Overactive Bladder
Conditions
Keywords
Beta-3 adrenergic receptor (β3-AR) agonists, incontinence, OAB, vibegron, urge urinary incontinence, Urinary bladder, overactive, Urologic Diseases, Lower Urinary Tract Symptoms, Urological Agents
Brief summary
This study is designed to evaluate the safety, tolerability, and efficacy of vibegron administered once daily in participants with OAB for up to 52 weeks.
Interventions
DRUGVibegron
single daily dose 75 mg
DRUGplacebos
placebo to match vibegron (experimental drug) and tolterodine (active comparator)
single daily dose of 4 mg
Sponsors
Urovant Sciences GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Has completed participation in study RVT-901-3003. 2. Has demonstrated ≥ 80% compliance with self-administration of Study Treatment in study RVT-901-3003.
Exclusion criteria
1. Has a change in history or current evidence of any clinically significant condition, therapy, lab abnormality, or other circumstance that might, in the opinion of the Investigator, confound the results of the study, interfere with the participant's ability to comply with study procedures, or make participation in the study not in the participant's best interest. 2. Has coronary or neurovascular interventions planned during the duration of the study. 3. Has uncontrolled hyperglycemia (defined as fasting blood glucose \>150 mg/dL or 8.33 mmol/L and/or non-fasting blood glucose \>200 mg/dL or 11.1 mmol/L) based on most recent available lab results in study RVT-901-3003 or, if in the opinion of the Investigator, is uncontrolled. 4. Has uncontrolled hypertension (systolic blood pressure of ≥ 180 mm Hg and/or diastolic blood pressure of ≥ 100 mm Hg) or has a resting heart rate (by pulse) \> 100 beats per minute. 5. Has clinically significant ECG abnormality which, in the opinion of the Investigator, exposes the participant to risk by participating in the study 6. Has alanine aminotransferase or aspartate aminotransferase \> 2.0 times the upper limit of normal (ULN), or bilirubin (total bilirubin) \> 1.5 x ULN (or \> 2.0 x ULN if secondary to Gilbert syndrome or pattern consistent with Gilbert syndrome) based on most recent available lab results in study RVT-901-3003. 7. Has an estimated glomerular filtration rate (eGFR) \< 30mL/min/1.73 m2 based on most recent available lab results in study RVT-901-3003. 8. Use of any prohibited medications as detailed in Section 7.7.3. 9. Plans to initiate or change the dosing of any medications listed in Section 7.7.5 during the study that in the opinion of the investigator is assessed to be clinical significant. 10. Has an allergy, intolerance, or a history of a significant clinical or laboratory adverse experience associated with any of the active or inactive components of the vibegron formulation or tolterodine formulation. 11. Is currently participating or has participated in a study with an investigational compound or device within 28 days of signing informed consent, not including participation in study RVT-901-3003. 12. Has a history of significant drug or alcohol abuse/dependence within a year of informed consent, as assessed by the investigator. 13. Has a varying sleep schedule anticipated during times when the voiding diaries are to be completed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | up to 56 weeks | Adverse events were collected in participants with overactive bladder (OAB) who previously completed treatment in Study RVT-901-3003. The treatment-emergent period was defined as the period of time from the first dose date of the active double-blind study treatment, whether in Study RVT-901-3003 or Study RVT-901-3004, through 28 days after the last dose of study treatment, or the date of initiation of another investigational agent or surgical intervention, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (CFB) at Week 52 in the Average Number of Micturitions Per 24 Hours in All Overactive Bladder (OAB) Participants | Baseline; Week 52 | A micturition/void is defined as Urinated in Toilet as indicated on the Patient Voiding Diary (PVD). The number of micturitions is defined as the number of times a participant voided in the toilet as indicated in the PVD. The average daily number of micturitions was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of micturitions that occurred on a Complete Diary Day (CDD) divided by the number of CDDs in the PVD. CFB was calculated as the post-BL value minus the BL value. Per 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures (MMRM) were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: OAB type (Wet versus Dry) and sex. |
| CFB at Week 52 in the Average Number of Urge Urinary Incontinence (UUI) Episodes Per 24 Hours in OAB Wet Participants | Baseline; Week 52 | The number of UUI episodes is defined as the number of times a participant had checked urge as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to urge was checked. The average daily number of UUI episodes was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of UUI episodes that occurred on a CDD divided by the number of CDDs in the PVD. CFB was calculated as the post-BL value minus the BL value. Per 24 hours corresponds to one Diary Day (i.e., time between when participant got up for the day each morning and time participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: sex. Only participants with evaluable data were analyzed. |
| CFB at Week 52 in the Average Number of Urgency Episodes (Need to Urinate Immediately) Over 24 Hours in All OAB Participants | Baseline; Week 52 | The number of urgency episodes is defined as the number of times a participant had checked need to urinate immediately on a CDD divided by the number of CDDs in the PVD. CFB is calculated as the post-BL value minus the BL value. Over 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: OAB type (Wet versus Dry) and sex. |
| CFB at Week 52 in the Average Number of Total Urinary Incontinence Episodes Over 24 Hours in OAB Wet Participants | Baseline; Week 52 | The number of total incontinence episodes is defined as the number of times a participant had checked the accidental urine leakage box in the PVD, including for reasons of urge, stress, or other. CFB was calculated as the post-BL value minus the BL value. Over 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: sex. hr = hour. |
Countries
United States
Participant flow
Pre-assignment details
Of the 506 participants with overactive bladder (OAB) who completed 12 weeks in Study RVT-901-3003 (NCT03492281) and were screened and randomized for this extension study, 505 received at least 1 dose of double-blind study drug (Safety Set Extension \[SAF-Ext\]: vibegron, N = 273; tolterodine, N = 232).
Participants by arm
| Arm | Count |
|---|---|
| 40 Weeks Vibegron 75 mg Participants who had been randomized to the placebo group in Study RVT-901-3003 were randomized to receive blinded study treatment of vibegron 75 mg once daily for 40 weeks. Participants were stratified by Baseline Overactive Bladder Type (Wet versus Dry) and sex. | 92 |
| 52 Weeks Vibegron 75 mg Participants who had been randomized in Study RVT-901-3003 to receive vibegron 75 milligrams (mg) were to continue their same treatment once daily in a blinded fashion for 40 weeks. Thus, through participation in both Study RVT-901-3003 and this extension study, participants originally randomized to vibegron 75 mg were to receive 52 weeks total of vibegron. Participants were stratified by Baseline Overactive Bladder Type (Wet versus Dry) and sex. | 181 |
| 40 Weeks Tolterodine ER 4 mg Participants who had been randomized to the placebo group in Study RVT-901-3003 were randomized to receive blinded study treatment of tolterodine extended release (ER) 4 mg once daily for 40 weeks. Participants were stratified by Baseline Overactive Bladder Type (Wet versus Dry) and sex. | 91 |
| 52 Weeks Tolterodine ER 4 mg Participants who had been randomized in Study RVT-901-3003 to receive tolterodine ER 4 mg were to continue their same treatment once daily in a blinded fashion for 40 weeks. Thus, through participation in both Study RVT-901-3003 and this extension study, participants originally randomized to tolterodine ER 4 mg were to receive 52 weeks total of tolterodine ER. Participants were stratified by Baseline Overactive Bladder Type (Wet versus Dry) and sex. | 141 |
| Total | 505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 3 | 4 | 4 |
| Overall Study | Captured as Other in the Database | 1 | 2 | 4 | 1 |
| Overall Study | Death | 1 | 0 | 0 | 0 |
| Overall Study | Did Not Receive Study Drug | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 4 | 6 | 3 | 2 |
| Overall Study | Physician Decision | 0 | 1 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Subject Withdrawn due to Sponsor | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 11 | 7 | 8 |
Baseline characteristics
| Characteristic | 40 Weeks Vibegron 75 mg | 52 Weeks Vibegron 75 mg | 40 Weeks Tolterodine ER 4 mg | 52 Weeks Tolterodine ER 4 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 58.8 years STANDARD_DEVIATION 13.69 | 62.1 years STANDARD_DEVIATION 12.39 | 62.1 years STANDARD_DEVIATION 12.14 | 60.6 years STANDARD_DEVIATION 12.98 | 61.1 years STANDARD_DEVIATION 12.78 |
| Overactive Bladder (OAB) Type Dry | 21 Participants | 35 Participants | 21 Participants | 33 Participants | 110 Participants |
| Overactive Bladder (OAB) Type Wet | 71 Participants | 146 Participants | 70 Participants | 108 Participants | 395 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 16 Participants | 8 Participants | 11 Participants | 39 Participants |
| Race/Ethnicity, Customized Black or African American | 14 Participants | 23 Participants | 10 Participants | 26 Participants | 73 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 72 Participants | 141 Participants | 72 Participants | 102 Participants | 387 Participants |
| Sex: Female, Male Female | 73 Participants | 140 Participants | 70 Participants | 112 Participants | 395 Participants |
| Sex: Female, Male Male | 19 Participants | 41 Participants | 21 Participants | 29 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 273 | 0 / 232 |
| other Total, other adverse events | 65 / 273 | 56 / 232 |
| serious Total, serious adverse events | 9 / 273 | 10 / 232 |
Outcome results
Primary
Number of Participants With the Indicated Type of Treatment-emergent Adverse Event
Adverse events were collected in participants with overactive bladder (OAB) who previously completed treatment in Study RVT-901-3003. The treatment-emergent period was defined as the period of time from the first dose date of the active double-blind study treatment, whether in Study RVT-901-3003 or Study RVT-901-3004, through 28 days after the last dose of study treatment, or the date of initiation of another investigational agent or surgical intervention, whichever occurred first.
Time frame: up to 56 weeks
Population: Safety Extension Set (SAF-Ext) Population: all participants who received at least 1 dose of double-blind study treatment. Participants were included in the treatment group corresponding to the study treatment they actually received. Adverse event datasets for Study RVT-901-3003 and Study RVT-901-3004 were combined for the safety analyses.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TEAE | 59 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TE SAE | 1 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any Grade ≥ 3 study drug-related TEAE | 1 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE leading to discontinuation of study drug | 4 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any Grade ≥ 3 TEAE | 10 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE of clinical interest | 41 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any treatment-emergent (TE) SAE | 9 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TEAE of clinical interest | 14 participants |
| Overall Vibegron 75 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE | 171 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TEAE of clinical interest | 10 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE | 126 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TEAE | 46 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any Grade ≥ 3 TEAE | 8 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any Grade ≥ 3 study drug-related TEAE | 1 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any treatment-emergent (TE) SAE | 10 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any study drug-related TE SAE | 2 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE leading to discontinuation of study drug | 8 participants |
| Overall Tolterodine ER 4 mg | Number of Participants With the Indicated Type of Treatment-emergent Adverse Event | Any TEAE of clinical interest | 32 participants |
Secondary
CFB at Week 52 in the Average Number of Total Urinary Incontinence Episodes Over 24 Hours in OAB Wet Participants
The number of total incontinence episodes is defined as the number of times a participant had checked the accidental urine leakage box in the PVD, including for reasons of urge, stress, or other. CFB was calculated as the post-BL value minus the BL value. Over 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: sex. hr = hour.
Time frame: Baseline; Week 52
Population: FAS-Ext-I Population. Only participants with evaluable data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Overall Vibegron 75 mg | CFB at Week 52 in the Average Number of Total Urinary Incontinence Episodes Over 24 Hours in OAB Wet Participants | -2.5 Urinary incontinence episodes over 24 hr | Standard Error 0.17 |
| Overall Tolterodine ER 4 mg | CFB at Week 52 in the Average Number of Total Urinary Incontinence Episodes Over 24 Hours in OAB Wet Participants | -1.9 Urinary incontinence episodes over 24 hr | Standard Error 0.19 |
95% CI: [-2.8, -2.2]
95% CI: [-2.3, -1.6]
Secondary
CFB at Week 52 in the Average Number of Urgency Episodes (Need to Urinate Immediately) Over 24 Hours in All OAB Participants
The number of urgency episodes is defined as the number of times a participant had checked need to urinate immediately on a CDD divided by the number of CDDs in the PVD. CFB is calculated as the post-BL value minus the BL value. Over 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: OAB type (Wet versus Dry) and sex.
Time frame: Baseline; Week 52
Population: FAS-Ext Population. Only participants with evaluable data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Overall Vibegron 75 mg | CFB at Week 52 in the Average Number of Urgency Episodes (Need to Urinate Immediately) Over 24 Hours in All OAB Participants | -3.4 urgency episodes over 24 hours | Standard Error 0.34 |
| Overall Tolterodine ER 4 mg | CFB at Week 52 in the Average Number of Urgency Episodes (Need to Urinate Immediately) Over 24 Hours in All OAB Participants | -3.2 urgency episodes over 24 hours | Standard Error 0.37 |
95% CI: [-4, -2.7]
95% CI: [-4, -2.5]
Secondary
CFB at Week 52 in the Average Number of Urge Urinary Incontinence (UUI) Episodes Per 24 Hours in OAB Wet Participants
The number of UUI episodes is defined as the number of times a participant had checked urge as the main reason for the leakage in the PVD, regardless of whether more than one reason for leakage in addition to urge was checked. The average daily number of UUI episodes was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of UUI episodes that occurred on a CDD divided by the number of CDDs in the PVD. CFB was calculated as the post-BL value minus the BL value. Per 24 hours corresponds to one Diary Day (i.e., time between when participant got up for the day each morning and time participant got up for the day the next morning as recorded in the PVD). Covariates included in the MMRM were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: sex. Only participants with evaluable data were analyzed.
Time frame: Baseline; Week 52
Population: Full Analysis Set Extension for Incontinence (FAS-Ext-I) Population: all randomized OAB Wet participants who were included in the FAS-I population in Study RVT-901-3003, who took at least 1 dose of double-blind study treatment in this extension study and had at least 1 subsequent evaluable CFB UUI measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Overall Vibegron 75 mg | CFB at Week 52 in the Average Number of Urge Urinary Incontinence (UUI) Episodes Per 24 Hours in OAB Wet Participants | -2.2 UUI episodes per 24 hours | Standard Error 0.15 |
| Overall Tolterodine ER 4 mg | CFB at Week 52 in the Average Number of Urge Urinary Incontinence (UUI) Episodes Per 24 Hours in OAB Wet Participants | -1.7 UUI episodes per 24 hours | Standard Error 0.17 |
95% CI: [-2.5, -1.9]
95% CI: [-2, -1.3]
Secondary
Change From Baseline (CFB) at Week 52 in the Average Number of Micturitions Per 24 Hours in All Overactive Bladder (OAB) Participants
A micturition/void is defined as Urinated in Toilet as indicated on the Patient Voiding Diary (PVD). The number of micturitions is defined as the number of times a participant voided in the toilet as indicated in the PVD. The average daily number of micturitions was calculated using the daily entries in the PVD (which was to be completed prior to each study visit) as the total number of micturitions that occurred on a Complete Diary Day (CDD) divided by the number of CDDs in the PVD. CFB was calculated as the post-BL value minus the BL value. Per 24 hours corresponds to one Diary Day (i.e., time between when the participant got up for the day each morning and time the participant got up for the day the next morning as recorded in the PVD). Covariates included in the mixed model for repeated measures (MMRM) were study visit, treatment, treatment by study visit interaction, Baseline, and the statistically significant terms in Study RVT-901-3003: OAB type (Wet versus Dry) and sex.
Time frame: Baseline; Week 52
Population: Full Analysis Set Extension (FAS-Ext) Population: all randomized OAB participants who took at least 1 dose of double-blind study treatment during this extension study and had at least 1 subsequent evaluable CFB micturition measurement in this extension study. Only participants with evaluable data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Overall Vibegron 75 mg | Change From Baseline (CFB) at Week 52 in the Average Number of Micturitions Per 24 Hours in All Overactive Bladder (OAB) Participants | -2.4 micturitions per 24 hours | Standard Error 0.24 |
| Overall Tolterodine ER 4 mg | Change From Baseline (CFB) at Week 52 in the Average Number of Micturitions Per 24 Hours in All Overactive Bladder (OAB) Participants | -2.0 micturitions per 24 hours | Standard Error 0.26 |
95% CI: [-2.9, -2]
95% CI: [-2.5, -1.5]