Neurourology and Urodynamics 34:685–692 (2015)
Results of a Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Study of Mirabegron, a b3-adrenoceptor Agonist, in Patients With Overactive Bladder in Asia Hann-Chorng Kuo,1* Kyu-Sung Lee,2 Yanqun Na,3 Rajeev Sood,4 Shigeru Nakaji,5 Yosuke Kubota,6 and Kentarou Kuroishi7 1
2
Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Urology, Peking University People’s Hospital, Beijing, People’s Republic of China 4 Department of Urology, DR Ram Manohar Lohia Hospital and PGI MER, New Delhi, India 5 Medical & Development Division, Astellas Pharma China Inc., Beijing, People’s Republic of China 6 Asian Development, Astellas Pharma Global Development, Tokyo, Japan 7 Data Science, Astellas Pharma Global Development, Tokyo, Japan
Aims: To assess the efficacy and safety of mirabegron 50 mg once daily compared with placebo and the active control, tolterodine extended-release (ER) 4 mg once daily, in patients with symptoms of overactive bladder (OAB) in Taiwan, Korea, China, and India. Methods: A 12-week multinational, randomized, double-blind, parallel-group placebo- and active-controlled trial. The primary efficacy endpoint was change from baseline to final visit in mean number of micturitions/24 hr. Secondary endpoints were: mean number of urgency episodes, incontinence episodes and urge incontinence episodes/24 hr, mean number of nocturia episodes per night, mean volume voided per micturition, and quality-of-life (QoL) scores as assessed by the King’s Health Questionnaire (KHQ). Results: Of 1,126 patients who were randomized to receive double-blind study drug, 921 patients (300, 311, and 310 in the placebo, mirabegron 50 mg, and tolterodine ER 4 mg groups, respectively) completed the treatment period. Demographic characteristics were similar across treatment groups. A statistically significant improvement versus placebo in mean number of micturitions/24 hr was seen with mirabegron 50 mg at all timepoints (P < 0.05) as well as final visit (0.57 with 95% confidence intervals [CIs] of [1.04, 0.09], P ¼ 0.019). There was no significant difference between treatment groups in improvement from baseline to final visit in any of the secondary outcome measures except volume voided per micturition. The overall incidence of drug-related adverse events was 17.2%, 15.8%, and 21.3%, in the placebo, mirabegron 50 mg, and tolterodine ER 4 mg groups, respectively. Conclusions: Mirabegron 50 mg once daily for 12 weeks was superior to placebo in reducing the frequency of micturitions in patients with symptoms of OAB in Taiwan, Korea, China, and India. Neurourol. Urodynam. 34:685–692, 2015. # 2014 Wiley Periodicals, Inc. Key words: clinical trial; efficacy; mirabegron; overactive bladder; phase III; randomized; safety
INTRODUCTION
Overactive bladder syndrome (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia.1 OAB affects more than 400 million people worldwide2 while the prevalence among adult men in the Asian region (India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Korea, Taiwan, China, Hong Kong, and Thailand) has been estimated at 29.9%.3 Antimuscarinics are first line pharmacotherapy for OAB.4 However, some patients have a suboptimal response to antimuscarinics or may experience adverse effects, such as dry mouth or constipation.5,6 Therefore, a high proportion of patients discontinue antimuscarinic therapy, with fewer than 25% remaining on treatment at 1 year.7 b3-adrenergic receptors are known to promote urine storage in the bladder by inducing detrusor relaxation in animal and human bladders.8,9 In humans, the b3-adrenoceptor is the predominant b-receptor sub-type in the urinary bladder.10 b3adrenoceptor agonists relax the detrusor smooth muscle during the bladder storage phase and increase bladder capacity.11 #
2014 Wiley Periodicals, Inc.
Mirabegron is the first b3-adrenoceptor agonist12 to have been approved for the treatment of OAB (in Japan, the United States, Europe, Canada, Australia, Hong Kong, and Korea). Pooled safety data indicate that dry mouth, the chief cause of treatment discontinuation with antimuscarinic agents, occurs
Robert Pickard led the peer-review process as the Associate Editor responsible for the paper. Potential Conflicts of Interest: This study was funded by Astellas Inc. HannChorng Kuo has acted as a consultant for Astellas; has received speaker honoraria and research grants from Astellas, Pfizer, GSK and Allergan; and has conducted clinical trials for Astellas and Allergan. Kyu-Sung Lee has acted as a consultant for Astellas and Pfizer; has conducted clinical trials for Astellas, Pfizer, GSK and Allergan; and has received speaker honoraria from Astellas, Pfizer, GSK and MSD. Shigeru Nakaji, Yosuke Kubota and Kentarou Kuroishi are employees of the study sponsor. Rajeev Sood and Yanqun Na have no conflicts of interest to declare. Grant sponsor: Astellas Correspondence to: Hann-Chorng Kuo, Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. E-mail: [email protected] Received 7 February 2014; Accepted 29 May 2014 Published online 17 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22645
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with low incidence with mirabegron.13 In addition, randomized, controlled trials in Europe, Australia, North America, and Japan,14–17 have shown that mirabegron reduces the number of micturitions and incontinence episodes in a 24-hr period compared with placebo. Moreover, the magnitude of the treatment response seen with mirabegron is similar to that of other OAB agents.18 This phase III study has been conducted in patients with symptoms of OAB in Asia to further evaluate the efficacy and safety of mirabegron 50 mg once daily compared with placebo. As in the pivotal phase III trial conducted in Europe and Australia14 the antimuscarinic, tolterodine extended-release (ER) 4 mg once daily, was included as an active control to provide context to the results obtained for mirabegron; however, no statistical comparisons of the mirabegron and tolterodine ER treatment arms were performed. MATERIALS AND METHODS Study Design and Participants
This 12-week multinational, multicenter, randomized, double-blind, parallel-group placebo- and active-controlled trial (clinicaltrials.gov identifier: NCT01043666) was conducted at 67 sites in Taiwan, Korea, China, and India. The study population consisted of male and female outpatients who met the legal minimum age requirement of the region (18 years in China and India; 20 years in Korea [at the time of the study]; and Taiwan) and who had symptoms of OAB for 3 months. The study consisted of a 2-week single-blind, placebo run-in period, followed by a 12-week double-blind treatment period. Following the run-in period, eligible subjects were randomized to receive mirabegron 50 mg, tolterodine ER 4 mg, or placebo orally, once daily after breakfast, for 12 weeks. Randomization was accomplished using a computer-generated randomization scheme (Cenduit GmbH, Allschwil, Switzerland) with stratification by site. Study visits took place at week 2 (visit 1; confirmation of eligibility criteria); week 0 (visit 2, end of run-in period); weeks 4, 8, and 12 (visits 3, 4, and 5), and week 14 (visit 6, follow-up visit conducted by telephone or site visit 14 days after the end of treatment). A micturition diary was completed over the 3-day period prior to visits 2, 3, 4, and 5. The study initiation date (date of first screening) was December 21, 2009, and the study completion date (date of last evaluation) was September 16, 2011. Inclusion criteria included: (1) symptoms of OAB for at least 12 weeks before initiation of the run-in period; (2) an average of 8 micturitions/24 hr; and (3) an average of 1 episode of urgency or urgency incontinence/24 hr, during a 3-day micturition diary period. Key exclusion criteria were: (1) stress urinary incontinence as a predominant symptom at screening; (2) urinary tract infection, urinary stone, interstitial cystitis, or a history of recurrent urinary tract infection; (3) confirmed postvoid residual (PVR) volume of 100 ml or a clinically significant lower urinary tract obstructive disease; (4) an average total daily urine volume >3000 ml (as recorded in a 3-day voiding diary period); (5) uncontrolled hypertension (sitting systolic blood pressure 180 mmHg or diastolic blood pressure 110 mmHg); (6) pulse rate 110 beats per minute (bpm) or 60 ms. Mean change from baseline to final visit in PVR volume was 0.6, 2.7 and 0.6 ml in the placebo, mirabegron 50 mg and tolterodine ER 4 mg groups, respectively. For both the mirabegron 50 mg and tolterodine ER 4 mg groups, the adjusted mean difference from placebo (95% CIs) in pulse rate was larger at 6 hr post-dose (1.57 [0.43, 2.71] and 2.72 [1.58, 3.87], respectively) than upon awakening (1.12 [0.01, 2.24] and 0.75 [0.37, 1.87], respectively). Also, at 6 hr post-dose, the adjusted mean difference from placebo in pulse rate was smaller in the mirabegron 50 mg group (1.57 bpm) than in the tolterodine ER 4 mg group (2.72 bpm). Adjusted mean differences from placebo in systolic blood pressure [SBP] and diastolic blood pressure [DBP] upon awakening were similar in the mirabegron 50 mg and tolterodine ER 4 mg groups (0.22 [1.38, 1.82] and 0.28 [1.33, 1.88], respectively).
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Fig. 2. Adjusted mean change from baseline ( standard error) at each visit in A: mean number of micturitions/24 hr; B: mean volume voided per micturition; C: mean number of incontinence episodes/24 hr; D: mean number of urgency episodes/24 hr; E: mean number of urgency incontinence episodes/24 hr; F: mean number of nocturia episodes (full analysis set) (gray line ¼ placebo; gold line ¼ mirabegron 50 mg; blue line ¼ tolterodine ER 4 mg). Adjusted mean differences for mirabegron and tolterodine versus placebo by time point are shown under each figure. Statistically significant treatment benefit relative to placebo (P < 0.05). BL, Baseline.
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TABLE II. Results for the Individual Domains of the King’s Health Questionnaire (QoL Analysis Set) With Placebo, Mirabegron 50 mg, and Tolterodine ER 4 mg at Final Visit
General health perception Mean change from baseline (SD) Adjusted mean difference versus Incontinence impact Mean change from baseline (SD) Adjusted mean difference versus Role limitations Mean change from baseline (SD) Adjusted mean difference versus Physical limitations Mean change from baseline (SD) Adjusted mean difference versus Social limitations Mean change from baseline (SD) Adjusted mean difference versus Personal relationships Mean change from baseline (SD) Adjusted mean difference versus Emotions Mean change from baseline (SD) Adjusted mean difference versus Sleep/energy Mean change from baseline (SD) Adjusted mean difference versus Severity measures Mean change from baseline (SD) Adjusted mean difference versus Bladder problems Mean change from baseline (SD) Adjusted mean difference versus
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
Placebo
Mirabegron 50 mg
Tolterodine ER 4 mg
n ¼ 302 3.81 21.23 na n ¼ 302 13.02 29.13 na n ¼ 301 13.79 28.85 na n ¼ 301 11.02 27.81 na n ¼ 301 8.16 27.00 na n ¼ 243 4.30 25.30 na n ¼ 302 7.98 25.30 na n ¼ 302 10.38 23.67 na n ¼ 302 14.13 16.43 na n ¼ 302 8.22 14.95 na
n ¼ 313 6.07 22.62 1.03 (3.97, 1.90); P ¼ 0.490 n ¼ 313 11.50 27.52 1.75 (2.46, 5.96); P ¼ 0.414 n ¼ 312 12.92 30.44 1.91 (2.07, 5.90); P ¼ 0.347 n ¼ 312 12.65 28.10 0.50 (3.44, 4.33); P ¼ 0.804 n ¼ 312 10.27 26.70 0.78 (4.37, 2.82); P ¼ 0.671 n ¼ 252 3.96 25.88 0.88 (3.12, 4.88); P ¼ 0.667 n ¼ 313 12.53 28.70 2.77 (6.50, 0.97); P ¼ 0.146 n ¼ 313 12.46 26.34 0.46 (3.79, 2.87); P ¼ 0.786 n ¼ 312 6.99 16.51 1.42 (3.80, 0.97); P ¼ 0.244 n ¼ 313 10.13 15.01 0.57 (2.65, 1.51); P ¼ 0.592
n ¼ 311 4.82 22.65 0.32 (2.63, 3.26); P ¼ 0.833 n ¼ 311 16.51 31.78 1.86 (6.08, 2.36); P ¼ 0.388 n ¼ 311 13.40 28.88 1.84 (2.15, 5.82); P ¼ 0.366 n ¼ 311 11.95 28.54 0.74 (3.19, 4.67); P ¼ 0.713 n ¼ 310 8.71 26.80 0.59 (3.00, 4.19); P ¼ 0.746 n ¼ 251 5.80 25.46 0.72 (4.71, 3.27); P ¼ 0.723 n ¼ 311 11.25 26.13 0.79 (4.54, 2.95); P ¼ 0.678 n ¼ 311 9.38 24.33 1.54 (1.80, 4.87); P ¼ 0.366 n ¼ 311 7.95 18.30 2.14 (4.52, 0.25); P ¼ 0.080 n ¼ 311 10.17 15.13 0.63 (2.71, 1.45); P ¼ 0.553
CI, confidence interval; na, not applicable; SD, standard deviation.
TABLE III. Incidence of Treatment Emergent Adverse Events (TEAEs) and Selected Cardiovascular TEAEs (SAF) Placebo (n ¼ 366) TEAEs 214 63 (17.2) Drug-relateda TEAEs, n (%) SAEs, n (%) 7 (1.9) Drug-related SAEs, n (%) 0 TEAEs leading to permanent discontinuation of study drug, n (%) 8 (2.2) Drug-related TEAEs leading to permanent discontinuation of study drug, n (%) 5 (1.4) 124 (33.9) Patients reporting a TEAE, n (%)b Most common (reported by 2% of patients in any treatment group); MedDRA (v 12.1) preferred term: Dry mouth 18 (4.9) Constipation 8 (2.2) Nasopharyngitis 8 (2.2) Dizziness 5 (1.4) Cardiovascular TEAEs TEAEs of potential QTc prolongation (%) 4 (1.1) Electrocardiogram QT prolonged 3 (0.8) Syncope 0 Sudden death 1 (0.3) Hypertension-related TEAEs 1 (0.3) Hypertension 0 Blood pressure increased 1 (0.3) TEAEs of potential cardiac arrhythmia 20 (5.5) 16 (4.4) Cardiac disordersc
Mirabegron 50 mg (n ¼ 366)
Tolterodine ER 4 mg (n ¼ 371)
191 58 (15.8) 5 (1.4) 0 9 (2.5) 5 (1.4) 105 (28.7)
260 79 (21.3) 6 (1.6) 1 (0.3) 11 (3.0) 9 (2.4) 128 (34.5)
18 8 9 5
(4.9) (2.2) (2.5) (1.4)
2 (0.5) 1 (0.3) 1 (0.3) 0 2 (0.5) 2 (0.5) 0 11 (3.0) 9 (2.5)
30 9 9 8
(8.1) (2.4) (2.4) (2.2)
4 (1.1) 4 (1.1) 0 0 4 (1.1) 3 (0.8) 1 (0.3) 8 (2.2) 4 (1.1)
Patients with one or more AEs within a level of MedDRA term were counted only once in that level. Summarized AEs were reported after the first dose and no more than 2 weeks after the last dose of double-blind study drug. SAE, serious adverse event; SAF, safety analysis set; TEAE, treatment emergent adverse event. a
Drug relatedness was based on investigator assessment.
b c
n (%) is number of patients reporting given event as a % of the total number of patients in the treatment group.
Cardiac disorders were summarized by system organ class of MedDRA.
Neurourology and Urodynamics DOI 10.1002/nau
Mirabegron 50 mg Once Daily for OAB in Asian Patients DISCUSSION
This trial confirms that mirabegron 50 mg is effective and well tolerated in patients with OAB. The incidence of TEAEs was similar to that seen in other trials. Moreover, mirabegron 50 mg demonstrated a statistically significant improvement relative to placebo in change from baseline to final visit in mean number of micturitions/24 hr, as well as mean volume voided/ micturition, but not in other efficacy variables including mean number of urgency episodes, urgency incontinence episodes and incontinence episodes/24 hr and mean number of nocturia episodes/night. In previous phase III trials conducted in Europe (Study 046),14 North America (Study 047),15 and Japan (Study 048)17 mirabegron resulted in statistically significant improvements from baseline to final visit relative to placebo in all endpoints evaluated (except for nocturia in the Japanese trial). A comparison of the results shows that the magnitude of the change from baseline to final visit with mirabegron in the current study is not smaller than that seen in the earlier trials, but the magnitude of the change from baseline to final visit with placebo is larger than seen in the Japanese trial for the outcomes of micturition, incontinence episodes, urgency and urge incontinence, and larger than seen in the European and North American trials for the outcome of urgency episodes. This large placebo effect may account for the lack of statistical significance in the current study between mirabegron and placebo in the frequency of episodes of urgency and of urgency urinary incontinence. In general, clinical studies of antimuscarinic drugs for OAB have been characterized by a substantial response in patients treated with placebo.20–22 Although the placebo response in drug studies for OAB is highly heterogeneous and has not been well characterized, factors that have been identified include OAB characteristics (e.g., OAB severity), types of endpoints (subjective rather than objective), level of prior and concomitant treatment (e.g., pelvic floor training) and size of the placebo arm.20,23 Indeed, it has been suggested that recruitment of more patients and of more severely affected patients might minimize the placebo response.20 In addition, nonspecific effects, such as increased awareness of the disease, the expectations of study participants and bladder training resulting from the use of bladder diaries, have been considered relevant.20,21 A comparison of patients enrolled in this trial with those of patients enrolled in the registration trials that were conducted in Europe (Study 046),14 North America (Study 047),15 and Japan (Study 048),17 reveals striking differences in baseline demographics. In the current trial, 25.1–26.5% of patients were aged 65 years compared with 38.0–39.2% in Study 048 in Japan, 36.1–38.8% in Study 046 in Europe, and 38.0–41.6% in Study 047 in the US. There was also greater male representation, with male patients making up 30.6–35.0% of all patients in the current trial compared with 15.6–17.1% of patients in Study 048, 27.1–28.4% in Study 046 and 23.8–27.1% in Study 047. Of particular note were differences in baseline disease severity: 37.9–40.3% of patients in the current trial had incontinence at baseline compared with 65.1–71.8% of patients in Study 048, 58.8–63.2% in Study 046, and 71.7–75.2% in Study 047. In addition, the inclusion criteria specified that the minimum duration of OAB symptoms must be 3 months in the current trial, compared with 6 months in Study 048 in Japan. It is possible that these differences may have played some role in the high placebo effect seen, and hence, the differences in efficacy results between this trial and those conducted previously.14–17
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Patients treated with mirabegron have previously demonstrated statistically significant improvements in healthrelated QoL measures versus placebo.14 In this study, mirabegron 50 mg did not have a statistically significant effect on QoL relative to placebo as assessed by the KHQ. However, all KHQ domain scores were improved and the improvement from baseline on all domains, except that of emotions, was greater than five points, the change in score that is said to be clinically meaningful.19 It is worth noting that the Overactive Bladder questionnaire was used to assess QoL in previous studies and this is the first clinical trial to employ the KHQ. CONCLUSIONS
This study demonstrated that mirabegron 50 mg once daily for 12 weeks was superior to placebo in reducing the frequency of micturitions in patients with symptoms of OAB in Taiwan, Korea, China and India. Mirabegron was well tolerated overall and no clinically relevant safety concerns were identified. ACKNOWLEDGMENTS
The study was funded and designed by Astellas in collaboration with the authors. ICMJE authorship criteria have been fulfilled in the preparation of this manuscript. Data were collected by the investigators at the study centers, and were monitored and analyzed by Astellas personnel or their designees. Editorial and graphical support were provided by Envision Scientific Solutions and supported by Astellas. AUTHOR CONTRIBUTIONS
This article has been prepared in accordance with ICMJE authorship guidelines. All authors have read and approved the final draft for submission. All authors had access to the study data. Specific contributions were made in the following areas: conception and design—K.S.L., Y.N., R.S., S.N., K.K.; acquisition of data—H.C.K., K.S.L., Y.N., R.S.; analysis and interpretation of data—H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.; drafting of the manuscript—H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.; critical revision of the manuscript for intellectual content—H.C.K., Y.N., R.S., S.N., Y.K., K.K.; and final version approval of publication— H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.
REFERENCES 1. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation SubCommittee of the International Continence Society. Am J Obstet Gynecol 2002;187:116–26. 2. Irwin DE, Kopp ZS, Agatep B, et al. Worldwide prevalence estimates of lower urinary tract symptoms, overactive bladder, urinary incontinence and bladder outlet obstruction. BJU Int 2011;108:1132–38. 3. Moorthy P, Lapitan MC, Quek PL, et al. Prevalence of overactive bladder in Asian men: An epidemiological survey. BJU Int 2004;93:528–31. 4. Yamaguchi O, Nishizawa O, Takeda M, et al. Clinical guidelines for overactive bladder. Int J Urol 2009;16:126–42. 5. Benner JS, Nichol MB, Rovner ES, et al. Patient reported reasons for discontinuing overactive bladder medication. BJU Int 2010;105:1276–82. 6. D’Souza AO, Smith MJ, Miller LA, et al. Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm 2008;14:291–301. 7. Brostrom S, Hallas J. Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 2009;65:309–14. 8. Yamaguchi O. b3-adrenoceptors in human detrusor muscle. Urology 2002;59:25–9.
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9. Yamanishi T, Chapple CR, Yasuda K, et al. Role of beta-adrenoceptor subtypes in mediating relaxation of the pig bladder trigonal muscle in vitro. Neurourol Urodyn 2003;22:338–42. 10. Yamaguchi O, Chapple CR. b3-adrenoceptors in urinary bladder. Neurourol Urodyn 2007;26:752–56. 11. Aizawa N, Igawa Y, Nishizawa O, et al. Effects of CL316,243, a beta 3-adrenoceptor agonist, and intravesical prostaglandin E2 on the primary bladder afferent activity of the rat. Neurourol Urodyn 2010;29:771–76. 12. Takasu T, Ukai M, Sato S, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2hydroxy-2-phenylethyl) amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 2007;321:642–7. 13. Nitti VW, KHullar V, van Kerrebroeck P, et al. Mirabegron for the treatment of overactive bladder: A prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract 2013;67:619–32. 14. Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a b3-adrenoceptor agonist, in patients with overactive bladder: Results from a randomised European-Australian Phase 3 trial. Eur Urol 2013;63:283–95. 15. Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized, doubleblind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the beta-3 adrenoceptor agonist, mirabegron in patients with symptoms of overactive bladder. Urology 2013;82:313–20.
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16. Nitti V, Auerbach S, Martin N, et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013;189: 1388–95. 17. Yamaguchi O, Marui E, Kakizaki H, et al. Phase III, randomised, double-blind, placebo-contrplled study of the b3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 2014;113:951–60. 18. Chapple CR, Khullar V, Gabriel Z, et al. The effects of antimuscarinic treatments in overactive bladder: An update of a systematic review and meta-analysis. Eur Urol 2008;54:543–62. 19. Kelleher CJ, Pleil AM, Reese PR, et al. How much is enough and who says so? The case of the King’s Health Questionnaire and overactive bladder. BJOG 2004;111:605–12. 20. Lee S, Malholtra B, Creanga D, et al. A meta-analysis of the placebo response in antimuscarinic drug trials for overactive bladder. BMC Med Res Methodol 2009;9:55. 21. Mangera A, Chapple CR, Kopp ZS, et al. The placebo effect in overactive bladder syndrome. Nat Rev Urol 2011;8:495–503. 22. Nabi G, Cody JD, Ellis G, et al. Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev 2006;(4): CD003781. 23. Yalcin I, Bump RC. The effect of previous treatment experience and incontinence severity on the placebo response of stress urinary incontinence. Am J Obstet Gynecol 2004;191:194–97.
Results of a Randomized, Double-Blind, Parallel-Group, Placebo- and Active-Controlled, Multicenter Study of Mirabegron, a b3-adrenoceptor Agonist, in Patients With Overactive Bladder in Asia Hann-Chorng Kuo,1* Kyu-Sung Lee,2 Yanqun Na,3 Rajeev Sood,4 Shigeru Nakaji,5 Yosuke Kubota,6 and Kentarou Kuroishi7 1
2
Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Urology, Peking University People’s Hospital, Beijing, People’s Republic of China 4 Department of Urology, DR Ram Manohar Lohia Hospital and PGI MER, New Delhi, India 5 Medical & Development Division, Astellas Pharma China Inc., Beijing, People’s Republic of China 6 Asian Development, Astellas Pharma Global Development, Tokyo, Japan 7 Data Science, Astellas Pharma Global Development, Tokyo, Japan
Aims: To assess the efficacy and safety of mirabegron 50 mg once daily compared with placebo and the active control, tolterodine extended-release (ER) 4 mg once daily, in patients with symptoms of overactive bladder (OAB) in Taiwan, Korea, China, and India. Methods: A 12-week multinational, randomized, double-blind, parallel-group placebo- and active-controlled trial. The primary efficacy endpoint was change from baseline to final visit in mean number of micturitions/24 hr. Secondary endpoints were: mean number of urgency episodes, incontinence episodes and urge incontinence episodes/24 hr, mean number of nocturia episodes per night, mean volume voided per micturition, and quality-of-life (QoL) scores as assessed by the King’s Health Questionnaire (KHQ). Results: Of 1,126 patients who were randomized to receive double-blind study drug, 921 patients (300, 311, and 310 in the placebo, mirabegron 50 mg, and tolterodine ER 4 mg groups, respectively) completed the treatment period. Demographic characteristics were similar across treatment groups. A statistically significant improvement versus placebo in mean number of micturitions/24 hr was seen with mirabegron 50 mg at all timepoints (P < 0.05) as well as final visit (0.57 with 95% confidence intervals [CIs] of [1.04, 0.09], P ¼ 0.019). There was no significant difference between treatment groups in improvement from baseline to final visit in any of the secondary outcome measures except volume voided per micturition. The overall incidence of drug-related adverse events was 17.2%, 15.8%, and 21.3%, in the placebo, mirabegron 50 mg, and tolterodine ER 4 mg groups, respectively. Conclusions: Mirabegron 50 mg once daily for 12 weeks was superior to placebo in reducing the frequency of micturitions in patients with symptoms of OAB in Taiwan, Korea, China, and India. Neurourol. Urodynam. 34:685–692, 2015. # 2014 Wiley Periodicals, Inc. Key words: clinical trial; efficacy; mirabegron; overactive bladder; phase III; randomized; safety
INTRODUCTION
Overactive bladder syndrome (OAB) is a syndrome characterized by urinary urgency, with or without urgency urinary incontinence, usually with frequency and nocturia.1 OAB affects more than 400 million people worldwide2 while the prevalence among adult men in the Asian region (India, Indonesia, Malaysia, Pakistan, Philippines, Singapore, Korea, Taiwan, China, Hong Kong, and Thailand) has been estimated at 29.9%.3 Antimuscarinics are first line pharmacotherapy for OAB.4 However, some patients have a suboptimal response to antimuscarinics or may experience adverse effects, such as dry mouth or constipation.5,6 Therefore, a high proportion of patients discontinue antimuscarinic therapy, with fewer than 25% remaining on treatment at 1 year.7 b3-adrenergic receptors are known to promote urine storage in the bladder by inducing detrusor relaxation in animal and human bladders.8,9 In humans, the b3-adrenoceptor is the predominant b-receptor sub-type in the urinary bladder.10 b3adrenoceptor agonists relax the detrusor smooth muscle during the bladder storage phase and increase bladder capacity.11 #
2014 Wiley Periodicals, Inc.
Mirabegron is the first b3-adrenoceptor agonist12 to have been approved for the treatment of OAB (in Japan, the United States, Europe, Canada, Australia, Hong Kong, and Korea). Pooled safety data indicate that dry mouth, the chief cause of treatment discontinuation with antimuscarinic agents, occurs
Robert Pickard led the peer-review process as the Associate Editor responsible for the paper. Potential Conflicts of Interest: This study was funded by Astellas Inc. HannChorng Kuo has acted as a consultant for Astellas; has received speaker honoraria and research grants from Astellas, Pfizer, GSK and Allergan; and has conducted clinical trials for Astellas and Allergan. Kyu-Sung Lee has acted as a consultant for Astellas and Pfizer; has conducted clinical trials for Astellas, Pfizer, GSK and Allergan; and has received speaker honoraria from Astellas, Pfizer, GSK and MSD. Shigeru Nakaji, Yosuke Kubota and Kentarou Kuroishi are employees of the study sponsor. Rajeev Sood and Yanqun Na have no conflicts of interest to declare. Grant sponsor: Astellas Correspondence to: Hann-Chorng Kuo, Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung-Yang Road, Hualien, Taiwan. E-mail: [email protected] Received 7 February 2014; Accepted 29 May 2014 Published online 17 August 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/nau.22645
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with low incidence with mirabegron.13 In addition, randomized, controlled trials in Europe, Australia, North America, and Japan,14–17 have shown that mirabegron reduces the number of micturitions and incontinence episodes in a 24-hr period compared with placebo. Moreover, the magnitude of the treatment response seen with mirabegron is similar to that of other OAB agents.18 This phase III study has been conducted in patients with symptoms of OAB in Asia to further evaluate the efficacy and safety of mirabegron 50 mg once daily compared with placebo. As in the pivotal phase III trial conducted in Europe and Australia14 the antimuscarinic, tolterodine extended-release (ER) 4 mg once daily, was included as an active control to provide context to the results obtained for mirabegron; however, no statistical comparisons of the mirabegron and tolterodine ER treatment arms were performed. MATERIALS AND METHODS Study Design and Participants
This 12-week multinational, multicenter, randomized, double-blind, parallel-group placebo- and active-controlled trial (clinicaltrials.gov identifier: NCT01043666) was conducted at 67 sites in Taiwan, Korea, China, and India. The study population consisted of male and female outpatients who met the legal minimum age requirement of the region (18 years in China and India; 20 years in Korea [at the time of the study]; and Taiwan) and who had symptoms of OAB for 3 months. The study consisted of a 2-week single-blind, placebo run-in period, followed by a 12-week double-blind treatment period. Following the run-in period, eligible subjects were randomized to receive mirabegron 50 mg, tolterodine ER 4 mg, or placebo orally, once daily after breakfast, for 12 weeks. Randomization was accomplished using a computer-generated randomization scheme (Cenduit GmbH, Allschwil, Switzerland) with stratification by site. Study visits took place at week 2 (visit 1; confirmation of eligibility criteria); week 0 (visit 2, end of run-in period); weeks 4, 8, and 12 (visits 3, 4, and 5), and week 14 (visit 6, follow-up visit conducted by telephone or site visit 14 days after the end of treatment). A micturition diary was completed over the 3-day period prior to visits 2, 3, 4, and 5. The study initiation date (date of first screening) was December 21, 2009, and the study completion date (date of last evaluation) was September 16, 2011. Inclusion criteria included: (1) symptoms of OAB for at least 12 weeks before initiation of the run-in period; (2) an average of 8 micturitions/24 hr; and (3) an average of 1 episode of urgency or urgency incontinence/24 hr, during a 3-day micturition diary period. Key exclusion criteria were: (1) stress urinary incontinence as a predominant symptom at screening; (2) urinary tract infection, urinary stone, interstitial cystitis, or a history of recurrent urinary tract infection; (3) confirmed postvoid residual (PVR) volume of 100 ml or a clinically significant lower urinary tract obstructive disease; (4) an average total daily urine volume >3000 ml (as recorded in a 3-day voiding diary period); (5) uncontrolled hypertension (sitting systolic blood pressure 180 mmHg or diastolic blood pressure 110 mmHg); (6) pulse rate 110 beats per minute (bpm) or 60 ms. Mean change from baseline to final visit in PVR volume was 0.6, 2.7 and 0.6 ml in the placebo, mirabegron 50 mg and tolterodine ER 4 mg groups, respectively. For both the mirabegron 50 mg and tolterodine ER 4 mg groups, the adjusted mean difference from placebo (95% CIs) in pulse rate was larger at 6 hr post-dose (1.57 [0.43, 2.71] and 2.72 [1.58, 3.87], respectively) than upon awakening (1.12 [0.01, 2.24] and 0.75 [0.37, 1.87], respectively). Also, at 6 hr post-dose, the adjusted mean difference from placebo in pulse rate was smaller in the mirabegron 50 mg group (1.57 bpm) than in the tolterodine ER 4 mg group (2.72 bpm). Adjusted mean differences from placebo in systolic blood pressure [SBP] and diastolic blood pressure [DBP] upon awakening were similar in the mirabegron 50 mg and tolterodine ER 4 mg groups (0.22 [1.38, 1.82] and 0.28 [1.33, 1.88], respectively).
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Fig. 2. Adjusted mean change from baseline ( standard error) at each visit in A: mean number of micturitions/24 hr; B: mean volume voided per micturition; C: mean number of incontinence episodes/24 hr; D: mean number of urgency episodes/24 hr; E: mean number of urgency incontinence episodes/24 hr; F: mean number of nocturia episodes (full analysis set) (gray line ¼ placebo; gold line ¼ mirabegron 50 mg; blue line ¼ tolterodine ER 4 mg). Adjusted mean differences for mirabegron and tolterodine versus placebo by time point are shown under each figure. Statistically significant treatment benefit relative to placebo (P < 0.05). BL, Baseline.
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TABLE II. Results for the Individual Domains of the King’s Health Questionnaire (QoL Analysis Set) With Placebo, Mirabegron 50 mg, and Tolterodine ER 4 mg at Final Visit
General health perception Mean change from baseline (SD) Adjusted mean difference versus Incontinence impact Mean change from baseline (SD) Adjusted mean difference versus Role limitations Mean change from baseline (SD) Adjusted mean difference versus Physical limitations Mean change from baseline (SD) Adjusted mean difference versus Social limitations Mean change from baseline (SD) Adjusted mean difference versus Personal relationships Mean change from baseline (SD) Adjusted mean difference versus Emotions Mean change from baseline (SD) Adjusted mean difference versus Sleep/energy Mean change from baseline (SD) Adjusted mean difference versus Severity measures Mean change from baseline (SD) Adjusted mean difference versus Bladder problems Mean change from baseline (SD) Adjusted mean difference versus
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
placebo (95% CIs)
Placebo
Mirabegron 50 mg
Tolterodine ER 4 mg
n ¼ 302 3.81 21.23 na n ¼ 302 13.02 29.13 na n ¼ 301 13.79 28.85 na n ¼ 301 11.02 27.81 na n ¼ 301 8.16 27.00 na n ¼ 243 4.30 25.30 na n ¼ 302 7.98 25.30 na n ¼ 302 10.38 23.67 na n ¼ 302 14.13 16.43 na n ¼ 302 8.22 14.95 na
n ¼ 313 6.07 22.62 1.03 (3.97, 1.90); P ¼ 0.490 n ¼ 313 11.50 27.52 1.75 (2.46, 5.96); P ¼ 0.414 n ¼ 312 12.92 30.44 1.91 (2.07, 5.90); P ¼ 0.347 n ¼ 312 12.65 28.10 0.50 (3.44, 4.33); P ¼ 0.804 n ¼ 312 10.27 26.70 0.78 (4.37, 2.82); P ¼ 0.671 n ¼ 252 3.96 25.88 0.88 (3.12, 4.88); P ¼ 0.667 n ¼ 313 12.53 28.70 2.77 (6.50, 0.97); P ¼ 0.146 n ¼ 313 12.46 26.34 0.46 (3.79, 2.87); P ¼ 0.786 n ¼ 312 6.99 16.51 1.42 (3.80, 0.97); P ¼ 0.244 n ¼ 313 10.13 15.01 0.57 (2.65, 1.51); P ¼ 0.592
n ¼ 311 4.82 22.65 0.32 (2.63, 3.26); P ¼ 0.833 n ¼ 311 16.51 31.78 1.86 (6.08, 2.36); P ¼ 0.388 n ¼ 311 13.40 28.88 1.84 (2.15, 5.82); P ¼ 0.366 n ¼ 311 11.95 28.54 0.74 (3.19, 4.67); P ¼ 0.713 n ¼ 310 8.71 26.80 0.59 (3.00, 4.19); P ¼ 0.746 n ¼ 251 5.80 25.46 0.72 (4.71, 3.27); P ¼ 0.723 n ¼ 311 11.25 26.13 0.79 (4.54, 2.95); P ¼ 0.678 n ¼ 311 9.38 24.33 1.54 (1.80, 4.87); P ¼ 0.366 n ¼ 311 7.95 18.30 2.14 (4.52, 0.25); P ¼ 0.080 n ¼ 311 10.17 15.13 0.63 (2.71, 1.45); P ¼ 0.553
CI, confidence interval; na, not applicable; SD, standard deviation.
TABLE III. Incidence of Treatment Emergent Adverse Events (TEAEs) and Selected Cardiovascular TEAEs (SAF) Placebo (n ¼ 366) TEAEs 214 63 (17.2) Drug-relateda TEAEs, n (%) SAEs, n (%) 7 (1.9) Drug-related SAEs, n (%) 0 TEAEs leading to permanent discontinuation of study drug, n (%) 8 (2.2) Drug-related TEAEs leading to permanent discontinuation of study drug, n (%) 5 (1.4) 124 (33.9) Patients reporting a TEAE, n (%)b Most common (reported by 2% of patients in any treatment group); MedDRA (v 12.1) preferred term: Dry mouth 18 (4.9) Constipation 8 (2.2) Nasopharyngitis 8 (2.2) Dizziness 5 (1.4) Cardiovascular TEAEs TEAEs of potential QTc prolongation (%) 4 (1.1) Electrocardiogram QT prolonged 3 (0.8) Syncope 0 Sudden death 1 (0.3) Hypertension-related TEAEs 1 (0.3) Hypertension 0 Blood pressure increased 1 (0.3) TEAEs of potential cardiac arrhythmia 20 (5.5) 16 (4.4) Cardiac disordersc
Mirabegron 50 mg (n ¼ 366)
Tolterodine ER 4 mg (n ¼ 371)
191 58 (15.8) 5 (1.4) 0 9 (2.5) 5 (1.4) 105 (28.7)
260 79 (21.3) 6 (1.6) 1 (0.3) 11 (3.0) 9 (2.4) 128 (34.5)
18 8 9 5
(4.9) (2.2) (2.5) (1.4)
2 (0.5) 1 (0.3) 1 (0.3) 0 2 (0.5) 2 (0.5) 0 11 (3.0) 9 (2.5)
30 9 9 8
(8.1) (2.4) (2.4) (2.2)
4 (1.1) 4 (1.1) 0 0 4 (1.1) 3 (0.8) 1 (0.3) 8 (2.2) 4 (1.1)
Patients with one or more AEs within a level of MedDRA term were counted only once in that level. Summarized AEs were reported after the first dose and no more than 2 weeks after the last dose of double-blind study drug. SAE, serious adverse event; SAF, safety analysis set; TEAE, treatment emergent adverse event. a
Drug relatedness was based on investigator assessment.
b c
n (%) is number of patients reporting given event as a % of the total number of patients in the treatment group.
Cardiac disorders were summarized by system organ class of MedDRA.
Neurourology and Urodynamics DOI 10.1002/nau
Mirabegron 50 mg Once Daily for OAB in Asian Patients DISCUSSION
This trial confirms that mirabegron 50 mg is effective and well tolerated in patients with OAB. The incidence of TEAEs was similar to that seen in other trials. Moreover, mirabegron 50 mg demonstrated a statistically significant improvement relative to placebo in change from baseline to final visit in mean number of micturitions/24 hr, as well as mean volume voided/ micturition, but not in other efficacy variables including mean number of urgency episodes, urgency incontinence episodes and incontinence episodes/24 hr and mean number of nocturia episodes/night. In previous phase III trials conducted in Europe (Study 046),14 North America (Study 047),15 and Japan (Study 048)17 mirabegron resulted in statistically significant improvements from baseline to final visit relative to placebo in all endpoints evaluated (except for nocturia in the Japanese trial). A comparison of the results shows that the magnitude of the change from baseline to final visit with mirabegron in the current study is not smaller than that seen in the earlier trials, but the magnitude of the change from baseline to final visit with placebo is larger than seen in the Japanese trial for the outcomes of micturition, incontinence episodes, urgency and urge incontinence, and larger than seen in the European and North American trials for the outcome of urgency episodes. This large placebo effect may account for the lack of statistical significance in the current study between mirabegron and placebo in the frequency of episodes of urgency and of urgency urinary incontinence. In general, clinical studies of antimuscarinic drugs for OAB have been characterized by a substantial response in patients treated with placebo.20–22 Although the placebo response in drug studies for OAB is highly heterogeneous and has not been well characterized, factors that have been identified include OAB characteristics (e.g., OAB severity), types of endpoints (subjective rather than objective), level of prior and concomitant treatment (e.g., pelvic floor training) and size of the placebo arm.20,23 Indeed, it has been suggested that recruitment of more patients and of more severely affected patients might minimize the placebo response.20 In addition, nonspecific effects, such as increased awareness of the disease, the expectations of study participants and bladder training resulting from the use of bladder diaries, have been considered relevant.20,21 A comparison of patients enrolled in this trial with those of patients enrolled in the registration trials that were conducted in Europe (Study 046),14 North America (Study 047),15 and Japan (Study 048),17 reveals striking differences in baseline demographics. In the current trial, 25.1–26.5% of patients were aged 65 years compared with 38.0–39.2% in Study 048 in Japan, 36.1–38.8% in Study 046 in Europe, and 38.0–41.6% in Study 047 in the US. There was also greater male representation, with male patients making up 30.6–35.0% of all patients in the current trial compared with 15.6–17.1% of patients in Study 048, 27.1–28.4% in Study 046 and 23.8–27.1% in Study 047. Of particular note were differences in baseline disease severity: 37.9–40.3% of patients in the current trial had incontinence at baseline compared with 65.1–71.8% of patients in Study 048, 58.8–63.2% in Study 046, and 71.7–75.2% in Study 047. In addition, the inclusion criteria specified that the minimum duration of OAB symptoms must be 3 months in the current trial, compared with 6 months in Study 048 in Japan. It is possible that these differences may have played some role in the high placebo effect seen, and hence, the differences in efficacy results between this trial and those conducted previously.14–17
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Patients treated with mirabegron have previously demonstrated statistically significant improvements in healthrelated QoL measures versus placebo.14 In this study, mirabegron 50 mg did not have a statistically significant effect on QoL relative to placebo as assessed by the KHQ. However, all KHQ domain scores were improved and the improvement from baseline on all domains, except that of emotions, was greater than five points, the change in score that is said to be clinically meaningful.19 It is worth noting that the Overactive Bladder questionnaire was used to assess QoL in previous studies and this is the first clinical trial to employ the KHQ. CONCLUSIONS
This study demonstrated that mirabegron 50 mg once daily for 12 weeks was superior to placebo in reducing the frequency of micturitions in patients with symptoms of OAB in Taiwan, Korea, China and India. Mirabegron was well tolerated overall and no clinically relevant safety concerns were identified. ACKNOWLEDGMENTS
The study was funded and designed by Astellas in collaboration with the authors. ICMJE authorship criteria have been fulfilled in the preparation of this manuscript. Data were collected by the investigators at the study centers, and were monitored and analyzed by Astellas personnel or their designees. Editorial and graphical support were provided by Envision Scientific Solutions and supported by Astellas. AUTHOR CONTRIBUTIONS
This article has been prepared in accordance with ICMJE authorship guidelines. All authors have read and approved the final draft for submission. All authors had access to the study data. Specific contributions were made in the following areas: conception and design—K.S.L., Y.N., R.S., S.N., K.K.; acquisition of data—H.C.K., K.S.L., Y.N., R.S.; analysis and interpretation of data—H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.; drafting of the manuscript—H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.; critical revision of the manuscript for intellectual content—H.C.K., Y.N., R.S., S.N., Y.K., K.K.; and final version approval of publication— H.C.K., K.S.L., Y.N., R.S., S.N., Y.K., K.K.
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