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Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony).
Eur Urol. 2015 Mar; 67(3):577-88.EU

Abstract

BACKGROUND

Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects.

OBJECTIVE

The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy.

DESIGN, SETTING, AND PARTICIPANTS

A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo.

INTERVENTION

A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters.

RESULTS AND LIMITATIONS

Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy.

CONCLUSIONS

Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo.

PATIENT SUMMARY

To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability.

TRIAL REGISTRATION

Clinical trials.gov: NCT01340027.

Authors+Show Affiliations

Bristol Urological Institute, Southmead Hospital, Bristol, UK. Electronic address: paul.abrams@bui.ac.uk.Guys and St Thomas' Hospitals, London, UK.Tufts University School of Medicine, Boston, MA, USA.II Department of Gynaecology, Medical University, Lublin, Poland.RK Statistics Ltd., Bakewell, UK.Astellas Pharma BV, Leiden, The Netherlands.Astellas Pharma BV, Leiden, The Netherlands.Astellas Pharma BV, Leiden, The Netherlands.Astellas Pharma BV, Leiden, The Netherlands.Astellas Pharma BV, Leiden, The Netherlands.

Pub Type(s)

Clinical Trial, Phase II
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24612659

Citation

Abrams, Paul, et al. "Combination Treatment With Mirabegron and Solifenacin in Patients With Overactive Bladder: Efficacy and Safety Results From a Randomised, Double-blind, Dose-ranging, Phase 2 Study (Symphony)." European Urology, vol. 67, no. 3, 2015, pp. 577-88.
Abrams P, Kelleher C, Staskin D, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015;67(3):577-88.
Abrams, P., Kelleher, C., Staskin, D., Rechberger, T., Kay, R., Martina, R., Newgreen, D., Paireddy, A., van Maanen, R., & Ridder, A. (2015). Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). European Urology, 67(3), 577-88. https://doi.org/10.1016/j.eururo.2014.02.012
Abrams P, et al. Combination Treatment With Mirabegron and Solifenacin in Patients With Overactive Bladder: Efficacy and Safety Results From a Randomised, Double-blind, Dose-ranging, Phase 2 Study (Symphony). Eur Urol. 2015;67(3):577-88. PubMed PMID: 24612659.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). AU - Abrams,Paul, AU - Kelleher,Con, AU - Staskin,David, AU - Rechberger,Tomasz, AU - Kay,Richard, AU - Martina,Reynaldo, AU - Newgreen,Donald, AU - Paireddy,Asha, AU - van Maanen,Rob, AU - Ridder,Arwin, Y1 - 2014/02/19/ PY - 2013/12/20/received PY - 2014/02/07/accepted PY - 2014/3/12/entrez PY - 2014/3/13/pubmed PY - 2015/12/15/medline KW - Combination therapy KW - Mirabegron KW - Overactive bladder KW - Solifenacin SP - 577 EP - 88 JF - European urology JO - Eur Urol VL - 67 IS - 3 N2 - BACKGROUND: Combining the β3-adrenoceptor agonist mirabegron and the antimuscarinic (AM) agent solifenacin may improve efficacy in the treatment of overactive bladder (OAB) while reducing the AM side effects. OBJECTIVE: The primary objective was to evaluate the efficacy of combinations of solifenacin/mirabegron compared with solifenacin 5mg monotherapy. The secondary objective was to explore the dose-response relationship and the safety/tolerability compared with placebo and monotherapy. DESIGN, SETTING, AND PARTICIPANTS: A phase 2, factorial design, randomised, double-blind, parallel-group, placebo- and monotherapy-controlled trial, conducted at 141 sites in 20 European countries. Male and female patients were aged ≥18 yr with symptoms of OAB for ≥3 mo. INTERVENTION: A total of 1306 patients (66.4% female) were randomised to 12 wk of treatment in 1 of 12 groups: 6 combination groups (solifenacin 2.5, 5, or 10 mg plus mirabegron 25 or 50 mg), 5 monotherapy groups (solifenacin 2.5, 5, or 10 mg, or mirabegron 25 or 50 mg), or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Change from baseline to end of treatment in mean volume voided per micturition (MVV) (primary end point) and mean numbers of micturitions per 24 h, incontinence episodes per 24 h, and urgency episodes per 24 h were analysed using an analysis of covariance model. Safety assessments included treatment-emergent adverse events (TEAEs), blood pressure, pulse rate, postvoid residual (PVR) volume, and laboratory and electrocardiography (ECG) parameters. RESULTS AND LIMITATIONS: Compared with solifenacin 5 mg monotherapy, all combinations with solifenacin 5 or 10 mg significantly improved MVV, with adjusted differences ranging from 18.0 ml (95% confidence interval [CI], 5.4-30.0) to 26.3 ml (95% CI, 12.0-41.0). Three combination groups significantly reduced micturition frequency compared with solifenacin 5 mg, ranging from -0.80 (95% CI, -1.39 to -0.22) to -0.98 (95% CI, -1.68 to -0.27). Five of six combinations significantly reduced urgency episodes compared with solifenacin 5 mg, ranging from -0.98 (95% CI, -1.78, to -0.18) to -1.37 (95% CI, -2.03 to -0.70). No dose-related trends in TEAEs, blood pressure, pulse rate, PVR volume, or laboratory or ECG parameters were observed between combination and monotherapy groups, although the incidence of constipation was slightly increased with combination therapy. CONCLUSIONS: Combination therapy with solifenacin/mirabegron significantly improved MVV, micturition frequency, and urgency compared with solifenacin 5 mg monotherapy. All combinations were well tolerated, with no important additional safety findings compared with monotherapy or placebo. PATIENT SUMMARY: To improve treatment of overactive bladder (OAB), mirabegron/solifenacin in combination was compared with each drug alone and placebo. Combination therapy improved OAB symptoms and had similar safety and acceptability. TRIAL REGISTRATION: Clinical trials.gov: NCT01340027. SN - 1873-7560 UR - https://www.unboundmedicine.com/medline/citation/24612659/Combination_treatment_with_mirabegron_and_solifenacin_in_patients_with_overactive_bladder:_efficacy_and_safety_results_from_a_randomised_double_blind_dose_ranging_phase_2_study__Symphony__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0302-2838(14)00131-6 DB - PRIME DP - Unbound Medicine ER -