comparative studies of the efficacy and safety of imidafenacin and other anti-MR agents have been reported with Japanese OAB patients (10–13). No comparative studies have been published regarding the efficacy and safety of imidafenacin in other ethnicities except Japanese. In this study, we compared the efficacy and tolerability of imidafenacin 0.1 mg twice daily and propiverine 20 mg once daily in Korean patients with symptoms of OAB.
Materials and methods Patients and study design This study was a prospective, randomised, doubleblinded, double-dummy, phase III multicentre trial at eight hospitals in Korea. The study protocol was approved by the Institutional Review Board of each institution, was in conformity with the ethical principles of the Declaration of Helsinki, and followed the International Conference on Harmonization Good Clinical Practice guidelines. Written informed consent was obtained from each patient before screening. Eligible criteria were OAB patients aged ≥ 19 years who had five or more UUI episodes per week, eight or more micturitions per day and one or more urgency frequency per day for ≥ 3 months. Patients with clinically significant stress urinary incontinence, significant bladder outlet obstruction, urinary tract infections, interstitial cystitis, previous or current malignant disease in the pelvic organs, indwelling catheters or intermittent catheterisation, any medical condition contraindicating the use of antimuscarinic medication (including narrow angle glaucoma and urinary or gastric retention), > 100 ml in postvoid residual (PVR) volume, > 3,000 ml in daily voided volume according to the voiding diary during the observation period, > 3.0 mg/dl in total bilirubin levels, > 2.5 times (or > 100 IU/l) in AST or ALT and > 2.0 mg/dl in serum creatinine levels were excluded. Other exclusion criteria included patients who were treated with non-pharmacological treatment for OAB including electrostimulation therapy or a bladder training program within 3 months before the run-in period; propiverine HCl within 4 weeks; concomitant medication of contraindicated drugs within 2 weeks; genitourinary tract surgery within 6 months before the run-in period; pregnant and nursing women. The study design is shown in Figure S1. After initial screening, patients were examined for suitability for the trial, and those taking contraindicated drugs were enrolled following 2 weeks of washout period. ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
During the 2-week run-in period, patients were prescribed placebo twice a day, and a voiding diary was taken for 1 week before the next visit (baseline). During the run-in period, past medical history, physical examination, 12-lead electrocardiography, laboratory tests including liver and renal function test were examined. In accordance with a predefined randomisation sequence created by a computer random number generator, eligible patients were randomised with a 1 : 1 ratio to either imidafenacin (group A) or propiverine (group B). During the treatment period, the double-blind, double-dummy method was used. All study medication and placebos were similar in appearance and smell. Treatment allocations were blinded to patients, investigators and all study personnel directly involved in conduct of the study. Group A took 0.1 mg tablets of imidafenacin twice a day and a propiverine placebo once a day while group B took 20 mg of propiverine HCl once a day and an imidafenacin placebo twice a day. Test drugs not taken by the patient were returned to check the patient’s medication compliance. If the compliance rate was above 80%, the patient was regarded as compliant. Patients were seen at 4, 8 and 12 weeks after treatment.
Assessment of efficacy and tolerability Seven-day voiding diaries were taken at baseline and at week 4, 8 and 12 after treatment. UUI, micturition and urgency episodes during the 7-day periods were recorded. Urine volume voided per micturition was recorded for at least three complete days. The severity of urgency for the past 1 week was assessed by the investigator during interviews with the patients at baseline, 4, 8 and 12 weeks after treatment using the Indevus Urgency Severity Scale, a 4-grade validated scale (none: no urgency; mild: awareness of urgency, but is easily tolerated; moderate: enough urgency discomfort that it interferes with or shortens your usual activity or tasks; severe: extreme urgency discomfort that abruptly stops all activity or tasks). The proportions of patients who improved by one or more grade during the treatment period were calculated. The primary efficacy outcome was the per cent change in the number of UUI per week from the baseline. The secondary efficacy outcomes were the changes in the number of micturitions per day, the urine volume voided per micturition, complete disappearance of incontinence episodes and the severity of urgency, as well as the per cent change of urgency episodes per day. The patients’ QOL was assessed using the Korean version of King’s Health Questionnaire (KHQ) (14) at baseline and 12 weeks. The
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Disclosures All authors declare no competing financial interests.
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Efficacy and safety of imidafenacin in Korean OAB patients
change in KHQ domain scores from the baseline to the end of the study was also evaluated. Safety and tolerability were evaluated by AEs, blood pressure, pulse rate, 12-lead electrocardiography and PVR volumes as measured by bladder scans at the baseline and 12 weeks. Laboratory tests were performed at the baseline, 4 and 12 weeks. At each visit, any AEs were checked by an investigator or self-reported through a self-reported questionnaire. The severity of dry mouth and constipation was assessed using a mild, moderate or severe three-point scale. A cardiologist at each participating centre confirmed electrocardiography parameters.
Statistical analysis Using one-sided of a-level of 0.05 with 80% power and assuming that non-inferiority margin to per cent change of UUI per week was 19.42% from prior Japanese phase 3 study (11), 62 patients per group were required. Allowing for a possible 25% dropout rate, we aimed to enrol 83 patients per group (total 166 patients). Non-inferiority analysis of primary efficacy outcome was primarily based on the per-protocol set (PPS) population, and analysis for the full analysis set (FAS) population was also performed. Analyses of secondary efficacy outcomes were two-sided with null hypotheses of no difference rejected if p-values were less than 0.5. Non-inferiority analysis of secondary efficacy outcomes was not performed. The PPS was defined as the subjects who were eligible and were compliant with the protocol. The FAS was defined as subjects who were eligible, received at least one dose of the study drug, and was examined at least once for the efficacy end-points. Analyses of safety were carried out based on the randomised subjects who received at least one dose of the study drug.
For statistical analyses, Fisher’s exact or chi-square tests were used to compare categorical variables between groups. Within each treatment group, paired t-test or Wilcoxon’s signed rank test was used to make comparisons between the baseline and end of the treatment. Between-group comparison was performed using t-test or Wilcoxon’s rank sum test. Data are expressed as the mean SD. Statistical analyses were performed using SAS v.9.1 (SAS Institute, Cary, NC, USA).
Results From November 2006 to November 2007, 256 patients were screened, of whom 162 (group A: 82, group B: 80) were randomised. Patient disposition is summarised in Figure 1. While there was no significant difference in dropout rate between the two groups (A: 14.6% [12/82] and B: 12.5% [10/80], p = 0.820), at least 85% of patients in each group (70 per group) completed the study. The main reasons for dropouts were consent withdrawal and AEs in both groups. The FAS and the PPS included 75 and 67 of group A vs. 76 and 64 of group B, respectively. Baseline demographic and clinical characteristics of the PPS are summarised in Table 1. The two groups were well balanced in sex distribution, age (mean age: A, 58.3 years vs. B, 56.1 year) and various clinical characteristics except the severity of urgency (Table 1). Covariate-adjusted analyses demonstrated that the severity of urgency did not affect the results of the primary efficacy outcome.
Efficacy Table 2 shows the mean changes in all efficacy variables from baseline to week 12 in the two groups. After 12 weeks of treatment, UUI episodes per week
Figure 1 Patient disposition ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
Table 1 Demographic and clinical characteristics of patients for per-protocol set population
Demographic Sex, n (%) Age (years) Weight (kg) Clinical Duration from onset of symptom (month) Neurological aetiology, n (%) Medical history, n (%) Previous treatment for incontinence, n (%) Previous treatment with propiverine, n (%) Concomitant medications, n (%) Urgency urinary incontinence episodes per week Micturitions per day Urgency episodes per day Urine volume per micturition (ml) Severity of urgency, n (%)
Postvoid residual volume (ml)
Group A (N = 67)
Group B (N = 64)
p-value
Male Female Mean SD Mean SD
10 (14.93) 57 (85.07) 58.31 11.45 60.72 8.48
9 (14.06) 55 (85.94) 56.13 11.29 60.09 7.31
1.000*
Mean SD Neurogenic bladder Detrusor instability No Yes No Yes No Yes No Yes Mean SD Mean SD Mean SD Mean SD Mild Moderate Severe Mean SD
18.58 42.34 0 (0) 67 (100) 8 (11.94) 59 (88.06) 7 (10.45) 60 (89.55) 2 (2.99) 65 (97.01) 21 (31.34) 46 (68.66) 24.37 16.66 10.2 2.16 5.25 2.94 162.91 54.54 10 (14.93) 42 (62.69) 15 (22.39) 15.85 20.62
16.5 32.35 4 (6.25) 60 (93.75) 9 (14.06) 55 (85.94) 13 (20.31) 51 (79.69) 5 (7.81) 59 (92.19) 24 (37.50) 40 (62.50) 22.27 16.71 11.35 3.6 5.17 3.36 155.44 57.09 20 (31.25) 25 (39.06) 19 (29.69) 19.48 25.22
0.179† 0.963† 0.279† 0.054* 0.798* 0.147* 0.267* 0.469* 0.235† 0.111† 0.598† 0.332† 0.017*
0.661†
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. *Fisher’s exact test. †Wilcoxon’s rank sum test.
decreased from 24.37 16.66 to 8.73 15.53 in the group A and from 22.27 16.71 to 8.12 17.23 in the group B. The per cent change from baseline in UUI per week was 69.14 38.86% and 70.36 48.23% in the group A and B, respectively (all p < 0.0001). The lower limit of 95% one-sided confidence interval of the difference between the groups was 11.43 in the PPS analysis and 11.33 in the FAS analysis. Hence, the lower limits were above the non-inferiority margin ( 19.42%). In addition, the extent of decrease in UUI per week was similar between the two groups (Table 2, between-group comparison p > 0.05). Compared with baseline, after 12 weeks of treatment, secondary efficacy outcomes including micturitions per day, urine volume voided per micturition and urgency episodes per day significantly improved in both the groups (Table 2). Comparison of the extent of improvement in efficacy outcomes between the groups showed that improvement in the severity of urgency was significantly greater in the group A than group B at week 4 (62.69% vs. 40.63%, p = 0.015) and week 12 (82.09% vs. 64.06%, p = 0.029). Similar findings were observed in the analysis in the FAS analysis (Table 2). ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Compared with baseline, patient QOL assessed by KHQ significantly improved in both groups at week 12 (Figure 2). Between-group comparison of each domain in the KHQ showed that improvement in the physical limitation domain was significantly greater in the group A than the group B (Figure 2D, p = 0.031).
Tolerability The proportions of patients discontinuing treatment owing to AEs were 4.94% (4/81) in group A and 6.33% (5/79) in B. The most frequently reported AEs resulting in discontinuation were dermatitis (n = 1), dyspepsia (n = 1), dry mouth (n = 1) and cystitis (n = 1) in the group A, and dry mouth (n = 3), headache (n = 1) and increased intraocular pressure (n = 1) in the group B. Adverse events were reported in 54.32% of the group A and 62.03% of group B (Table 3A, p = 0.323). Dry mouth, the most common AE, was reported in 28.40% of group A and 30.38% of group B (p = 0.783). As shown in Table 3B, severity of dry mouth was mild (23.46%) or moderate (4.94%) in the group A, whereas it was mild (15.19%),
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Efficacy and safety of imidafenacin in Korean OAB patients
Table 2 Changes in efficacy outcomes
PPS population Group A (N = 67)
FAS population p-value† (A vs. B)
Group B (N = 64)
Primary efficacy outcome Urgency urinary incontinence episodes per week, Mean SD Baseline 24.37 16.66 22.27 Week 4 12.47 18.46 11.29 Week 8 9.31 13.46 9.42 Week 12 (End-point) 8.73 15.53 8.12 % change from baseline 69.14 38.86 70.36 95% CI of difference vs. Propiverine 11.43–13.87 p-value*,‡ < 0.0001 < 0.0001 Secondary efficacy outcomes Micturitions per day, Mean SD Baseline 10.20 2.16 11.35 Week 4 8.97 2.31 9.59 Week 8 8.72 2.06 9.55 Week 12 (End-point) 8.61 2.30 9.37 Change from baseline 1.59 1.82 1.99 p-value*,‡ < 0.0001 < 0.0001 Urine volume voided per micturition (ml), Mean SD Baseline 162.91 54.54 155.44 Week 4 178.42 60.85 179.66 Week 8 180.53 67.68 179.39 Week 12 (End-point) 184.43 66.88 180.69 Change from baseline 21.52 41.1 25.25 p-value*,‡ < 0.0001 < 0.0001 Urgency episodes per day, Mean SD Baseline 5.25 2.94 5.17 Week 4 3.07 3.06 3.60 Week 8 2.58 3.01 2.78 Week 12 (End-point) 2.29 3.26 2.39 % change from baseline 59.21 45.21 57.14 p-value*,‡ < 0.0001 < 0.0001 Complete disappearance of incontinence episodes (%) Baseline 0 0 Week 4 14.93 15.87 Week 8 19.4 28.13 Week 12 (End-point) 32.84 40.63 Severity of urgency (%, ≥ 1 grade improvement compared with baseline) Baseline – – Week 4 62.69 40.63 Week 8 77.61 64.06 Week 12 (End-point) 82.09 64.06
16.71 18.23 18.6 17.23 48.23
0.235§ 0.213§ 0.190§ 0.287§ 0.399§
Group A (N = 75)
p-value† (A vs. B)
Group B (N = 76)
24.80 18.63 13.41 20.98 10.23 17.24 9.71 18.80 69.17 38.80 11.33–12.38 < 0.0001
< 0.0001
23.63 12.19 10.49 9.34 69.70
18.19 22.09 21.20 20.08 46.98
0.441§ 0.130§ 0.299§ 0.462§ 0.528§
3.60 3.23 3.26 3.25 2.48
0.111§ 0.327§ 0.351§ 0.301§ 0.367§
10.41 9.14 8.73 8.64 1.69 < 0.0001
2.55 2.55 2.19 2.40 1.86
11.37 9.58 9.56 9.49 2.00 < 0.0001
3.58 3.26 3.21 3.19 2.47
0.160§ 0.502§ 0.287§ 0.147§ 0.495§
57.09 75.93 70.95 74.22 47.42
0.332§ 0.668§ 0.897§ 0.680§ 0.545§
161.84 178.34 180.76 184.36 22.92 < 0.0001
53.09 59.66 66.71 66.11 40.36
153.42 176.41 175.63 177.55 25.05 < 0.0001
55.80 71.87 69.75 71.42 45.90
0.260§ 0.480§ 0.605§ 0.478§ 0.732§
3.36 3.56 3.45 3.40 44.12
0.598§ 0.522§ 0.845§ 0.521§ 0.531§
5.24 3.15 2.64 2.38 59.57 < 0.0001
3.07 3.29 3.29 3.51 44.70
5.14 3.57 2.86 2.51 57.18 < 0.0001
3.40 3.88 3.68 3.62 43.36
0.580§ 0.788§ 0.804§ 0.433§ 0.462§
0 13.33 20.83 33.33
1.000¶ 0.305¶ 0.371¶
0.015¶ 0.123¶ 0.029¶
–
0 20 29.17 39.73
0.381¶ 0.336¶ 0.491¶
43.42 65.28 66.67
0.034¶ 0.199¶ 0.034¶
– 61.33 76.39 83.33
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. PPS, Per protocol set; FAS, full analysis set; CI, confidence interval; SD, standard deviation. *Comparison between baseline and end-point within each group. †Comparison between Group A and B. ‡Wilcoxon’s Signed Rank Test. §Wilcoxon’s Rank Sum Test. ¶Fisher’s Exact Test.
moderate (13.92%) and severe (1.27%) in the group B (p = 0.042). The incidence of constipation was lower in the group A than group B without statistical significance (4.94% vs. 12.66%, p = 0.084). There were no significant differences in the risk of blurred
vision (mild in all cases), dyspepsia (mild in most cases) and pyuria (mild in all cases) between the groups (Table 3A). Postvoid residual volumes of the safety populations at baseline were 14.96 19.45 ml in group A and ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
(A)
(B)
(D)
(G)
(C)
(E)
(F)
(H)
(I)
Figure 2 Change from baseline in the King’s Health Questionnaire during 12 weeks of treatment. Data are shown as the mean + SD at baseline and 12 weeks. Comparison between baseline and end-point (12 weeks) within each group was performed using Wilcoxon’s signed rank test or paired t-test, and between-group comparison was performed using Wilcoxon’s rank sum test. *p < 0.0001 vs. baseline; †p < 0.001 vs. baseline; ‡p < 0.05 vs. baseline; §p < 0.05 betweengroup comparison
20.28 25.19 ml in group B (p = 0.377). The PVR volumes at week 12 were 20.58 30.73 ml in group A and 24.84 44.87 ml in group B, respectively (p = 0.515). Compared with baseline, there were no significant increases in the PVR volumes at week 12 in both the groups. No patients underwent urinary retention or voiding difficulty in either group. There were no clinically relevant changes in physical examination, vital signs, electrocardiography including QT interval prolongation and arrhythmia, cognitive dysfunction and laboratory tests in both the groups. In the group B, there was statistically significant decrease (mean SD = 4.49 13.81) in the systolic blood pressure at week 12 compared with baseline (Wilcoxon’s signed rank p = 0.017). However, clinically significant hypotension was not observed in either group.
Discussion In this randomised propiverine-controlled clinical trial, 0.1 mg of imidafenacin twice daily was effective ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
for improving the OAB symptoms of Korean patients for at least 3 months. In addition, we confirmed that imidafenacin was not inferior to propiverine for the reduction of UUI episodes per week: overall per cent reduction in weekly UUI was about 70% in both drugs (mean reduction of UUI episodes: imidafenacin 15.64 per week vs. propiverine 14.15 per week). In the Japanese double-blind, placebo and propiverine-controlled phase 3 trial including large numbers of randomised patients (781 patients), per cent change from baseline in UUI per week was 68.54 36.58% and 73.08 43.15% in the imidafenacin and propiverine group (11), similar to our results. Regarding the primary efficacy outcome, in a US multicentre trial (15), changes in weekly UUI episodes of extended-release oxybutynin 10 mg and tolterodine 4 mg were 69.1% and 72.8%, respectively. In our previous study with other OAB drugs in Korean OAB patients (16), per cent decrease in mean daily (not weekly) UUI episode with 5 mg solifenacin was 59.4%, 10 mg solifenacin was 57.6% and 4 mg tolterodine was 52.3%. Thus, results from
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Table 3 Adverse events (A) that occurred in more than 2% of patients and severity of major adverse events (B) in
both the groups
Adverse events
Group A (N = 81) n (%)
Group B (N = 79) n (%)
p-value
(A) Total Dry mouth Dyspepsia Pyuria Constipation Cystitis Vision blurred Nausea oedema peripheral Thirst Dry eye Pruritus Abdominal pain upper Abdominal discomfort Headache Urinary tract infection
44 (54.32) 23 (28.40) 5 (6.17) 5 (6.17) 4 (4.94) 3 (3.70) 2 (2.47) 2 (2.47) 2 (2.47) 1 (1.23) 1 (1.23) 1 (1.23) 0 (0) 0 (0) 0 (0) 0 (0)
49 (62.03) 24 (30.38) 2 (2.53) 4 (5.06) 10 (12.66) 2 (2.53) 4 (5.06) 2 (2.53) 0 (0) 3 (3.80) 2 (2.53) 2 (2.53) 3 (3.80) 2 (2.53) 2 (2.53) 2 (2.53)
0.323* 0.783* 0.443† 1.000† 0.084* 1.000† 0.440† 1.000† 0.497† 0.364† 0.618† 0.618† 0.118† 0.242† 0.242† 0.242†
Group A (N = 81), n (%)
Group B (N = 79), n (%)
Adverse events
Mild
Moderate
Severe
Mild
Moderate
Severe
(B) Dry mouth‡ Dyspepsia Pyuria Constipation Vision blurred Dry eye
19 (23.46) 3 (3.70) 5 (6.17) 3 (3.70) 2 (2.47) 1 (1.23)
4 1 0 1 0 0
0 1 0 0 0 0
12 (15.19) 2 (2.53) 4 (5.06) 7 (8.86) 4 (5.06) 2 (2.53)
11 (13.92) 0 (0) 0 (0) 4 (5.06) 0 (0) 0 (0)
1 0 0 0 0 0
(4.94) (1.23) (0) (1.23) (0) (0)
(0) (1.23) (0) (0) (0) (0)
(1.27) (0) (0) (0) (0) (0)
Group A: imidafenacin 0.1 mg twice daily, Group B: propiverine 20 mg once daily. *v2 Test. †Fisher’s Exact Test. ‡Fisher’s exact p-value (between-group comparison) = 0.042.
our study and other clinical trials indicate that 0.1 mg of imidafenacin twice daily improves OAB symptoms like other anti-MR agents. The magnitudes of changes in the secondary efficacy outcomes including micturitions per day, the urine volume voided per micturition, urgency episodes per day and complete disappearance of incontinence episodes were similar at each evaluation period between the two groups. Interestingly, we found that while baseline severity of urgency was significantly worse in the imidafenacin group, imidafenacin was more effective than propiverine in improving the severity of urgency at week 4 and week 12. In addition to improvement in voiding parameters, the 12-week treatment of imidafenacin significantly decreased the KHQ scores in all domains from baseline, demonstrating statistically significant improvements of patient QOL. Of note, our finding that improvement in the physical limita-
tion domain was significantly greater in group A than group B (p = 0.031) may indicate superiority of imidafenacin in terms of QOL. This finding is different from the Japanese phase 3 trial (11) in which propiverine was associated with significantly greater improvement than imidafenacin in the domains of role limitation, emotions and symptom severity. Further studies are needed to understand the change in patient QOL after the treatment of imidafenacin. Imidafenacin was well tolerated by patients with only a few discontinuations caused by AEs, and most AEs were mild in severity. Although the incidence of dry mouth, the most common AE of anti-MR drugs, was not significantly different between the imidafenacin and propiverine group (group A: 28.40% vs. B: 30.38%, p = 0.783), severity of dry mouth was significantly lower in the imidafenacin group than the propiverine group (p = 0.042). This finding is in line with other studies in which imidafenacin is ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
Efficacy and safety of imidafenacin in Korean OAB patients
preferable to other anti-MR agents including solifenacin (12,13), propiverine (11) in terms of safety profile. For example, in the Japanese phase 3 trial, dry mouth was reported in 31.5% and 39.9% of imidafenacin and propiverine group, significantly lower in the imidafenacin group (p = 0.03). Zaitsu et al. (13) found that although the incidence of dry mouth was 71.4% after 52 weeks of imidafenacin and 90% after 52 weeks of solifenacin treatment (p > 0.05), the severity of dry mouth was significantly lower in the imidafenacin group (p = 0.0092). The possible mechanisms of less dry mouth in our study and the aforementioned studies (11–13) are attributable to a higher selectivity of imidafenacin for the bladder over other organs. For example, in an in vivo rat model, the relative bladder selectivity of imidafenacin was reported to be 15-fold higher over salivary gland, 150-fold higher over colon and 50-fold higher over heart, respectively, than that of propiverine (17). In addition, imidafenacin has higher affinities for M3 and M1 receptors and higher selectivity for the urinary bladder than for the salivary gland (7,8). In our study, the risk of constipation was lower in the group A than group B (p = 0.084). In another study by Zaitsu et al. (13), the incidence and severity of constipation were significantly lower in the imidafenacin group than solifenacin group (p = 0.0013). Integrating these findings, we believe that imidafenacin has more favourable safety profile than propiverine. Consistent with other reports (10,11,13), after 12 weeks of treatment with 0.1 mg of imidafenacin twice daily, none of our patients experienced urinary retention requiring catheterisation, and there were no significant increases in the PVR volumes. We did not find any cardiac AEs and cognitive dysfunction, which are rare but possible AEs of anti-MR agents (18–20). Regarding cognitive dysfunction, a study of Yamamoto and colleagues using positron emission tomography scans in monkeys showed that in contrast to dose-dependent cognitive dysfunction caused by oxybutinin, imidafenacin did not induce discernible cognitive impairment (20). Although the M1
References 1 Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: results of the EPIC study. Eur Urol 2006; 50: 1306–14; discussion 14-5. 2 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. 3 Liberman JN, Hunt TL, Stewart WF et al. Healthrelated quality of life among adults with symptoms
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receptor is the most abundant in the cerebral cortex of brain, M2-M5 receptors are also differentially expressed between brain regions and the other MR subtypes, specifically M2 receptor, are involved in cognitive function (21). Taken together higher affinity of imidafenacin for M1 receptors in addition to higher selectivity for the bladder over other organs and the results of aforementioned study in which imidafenacin was not associated with more common cognitive impairment (20), further studies are needed to clarify the mechanism of cognitive dysfunction related to anticholinergics. Although several studies demonstrated long-term efficacy, safety and tolerability of imidafenacin up to 1 year in Japanese OAB patients (12,13), it has been unknown if the practical effectiveness of imidafenacin is applicable to ethnic groups other than Japanese (22). From our results, we confirmed the efficacy and tolerability of imidafenacin in Korean patients with OAB for at least 3 months. To our knowledge, this study is the first report demonstrating the efficacy and safety of imidafenacin in ethnicities other than Japanese.
Conclusions After the 12-week treatment of imidafenacin 0.1 mg twice daily, all the OAB symptoms and QOL improved. Imidafenacin was not inferior to propiverine for the reduction of UUI episodes, and associated with significantly greater improvement in the physical limitation domain than propiverine. After imidafenacin medication, the discontinuation rates caused by AEs were low, and the severity of dry mouth was significantly lower than propiverine. Our results indicate that imidafenacin is a safe and effective drug for Korean patients with OAB.
Acknowledgements This study was supported by a grant from the LG Life Sciences Ltd., Seoul, Korea.
of overactive bladder: results from a U.S. community-based survey. Urology 2001; 57: 1044–50. 4 Gill SS, Mamdani M, Rochon PA. Management of overactive bladder. N Engl J Med 2004; 350: 2213. 5 Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology 2000; 55: 33–46; discussion 50. 6 Kelleher CJ, Cardozo LD, Khullar V, Salvatore S. A medium-term analysis of the subjective efficacy of treatment for women with detrusor instability and low bladder compliance. Br J Obstet Gynaecol 1997; 104: 988–93.
7 Kobayashi F, Yageta Y, Segawa M, Matsuzawa S. Effects of imidafenacin (KRP-197/ONO-8025), a new anti-cholinergic agent, on muscarinic acetylcholine receptors. High affinities for M3 and M1 receptor subtypes and selectivity for urinary bladder over salivary gland. Arzneimittelforschung 2007; 57: 92–100. 8 Kobayashi F, Yageta Y, Yamazaki T et al. Pharmacological effects of imidafenacin (KRP-197/ ONO-8025), a new bladder selective anti-cholinergic agent, in rats. Comparison of effects on urinary bladder capacity and contraction, salivary secretion and performance in the Morris water maze task. Arzneimittelforschung 2007; 57: 147–54.
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9 Yamada S, Seki M, Ogoda M, Fukata A, Nakamura M, Ito Y. Selective binding of bladder muscarinic receptors in relation to the pharmacokinetics of a novel antimuscarinic agent, imidafenacin, to treat overactive bladder. J Pharmacol Exp Ther 2011; 336: 365–71. 10 Homma Y, Yamaguchi T, Yamaguchi O. A randomized, double-blind, placebo-controlled phase II dose-finding study of the novel anti-muscarinic agent imidafenacin in Japanese patients with overactive bladder. Int J Urol 2008; 15: 809–15. 11 Homma Y, Yamaguchi O. A randomized, double-blind, placebo- and propiverine-controlled trial of the novel antimuscarinic agent imidafenacin in Japanese patients with overactive bladder. Int J Urol 2009; 16: 499–506. 12 Yokoyama T, Koide T, Hara R, Fukumoto K, Miyaji Y, Nagai A. Long-term safety and efficacy of two different antimuscarinics, imidafenacin and solifenacin, for treatment of overactive bladder: a prospective randomized controlled study. Urol Int 2013; 90: 161–7. 13 Zaitsu M, Mikami K, Ishida N, Takeuchi T. Comparative evaluation of the safety and efficacy of long-term use of imidafenacin and solifenacin in patients with overactive bladder: a prospective,
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20 Yamamoto S, Maruyama S, Ito Y et al. Effect of oxybutynin and imidafenacin on central muscarinic receptor occupancy and cognitive function: a monkey PET study with [(11)C](+)3-MPB. Neuroimage 2011; 58: 1–9. 21 Seeger T, Fedorova I, Zheng F et al. M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity. J Neurosci 2004; 24: 10117–27. 22 Masumori N. Long-term safety, efficacy, and tolerability of imidafenacin in the treatment of overactive bladder: a review of the Japanese literature. Patient Prefer Adherence 2013; 7: 111–20.
Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Study design. Paper received April 2013, accepted July 2013
ª 2013 John Wiley & Sons Ltd Int J Clin Pract, February 2014, 68, 2, 188–196
