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)

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

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.

Study Overview

• Status: Completed
• Conditions: Overactive Bladder
• Intervention / Treatment: Drug: Placebo; Drug: Mirabegron; Drug: Tamsulosin

• Study Type: Interventional
• Enrollment (Actual): 568
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Aichi, Japan
    • Site JP81046
  • Chiba, Japan
    • Site JP81009
  • Chiba, Japan
    • Site JP81045
  • Fukuoka, Japan
    • Site JP81041
  • Fukuoka, Japan
    • Site JP81042
  • Fukuoka, Japan
    • Site JP81043
  • Fukuoka, Japan
    • Site JP81044
  • Fukuoka, Japan
    • Site JP81048
  • Gunma, Japan
    • Site JP81004
  • Gunma, Japan
    • Site JP81005
  • Hokkaido, Japan
    • Site JP81001
  • Hokkaido, Japan
    • Site JP81002
  • Hokkaido, Japan
    • Site JP81003
  • Hyogo, Japan
    • Site JP81038
  • Hyogo, Japan
    • Site JP81039
  • Hyogo, Japan
    • Site JP81040
  • Kanagawa, Japan
    • Site JP81024
  • Kanagawa, Japan
    • Site JP81056
  • Kochi, Japan
    • Site JP81051
  • Kochi, Japan
    • Site JP81052
  • Kumamoto, Japan
    • Site JP81047
  • Osaka, Japan
    • Site JP81030
  • Osaka, Japan
    • Site JP81036
  • Osaka, Japan
    • Site JP81025
  • Osaka, Japan
    • Site JP81026
  • Osaka, Japan
    • Site JP81027
  • Osaka, Japan
    • Site JP81028
  • Osaka, Japan
    • Site JP81029
  • Osaka, Japan
    • Site JP81031
  • Osaka, Japan
    • Site JP81032
  • Osaka, Japan
    • Site JP81033
  • Osaka, Japan
    • Site JP81034
  • Osaka, Japan
    • Site JP81035
  • Osaka, Japan
    • Site JP81037
  • Osaka, Japan
    • Site JP81053
  • Osaka, Japan
    • Site JP81054
  • Saitama, Japan
    • Site JP81006
  • Saitama, Japan
    • Site JP81007
  • Saitama, Japan
    • Site JP81008
  • Shizuoka, Japan
    • Site JP81050
  • Tokyo, Japan
    • Site JP81010
  • Tokyo, Japan
    • Site JP81011
  • Tokyo, Japan
    • Site JP81012
  • Tokyo, Japan
    • Site JP81013
  • Tokyo, Japan
    • Site JP81014
  • Tokyo, Japan
    • Site JP81015
  • Tokyo, Japan
    • Site JP81016
  • Tokyo, Japan
    • Site JP81017
  • Tokyo, Japan
    • Site JP81018
  • Tokyo, Japan
    • Site JP81019
  • Tokyo, Japan
    • Site JP81020
  • Tokyo, Japan
    • Site JP81021
  • Tokyo, Japan
    • Site JP81022
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Site KR00001
  • Seoul, Korea, Republic of
    • Site KR00002
  • Seoul, Korea, Republic of
    • Site KR00003
  • Seoul, Korea, Republic of
    • Site KR00004
  • Seoul, Korea, Republic of
    • Site KR00005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mirabegron 50 mg; Participants who received mirabegron 50 mg once a day along with tamsulosin 0.2 mg for 12 weeks	Drug: Mirabegron; Oral tablet; Other Names: YM178; Drug: Tamsulosin; Oral tablet
Experimental: Placebo; Participants who received matching placebo once a day along with tamsulosin 0.2 mg for 12 weeks.	Drug: Placebo; Oral tablet; Drug: Tamsulosin; Oral tablet

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Collaborators: Astellas Pharma Singapore Pte. Ltd.

Publications and helpful links

General Publications

• Kakizaki H, Lee KS, Katou D, Yamamoto O, Sumarsono B, Uno S, Yamaguchi O. Mirabegron Add-On Therapy to Tamsulosin in Men with Overactive Bladder: Post Hoc Analyses of Efficacy from the MATCH Study. Adv Ther. 2021 Jan;38(1):739-757. doi: 10.1007/s12325-020-01517-5. Epub 2020 Nov 27.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2016
• Primary Completion (Actual): July 21, 2017
• Study Completion (Actual): July 21, 2017

Study Registration Dates

• First Submitted: January 13, 2016
• First Submitted That Met QC Criteria: January 13, 2016
• First Posted (Estimate): January 14, 2016

Study Record Updates

• Last Update Posted (Actual): April 9, 2019
• Last Update Submitted That Met QC Criteria: March 27, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Mirabegron; Tamsulosin; Overactive bladder; Benign prostatic hypertrophy
• Additional Relevant MeSH Terms: Urologic Diseases; Urinary Bladder Diseases; Lower Urinary Tract Symptoms; Urological Manifestations; Prostatic Diseases; Pathological Conditions, Anatomical; Urinary Bladder, Overactive; Prostatic Hyperplasia; Hypertrophy; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Adrenergic beta-3 Receptor Agonists; Tamsulosin; Mirabegron
• Other Study ID Numbers: 178-MA-3016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes