A Phase 4 Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Male Subjects With Overactive Bladder (OAB) Symptoms, While Taking the Alpha Blocker for Benign Prostatic Hypertrophy (BPH)

Study Overview
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Brief Summary
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The primary objective of the study was to investigate the efficacy of mirabegron versus placebo in male patients with OAB symptoms while taking the alpha blocker, tamsulosin, for BPH.

Official Title
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A Phase 4, Double-blind, Randomized, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Mirabegron in Japanese and Korean Male Patients With Overactive Bladder Under Treatment With the α-Blocker Tamsulosin for Benign Prostatic Hyperplasia

Conditions
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Overactive Bladder

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Placebo
* Drug: Tamsulosin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: at Visit 1 (Screening): Patient had been under treatment with tamsulosin 0.2mg for at least 4 weeks before the start of the Screening period. Patient with a history of an average of at least 2 episodes of urgency per 24 hours and an average of 8 or more micturitions per 24 hours during the last 3 days before the start of the Screening period (verified by interview). Patient who had no wish to have children in the future (Unique to Japan). Male subjects and their female spouses/partners who were of childbearing potential must be using highly effective contraception consisting of two forms of birth control (at least one of which must be a barrier method), starting at Screening, continuing throughout the study period, and for 28 days after the final study drug administration. Subject must not donate sperm, starting at Screening, continuing throughout the study period, and for 28 days after the final study drug administration. Patient was willing and able to complete the micturition diary and questionnaires correctly. Subject agreed not to participate in another interventional study while receiving treatment in this study. at Visit 2 (Baseline): Subject with an average of at least 2 episodes of urgency per 24 hours and an average of 8 or more micturitions per 24 hours based on a 3-day micturition diary from the Screening period. Exclusion Criteria: at Visit 1 (Screening): Patient with suspected symptoms of OAB, with onset only transient (e.g., drug-induced, psychogenic). Patient with PVR urine volume >100 mL or Q max <5 mL/sec. Patient with prostate-specific antigen (PSA) ≥4 ng/mL. Patient with neurogenic bladder (e.g., spinal-cord lesions or other damage that will clearly affect urination; multiple sclerosis; Parkinson's disease) or a history of surgery that caused damage to the pelvic plexus. Patient with urethral stricture or bladder-neck stenosis. Patient with diabetic neuropathy complications. Patient who had undergone a surgical procedure, previous pelvic radiation therapy, or hyperthermia therapy that may affect urinary tract function. Patient with significant stress incontinence or postsurgical prostate incontinence, as determined by the Investigator. Patient with an indwelling catheter or practices intermittent self-catheterization. Patient with 3 or more episodes of recurrent urinary tract infection (UTI) within the last 6 months. Patient with a UTI; prostatitis; chronic inflammation, such as interstitial cystitis; urinary calculus; or previous or current malignant disease of the pelvic organs. Patient with a concurrent malignancy or history of any malignancy (within the past 5 years), except for non-metastatic basal-cell or squamous-cell carcinoma of the skin that had been treated successfully. Patient with serious heart disease, liver disease, kidney disease, immunological disease, lung disease. Patient who had received intravesical injection within the last 12 months with botulinum toxin, resiniferatoxin, or capsaicin. Patient who had received electrostimulation therapy for OAB. Patient who had received a bladder training program or pelvic floor exercises <28 days prior to the start of the Screening period. Patient with postural hypotension or syncope, hypokalemia, or closed-angle glaucoma. Patient with evidence of QT prolongation on electrocardiogram (ECG), defined as QTcF >450 msec. Patient with severe uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) >180 mmHg and/or diastolic blood pressure (DBP) >110 mmHg. Patient with a clinically significant ECG abnormality, as determined by the Investigator. Patient who had severe renal impairment, defined as an estimated glomerular filtration rate of <29 mL/min/1.73m2; end-stage renal disease; or is undergoing dialysis. Patient with aspartate transaminase (AST) or alanine transaminase (ALT) >2 times the upper limit of normal (ULN), or gamma-glutamyl transferase (γ-GT) >3 times the ULN and considered clinically significant by the Investigator. Patient with moderate or severe hepatic impairment, defined as Child-Pugh Class B or C. Patient with hypersensitivity to any of the components of mirabegron, other beta-adrenergic receptor (β-AR) agonists, or any of the inactive ingredients. Patient with ongoing alcohol and/or drug abuse. Patient with or a history of mood disorder, neurotic disorder, or schizophrenia. Patient with dementia, cognitive dysfunction, or clinically significant cerebrovascular disorder. Patient who had been treated with an experimental device <84 days or received an investigational agent <84 days prior to the start of the Screening period. Patient had used any prohibited concomitant medication <28 days (but, <1 year for 5α-reductase inhibitors) before the start of the Screening period. Patient with any clinically significant condition, which in the opinion of the Investigator, made the subject unsuitable for study participation. Patient who was involved in the conduct of the study as an employee of the Astellas group, a third party associated with the study, or the study site team. at Visit 2 (Baseline): Subject fulfills any exclusion criteria of Visit 1 at Visit 2. Subject was noncompliant during the 4 week tamsulosin Screening period, defined as taking less than 80% or greater than 120% of prescribed dose of study medication. Subject had an average total daily urine volume >3000 mL, as recorded in the 3-day micturition diary.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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Male

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 |
| --- | --- |
| Experimental: Mirabegron 50 mg<br>Participants who received mirabegron 50 mg once a day along with tamsulosin 0.2 mg for 12 weeks | Drug: Mirabegron<br>* Oral tablet<br>* Other names: YM178;Drug: Tamsulosin<br>* Oral tablet<br>|
| Experimental: Placebo<br>Participants who received matching placebo once a day along with tamsulosin 0.2 mg for 12 weeks. | Drug: Placebo<br>* Oral tablet<br>Drug: Tamsulosin<br>* Oral tablet<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 (EoT) in Mean Number of Micturitions Per 24 Hours | A micturition was defined as any voluntary micturition (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to Weeks 4, 8, 12 in Mean Number of Micturitions Per 24 Hours | A micturition was defined as any voluntary micturition (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and week 4, 8 and 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to EoT in Mean Number of Urgency Episodes Per 24 Hours | An urgency episode was defined as a complaint of a sudden, compelling desire to pass urine, which is difficult to defer. The mean number of urgency episodes per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Mean Number of Urgency Incontinence Episodes Per 24 Hours | An urgency incontinence episode was defined as any episode when both urgency and incontinence occurred concurrently. The mean number of urgency incontinence episodes per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Mean Number of Incontinence Episodes Per 24 Hours | An incontinence episode was defined as the complaint of any involuntary leakage of urine. The mean number of incontinence episodes per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Mean Number of Nocturia Episodes | A nocturia episode was defined as a micturition episode initiated between night time. Night time was defined as the period between sleep onset time and the wake-up time the following day (micturitions at the same time as the wake-up time were excluded). The mean number of nocturia episodes per 24 hours was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Mean Volume Voided Per Micturition | The mean volume voided per micturition was calculated from data recorded by participants on a 3-day micturition diary before each visit. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Total Overactive Bladder Symptom Score (OABSS) | The OABSS is a 4-item questionnaire that assesses urinary frequency. Total score was the sum total of the score of each item (ranges: 0-15). Negative change means improvement. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in OABSS Subscale Scores | Each OABSS subscale score was based on each question in the questionnaire: Daytime Frequency (How many times do you typically urinate from waking in the morning until sleeping at night? where scores range from 0-2), Nighttime Frequency (How many times do you typically wake up to urinate from sleeping at night until waking in the morning? where scores range from 0-3), Urgency (How often do you have a sudden desire to urinate, which is difficult to defer? where scores range from 0-5), Urgency Incontinence (How often do you leak urine because you cannot defer the sudden desire to urinate? where scores range from 0-5). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Total International Prostate Symptom Score (IPSS) | The IPSS included an 7-item questionnaire that assesses urinary frequency and incomplete voiding along with a QoL assessment. Total IPSS score was the sum total of the score (range: 0-35) of each item (Questions 1-7). Negative change means improvement. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in IPSS Subscale Scores | IPSS subscale scores was calculated by following each formula. Storage subscale was derived as sum of scores for questions 2, 4, and 7 (range: 1-15). Voiding subscale-1 was derived as sum of scores for questions 3, 5, and 6 (range: 1-15). Voiding subscale-2 was derived as sum of voiding subscale-1 and the score for question 1 (range: 1-20). Individual scores and IPSS Quality of Life (QoL) score was the score of each item (range: 1-6) (Questions 1-7 and QoL item). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Symptom Bother as Assessed by the Overactive Bladder Questionnaire (OAB-q) | The OAB-q was a 33-item questionnaire, which consisted of an 8-item symptom bother scale and 25 health-related QoL items that form 4 subscales (coping, concern, sleep, and social interaction) and a total health-related QoL score. Symptom Bother was derived as sum of scores for questions 1-8 (range: 0-100). Higher Symptom Bother is indicative of greater symptom bother. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Total Health-Related QoL (HRQoL) Scores as Assessed by the OAB-q | The OAB-q was a 33-item questionnaire, which consisted of an 8-item symptom bother scale and 25 health-related QoL items that form 4 subscales (coping, concern, sleep, and social interaction) and a total health-related QoL score. Total HRQL score was derived as sum of HRQL subscale scores (range: 25-150). Higher total HRQL score is indicative of better HRQL. | Baseline and EoT (up to 12 weeks) | 
| Number of Participants With Adverse Events | Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) with onset during the double-blind treatment period or an AE with onset during the screening period with worsening severity during the double-blind treatment period. The investigator assessed the severity of AEs as follows: Mild: No disruption of normal daily activities; Moderate: Affected normal daily activities; Severe: Inability to perform daily activities. A drug-related TEAE was a TEAE with at least a possible relationship to the study drug as assessed by the investigator. Serious TEAE was an AE considered serious. | From first dose of study drug up to Week 12 | 
| Change From Baseline to EoT in Postvoid Residual (PVR) Volume | PVR was measured by ultrasonography. | Baseline and EoT (up to 12 weeks) | 
| Change From Baseline to EoT in Maximum Urine Flow Rate (Qmax) | Urine flow rate was volume voided per micturition (voided volume) divided by time for the micturition (flow time). | Baseline and EoT (up to 12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tamsulosin, Overactive bladder, Benign prostatic hypertrophy, Mirabegron