Study to Assess the Efficacy and Safety of the Beta-3 Agonist Mirabegron (YM178) in Patients With Symptoms of Overactive Bladder

Study Overview
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Brief Summary
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The study is intended to test efficacy, safety and tolerability of two doses of Mirabegron against placebo and compare the efficacy and safety with active comparator in patients with symptoms of overactive bladder.

Official Title
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A Randomized, Double-Blind, Parallel Group, Placebo and Active Controlled, Multicenter Study to Assess the Efficacy and Safety of Mirabegron in Subjects With Symptoms of Overactive Bladder

Conditions
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Urinary Bladder, Overactive

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Tolterodine
* Drug: Placebo to Mirabegron
* Drug: Placebo to Tolterodine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is willing and able to complete the micturition diary and questionnaires correctly Subject has symptoms of overactive bladder (urinary frequency and urgency with or without urge incontinence) for ≥ 3 months Subject experiences frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period Subject must experience at least 3 episodes of urgency (grade 3 or 4) with or without incontinence, during the 3-day micturition diary period Exclusion Criteria: Subject is breastfeeding, pregnant, intends to become pregnant during the study, or of childbearing potential, sexually active and not practicing a highly reliable method of birth control Subject has significant stress incontinence or mixed stress/urge incontinence where stress is the predominant factor Subject has an indwelling catheter or practices intermittent self-catheterization Subject has diabetic neuropathy Subject has evidence of a symptomatic urinary tract infection, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs Subject receives non-drug treatment including electro-stimulation therapy Subject has severe hypertension Subject has a known or suspected hypersensitivity to tolterodine, other anticholinergics, YM178, other beta-adrenoreceptor (ß-AR) agonists, or lactose or any of the other inactive ingredients Subject has been treated with any investigational drug or device within 30 days (90 days in the UK) Subject had an average total daily urine volume > 3000 mL as recorded in the 3-day micturition diary period Subject has serum creatinine >150 umol/L, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2x upper limit of normal range (ULN), or gamma glutamyl transferase (γ-GT) > 3x ULN Subject has a clinically significant abnormal electrocardiogram (ECG)

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received matching mirabegron placebo tablets and matching tolterodine slow release (SR) placebo capsules orally once a day for 12 weeks. | Drug: Placebo to Mirabegron<br>* Matching mirabegron placebo tablets.<br>Drug: Placebo to Tolterodine<br>* Matching tolterodine placebo capsules.<br>|
| Experimental: Mirabegron 50 mg<br>Participants received mirabegron 50 mg tablets and matching tolterodine SR placebo capsules orally once a day for 12 weeks. | Drug: Mirabegron<br>* Tablets<br>* Other names: YM178;Drug: Placebo to Tolterodine<br>* Matching tolterodine placebo capsules.<br>|
| Experimental: Mirabegron 100 mg<br>Participants received mirabegron 100 mg tablets and matching tolterodine SR placebo capsules orally once a day for 12 weeks. | Drug: Mirabegron<br>* Tablets<br>* Other names: YM178;Drug: Placebo to Tolterodine<br>* Matching tolterodine placebo capsules.<br>|
| Active Comparator: Tolterodine SR 4 mg<br>Participants received tolterodine SR 4 mg capsules and matching mirabegron placebo tablets orally once a day for 12 weeks. | Drug: Tolterodine<br>* Capsules<br>Drug: Placebo to Mirabegron<br>* Matching mirabegron placebo tablets.<br>|

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 (Final 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 patient in a micturition diary for 3-days before the Baseline and Week 12 clinic visits. Least Squares (LS) Means were generated from an analysis of covariance (ANCOVA) model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Week 12 (final visit) | 
| Change From Baseline to End of Treatment (Final Visit) in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (urinations) per 24 hours was derived from the number of times a patient urinates (excluding incontinence only episodes) per day recorded by the patient in a micturition diary for 3-days before the Baseline and Week 12 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Final Visit in Mean Volume Voided Per Micturition | The average volume voided per micturition was calculated from the volume of each micturition measured by the patient and recorded in a micturition diary for 3 days before the Baseline and Week 12 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Week 12 | 
| Change From Baseline to Week 4 in Mean Number of Incontinence Episodes Per 24 Hours | The average number of incontinence episodes (any involuntary leakage of urine) per 24 hours was derived from the number of incontinence episodes recorded by the patient in a micturition diary for 3-days before the Baseline and Week 4 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Week 4 | 
| Change From Baseline to Week 4 in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (urinations) per 24 hours was calculated from the number of micturitions recorded by the patient in a micturition diary for 3-days before the Baseline and Week 4 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Week 4 | 
| Change From Baseline to Week 8 and Week 12 in Mean Number of Incontinence Episodes Per 24 Hours | The average number of incontinence episodes (any involuntary leakage of urine) per 24 hours was derived from the number of incontinence episodes recorded by the patient in a micturition diary for 3-days before the Baseline, Week 8 and Week 12 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 8 and 12 | 
| Change From Baseline to Week 8 and Week 12 in Mean Number of Micturitions Per 24 Hours | The average number of micturitions (urinations) per 24 hours was calculated from the number of micturitions recorded by the patient in a micturition diary for 3-days before the Baseline, Week 8 and 12 clinic visits. LS Means were generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 8 and 12 | 
| Change From Baseline to Week 4, Week 8 and Week 12 in Mean Volume Voided Per Micturition | The average volume voided per micturition was calculated from the volume of each micturition measured by the patient and recorded in a micturition diary for 3 days before the Baseline and Week 4, 8 and 12 clinic visits. LS Means generated from an ANCOVA model with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours | The involuntary leakage of urine accompanied by or immediately proceeded by urgency, derived from the number of incontinence episodes classified by the patient in a 3-day micturition diary as 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. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Urgency Episodes (Grades 3 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 patient 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 delay voiding a short while; 3: Severe urgency, could not delay voiding; 4: Urge incontinence, leaked before arriving to the toilet. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Level of Urgency | Average of patients' ratings on the degree of urgency associated with each micturition and/or incontinence episode recorded in a 3-day micturition diary according to the following 5-point categorical scale (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. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final 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 patient urinated (excluding incontinence only episodes) during sleeping time per day was derived from the 3-day patient micturition diary. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Mean Number of Pads Used Per 24 Hours | The average number of times a patient records a new pad used per day during the 3-day micturition diary period. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Percentage of Participants With Zero Incontinence Episodes at Week 4, Week 8, Week 12 and the Final Visit | 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 patient. | Weeks 4, 8 and 12 | 
| Percentage of Participants With ≥ 50% Reduction in Incontinence Episodes at Weeks 4, 8, 12 and the Final Visit | The percentage of participants with at least 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 patient micturition diary. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Symptom Bother Score | 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. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit 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. LS Means are from an ANCOVA with treatment group, gender, and geographic region as fixed factors and baseline as a covariate. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Work Time Missed | The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent of work time missed is derived from the number of hours of work missed due to OAB symptoms as a percentage of total hours that should have been worked. A higher percentage indicates more hours missed. A negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Impairment While Working | The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent impairment while working was derived from the patient's assessment of the degree to which OAB affected their productivity while working. A higher percentage indicates greater impairment and less productivity. A negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Overall Work Impairment | The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with work productivity in the last 7 days. Percent overall work impairment takes into account both hours missed due to OAB symptoms and the patient's assessment of the degree to which OAB affected their productivity while working. A higher percentage indicates greater impairment and less productivity. A negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Week 12 and Final Visit in Work Productivity and Activity Impairment (WPAI): Percent Activity Impairment | The Work Productivity and Activity Impairment: Specific Health Problem (WPAI:SHP) questionnaire was used to assess the degree and extent to which overactive bladder (OAB) symptoms interfered with daily activities over the last 7 days. Percent activity impairment is derived from the patient's assessment of the degree to which OAB affected their regular daily activities. A higher percentage indicates greater impairment. A negative change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Final Visit 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 Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit. | Baseline and Week 12 | 
| Change From Baseline to Final Visit 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 Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit. | Baseline and Week 12 | 
| Change From Baseline to Final Visit 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 Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available at that Visit. | Baseline and Week 12 | 
| Change From Baseline to Final Visit 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 Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit. | Baseline and Week 12 | 
| Change From Baseline to Final Visit 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 Final Visit health status and reports the number of patients in that category. Missing data indicates patients with no data available for that Visit. | Baseline and Week 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in the 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 Weeks 4, 8 and 12 | 
| Change From Baseline to Week 12 and Final Visit 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'. LS means are from an ANCOVA model with treatment group, gender, and geographical regions as fixed factors and baseline as a covariate. A negative change from Baseline score indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Week 12 and Final Visit 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). LS means are from an ANCOVA model with treatment group, gender, and geographical regions as fixed factors and baseline as a covariate. A positive change from baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and Final Visit in Number of Non-study Related Visits to Physician | The number of times the patient visited a physician's office during the 4 weeks prior to each study visit (excluding study visits) because of the patient's bladder condition. | Baseline and Weeks 4, 8 and 12 | 
| Percentage of Participants With Improvement in Patient Perception of Bladder Condition (PPBC) at Week 12 and Final Visit | 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 from Baseline to post-baseline and a major improvement was defined as at least a 2 point improvement from Baseline to post-baseline in PPBC score. | Baseline and Week 12 | 

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