A Randomized, Double-Blind, Multi-Centre Study to Evaluate the Efficacy and Safety of Adding Mirabegron to Solifenacin in Incontinent OAB Subjects Who Have Received Solifenacin for 4 Weeks and Warrant Additional Relief for Their OAB Symptoms
Overview
- Phase
- Phase 3
- Intervention
- mirabegron 25 mg
- Conditions
- Urinary Bladder Diseases
- Sponsor
- Astellas Pharma Europe Ltd.
- Enrollment
- 2174
- Locations
- 217
- Primary Endpoint
- Change From Baseline to End of Treatment (EoT) in Mean Number of Incontinence Episodes Per 24 Hours
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
The purpose of this study was to see if adding a new type of medication recently approved to treat overactive bladder (mirabegron) to an antimuscarinic treatment (solifenacin) would be more effective in controlling incontinence than when using the antimuscarinic treatment alone.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Main Inclusion at Screening:
- •Subject has symptoms of OAB (urinary frequency and urgency with urgency incontinence) for \>= 3 months prior to the screening visit
- •Subject is willing and able to complete the micturition diary and questionnaires correctly, including collection and measurement of urine output for 3 days prior to each visit;
- •Subject has symptoms of "wet" OAB (urinary frequency and urgency with incontinence or mixed incontinence with predominant urgency incontinence), and reports an average of at least 2 incontinence episodes per day.
- •Main Inclusion at Run-in (Visit 2):
- •Subject experiences on average at least 1 episode of urgency (grade 3 or 4) with or without incontinence per 24-hour period during the 3-day micturition diary period.
- •Subject experiences on average at least 2 incontinence episodes per 24-hour period during the 3-day micturition diary period.
- •Subject experiences on average at least 8 micturitions (excluding incontinence episodes) per 24-hour period during the 3-day micturition diary period.
- •Main Inclusion at Randomization (Visit 3):
- •Subject experiences at least 1 incontinence episode during the 3-day micturition diary period and wishes to increase their treatment for OAB symptoms.
Exclusion Criteria
- •Main Exclusion at Screening:
- •Subject in the opinion of the investigator has clinically significant Bladder Outlet Obstruction (BOO).
- •Subject has significant Post-void residual (PVR) volume (PVR \> 150 ml).
- •Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the investigator
- •Subject has an indwelling catheter or practices intermittent self catheterization.
- •Subject has evidence of a UTI.
- •Subject has chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs
- •Subject has moderate to severe hepatic impairment
- •Subject has severe renal impairment or End Stage Renal disease
- •Subject has a clinically significant abnormal Electrocardiogram (ECG)
Arms & Interventions
Combination (solifenacin + mirabegron)
Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: mirabegron 25 mg
Combination (solifenacin + mirabegron)
Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: mirabegron 50 mg
Combination (solifenacin + mirabegron)
Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: solifenacin 5 mg
Combination (solifenacin + mirabegron)
Participants received solifenacin 5 mg, mirabegron 25 mg and solifenacin 10 mg matching placebo once daily for the first 4 weeks of double-blind period. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron tablet was replaced by a 50 mg mirabegron tablet. Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: solifenacin 10 mg matching placebo
Solifenacin 5 mg
Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period
Intervention: solifenacin 5 mg
Solifenacin 5 mg
Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period
Intervention: mirabegron 25 mg matching placebo
Solifenacin 5 mg
Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period
Intervention: mirabegron 50 mg matching placebo
Solifenacin 5 mg
Participants received solifenacin 5 mg, mirabegron 25 mg matching placebo and solifenacin 10 mg matching placebo once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period
Intervention: solifenacin 10 mg matching placebo
Solifenacin 10 mg
Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: solifenacin 10 mg
Solifenacin 10 mg
Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: mirabegron 25 mg matching placebo
Solifenacin 10 mg
Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: mirabegron 50 mg matching placebo
Solifenacin 10 mg
Participants received solifenacin 5 mg matching placebo, mirabegron 25 mg matching placebo and solifenacin 10 mg once daily. For the last 8 weeks of the double-blind treatment period, the 25 mg mirabegron matching placebo tablet was replaced by a 50 mg mirabegron matching placebo tablet (to maintain the blind). Placebo was given for the 2 week single-blind safety follow-up period.
Intervention: solifenacin 5 mg matching placebo
Outcomes
Primary Outcomes
Change From Baseline to End of Treatment (EoT) in Mean Number of Incontinence Episodes Per 24 Hours
Time Frame: Baseline and end of treatment (up to 12 weeks)
The mean number of incontinence episodes (complaint of any involuntary leakage of urine) per day was derived from number of incontinence episodes recorded on valid diary days during the 3-day micturition diary period divided by the number of valid diary days during the 3-day micturition diary period. The analysis population consisted of the Full Analysis Set (FAS) which comprised of all the Randomized Analysis Set's (RAS) participants who met the following criteria: took at least 1 dose of double-blind study drug after randomization, reported at least 1 micturition in the baseline diary \& at least 1 micturition postbaseline \& reported at least 1 incontinence episode in the baseline diary. For participants who withdrew before EoT (week 12) and have no measurement available for that diary period, the Last Observation Carried Forward (LOCF) value during the double-blind study period was used as EoT value to derive the primary variable.
Secondary Outcomes
- Change From Baseline in Mean Number of Pads Per 24 Hours(Baseline and weeks 4, 8 & 12)
- Number of Pads Used During the 3-Day Diary(Weeks 4, 8 and 12)
- Change From Baseline in Mean Number of Nocturia Episodes(Baseline and weeks 4, 8 & 12)
- Number of Nocturia Episodes Reported Over 3-Day Diary(Weeks 4, 8 and 12)
- Number of Participants With Change From Baseline to EoT in Euroqol European Quality of Life-5 Dimensions (EQ-5D) Subscale Score: Mobility(Baseline and EoT (up to 12 weeks))
- Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Self-care(Baseline and EoT (up to 12 weeks))
- Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Usual Activities(Baseline and EoT (up to 12 weeks))
- Change From Baseline in Overactive Bladder Symptom (OAB-q) Symptom Bother Score(Baseline and weeks 4, 8 & 12)
- Change From Baseline in OAB-q HRQL Subscale Score: Concern(Baseline and weeks 4, 8 & 12)
- Change From Baseline in Mean Number of Micturitions Per 24 Hours(Baseline and weeks 4, 8 & 12)
- Change From Baseline to Weeks 4, 8 & 12 in Mean Number of Incontinence Episodes Per 24 Hours(Baseline and weeks 4, 8 & 12)
- Number of Incontinence Episodes Reported During the 3-Day Diary(Weeks 4, 8 and 12)
- Change From Baseline in Mean Volume Voided (MVV) Per Micturition(Baseline and weeks 4, 8 & 12)
- Change From Baseline to EoT in Corrected Micturition Frequency (CMF)(Baseline and EoT (up to 12 weeks))
- Change From Baseline in Mean Number of Urgency Incontinence (UI) Episodes Per 24 Hours(Baseline and weeks 4, 8 & 12)
- Number of UI Episodes Reported During the 3-Day Diary(Weeks 4, 8 and 12)
- Change From Baseline in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours(Baseline and weeks 4, 8 & 12)
- Percentage of Participants With Zero Incontinence Episodes Postbaseline(Weeks 4, 8 and 12)
- Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Pain/Discomfort(Baseline and EoT (up to 12 weeks))
- Number of Participants With Change From Baseline to EoT in EQ-5D Subscale Score: Anxiety/Depression(Baseline and EoT (up to 12 weeks))
- Change From Baseline in OAB-q Health-Related Quality of Life (HRQL) Total Score(Baseline and weeks 4, 8 & 12)
- Change From Baseline in OAB-q HRQL Subscale Score: Coping(Baseline and weeks 4, 8 & 12)
- Change From Baseline in Treatment Satisfaction - Visual Analogue Scale (TS-VAS) Score(Baseline and weeks 4, 8 & 12)
- Change From Baseline in OAB-q HRQL Subscale Score: Sleep(Baseline and weeks 4, 8 & 12)
- Percentage of Participants With at Least a 10-Point Improvement From Baseline in OAB-q Symptom Bother Score(Weeks 4, 8 and 12)
- Percentage of Participants With at Least a 1-Point Improvement From Baseline in PPBC(Weeks 4, 8 and 12)
- Percentage of Participants With Major (at Least 2-Point) Improvement From Baseline in PPBC(Weeks 4, 8 and 12)
- Number of Participants With Adverse Events (AEs)(From first dose of double blind treatment until 30 days after last dose (up to 16 weeks))
- Change From Baseline in Post Void Residual (PVR) Volume(Baseline and weeks 4, 8 & 12)
- Change From Baseline in OAB-q HRQL Subscale Score: Social Interaction(Baseline and weeks 4, 8 & 12)
- Percentage of Participants With at Least a 50% Decrease From Baseline in Mean Number of Incontinence Episodes Per 24 Hours(Weeks 4, 8 and 12)
- Change From Baseline in Patient Perception Bladder Control (PPBC) Score(Baseline and weeks 4, 8 & 12)
- Number of Participants in Each Category of Patient and Clinician Global Impression of Change Scales (PGIC and CGIC)(End of treatment (up to 12 weeks))
- Percentage of Participants With a Mean of at Least 8 Micturitions Per 24 Hours at Baseline and Less Than 8 Micturitions Per 24 Hours Postbaseline(Weeks 4, 8 and 12)
- Percentage of Participants With at Least a 10-Point Improvement From Baseline in HRQL Total Score(Weeks 4, 8 and 12)