A strategy utilizing ambulatory monitoring and home and clinic blood pressure measurements to optimize the safety evaluation of noncardiovascular drugs with potential for hemodynamic effects: a report from the SYNERGY trial.

OBJECTIVE: The aim of this study was to perform a blood pressure (BP) safety evaluation in patients with an overactive bladder receiving solifenacin (an antimuscarinic agent), mirabegron (a ß3-adrenoceptor agonist), or both compared with placebo in the SYNERGY trial. PATIENTS AND METHODS: 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; mirabegron 50 mg; mirabegron 25 mg; or placebo for a double-blind 12-week treatment period. Systolic BP, diastolic BP, and heart rate were measured by ambulatory BP monitoring, and in the clinic or home. RESULTS: A total of 715 patients were analyzed in an ambulatory BP monitoring substudy. At the end of treatment, ambulatory BP monitoring measurements showed no consistent increases from baseline in the mean 24-h systolic BP or diastolic BP for combination versus monotherapy groups or for monotherapy groups versus placebo. Analysis of 1-h BP averages during the 6 h range that included the Tmax values of both study drugs showed no significant BP effects. Shift analysis (switch between different normotension/hypertension stages) did not show differences among the active and placebo groups, nor did outlier analysis of major BP changes differ between placebo and active treatment. Similarly, there were no significant signals in the 24-h heart rate. Office and home measurements were consistent with ambulatory BP monitoring findings. CONCLUSIONS: A paradigm of ambulatory BP monitoring analysis designed to test BP safety of noncardiovascular drugs showed that solifenacin plus mirabegron combination therapy during 12 weeks produced no meaningful changes in BP or heart rate.

A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the ß3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder.

OBJECTIVE: To assess the efficacy and tolerability of mirabegron 25 mg and 50 mg once-daily vs placebo in patients with overactive bladder (OAB). MATERIALS AND METHODS: Patients ≥18 years with OAB symptoms were recruited to a 2-week, single-blind, placebo run-in. Those with ≥8 micturitions per 24 hours and ≥3 urgency episodes were randomized 1:1:1 to once-daily mirabegron 25 mg or 50 mg, or placebo for 12 weeks. Primary endpoints were changes to final visit in mean number of incontinence episodes and micturitions per 24 hours. Key secondary endpoints were changes to final visit in mean volume voided or micturition, change to week 4 in mean number of incontinence episodes and micturitions per 24 hours, changes to final visit in mean level of urgency, number of urgency incontinence episodes, and urgency (grade 3 or 4) episodes per 24 hours. Patient-reported outcomes were assessed using the OAB-questionnaire, Patient Perception of Bladder Condition, and Treatment-Satisfaction-Visual Analog Scale. RESULTS: Both mirabegron groups demonstrated statistically significant improvements in coprimary endpoints vs placebo. Mirabegron 50 mg demonstrated significantly greater improvements vs placebo in the following: change to final visit in mean volume voided per micturition and change to week 4 in mean number of incontinence episodes per 24 hours. Statistically significant improvements vs placebo were demonstrated by mirabegron 50 mg in all patient-reported outcome scales with no increase in the incidence of treatment-emergent adverse events vs placebo. CONCLUSION: Mirabegron 25 mg and 50 mg were associated with significant improvements in efficacy measures of incontinence episodes and micturition frequency. Mirabegron was well tolerated vs placebo.