A phase II dose-ranging study of mirabegron in patients with overactive bladder

Christopher R Chapple, Vladimir Dvorak, Pjotr Radziszewski, Philip Van Kerrebroeck, Jean Jacques Wyndaele, Brigitte Bosman, Peter Boerrigter, Ted Drogendijk, Arwin Ridder, Ingrid Van Der Putten-Slob, Osamu Yamaguchi, Dragon Investigator Group, F Keuppens, Dirk De Ridder, L Dewilde, Jean-Jacques Wyndaele, V Vik, J Zmrhal, Z Adamik, Vladimir Dvořák, M Halaska, J Krhut, J Liehne, Alois Martan, M Indig, W Hechelmann, M Markov, J Knipphals, J Willgerodt, Wolfgang Warnack, DetlefMüller, E Mucke-Str, H P Fischer, Timo Liebald, Jens Schneider, M Voß, W Jörger, W Grohmann, Elke Hessdörfer, Torsten Sørensen, Flemming Sørensen, John Krogh, L Prieto, Javier Cambronero Santos, Policlínico de Vigo, P Arañó Bertran, Miguel A Jimenez Cidre, J Rosa Arias, Miguel Unda, J Benejam, Montserrat Espuña, G Amarenco, F Haab, J-J Labat, Christopher Chapple, J Malone Lee, P M Toozs-Hobson, M Lucas, R Thakar, S J Foley, S R Hill, A Monga, S Venn, K Erdei, L Farkas, L Kiss, G Nagy, László Pajor, József Pintér, Giuseppe Vespasiani, R Damiano, R M Scarpa, P Bolis, Viale Borri, R Milani, G Morgia, P Di Benedetto, P Ferrari, Antonio Carbone, Ph E V A van Kerrebroeck, P H M Van de Weijer, E Koldewijn, Catharina Ziekenhuis, H Franke, Christopher R Chapple, Vladimir Dvorak, Pjotr Radziszewski, Philip Van Kerrebroeck, Jean Jacques Wyndaele, Brigitte Bosman, Peter Boerrigter, Ted Drogendijk, Arwin Ridder, Ingrid Van Der Putten-Slob, Osamu Yamaguchi, Dragon Investigator Group, F Keuppens, Dirk De Ridder, L Dewilde, Jean-Jacques Wyndaele, V Vik, J Zmrhal, Z Adamik, Vladimir Dvořák, M Halaska, J Krhut, J Liehne, Alois Martan, M Indig, W Hechelmann, M Markov, J Knipphals, J Willgerodt, Wolfgang Warnack, DetlefMüller, E Mucke-Str, H P Fischer, Timo Liebald, Jens Schneider, M Voß, W Jörger, W Grohmann, Elke Hessdörfer, Torsten Sørensen, Flemming Sørensen, John Krogh, L Prieto, Javier Cambronero Santos, Policlínico de Vigo, P Arañó Bertran, Miguel A Jimenez Cidre, J Rosa Arias, Miguel Unda, J Benejam, Montserrat Espuña, G Amarenco, F Haab, J-J Labat, Christopher Chapple, J Malone Lee, P M Toozs-Hobson, M Lucas, R Thakar, S J Foley, S R Hill, A Monga, S Venn, K Erdei, L Farkas, L Kiss, G Nagy, László Pajor, József Pintér, Giuseppe Vespasiani, R Damiano, R M Scarpa, P Bolis, Viale Borri, R Milani, G Morgia, P Di Benedetto, P Ferrari, Antonio Carbone, Ph E V A van Kerrebroeck, P H M Van de Weijer, E Koldewijn, Catharina Ziekenhuis, H Franke

Abstract

Introduction and hypothesis: Mirabegron is a potent and selective β3-adrenoceptor agonist that may represent an alternative treatment option in place of antimuscarinics for patients with overactive bladder.

Methods: Patients completed a single-blinded, 2-week placebo run-in period followed by 12 weeks of randomized (n = 928) double-blinded treatment with mirabegron oral controlled absorption system (OCAS) 25, 50, 100, or 200 mg once-daily (QD), placebo or tolterodine extended release (ER) 4 mg QD. The primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes/24 h. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes/24 h; severity of urgency; nocturia; and quality of life measures. Safety parameters included vital signs, adverse events, laboratory tests, electrocardiogram measurements and post-void residual volume.

Results: Mirabegron 25, 50, 100, and 200 mg resulted in dose-dependent reductions (improvements) from baseline to end-of-treatment in micturition frequency of 1.9, 2.1, 2.1, and 2.2 micturitions/24 h respectively, versus 1.4 micturitions/24 h with placebo (p ≤ 0.05 for the mirabegron 50-, 100-, and 200-mg comparisons). There was a statistically significant improvement with mirabegron compared with placebo for most secondary endpoints including quality of life variables. While there was a significant (p < 0.05) increase from baseline in pulse rate in the mirabegron 100-mg and 200-mg groups, this was not associated with an increased incidence of cardiovascular adverse events.

Conclusions: The favorable efficacy and tolerability of mirabegron in this phase II dose-finding study has led to its successful advancement into a phase III clinical development program.

Figures

Fig. 1
Fig. 1
Disposition of subjects. MIRA mirabegron, TOL tolterodine, AE adverse event, CW consent withdrawn, PV protocol violation, LOE lack of efficacy, LTFU lost to follow-up. MIRA and TOL were administered once daily. Asterisks: In the mirabegron 100-mg group, 169 patients were randomized and 168 received treatment. Dagger: Other reasons for discontinuation included laboratory value out of range and medical advice to stop study drug (25-mg group); noncompliance and patient decision (50-mg group); and a patient stopped taking the study drug during hospitalization for arthroscopy of the knee (200-mg group)

References

    1. Sexton CC, Coyne KS, Kopp ZS, Irwin DE, Milsom I, Aiyer LP, et al. The overlap of storage, voiding and postmicturition symptoms and implications for treatment seeking in the USA, UK and Sweden: EpiLUTS. BJU Int. 2009;103(Suppl 3):12–23. doi: 10.1111/j.1464-410X.2009.08369.x.
    1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Urol. 2003;61:37–49. doi: 10.1016/S0090-4295(02)02243-4.
    1. Abrams P, Andersson KE, Buccafusco JJ, Chapple C, de Groat WC, Fryer AD, et al. Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol. 2006;148:565–578. doi: 10.1038/sj.bjp.0706780.
    1. D'Souza AO, Smith MJ, Miller LA, Doyle J, Ariely R. 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.
    1. Benner JS, Nichol MB, Rovner ES, Jumadilova Z, Alvir J, Hussein M, et al. Patient-reported reasons for discontinuing overactive bladder medication. BJU Int. 2010;105:1276–1282. doi: 10.1111/j.1464-410X.2009.09036.x.
    1. Igawa Y, Yamazaki Y, Takeda H, Hayakawa K, Akahane M, Ajisawa Y, et al. Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol. 1999;126:819–825. doi: 10.1038/sj.bjp.0702358.
    1. Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T, et al. Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther. 1999;288:1367–1373.
    1. Fujimura T, Tamura K, Tsutsumi T, Yamamoto T, Nakamura K, Koibuchi Y, et al. Expression and possible functional role of the beta3-adrenoceptor in human and rat detrusor muscle. J Urol. 1999;161:680–685. doi: 10.1016/S0022-5347(01)61994-3.
    1. Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol. 2003;170:649–653. doi: 10.1097/01.ju.0000067621.62736.7c.
    1. Kumar V, Templeman L, Chapple CR, Chess-Williams R. Recent developments in the management of detrusor overactivity. Curr Opin Urol. 2003;13:285–291. doi: 10.1097/00042307-200307000-00004.
    1. Cartwright R, Srikrishna S, Cardozo L, Robinson D. Validity and reliability of the patient's perception of intensity of urgency scale in overactive bladder. BJU Int. 2011;107:1612–1617. doi: 10.1111/j.1464-410X.2010.09684.x.
    1. Donovan JL, Abrams P, Peters TJ, Kay HE, Reynard J, Chapple C, et al. The ICS-'BPH' Study: the psychometric validity and reliability of the ICSmale questionnaire. Br J Urol. 1996;77:554–562. doi: 10.1046/j.1464-410X.1996.93013.x.
    1. Jackson S, Donovan J, Brookes S, Eckford S, Swithinbank L, Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing. Br J Urol. 1996;77:805–812. doi: 10.1046/j.1464-410X.1996.00186.x.
    1. Coyne K, Revicki D, Hunt T, Corey R, Stewart W, Bentkover J, et al. Psychometric validation of an overactive bladder symptom and health-related quality of life questionnaire: the OAB-q. Qual Life Res. 2002;11:563–574. doi: 10.1023/A:1016370925601.
    1. Committee for Medicinal Products for Human Use (CHMP) guideline on the choice of the non-inferiority margin (2006) Stat Med 25:1628–1638
    1. Chapple CR, Khullar V, Gabriel Z, Muston D, Bitoun CE, Weinstein D. The effects of antimuscarinic treatments in overactive bladder: an update of a systematic review and meta-analysis. Eur Urol. 2008;54:543–562. doi: 10.1016/j.eururo.2008.06.047.
    1. Kessler TM, Bachmann LM, Minder C, Lohrer D, Umbehr M, Schunemann HJ, et al. Adverse event assessment of antimuscarinics for treating overactive bladder: a network meta-analytic approach. PLoS One. 2011;6:e16718. doi: 10.1371/journal.pone.0016718.
    1. Novara G, Galfano A, Secco S, D'Elia C, Cavalleri S, Ficarra V, et al. A systematic review and meta-analysis of randomized controlled trials with antimuscarinic drugs for overactive bladder. Eur Urol. 2008;54:740–763. doi: 10.1016/j.eururo.2008.06.080.
    1. Nabi G, Cody JD, Ellis G, Herbison P, Hay-Smith J (2006) Anticholinergic drugs versus placebo for overactive bladder syndrome in adults. Cochrane Database Syst Rev CD003781
    1. Andersson KE, Sarawate C, Kahler KH, Stanley EL, Kulkarni AS. Cardiovascular morbidity, heart rates and use of antimuscarinics in patients with overactive bladder. BJU Int. 2010;106:268–274. doi: 10.1111/j.1464-410X.2009.09073.x.
    1. Olshansky B, Ebinger U, Brum J, Egermark M, Viegas A, Rekeda L. Differential pharmacological effects of antimuscarinic drugs on heart rate: a randomized, placebo-controlled, double-blind, crossover study with tolterodine and darifenacin in healthy participants > or = 50 years. J Cardiovasc Pharmacol Ther. 2008;13:241–251. doi: 10.1177/1074248408325404.

Source: PubMed

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