A Study to Evaluate the Efficacy, Safety and Tolerability of Mirabegron and Solifenacin Succinate Alone and in Combination for the Treatment of Overactive Bladder

Study Overview
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Brief Summary
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The purpose of this study is to examine how well two medicines in combination (solifenacin succinate and mirabegron) work in the treatment of bladder problems over a 12-week period.

Official Title
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A Randomized, Double-Blind, Factorial, Parallel-Group, Active and Placebo-Controlled, Multicenter Dose-Ranging Study to Evaluate the Efficacy, Safety and Tolerability of Six Dose Combinations of Solifenacin Succinate and Mirabegron Compared to Mirabegron and Solifenacin Succinate Monotherapies in the Treatment of Overactive Bladder.

Conditions
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Urologic Diseases, Urinary Bladder Diseases, Urological Manifestations, Signs and Symptoms, Urinary Bladder, Overactive

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Solifenacin succinate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion Criteria at Visit 1/Screening: Subject has a Body Mass Index (BMI) of between 18 and 35 kg/m^2 and a total body weight between 50 and 95 kg; Subject is willing and able to complete the micturition diary and questionnaires correctly and is willing and able to measure his/her vital signs at home at stipulated time points, using the device provided by the study personnel, and to adequately record the readings; Subject has symptoms of overactive bladder (OAB; urinary frequency, urgency and/or urgency incontinence) for at least 3 months. Inclusion Criteria at Visit 3/Baseline: Subject has experienced frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period (incontinence episode should not be counted as a micturition); Subject must experience at least 1 episode of urgency (grade 3 or 4) per 24-hour period (with or without urgency incontinence) during the 3 day micturition diary period. Exclusion Criteria: Exclusion Criteria at Visit 1/Screening: Subject is breastfeeding, pregnant or intends to become pregnant during the study. The pregnancy test (Beta Human Chorionic Gonadotropin in serum) at Screening must be negative in women of childbearing potential; Female subjects of childbearing potential and not using a highly effective method of birth control during the study and for 30 days after final study drug administration. Male subjects (unless surgically sterile) with female spouses/partners who are of childbearing potential, and not using a barrier method of contraception during the study and for 30 days after final study drug administration. In addition, female spouses/partners of male subjects and who are of childbearing potential should also use a highly effective method of birth control during the study and for 30 days after final study drug administration. Highly effective methods of birth control are defined as those, alone or in combination, that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Subject has significant post-void residual (PVR) volume (> 150 mL); Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the Investigator (for female subjects confirmed by the cough provocation test); Subject has a neurological cause for detrusor overactivity; Subject has an indwelling catheter or practices intermittent self-catheterization; Subject has diabetic neuropathy; 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 had previous lower urinary tract or pelvic floor surgery (except cystoscopy); Subject has had intravesical treatment in the past 12 months with e.g., botulinum toxin, resiniferatoxin, capsaicin; Subject has uncontrolled narrow angle glaucoma, urinary or gastric retention, severe ulcerative colitis or Crohn's Disease, toxic megacolon, myasthenia gravis or any other condition which makes the use of anticholinergics contraindicated; Subject has clinically significant cardiovascular or cerebrovascular diseases within 6 months prior to Screening, such as myocardial infarction, uncontrolled angina, significant ventricular arrhythmias, heart failure and stroke; Subject is receiving current non-drug treatment including electro-stimulation therapy (with the exception of a bladder training program or pelvic floor exercises which started more than 30 days prior to Screening); Subject is using medications intended to treat OAB or prohibited medications. Subject has known or suspected hypersensitivity to solifenacin succinate, mirabegron or any of their excipients; Subject has any significant neurological disease or defect affecting bladder function (e.g., neurogenic bladder, systemic or central neurological disease such as multiple sclerosis [MS] and Parkinson's disease); Subject has severe hypertension which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or an average diastolic blood pressure ≥ 110 mmHg; Exclusion Criteria at Visit 2/Placebo Run-In: Subject has evidence of a urinary tract infection (UTI) (urine culture containing > 100,000 cfu/mL). The subject can be enrolled into the study after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). However, the subject must be re screened if the initial screening visit was > 28 days; Subject has a QT interval > 450 ms or is at risk of QT prolongation (e.g., family history of long QT syndrome, hypokalaemia) or is on drug treatment known to be associated with QT prolongation; Subject has clinically significant abnormalities on the 12 lead electrocardiogram (ECG); Subject has serum creatinine > 150 µmol/L, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2x upper limit of normal (ULN), gamma-glutamyltransferase (γ-GT) > 3x ULN, or total bilirubin > 2x ULN, as assessed in Screening samples; Exclusion Criteria at Visit 3/Baseline: Subject had an average total daily urine volume > 3000 mL as recorded in the micturition diary period; Subject has severe hypertension which is defined as a sitting average systolic blood pressure ≥ 180 mmHg and/or an average diastolic blood pressure ≥ 110 mmHg.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received matching placebo tablets orally once a day for 12 weeks | Drug: Placebo<br>* oral<br>|
| Active Comparator: Mirabegron 25 mg<br>Participants received mirabegron 25 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;|
| Active Comparator: Mirabegron 50 mg<br>Participants received mirabegron 50 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;|
| Active Comparator: Solifenacin 2.5 mg<br>Participants received solifenacin 2.5 mg tablets orally once a day for 12 weeks | Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Active Comparator: Solifenacin 5 mg<br>Participants received solifenacin 5 mg tablets orally once a day for 12 weeks | Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Active Comparator: Solifenacin 10 mg<br>Participants received solifenacin 10 mg tablets orally once a day for 12 weeks | Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 2.5 mg and Mirabegron 25 mg<br>Participants received solifenacin 2.5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 2.5 mg and Mirabegron 50 mg<br>Participants received solifenacin 2.5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 5 mg and Mirabegron 25 mg<br>Participants received solifenacin 5 mg and mirabegron 25 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 5 mg and Mirabegron 50 mg<br>Participants received solifenacin 5 mg and mirabegron 50 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 10 mg and Mirabegron 25 mg<br>Participants received solifenacin 10 mg and mirabegron 25 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|
| Experimental: Solifenacin 10 mg and Mirabegron 50 mg<br>Participants received solifenacin 10 mg and mirabegron 50 mg tablets orally once a day for 12 weeks | Drug: Mirabegron<br>* oral<br>* Other names: YM178;Drug: Solifenacin succinate<br>* oral<br>* Other names: Vesicare;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment (EOT) in Mean Volume Voided Per Micturition | The average volume voided per micturition was calculated from the volume of each micturition measured by the participant and recorded in a micturition diary for 3 days before the Baseline and Week 12 clinic visits. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to End of Treatment in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (urinations) per 24 hours was derived from the number of urinations (excluding incontinence only episodes) per day recorded by the participant in the micturition diary for 3-days before the Baseline and Week 12 clinic visits. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Mean Number of Incontinence Episodes Per 24 Hours | The average number of incontinence episodes (any involuntary leakage of urine) per day was derived from the number of incontinence episodes recorded by the participant in the micturition diary for 3-days before the Baseline and Week 12 clinic visits. | Baseline and Week 12 | 
| Change From Baseline to Each Visit in Mean Volume Voided Per Micturition | The average volume voided per micturition was calculated from the volume of each micturition measured by the participant and recorded in a micturition diary for 3 days before the Baseline and each post-baseline clinic visit. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (urinations) per 24 hours was derived from the number of urinations (excluding incontinence only episodes) per day recorded by the participant in the micturition diary for 3-days before the Baseline and each post-baseline clinic visit. | Baseline and Weeks 2, 4, 8 and 12 | 
| Percentage of Participants With a Micturition Response | A responder is defined as a participant with at most 8 micturitions per 24 hours post-baseline and a negative change (i.e. an improvement) from Baseline. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Incontinence Episodes Per 24 Hours | The average number of incontinence episodes (any involuntary leakage of urine) per day was derived from the number of incontinence episodes recorded by the participant in the micturition diary for 3-days before the Baseline and each post-baseline clinic visit. | Baseline and Weeks 2, 4, 8 and 12 | 
| Percentage of Participants With Zero Incontinence Episodes Post-baseline | The percentage of participants with no incontinence episodes for the 3 days prior to each clinic visit derived from the micturition diary recorded by the participant. | Weeks 2, 4, 8 and 12 | 
| Percentage of Participants With 50% Reduction in Incontinence Episodes | The percentage of participants with at least a 50% decrease from Baseline in mean number of incontinence episodes per 24 hours during the 3 days prior to each clinic visit derived from the participant's micturition diary. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours | Urgency incontinence is the involuntary leakage of urine accompanied by or immediately preceded by urgency, and was derived from the number of incontinence episodes classified by the participant in a 3-day micturition diary as Grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale: 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could postpone voiding a short while; 3 = Severe urgency, could not postpone voiding; 4 = Urge incontinence, leaked before arriving to the toilet. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours | The average number of urgency episodes (the sudden, compelling desire to pass urine, which is difficult to defer), derived from urgency episodes classified by the participant in the 3-day micturition diary as grade 3 or 4 on the Patient Perception of Intensity of Urgency Scale: 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Level of Urgency | Average of participants' ratings on the degree of urgency associated with each micturition and/or incontinence episode recorded in the 3-day micturition diary according to the Patient Perception of Intensity of Urgency Scale: 0: No urgency; 1: Mild urgency; 2: Moderate urgency, could delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Pads Used Per 24 Hours | The average number of times a participant recorded a new pad used per day during the 3-day micturition diary period. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to Each Visit in Mean Number of Nocturia Episodes Per 24-Hours | Nocturia is defined as waking at night one or more times to void. The average number of times a participant urinated (excluding incontinence only episodes) during sleeping time per day was derived from the 3-day micturition diary. | Baseline and Weeks 2, 4, 8 and 12 | 
| Change From Baseline to End of Treatment in Patient Perception of Bladder Condition (PPBC) | The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. A negative change from Baseline score indicates improvement. | Baseline and Week 12 | 
| Percentage of Participants With Improvement in PPBC | The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. Improvement was defined as at least a 1-point improvement (decrease) from Baseline in PPBC score. | Baseline and Week 12 | 
| Percentage of Participants With Major Improvement in PPBC | The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. Major improvement was defined as at least a 2-point improvement (decrease) from Baseline in PPBC score. | Baseline and Week 12 | 
| Percentage of Participants With Deterioration in PPBC | The PPBC scale is a global assessment tool that asks patients to rate their impression of their current bladder condition on a 6-point scale from 1: 'Does not cause me any problems at all'; 2: 'Causes me some very minor problems'; 3: 'Causes me some minor problems'; 4: 'Causes me (some) moderate problems'; 5: 'Causes me severe problems' and 6: 'Causes me many severe problems'. Deterioration was defined as at least a 1 point increase from Baseline in PPBC score. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Symptom Bother Score as Assessed by the Overactive Bladder Questionnaire (OAB-q) | Overactive bladder symptoms were assessed using the symptom bother scale of the overactive bladder questionnaire. The symptom bother scale consists of 8 questions answered by the participant on a scale from 1-6. The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 to 100, with 100 indicating worst severity. A negative change from Baseline in symptom bother score indicates improvements. | Baseline and Week 12 | 
| Percentage of Participants With a Symptom Bother Response | Overactive bladder symptoms were assessed using the symptom bother scale of the overactive bladder questionnaire. The symptom bother scale consists of 8 questions answered by the participant on a scale from 1-6. The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 to 100, with 100 indicating worst severity. Symptom bother response is defined as improvement (decrease) of at least 10 points from Baseline. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Health-related Quality of Life (HRQL) Total Score | Health-related quality of life was assessed by the HRQL subscales (coping, concern, sleep and social interaction) of the overactive bladder questionnaire (OABq). The HRQL total score was calculated by adding the 4 HRQL subscale scores, and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from Baseline in HRQL score indicates improvements. | Baseline and Week 12 | 
| Percentage of Participants With a Health-related Quality of Life Total Score Response | Health-related quality of life was assessed by the HRQL subscales (coping, concern, sleep and social interaction) of the overactive bladder questionnaire (OABq). The HRQL total score was calculated by adding the 4 HRQL subscale scores, and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. HRQL response is defined as improvement (decrease) of at least 10 points from Baseline. | Baseline and Week 12 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Mobility Score | The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state: I have no problems in walking about; I have some problems in walking about; I am confined to bed. In the table below, each row title lists Baseline health status first followed by End of Treatment health status and reports the number of patients in that category. | Baseline and Week 12 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Self-care Score | The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state: I have no problems with self-care; I have some problems washing or dressing myself; I am unable to wash or dress myself. In the table below, each row title lists Baseline health status first followed by End of Treatment health status and reports the number of patients in that category. | Baseline and Week 12 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Usual Activities Score | The EQ-5D is a standardized, nondisease-specific instrument for describing health status. Participants were asked which statement best describes their health state with regard to usual activities (work, study or leisure): I have no problems performing my usual activities; I have some problems performing my usual activities; I am unable to perform my usual activities. In the table below, each row title lists Baseline health status first followed by End of Treatment health status and reports the number of patients in that category. | Baseline and Week 12 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Pain/Discomfort Score | The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state: I have no pain or discomfort; I have moderate pain or discomfort; I have extreme pain or discomfort. In the table below, each row title lists Baseline health status first followed by End of Treatment health status and reports the number of participants in that category. | Baseline and Week 12 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) Anxiety/Depression Score | The EQ-5D is an international, standardized, nondisease-specific (i.e., generic) instrument for describing and valuing health status. Participants were asked to indicate which of the following statements best describes their health state: I am not anxious or depressed; I am moderately anxious or depressed; I am extremely anxious or depressed. In the table below, each row title lists Baseline health status first followed by End of Treatment health status and reports the number of patients in that category. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) | The EQ-5D is an international, standardized, generic instrument for describing and evaluating health status. Health status is assessed by patients evaluating their health on a vertical, visual analog scale from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). On the EQ-5D VAS, a positive change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Work Productivity and Activity Impairment (WPAI) | This 6-item assessment measures productivity losses during the past 7 days and includes measures on work time missed due to health, impairment while working due to health (the participant's assessment of the degree to which health affected their productivity while working), overall work impairment due to health (takes into account both hours missed due to health and the participant's assessment of the degree to which health affected their productivity while working) and activity impairment due to health (the degree in which health problems affected their ability to do regular daily activities). Scores for each measure are expressed from 0 to 100 with higher numbers indicating greater impairment and less productivity, i.e., worse outcomes. A negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to End of Treatment in Treatment Satisfaction on Visual Analog Scale (TS-VAS) | The TS-VAS is a visual analog scale (VAS) that asks patients to rate their satisfaction with treatment by placing a vertical mark on a 10 cm line where the endpoints are labeled 'No, not at all' on the left (=0) to 'Yes, completely satisfied' on the right (=10). A positive change from Baseline indicates improvement. | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Urinary incontinence, Overactive bladder (OAB), Micturition, Frequency, YM178, Urgency incontinence, Urgency