EMPOWUR: Vibegron Versus Placebo and Tolterodine in Overactive Bladder
EMPOWUR was an international, double-blind, placebo- and active-controlled phase 3 trial in 1,518 adults with overactive bladder (OAB), randomized 5:5:4 to vibegron 75 mg, placebo or tolterodine extended release 4 mg once daily for 12 weeks. Vibegron reduced daily micturitions by an adjusted mean of 1.8 versus 1.3 with placebo and urge incontinence episodes by 2.0 versus 1.4 in patients with urge incontinence at baseline, meeting both co-primary endpoints.[1]
- Design and population
- International, double-blind, placebo- and active-controlled randomized trial. Adults with overactive bladder for at least 3 months, 85.2% women, 42.9% aged 65 or older, including up to 25% without urge incontinence.
- Arms
- Vibegron 75 mg once daily versus placebo versus tolterodine extended release 4 mg once daily
- Report and follow-up
- 2020 · 12 weeks of treatment; 1,518 randomized, 90.4% completed
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| Co-primary: least-squares mean change from baseline to week 12 in average daily micturitions (all patients); difference is vibegron minus placebo (episodes per day); tested at two-sided alpha 0.05 in a predefined hierarchy | −1.8 vs −1.3 vs −1.6 | difference -0.5; CI -0.8–-0.2; P <0.001 | Met |
| Co-primary: least-squares mean change from baseline to week 12 in average daily urge incontinence episodes in OAB wet patients; difference is vibegron minus placebo (episodes per day); tested after micturitions in the hierarchy | −2.0 vs −1.4 vs −1.8 | difference -0.6; CI -0.9–-0.3; P <0.0001 | Met |
| Least-squares mean change from baseline to week 12 in average daily urgency episodes; difference is vibegron minus placebo (episodes per day); first key secondary endpoint in the hierarchy | −2.7 vs −2.0 vs −2.5 | difference -0.7; CI -1.1–-0.2; P 0.0020 | Met |
| Least-squares mean change from baseline to week 12 in average volume voided per micturition; difference is vibegron minus placebo (mL) | +23.5 mL vs +2.2 mL vs +15.5 mL | difference 21.2; CI 14.3–28.1; P <0.0001 | Met |
| OAB wet patients with at least 75% reduction from baseline in average daily urge incontinence episodes at week 12 | 52.4% vs 36.8% vs 47.6% | P <0.0001 | Met |
Harms: Any adverse event: 211/545 (38.7%) vs 180/540 (33.3%) vs 166/430 (38.6%); Adverse event of clinical interest: 36/545 (6.6%) vs 40/540 (7.4%) vs 38/430 (8.8%); Serious adverse events: 8/545 (1.5%) vs 6/540 (1.1%) vs 10/430 (2.3%)
Design
Patients were randomized at 199 sites in the United States, Canada, Poland, Hungary, Latvia and Lithuania, beginning March 26, 2018; the last patient completed treatment on January 7, 2019. The sponsor was Urovant Sciences, and 89.6% of the full analysis set (1,311 of 1,463) was enrolled in the United States.[1][2][3][4]
Adults with OAB for at least 3 months qualified on a 7-day diary as OAB wet (an average of at least 8 micturitions and at least 1 urge incontinence episode per day) or OAB dry (at least 8 micturitions, at least 3 urgency episodes and fewer than 1 urge incontinence episode per day). Dry OAB was capped at 25% of the study and men at 15%; patients with a urine output above 3,000 mL were not enrolled.[1][3] Exclusions relevant to surgical practice were lower urinary tract pathology that could explain the symptoms, surgery for stress incontinence, prolapse or BPH within 6 months, stage 2 or greater prolapse or pessary use, a history of postvoid residual above 150 mL, catheter dependence, intradetrusor botulinum toxin within 9 months, bladder training or electrostimulation within 28 days, more than 3 urinary tract infections a year, and injury, surgery or neurodegenerative disease affecting the lower urinary tract or its nerve supply. Uncontrolled hypertension (systolic at least 180 or diastolic at least 100 mm Hg) also excluded patients.[4]
Screening lasted 1 to 5 weeks, followed by a 28-day washout and a 2-week single-blind placebo run-in; 3,149 patients were screened for the 1,518 randomized.[1][4] Randomization was stratified by sex and by wet versus dry OAB, and each arm received matching placebos for the other two treatments. Treatment lasted 12 weeks, with a 4-week follow-up safety evaluation.[1] The co-primary endpoints were the change from baseline to week 12 in average daily micturitions (all patients) and in urge incontinence episodes (OAB wet patients), taken from 7-day diaries completed at baseline and weeks 2, 4, 8 and 12. Urgency episodes, volume voided per micturition and the proportion of OAB wet patients with at least a 75% reduction in urge incontinence episodes were key secondary measures.[1] Analyses used mixed models for repeated measures in the 1,463 patients with at least one evaluable post-baseline measurement (1,127 wet OAB patients for urge incontinence), and responder proportions used Cochran-Mantel-Haenszel risk differences with multiple imputation. The co-primary and key secondary endpoints were tested in a predefined hierarchical order at two-sided alpha 0.05. Efficacy was compared formally between vibegron and placebo; tolterodine versus placebo was supportive with nominal P values, and vibegron was not compared with tolterodine.[1] The planned 500, 500 and 400 patients gave about 98% power to detect a 0.60 difference in micturitions (SD 2.20) and a 0.51 difference in urge incontinence episodes (SD 1.68).[1] The OAB-q coping score was a key secondary endpoint in a gatekeeping procedure at two-sided alpha 0.05.[5]
Results
At baseline the full analysis set averaged 11.5 micturitions, 8.1 urgency episodes and 150.5 mL per micturition a day, and wet OAB patients averaged 3.5 urge incontinence episodes a day.[1] At week 12 the adjusted mean change in daily micturitions was −1.8 with vibegron (492 patients), −1.3 with placebo (475) and −1.6 with tolterodine (378); the difference between vibegron and placebo was −0.5 (95% CI −0.8 to −0.2; P < 0.001). Among OAB wet patients, daily urge incontinence episodes changed by −2.0 (383 patients), −1.4 (372) and −1.8 (286), a vibegron-minus-placebo difference of −0.6 (95% CI −0.9 to −0.3; P < 0.0001). Tolterodine versus placebo, a supportive comparison, differed by −0.3 micturitions (95% CI −0.6 to 0.1; P = 0.0988) and −0.4 urge incontinence episodes (95% CI −0.7 to −0.1; P = 0.0123). Both differences from placebo with vibegron were significant from week 2 (prespecified exploratory time point).[1]
Among the key secondary endpoints, urgency episodes changed by −2.7 with vibegron, −2.0 with placebo and −2.5 with tolterodine (vibegron versus placebo −0.7, 95% CI −1.1 to −0.2; P = 0.0020; tolterodine versus placebo −0.4, 95% CI −0.9 to 0.0; P = 0.0648). Volume voided per micturition rose by 23.5 mL with vibegron, 2.2 mL with placebo and 15.5 mL with tolterodine (vibegron versus placebo 21.2 mL, 95% CI 14.3 to 28.1; P < 0.0001; tolterodine versus placebo 13.3 mL, 95% CI 5.9 to 20.7; P < 0.001).[1] In OAB wet patients, a 75% or greater reduction in urge incontinence episodes occurred in 52.4% on vibegron, 36.8% on placebo and 47.6% on tolterodine (P < 0.0001 for vibegron versus placebo); the registry's sex-adjusted percentages were 49.3% and 32.8%, a difference of 16.5 points (95% CI 9.7 to 23.4).[1][4] Complete resolution of urge incontinence at week 12 in OAB wet patients, a secondary endpoint reported in the registry results, occurred in an estimated 25.3% on vibegron versus 19.0% on placebo (difference 6.3 points, 95% CI 0.4 to 12.1).[4] Vibegron was numerically greater than tolterodine on every primary and key secondary endpoint, and improvement over placebo was present from week 2.[1][5] Response in patients who had previously taken an anticholinergic or beta-3 agonist was similar to that in treatment-naive patients.[1]
On the OAB-q, the coping score improved by 16.5 points with vibegron and 12.9 with placebo (difference 3.6, 95% CI 1.2 to 6.0; P = 0.0039). The symptom bother score differed by −6.9 points (95% CI −9.2 to −4.6), and 70.1% versus 58.3% reached a 10-point improvement in symptom bother in a post hoc analysis (odds ratio 1.89, 95% CI 1.43 to 2.50).[5]
In the 40-week double-blind extension, 506 patients who had completed the 12-week study continued on vibegron or tolterodine, with placebo completers randomized 1:1 to vibegron or tolterodine; there was no placebo arm. Among patients treated with vibegron or tolterodine for 52 weeks, micturitions changed by −2.4 and −2.0 and urge incontinence episodes by −2.2 versus −1.7 (P < 0.05). In exploratory analyses of OAB wet patients treated for 52 weeks, a 75% or greater reduction in urge incontinence episodes occurred in 61.0% on vibegron versus 54.4% on tolterodine, and a 100% reduction in 40.8% versus 34.2%.[7]
Post hoc subgroup analyses were consistent with the overall result. In OAB dry patients (123 on vibegron, 115 on placebo) vibegron reduced urgency episodes by 1.0 more than placebo (95% CI −2.0 to −0.1) and micturitions by 0.8 more (95% CI −1.5 to −0.1); in OAB wet patients (403 and 405) the differences were −0.6 (95% CI −1.0 to −0.1) and −0.5 (95% CI −0.8 to −0.1).[3] Among 628 patients aged 65 or older, 50.0% (96/192) of OAB wet patients on vibegron and 29.8% (50/168) on placebo had at least a 75% reduction in urge incontinence episodes (P < 0.0001).[2]
Surgery and treatment delivery
Treatment was oral, once daily each morning. Of the 1,518 randomized patients, 1,373 (90.4%) completed 12 weeks: 502 of 547 on vibegron, 486 of 540 on placebo and 385 of 431 on tolterodine.[1][4] The full analysis set comprised 526, 520 and 417 patients.[1] The run-in required at least 80% compliance with study medication before randomization.[2]
Adverse events
Any adverse event occurred in 211/545 (38.7%) on vibegron, 180/540 (33.3%) on placebo and 166/430 (38.6%) on tolterodine, and adverse events led to discontinuation in 9 (1.7%), 6 (1.1%) and 14 (3.3%). Events above 2.0% on vibegron and more frequent than placebo were headache (22, 4.0% versus 13, 2.4%), nasopharyngitis (15, 2.8% versus 9, 1.7%), diarrhea (12, 2.2% versus 6, 1.1%) and nausea (12, 2.2% versus 6, 1.1%). Hypertension, a predefined event of interest, occurred in 9/545 (1.7%) on vibegron, 9/540 (1.7%) on placebo and 11/430 (2.6%) on tolterodine, and blood pressure increase in 4 (0.7%), 5 (0.9%) and 8 (1.9%); tachycardia was reported by none on vibegron or placebo and 0.2% on tolterodine. Dry mouth was reported by 9/545 (1.7%) on vibegron, 5/540 (0.9%) on placebo and 28/430 (6.5%) on tolterodine. Urinary tract infection occurred in 27/545 (5.0%), 33/540 (6.1%) and 25/430 (5.8%), and urinary retention in 3/545 (0.6%), 2/540 (0.4%) and 3/430 (0.7%).[1] Serious adverse events occurred in 8/545 (1.5%), 6/540 (1.1%) and 10/430 (2.3%). The two vibegron events judged possibly or probably related by the investigator, but not the sponsor, were pneumonia and noncardiac chest pain; the single death, from stroke, urinary tract infection and sepsis, was in the tolterodine arm.[1]
In the extension, any treatment-emergent adverse event occurred in 171/273 (62.6%) on vibegron and 126/232 (54.3%) on tolterodine, serious events in 9/273 (3.3%) and 10/232 (4.3%), and discontinuation for adverse events in 4/273 (1.5%) and 8/232 (3.4%). Hypertension was reported by 8.8% and 8.6%, urinary tract infection by 6.6% and 7.3%, and dry mouth by 1.8% and 5.2%.[7][8] In the 12-week phase, among patients aged 65 or older, hypertension occurred in 3/246 (1.2%) on vibegron, 7/228 (3.1%) on placebo and 5/171 (2.9%) on tolterodine; among those aged 75 or older, urinary retention occurred in 2/75 (2.7%) on vibegron, none of 60 on placebo and 2/48 (4.2%) on tolterodine.[2]
Limitations
The placebo-controlled phase lasted 12 weeks; the extension had no placebo arm, and its 52-week efficacy figures cover only patients who stayed on the same drug. Tolterodine served as a reference arm without a comparison against vibegron. Women made up 85.2% of the full analysis set and men were capped at 15% (77 of 526 in the vibegron efficacy population), and the subgroup analyses by age and OAB type were not powered.[1][2][3] The exclusion list removed patients with stage 2 or greater prolapse, elevated postvoid residual, catheter dependence, recent botulinum toxin or electrostimulation, and neurologic disease; the population included both patients new to OAB medication and those previously treated.[4][6] Outcomes were diary-based, and three authors were affiliated with the sponsor, Urovant Sciences.[1]
In conversation
COURAGE tested the same 75-mg dose against placebo for 24 weeks in men taking BPH drugs (Study 3005 in the label); EMPOWUR limited men to 15% of enrollment.[1][6]
Guidelines and approvals
- AUA/SUFU (2024). Clinicians should offer antimuscarinic medications or beta-3 agonists to patients with OAB to improve urgency, frequency and urgency urinary incontinence . The guideline lists EMPOWUR among the beta-3 agonist trials with a tolterodine or imidafenacin control arm and concludes that antimuscarinics and beta-3 agonists have similar efficacy.[9]
- EAU male LUTS guideline (March 2026). The text describes EMPOWUR as showing reductions in micturitions, urgency episodes and urgency incontinence, notes that 85% of its population was female, and recommends beta-3 agonists in men with moderate-to-severe storage LUTS , with a footnote that further evidence is awaited for vibegron.[10]
- FDA (December 23, 2020). Vibegron (Gemtesa) was approved under NDA 213006.[11] The current label lists OAB with symptoms of urge urinary incontinence, urgency and urinary frequency in adults, and in adult men on pharmacologic BPH therapy since December 2024, and draws its adult efficacy data from EMPOWUR (Study 3003).[6]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2020-02-18 | 12-week randomized report · primary | — | Co-primary: least-squares mean change from baseline to week 12 in average daily micturitions (all patients); difference is vibegron minus placebo (episodes per day); tested at two-sided alpha 0.05 in a predefined hierarchy: −1.8 vs −1.3 vs −1.6; difference -0.5; CI -0.8–-0.2; P <0.001 Met Co-primary: least-squares mean change from baseline to week 12 in average daily urge incontinence episodes in OAB wet patients; difference is vibegron minus placebo (episodes per day); tested after micturitions in the hierarchy: −2.0 vs −1.4 vs −1.8; difference -0.6; CI -0.9–-0.3; P <0.0001 Met Least-squares mean change from baseline to week 12 in average daily urgency episodes; difference is vibegron minus placebo (episodes per day); first key secondary endpoint in the hierarchy: −2.7 vs −2.0 vs −2.5; difference -0.7; CI -1.1–-0.2; P 0.0020 Met Least-squares mean change from baseline to week 12 in average volume voided per micturition; difference is vibegron minus placebo (mL): +23.5 mL vs +2.2 mL vs +15.5 mL; difference 21.2; CI 14.3–28.1; P <0.0001 Met OAB wet patients with at least 75% reduction from baseline in average daily urge incontinence episodes at week 12: 52.4% vs 36.8% vs 47.6%; P <0.0001 Met OAB wet patients with 100% reduction in daily urge incontinence episodes at week 12, sex-adjusted percentage; difference in percentage points: 25.3% vs 19.0% vs 20.9%; difference 6.3; CI 0.4–12.1; P 0.0360 | Staskin D, Frankel J, Varano S, et al. International phase III, randomized, double-blind, placebo and active controlled study to evaluate the safety and efficacy of vibegron in patients with symptoms of overactive bladder: EMPOWUR. *J Urol.* 2020;204(2):316-324. doi:10.1097/JU.0000000000000807 DOI |
| 2020-12-28 | 52-week extension · updated | — | Least squares mean change from baseline to week 52 in daily micturitions, patients on the same drug for 52 weeks: −2.4 vs −2.0; — Least squares mean change from baseline to week 52 in daily urge incontinence episodes, OAB wet patients: −2.2 vs −1.7; P <0.05 Least squares mean change from baseline to week 52 in daily urgency episodes: −3.4 vs −3.2; — Least squares mean change from baseline to week 52 in daily total incontinence episodes, OAB wet patients: −2.5 vs −1.9; P <0.05 OAB wet patients with at least 75% reduction in urge incontinence episodes at week 52, 52-week treatment groups only: 61.0% vs 54.4%; — OAB wet patients with 100% reduction in urge incontinence episodes at week 52, 52-week treatment groups only: 40.8% vs 34.2%; — | Staskin D, Frankel J, Varano S, et al. Once-daily vibegron 75 mg for overactive bladder: long-term safety and efficacy from a double-blind extension study of the international phase 3 trial (EMPOWUR). *J Urol.* 2021;205(5):1421-1429. doi:10.1097/JU.0000000000001574 DOI |
| 2021-01-20 | Age 65 and 75 and older subpopulations · post-hoc | — | Change in daily micturitions at week 12, vibegron versus placebo, patients aged 65 or older (FAS n=628): FAS: 242 vibegron, 220 placebo, 166 tolterodine. Subgroup analysis; trial not powered within subgroups.; P <0.0001 Change in daily micturitions at week 12, vibegron versus placebo, patients aged 75 or older (FAS n=179): FAS: 75 vibegron, 57 placebo, 47 tolterodine. Post hoc model without sex or region.; P <0.05 Change in daily urge incontinence episodes at week 12, vibegron versus placebo, patients aged 65 or older: —; P <0.001 Change in daily urgency episodes at week 12, vibegron versus placebo, patients aged 65 or older: Same P value (<0.01) in patients aged 75 or older.; P <0.01 OAB wet patients aged 65 or older with at least 75% reduction in urge incontinence episodes at week 12: 50.0% (96/192) vs 29.8% (50/168) vs 43.0% (55/128); P <0.0001 | Varano S, Staskin D, Frankel J, et al. Efficacy and safety of once-daily vibegron for treatment of overactive bladder in patients aged ≥65 and ≥75 years: subpopulation analysis from the EMPOWUR randomized, international, phase III study. *Drugs Aging.* 2021;38(2):137-146. doi:10.1007/s40266-020-00829-z DOI |
| 2021-01-22 | Patient-reported outcomes · pro | — | OAB-q coping score, least squares mean change from baseline to week 12 (higher is better); difference is vibegron minus placebo (points): +16.5 vs +12.9; difference 3.6; CI 1.2–6; P 0.0039 Met OAB-q symptom bother score, least squares mean difference vibegron minus placebo at week 12 (lower is better; points): No multiplicity adjustment.; difference -6.9; CI -9.2–-4.6; P <0.0001 OAB-q total score, least squares mean difference vibegron minus placebo at week 12 (higher is better; points): No multiplicity adjustment.; difference 3.8; CI 1.7–5.8; P <0.001 Patients with at least a 10-point improvement in OAB-q symptom bother at week 12; effect is odds ratio vibegron versus placebo: 70.1% vs 58.3%; OR 1.89; CI 1.43–2.5; P <0.0001 | Frankel J, Varano S, Staskin D, et al. Vibegron improves quality-of-life measures in patients with overactive bladder: patient-reported outcomes from the EMPOWUR study. *Int J Clin Pract.* 2021;75(5):e13937. doi:10.1111/ijcp.13937 DOI |
| 2022-04-13 | OAB dry and wet subgroups · post-hoc | — | Least squares mean change from baseline to week 12 in daily urgency episodes, OAB dry (n=123 vibegron, 115 placebo); difference is vibegron minus placebo: −2.6 vs −1.6; difference -1; CI -2–-0.1 Least squares mean change from baseline to week 12 in daily urgency episodes, OAB wet (n=403 vibegron, 405 placebo); difference is vibegron minus placebo: −3.0 vs −2.4; difference -0.6; CI -1–-0.1 Least squares mean change from baseline to week 12 in daily micturitions, OAB dry; difference is vibegron minus placebo: −1.8 vs −1.0; difference -0.8; CI -1.5–-0.1 Least squares mean change from baseline to week 12 in daily micturitions, OAB wet; difference is vibegron minus placebo: −2.1 vs −1.7; difference -0.5; CI -0.8–-0.1 OAB dry patients with at least 50% reduction in daily urgency episodes at week 12: 36.9% vs 23.1% vs 29.0%; P <0.05 | Staskin D, Frankel J, Varano S, et al. Vibegron for the treatment of patients with dry and wet overactive bladder: a subgroup analysis from the EMPOWUR trial. *Int J Clin Pract.* 2022;2022:6475014. doi:10.1155/2022/6475014 DOI |
References
1. Staskin D, Frankel J, Varano S, et al. "International Phase III, Randomized, Double-Blind, Placebo and Active Controlled Study to Evaluate the Safety and Efficacy of Vibegron in Patients with Symptoms of Overactive Bladder: EMPOWUR." J Urol. 2020;204(2):316-324. doi:10.1097/JU.0000000000000807
2. Varano S, Staskin D, Frankel J, et al. "Efficacy and Safety of Once-Daily Vibegron for Treatment of Overactive Bladder in Patients Aged ≥65 and ≥75 Years: Subpopulation Analysis from the EMPOWUR Randomized, International, Phase III Study." Drugs Aging. 2021;38(2):137-146. doi:10.1007/s40266-020-00829-z
3. Staskin D, Frankel J, Varano S, et al. "Vibegron for the Treatment of Patients with Dry and Wet Overactive Bladder: A Subgroup Analysis from the EMPOWUR Trial." Int J Clin Pract. 2022;2022:6475014. doi:10.1155/2022/6475014
4. ClinicalTrials.gov. "A Study to Examine the Safety and Efficacy of a New Drug in Patients With Symptoms of Overactive Bladder (OAB)." Identifier NCT03492281. clinicaltrials.gov
5. Frankel J, Varano S, Staskin D, et al. "Vibegron Improves Quality-of-Life Measures in Patients with Overactive Bladder: Patient-Reported Outcomes from the EMPOWUR Study." Int J Clin Pract. 2021;75(5):e13937. doi:10.1111/ijcp.13937
6. Sumitomo Pharma America, Inc. GEMTESA (vibegron) tablets: US prescribing information. Revised February 2025. Sections 1, 6.1 and 14.1. Manufacturer label
7. Staskin D, Frankel J, Varano S, et al. "Once-Daily Vibegron 75 mg for Overactive Bladder: Long-Term Safety and Efficacy from a Double-Blind Extension Study of the International Phase 3 Trial (EMPOWUR)." J Urol. 2021;205(5):1421-1429. doi:10.1097/JU.0000000000001574
8. ClinicalTrials.gov. "An Extension Study to Examine the Safety and Tolerability of a New Drug in Patients With Symptoms of Overactive Bladder (OAB)." Identifier NCT03583372. clinicaltrials.gov
9. American Urological Association and Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction. The AUA/SUFU Guideline on the Diagnosis and Treatment of Idiopathic Overactive Bladder. 2024. Statement 16.
10. European Association of Urology. EAU Guidelines on Management of Non-Neurogenic Male Lower Urinary Tract Symptoms (LUTS). Update March 2026. Section 5.2.4.
11. U.S. Food and Drug Administration. "Drugs@FDA: GEMTESA (vibegron) tablets, NDA 213006." accessdata.fda.gov