Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) symptoms are frequently reported together [1]. However, limited data are available on the efficacy and safety of OAB medications for treating patients with these conditions. The PLUS study investigated the use of mirabegron vs. placebo for treating OAB symptoms in men concurrently receiving tamsulosin for lower urinary tract symptoms (LUTS) due to underlying BPH. The safety findings from this study are reported herein.

PLUS was a 12-week, phase IV, randomised, double-blind, multi-centre trial that was conducted in North America and Europe. Eligible patients had to be ≥40 years old, have received tamsulosin for ≥2 months, have a prostate specific antigen level of <10 ng/mL, and experience ≥8 micturitions/day and ≥2 urgency episodes/day at randomisation. After a 4-week run-in period with tamsulosin, patients were randomised to receive either mirabegron 25 mg or placebo. After a further 4 weeks, all patients were titrated to receive mirabegron 50 mg or placebo equivalent for 8 more weeks. Safety was assessed in terms of treatment-emergent adverse events (TEAEs), which included TEAEs of special interest (acute urinary retention requiring catheterisation, events suggestive of urinary tract infections, cardiovascular events, events related to blood pressure and heart rate, and benign prostatic obstruction [BPO] requiring surgery). Changes from Baseline/Screening to week 12/end of treatment (EoT) in post-void residual (PVR) volume and maximum urinary flow (Qmax) were also assessed as additional safety endpoints. Both home- and office-based monitoring were used to assess vital signs and 12-lead electrocardiograms (ECGs) were performed at each study visit.

Of 706 men in the Safety Analysis Set (354 tamsulosin plus placebo patients and 352 tamsulosin plus mirabegron patients), mean age was 65.0 ± 8.9 years, 399 (56.5%) patients were ≥65 years old, and the majority of the patients were white (649 [91.9%] patients). The most commonly reported comorbidity for both groups was hypertension (tamsulosin plus placebo group: 200/339 [59.0%] patients, tamsulosin plus mirabegron group: 186/337 [55.2%] patients; full analysis set data). Overall, a slightly higher frequency of TEAEs was observed in the tamsulosin plus placebo group (111 [31.4%] patients) compared with the tamsulosin plus mirabegron group (91 [25.9%] patients, Table 1). Conversely, a higher incidence of drug-related TEAEs was observed for the tamsulosin plus mirabegron group (42 [11.9%] patients vs. 21 [5.9%] tamsulosin plus placebo patients). The majority of the patients in both treatment groups experienced TEAEs that were either mild (123 [60.9%] patients) or moderate (66 [32.7%] patients) in severity. No deaths were reported during the study. In total, eight (2.3%) patients from the tamsulosin plus placebo group and 10 (2.8%) patients from the tamsulosin plus mirabegron group experienced a serious TEAE and three (0.8%) and six (1.7%) patients from the tamsulosin plus placebo and tamsulosin plus mirabegron groups respectively experienced a TEAE that led to study drug discontinuation. Three patients reported drug-related serious TEAEs; two (0.6%) tamsulosin plus mirabegron patients experienced events of acute myocardial infarction with cerebral infarction and angina pectoris and one (0.3%) tamsulosin plus placebo patient experienced an event of lacunar stroke. Overall, the most commonly reported TEAEs were hypertension (17 [2.4%] patients), headache (14 [2.0%] patients), and nasopharyngitis (13 [1.8%] patients). Similar incidences were noted in both treatment groups with the exception of hypertension, which occurred more frequently in the tamsulosin plus placebo group (11 [3.1%] patients) than in the tamsulosin plus mirabegron group (six [1.7%] patients). Most TEAEs of special interest were infrequently reported. The only special interest TEAE that was reported by ≥1% of the patients from either group was urinary retention, which was reported at a higher frequency in the tamsulosin plus mirabegron group (six [1.7%] patients) compared with the tamsulosin plus placebo group (one [0.3%] patient). Two tamsulosin plus mirabegron patients (0.6%) required catheterisation, although neither event led to study drug discontinuation. One of these events occurred in the study follow-up period (after the patient had completed study drug) and was associated with unrelated elective surgery requiring anaesthesia. No cases of BPO that required surgery were reported during the study. The increases from Baseline to week 12/EoT in mean PVR volume were greater for the tamsulosin plus mirabegron group (mean change: 14.7 mL, 95% confidence interval [CI]: 8.5, 21.0 mL) than for the tamsulosin plus placebo group (mean change: 3.8 mL, 95% CI: –0.9, 8.4 mL). No clinically significant changes from Screening to week 12/EoT were observed for Qmax, although a larger mean decrease was recorded for the tamsulosin plus mirabegron group (mean change: –1.8 mL/sec, 95% CI: –3.76, 0.10 mL/sec) compared with the tamsulosin plus placebo group (mean change: 0.0 mL/sec, 95% CI: –1.10, 1.08 mL/sec). For both treatment groups, there were no clinically meaningful changes from Baseline to EoT in mean blood pressure or pulse rate for either the home- or office-based assessments (Figure 1). In addition, similar ECG parameters were observed for both treatment groups (changes from Baseline to week 12/EoT in QT interval corrected for heart rate by Fridericia’s formula [QTcF] – tamsulosin plus placebo: >30–<60 ms: three [1.0%] patients, ≥60 ms: zero patients; tamsulosin plus mirabegron: >30–<60 ms: three [1.0%] patients, ≥60 ms: one [0.3%] patient).

Mirabegron treatment was well tolerated in the PLUS study and the TEAE results obtained were consistent with its known safety profile. The changes in mean PVR volume and Qmax were not considered to be clinically relevant. Furthermore, no clinically meaningful changes from Baseline in either blood pressure or pulse rate were seen for either treatment group. These results underscore the safety of mirabegron add-on therapy in men with BPH.

No unexpected safety concerns were apparent among men who were receiving treatment with tamsulosin for LUTS due to BPH and who subsequently received add-on therapy with mirabegron or placebo.

Suarez O, Osborn D, Kaufman M, Reynolds WS, Dmochowski R. Mirabegron for male lower urinary tract symptoms. Curr Urol Rep 2013;14:580-4.