Asha Paireddy

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)

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.

Efficacy and safety of combinations of mirabegron and solifenacin compared with monotherapy and placebo in patients with overactive bladder (SYNERGY study)

To evaluate the potential of solifenacin 5 mg combined with mirabegron 25 or 50 mg to deliver superior efficacy compared with monotherapy, with acceptable tolerability, in the general overactive bladder (OAB) population with urinary incontinence (UI).

Patient‐reported outcomes from SYNERGY, a randomized, double‐blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients

To evaluate patient‐reported outcomes (PROs) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder (OAB) from the SYNERGY trial.

Electronic bladder diaries of differing duration versus a paper diary for data collection in overactive bladder.

This observational study compared data values, reliability, consistency and compliance collected by electronic and paper diaries of differing durations.

Cardiovascular Safety of the β3‐Adrenoceptor Agonist Mirabegron and the Antimuscarinic Agent Solifenacin in the SYNERGY Trial

There have been concerns that treatment of overactive bladder with β3‐adrenoceptor agonists may potentially have detrimental cardiovascular (CV) side effects. We evaluated the CV safety of mirabegron, a β3‐adrenoceptor agonist, alone and in combination therapy with the antimuscarinic agent solifenacin. The SYNERGY trial was a multinational, multicenter, randomized, double‐blind, parallel‐group, placebo and active‐controlled phase 3 trial. Patients were randomized to receive solifenacin 5 mg + mirabegron 50 mg (combination 5 + 50 mg), solifenacin 5 mg + mirabegron 25 mg (combination 5 + 25 mg), solifenacin 5 mg monotherapy, mirabegron 25 mg monotherapy, mirabegron 50 mg monotherapy, or placebo for a 12‐week double‐blind treatment period. A total of 3398 patients were included in the study. Mean changes from baseline to the end of therapy in ECG parameters were similar across treatment groups, although there was an increase in heart rate of 1 beat/minute in the mirabegron treatment groups. There were no clinically meaningful differences in change from baseline in QTcF between monotherapies and placebo and between monotherapies and combination therapy. There were very few major CV events: 1 of 853 (0.1%) with a nonfatal myocardial infarction in the combination 5 + 25 mg group, 2 of 848 (0.2%) with a nonfatal stroke in the combination 5 + 50 mg group, and no events in the other groups. This CV safety analysis of the combination of mirabegron and solifenacin showed rates of CV events comparable with those for monotherapy treatments based on assessments of vital signs, electrocardiograms, and adjudicated CV events.

PNFLBA-09 LONG-TERM COMBINATION TREATMENT WITH SOLIFENACIN AND MIRABEGRON IS EFFECTIVE AND WELL TOLERATED IN PATIENTS WITH OVERACTIVE BLADDER

INTRODUCTION AND OBJECTIVES: The objective of this Phase III study was to evaluate the safety and efficacy of long-term solifenacin and mirabegron combination (COMBN) treatment compared with solifenacin (SOLI) and mirabegron (MIRA) alone. METHODS: This was a randomized, double-blind, parallelgroup study. Adult patients with symptoms of overactive bladder (OAB) for 3 m and 3 incontinence episodes in 7 d were eligible. After a 2-wk washout period, patients were randomized (4:1:1) to receive COMBN (SOLI 5 mg + MIRA 50 mg), SOLI (5 mg), or MIRA (50 mg) for a duration of 12 m. The primary safety variable was frequency of treatment-emergent adverse events (TEAEs). The change from Baseline to end of treatment (EoT) in mean number of incontinence episodes/24 h and micturitions/24 h were primary efficacy variables. Key secondary efficacy variables were change from Baseline to EoT in mean volume voided per micturition, OAB questionnaire Symptom Bother score, and treatment satisfaction-visual analog scale score. All efficacy variables were evaluated using analysis of covariance models. RESULTS: In total, 1,819 patients received COMBN (n1⁄41,210), SOLI (n1⁄4303), or MIRA (n1⁄4306) and all groups had similar demographics. Overall, 856 (47.2%) patients experienced 1 TEAE (Table 1). A slightly increased frequency of TEAEs was observed in the COMBN group. The most common TEAEs in each group were dry mouth (COMBN and SOLI) and nasopharyngitis (MIRA). The changes from Baseline to EoT in the mean number of incontinence episodes and micturitions were significantly greater with COMBN treatment compared with SOLI and MIRA (Table 2). COMBN treatment was also significantly superior to SOLI and MIRA for all key secondary efficacy variables. CONCLUSIONS: COMBN (SOLI + MIRA) treatment over 12 m was well tolerated and no new safety concerns were apparent. Clinically relevant improvements in efficacy were observed with COMBN treatment compared with each monotherapy over the 12 m study period.