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

Study Overview
=================
Brief Summary
-----------------
The study is intended to test the safety, tolerability, efficacy of two doses of long term once daily (qd) treatment of Mirabegron in patients with symptoms of overactive bladder and secondly to compare these with active comparator.

Detailed Description
-----------------
Patients who completed 178-CL-046 (NCT00689104) or 178-CL-047 (NCT00662909) or new patients could be enrolled in this study if eligible.

Official Title
-----------------
A Randomized, Double-Blind, Parallel Group, Active Controlled, Multi-center Long-term Study to Assess the Safety and Efficacy of the Beta-3 Agonist Mirabegron (YM178) 50 mg qd and 100 mg qd in Subjects With Symptoms of Overactive Bladder

Conditions
-----------------
Urinary Bladder, Overactive

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is willing and able to complete the micturition diary and questionnaires correctly Patient has symptoms of overactive bladder for ≥ 3 months Patient experiences frequency of micturition on average ≥ 8 times per 24-hour period during the 3-day micturition diary period Patient 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: Patient 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 Patient has significant stress incontinence or mixed stress/urge incontinence where stress is the predominant factor Patient has an indwelling catheter or practices intermittent self-catheterization Patient has diabetic neuropathy Patient 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 Patient receives non-drug treatment including electro-stimulation therapy Patient has severe hypertension Patient 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 Patient has been treated with any investigational drug or device within 30 days (90 days in the UK for all clinical studies except 178-CL-046) Patient had an average total daily urine volume > 3000 mL as recorded in the 3-day micturition diary period Patient has serum creatinine >150 umol/L, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2x upper limit of normal range (ULN), or gamma-glutamyl transpeptidase (γ-GT) > 3x ULN Patient has a clinically significant abnormal electrocardiogram (ECG)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With and Severity of Treatment-emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a patient administered a study drug and which did not necessarily have a causal relationship with the treatment. The investigator assessed the severity of each AE, including abnormal laboratory values, as follows: Mild: No disruption of normal daily activities; Moderate: Affected normal daily activities; Severe: Inability to perform daily activities. | From the first dose of double-blind study drug up until 30 days after the last dose of study drug, up to 13 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Months 1, 3, 6, 9, 12 and 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 prior to clinic visits at Baseline and months 1, 3, 6, 9 and 12/end of treatment. Least squares (LS) means were generated from the analysis of covariance (ANCOVA) model with treatment group, previous study history, gender and geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 12 and 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 prior to clinic visits at Baseline and months 1, 3, 6, 9 and 12/end of treatment. Least squares (LS) means were generated from the analysis of covariance (ANCOVA) model with treatment group, previous study history, gender and geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 12 and 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 prior to clinic visits at Baseline and months 1, 3, 6, 9 and 12/end of treatment. LS means were generated from the ANCOVA model with treatment group, previous study history, gender and geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in Mean Number of Urgency Incontinence Episodes Per 24 Hours | The involuntary leakage of urine accompanied 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 time; 3=Severe urgency, could not postpone voiding; 4=Urge incontinence, leaked before arriving to toilet. LS means are from the ANCOVA model with treatment group, previous study history, gender and geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 12 and Final 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 that is difficult to defer) derived from 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 delay voiding a short time; 3=Severe urgency, could not delay voiding; 4=Urge incontinence, leaked before arriving to the toilet. LS means are from an ANCOVA model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 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 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 generated from an ANCOVA model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 12 and Final Visit in the 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 model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 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 model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Percentage of Participants With Zero Incontinence Episodes at Months 1, 3, 6, 9 and 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. | Months 1, 3, 6, 9 and 12 | 
| Percentage of Participants With ≥ 50% Reduction in Incontinence Episodes at Months 1, 3, 6, 9 and 12 and the Final Visit | 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 patient micturition diary. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 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 patient 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 model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 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 model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Month 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'. A negative change from Baseline score indicates improvement. LS means are from an ANCOVA model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Month 12 | 
| Change From Baseline to Month 12 and Final Visit in Treatment Satisfaction-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. LS means are from an ANCOVA model with treatment group, previous study history, gender & geographical regions as fixed factors and baseline as a covariate. | Baseline and Month 12 | 
| Change From Baseline to Months 3, 6, 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 Months 3, 6 and 12 | 
| Change From Baseline to Months 3, 6, 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 Months 3, 6 and 12 | 
| Change From Baseline to Months 3, 6, 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 Months 3, 6 and 12 | 
| Change From Baseline to Months 3, 6, 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 and less productivity. A negative change from baseline indicates improvement. | Baseline and Months 3, 6 and 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 evaluating 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 Month 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 evaluating 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 Month 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 Month 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 evaluating 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 Month 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 Month 12 | 
| Change From Baseline to Months 1, 3, 6, 9, 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 Months 1, 3, 6, 9 and 12 | 
| Change From Baseline to Months 3, 6, 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 Months 3, 6 and 12 | 
| Percentage of Participants With Improvement 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'. Improvement was defined as at least a one point improvement from Baseline to post-baseline and a major improvement was defined as at least a two point improvement from Baseline to post-baseline in PPBC score. | Baseline and Month 12 | 
| Safety as Assessed by Adverse Events (AEs), Vital Signs, Laboratory Tests, Physical Examination and Electrocardiogram | An abnormality identified during a medical test was defined as an AE if the abnormality induced clinical signs or symptoms, required active intervention, interruption or discontinuation of study drug or was clinically significant. The Investigator assessed each AE for causal relationship (not related, possible or probable) to study drug. A serious AE (SAE) was any untoward medical occurrence that: resulted in death, was life-threatening, resulted in significant disability/incapacity or congenital anomaly/birth defect, required or prolonged hospitalization or was a medically important event. The data reported represent the number of participants with adverse events in each category. | From the first dose of double-blind study drug up until 30 days after the last dose of study drug, up to 13 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Frequency, Overactive Bladder, Urgency, Urinary urge incontinence, Urinary incontinence, Micturition