Table 2.

Key clinical trials

Clinical trial	Length of trial/treatment	Population	BPH regimen or BOO/PVR criteria	Endpoints	AEs
Victor trial (NCT00771394) [51]	12-week, double-blind, placebo-controlled Treatment: 5 mg solifenacin + 0.4 mg tamsulosin or placebo + 0.4 mg tamsulosin once daily for 12 weeks	Men age ≥ 45 years Had residual OAB symptoms documented via bladder diary (mean ≥ 8 micturitions, ≥ 1 more urgency episodes per 24 h) after taking 0.4 mg tamsulosin once daily for ≥ 4 weeks Solifenacin + tamsulosin (n = 202) Placebo + tamsulosin (n = 195)	PVR volume ≤ 200 mL and peak flow rate ≥ 5 mL/s before randomization PSA ≤ 10 ng/mL	Solifenacin + tamsulosin vs placebo + tamsulosin showed reductions in frequency but were not statistically significant Statistically significant reductions in urgency with solifenacin + tamsulosin vs placebo + tamsulosin	Treatment-related TEAEs were more frequent in the solifenacin + tamsulosin vs placebo plus tamsulosin groups Solifenacin + tamsulosin group had 7 (3%) patients with urinary retention and 3 required catheterization; no patients on placebo + tamsulosin reported urinary retention
Prospective study [52]	June 2009 to April 2011 Patients treated for 1 week with 0.4 mg tamsulosin, and an additional 4-week period with tamsulosin or tamsulosin + fesoterodine combination	Men age ≥ 50 years Men with LUTS storage symptoms from OAB and BOO Tamsulosin (n = 23) Tamsulosin + fesoterodine (n = 24)	PVR volume < 200 mL Qmax > 10 mL/s Prostate volume < 60 cm3 PSA < 4 ng/mL	At the end of treatment period, there was no statistically significant difference in Qmax, and PVR between patients with tamsulosin + fesoterodine and patients treated only with tamsulosin After the second visit (after 1 week of treatment) and third visit (from baseline to week 6), men receiving fesoterodine + tamsulosin had significant improvement in storage and total IPSS scores vs tamsulosin alone	Overall, 4 (16.6%) patients reported dry mouth and 1 (4.1%) reported constipation 1 (4.1%) patient from the tamsulosin + fesoterodine treatment group reported increased voiding difficulties, but no patients required catheterization and no urinary retention was reported In the tamsulosin alone group, 1 patient reported dizziness
SATURN Trial (NCT00510406) [53]	12-week double-blind, parallel-group, placebo-controlled, multicenter, dose-ranging study Treatment: Placebo Tamsulosin 0.4 mg monotherapy Solifenacin 3, 6, or 9 mg + tamsulosin 0.4 mg Dose-matched solifenacin monotherapy	Men age ≥ 45 years Diagnosed with LUTS (both voiding and storage symptoms) Placebo (n = 92) Tamsulosin 0.4 mg (n = 177) Solifenacin 3 mg (n = 43) Solifenacin 6 mg (n = 43) Solifenacin 9 mg (n = 43) Solifenacin 3 mg + tamsulosin 0.4 mg (n = 179) Solifenacin 6 mg + tamsulosin 0.4 mg (n = 178) Solifenacin 9 mg + tamsulosin 0.4 mg (n = 175)	PVR volume ≤ 200 mL Qmax of 4.0–15.0 mL/s Volume voided during free flow ≥ 120 mL No minimum or maximum prostate size	In the total study population, IPSS subscores were not significantly different in patients receiving solifenacin and α-blocker compared with α-blocker alone In the total study population, there were significant improvements in micturition frequency, total urgency and frequency score, and voided volume with increasing solifenacin dose + tamsulosin vs tamsulosin alone In a subgroup of patients stratified by baseline storage symptom severity, there were statistically significant improvements in IPSS storage subscore, urgency episodes, micturition frequency, total urgency score, voided volume with solifenacin + tamsulosin vs tamsulosin alone	Treatment-related dry mouth was reported in 47 (8.8%) patients treated with solifenacin + tamsulosin vs 4 (2.3%) treated with tamsulosin alone PVR volume increase was not considered clinically relevant Acute urinary retention was low in both treatment groups   5 occurred within the first 32 days of treatment and 4 required catheterization (1 patient in group: solifenacin 9 mg, tamsulosin monotherapy, solifenacin 3 mg + tamsulosin, solifenacin 9 mg + tamsulosin)
MATCH Trial (NCT02656173) [63]	12-week double-blind placebo-controlled study Treatment: Tamsulosin 0.2 mg + mirabegron 50 mg Tamsulosin 0.2 mg + placebo	Men age ≥ 40 years Average of ≥ 2 episodes of urgency/day and average of ≥ 8 micturitions/day last 3 days before screening period Treatment with tamsulosin 0.2 mg for ≥ 4 weeks before screening period Tamsulosin + mirabegron (n = 283) Tamsulosin + placebo (n = 282)	PVR volume ≤ 100 mL Qmax ≥ 5 mL/s PSA < 4 ng/mL	Mirabegron combination therapy was statistically significant vs placebo in improving mean number of micturitions/day; and mean volume voided/micturition, OAB symptom score, and IPSS total	Treatment-related TEAEs were lower in the placebo group vs mirabegron group Incidences of urination-related events were 1.4% in mirabegron group and 0.4% in placebo group Increased residual urine volume was reported in 3 (1.1%) patients in mirabegron group and 1 (0.4%) patient in placebo group
Phase 4 PLUS Study (NCT02757768) [62]	12-week double-blind, multicenter study Treatment: Tamsulosin 0.4 mg + 25 mg mirabegron and at week 4 dose titrated to 50 mg Tamsulosin 0.4 mg + matched placebo	Men age ≥ 40 years Diagnosed with BPH-associated LUTS Received tamsulosin 0.4 mg daily for ≥ 2 months OAB symptoms (≥ 8 micturitions per day and ≥ 2 more urgency episodes per day) Tamsulosin + mirabegron (n = 337) Tamsulosin + placebo (n = 339)	PVR volume < 200 mL PSA > 4 ng/mL or 4 to < 10 ng/mL with a negative biopsy within 2 years Qmax ≥ 5.0 mL/s with a minimum volume voided of 125 mL Excluded if had clinically significant bladder outlet obstruction determined by investigator	Tamsulosin + mirabegron statistically significantly reduced the mean number of daily micturitions and urgency episodes compared with tamsulosin plus placebo; there were no significant differences between the total IPSS scores between groups Rates of UUI did not significantly differ between groups	Fewer TEAEs with tamsulosin + mirabegron vs tamsulosin + placebo Drug-related adverse events and urinary retention rates were higher in the tamsulosin + mirabegron vs tamsulosin + placebo group
COURAGE Trial (NCT03902080) [27]	24-week double-blind treatment period Treatment: Vibegron 75 mg + α-blocker with/without 5-ARI Placebo + α-blocker with/without 5-ARI	Men age ≥ 45 years Persistent OAB symptoms (≥ 8 micturitions and ≥ 3 urgency episodes per day) for ≥ 2 months Diagnosed with BPH and treated with α-blocker (initiated ≥ 3 months before screening) with/without 5-ARI (initiated ≥ 6 months before screening) Vibegron (n = 538) Placebo (n = 542)	Urodynamic assessment of BOO and detrusor dysfunction were not criteria for the study PVR < 100 mL Qmax  ≥ 5.0 mL/s required to have at baseline	Vibegron vs placebo was associated with significant reductions in daily micturitions, urgency episodes, nocturia episodes, UUI episodes, IPSS storage score, and volume voided vs placebo	Vibegron was well tolerated, with similar rates of TEAE in the vibegron group vs placebo group (9.9% vs 9.4%) Urinary retention AEs were slightly higher in the vibegron combination therapy vs BPH medication alone, but the rates were < 1% for both treatment groups
COURAGE Extension Trial (NCT04103450) [65]	Open-label extension trial consisting of a 28-week treatment period In the COURAGE trial, participants assigned to vibegron continued vibegron for an additional 28 weeks, defined as 52-week cohort; and those assigned to placebo, received vibegron for 28 weeks, defined as 28-week cohort	Same as COURAGE trial Participants who completed the 24-week COURAGE trial were eligible to enroll in the extension trial 52-week cohort (n = 142) 28-week cohort (n = 134)	Same as COURAGE trial	52-week cohort demonstrated sustained improvements in mean daily micturitions, urgency episodes, nightly nocturia episodes, and daily UUI episodes throughout the extension 28-week cohort demonstrated improvements from extension trial baseline (week 24) in mean daily micturitions, daily urgency episodes, and nocturia episodes	Rates of AEs with vibegron were similar to the double-blind treatment in the 24-week COURAGE trial There were 2 discontinuations of urinary retention, but not related to treatment No clinically relevant changes from baseline in mean PVR urine volume No participants had PVR urine volume ≥ 200 mL at ≥ 2 consecutive assessments
Bladder Function and Safety Analysis of the COURAGE Trial (NCT03902080) [66]	Same as COURAGE trial 24-week double-blind treatment period Additional safety was assessed in the safety analysis set, consisting of all participants who received ≥ 1 dose of double-blind study medication Urodynamic parameters were assessed in the urodynamic evaluable set, randomized participants in the urodynamic substudy who received ≥ 1 dose of double-blind study medication and had Qmax and PdetQmax measurements at baseline and at 12 weeks	Same as COURAGE trial Safety analysis set (vibegron, n = 553; placebo, n = 551) Urodynamic evaluable set (vibegron, n = 21; placebo, n = 22)	Same as COURAGE trial	In the safety analysis set:  Differences in PVR and Uroflow-Qmax between vibegron and placebo were minimal from baseline to week 12 and week 24  Change from baseline to week 24 in peak flow rate was similar between groups  Only 20 (3.7%) and 7 (1.3%) participants receiving vibegron and placebo, respectively, had PVR increases ≥ 100 mL at > 1 consecutive visit; no participants receiving vibegron had increases ≥ 200 mL at > 1 consecutive visit In the urodynamic evaluable set:  There are no negative effects of vibegron on urodynamic function and no change in detrusor contractility or obstruction in men with BPH	Urinary retention was reported as an AE for 5 (0.9%) in the vibegron group and 4 (0.7%) in the placebo group Residual urine volume increased in 1 (0.2%) and 3 (0.5%) participants receiving vibegron and placebo, respectively, at the level of protocol-defined AE (elevated PVR considered clinically significant by the investigator but not meeting the protocol definition of urinary retention)

5-ARI 5α-reductase inhibitors, AE adverse event, BPH benign prostatic hyperplasia, BOO bladder outlet obstruction, IPPS International Prostate Symptom Score, OAB overactive bladder, P_detQ_max detrusor pressure at peak flow rate, PSA prostate-specific antigen, PVR postvoid residual urine volume, Q_max peak flow rate, Uroflow-Q_max maximum urinary flow rate, TEAE treatment-emergent adverse event, UUI urge urinary incontinence