Mirabegron Vs Placebo Add-on Therapy in Men With Overactive Bladder Symptoms Receiving Tamsulosin for Underlying Benign Prostatic Hyperplasia: A Safety Analysis From the Randomized, Phase 4 PLUS Study

Abstract

OBJECTIVE To analyze the safety of mirabegron add-on therapy in men with overactive bladder symptoms concurrently receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia. METHODS The Phase 4 PLUS study comprised a 4-week run-in period (tamsulosin [0.4 mg]) and a 12-week randomized treatment period (add-on treatment: mirabegron [25 mg] or placebo). Doses were increased to mirabegron 50 mg or matched placebo after 4 weeks. Safety assessments: treatmentemergent adverse events (TEAEs), vital signs, 12-lead electrocardiograms, and changes in postvoid residual volume and maximum urinary flow (Q max). RESULTS The safety analysis set included 352 tamsulosin plus mirabegron (TAM + MIRA) and 354 tamsulosin plus placebo (TAM + PL) patients. The frequency of overall TEAEs was higher with TAM + PL, although a higher incidence of drug-related TEAEs was observed with TAM + MIRA. Most TEAEs were mild or moderate in severity. Drug-related serious TEAEs were reported for 3 patients (2 TAM + MIRA patients: acute myocardial infarction with cerebral infarction and angina pectoris, 1 TAM + PL patient: lacunar stroke). Hypertension, headache, and nasopharyngitis were the most common TEAEs. Special interest TEAEs were infrequently reported. The most common was urinary retention and 2 TAM + MIRA patients required catheterization (neither led to discontinuation). No major changes in blood pressure or pulse rate were noted and similar electrocardiogram parameters were observed for both groups. Changes in mean postvoid residual volume and Q max were not clinically meaningful. CONCLUSION No unexpected safety concerns were noted in men receiving tamsulosin for lower urinary tract symptoms associated with benign prostatic hyperplasia who subsequently received mirabegron add-on therapy. UROLOGY 00: 1−8, 2020.

Concentration-dependent alpha1-Adrenoceptor Antagonism and Inhibition of Neurogenic Smooth Muscle Contraction by Mirabegron in the Human Prostate

“…Both studies were not placebo-controlled and did not include more than 50 patients. Consequently, these findings were not confirmed by a placebo-controlled, double-blinded phase four study, suggesting that add-on of mirabegron to an α 1 -blocker does not result in clinical meaningful improvements of maximum urinary flow rate ( Herschorn et al, 2021 ). Plasma levels corresponding to a concentration of 5 µM in vitro and calculable effects on voiding symptoms would require dosages highly exceeding the established standard dosages of 50–100 mg daily.…”

Effects of β3-adrenoceptor agonist on acute urinary retention in a rat model

“…Data are represented as mean ± SD, a Student's t test risk of increasing urinary retention [20]. In a randomized trial [21], add-on mirabegron while receiving tamsulosin with BPH, associated with increasing the PVR (mean change 14.7 mL, 95% CI 8.5, 21.0 mL). However, add-on mirabegron was not associated with clinically meaningful changes in PVR volume, six of 352 (1.7%) men experienced a urinary retention.…”

Practice-changing publications in functional urology: A case-based approach

“…Two large, randomized, placebo-controlled trials were published in 2020 demonstrating both efficacy and safety of the addition of mirabegron to tamsulosin for management of storage symptoms in male patients. [6][7][8] The MATCH study included Japanese and Korean men treated with tamsulosin for benign prostatic hyperplasia (BPH). 6 All study participants received tamsulosin 0.2 mg plus one placebo tablet once daily for a four-week, single-blind screening period, followed by either for tamsulosin 0.2 mg plus one placebo tablet (in the control group) or tamsulosin 0.2 mg plus mirabegron 50 mg (in the treatment group) for 12 weeks.…”

“…6 The PLUS study was a multicenter, randomized, doubleblind, placebo-controlled study carried out in North America and Europe. 7,8 The study began with a four-week, open label, run-in period during which all patients received tamsulosin 0.4 mg daily. This was followed by randomization to either tamsulosin 0.4 mg plus mirabegron 25 mg daily for four weeks, then tamsulosin 0.4 mg plus mirabegron 50 mg daily for eight weeks (in the treatment group), or tamsulosin 0.4 mg plus placebo daily for 12 weeks (in the control group).…”

“…Urinary retention, as defined at the investigator's discretion with no specific need for catheterization, occurred in one patient in the control group and six in the treatment group, with only two patients in the treatment group requiring catheterization. 7,8 The MATCH and PLUS trials showed very low risk of adverse events, and in particular very low rates of urinary retention or catheterization. While improvement in voiding parameters based on voiding diaries were small, change in MVV did reach statistical significance in both studies, and both trials reported significant change in subjective symptoms based on a variety of questionnaires.…”