A Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men With OAB Symptoms While Taking Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)

Study Overview
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Brief Summary
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The purpose of the study was to assess the efficacy, safety, and tolerability of mirabegron versus placebo in men with overactive bladder (OAB) symptoms while taking tamsulosin hydrochloride for lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH).

Detailed Description
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At Screening (Visit 1), participants entered into a 4-week open label tamsulosin hydrochloride 0.4 mg QD run-in period prior to being randomized into the 12-week double-blind treatment period (Visit 2). At conclusion of the 4-week tamsulosin hydrochloride run-in period, participants completed a 3-day diary just prior to Baseline (Visit 2). Approximately 7 days prior to Visit 2 participants received a phone call reminding them about the diary and to answer any questions. If participants met all entry criteria at the end of the tamsulosin hydrochloride run-in period, participants were randomized to 1 of 2 treatment groups (mirabegron or placebo) for 12 weeks of treatment in addition to the continuation of tamsulosin hydrochloride 0.4 mg QD. Those participants randomized to Mirabegron started at 25 mg and increased to 50 mg after 4 weeks. Those participants randomized to placebo started blinded product matched to the mirabegron 25 mg tablet and increased to blinded product matched to 50 mirabegron after 4 weeks. Once a participant increased dose, the participant remained on that dose for the remainder of the study unless for safety reasons was required to discontinue study drug. A training diary was completed in the first 2 weeks of the tamsulosin hydrochloride run-in period. During this evaluation period at least one telephone contact took place with the participant. Diaries were completed at home, using the electronic patient-reported outcome (ePRO) device, for 3 consecutive days prior to each visit: Baseline (Visit 2), Week 4 (Visit 3), Week 8 (Visit 4), and Week 12/End of Treatment (Visit 5). Site staff contacted the participant approximately 7 days prior to the scheduled visit to remind the participant to complete the electronic diary, review completion instruction and review changes to concomitant medications and adverse events (if applicable). Three days before Visits 2 (Baseline), 3 (Week 4), 4 (Week 8), and 5 (Week 12), participants completed a 3-day diary, using the ePRO device in which the participant recorded micturition frequency, urgency (PPIUS), incontinence and volume voided. In addition, the diary captured morning and evening blood pressure and pulse rate measurements via Home Blood Pressure Monitoring (HBPM). At Visit 1, International Prostate Symptom Score (IPSS) was completed. At Visits 2, 3, 4, and 5, participants completed the IPSS, EQ-5D-5L, OAB-q, PPBC, and TS-VAS. Maximum urinary flow (Qmax) was measured at Visit 1 (Screening/tamsulosin hydrochloride run-in) and Visit 5 (Week 12/End of Treatment). Post-void residual volume (PVR) was assessed at Screening/tamsulosin hydrochloride run-in (Visit 1), Baseline (Visit 2) and at Week 4 (Visit 3), Week 8 (Visit 4), and Week 12/End of Treatment (Visit 5). A follow-up phone call (Visit 6) was conducted 4-weeks after End of Treatment (Visit 5). Total study participation was approximately 20 weeks.

Official Title
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A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men With Overactive Bladder (OAB) Symptoms While Taking the Alpha Blocker Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)

Conditions
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Benign Prostatic Hyperplasia, Overactive Bladder

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria assessed at Visit 1 (Screening): Men ≥40 years of age with history of overactive bladder (OAB) symptoms (frequency of ≥8 micturitions per day and urgency episodes of ≥2 per day) while taking tamsulosin hydrochloride for at least 2 months to treat LUTS due to BPH. Subject has symptoms of OAB (urinary frequency and urgency with or without incontinence) for ≥3 months prior to Screening. Subject has an International Prostate Symptom Score (IPSS) score ≥8. Subject has Prostate-Specific Antigen (PSA) <4 ng/mL or ≥4 but < 10 ng/mL with a prostate biopsy that is negative for cancer in the past 2 years. Subject is willing and able to complete the 3-day diary (including urine volumes, vital signs measurements), and Quality of Life questionnaires. Subject and the subject's spouses/partners who are of childbearing potential must be using a highly effective birth control, which includes established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS). Birth control must be practiced from Screening and continue throughout the study and for 30 days after the final study drug administration. In addition, sperm donation will not be allowed throughout the study and for 30 days after the final study drug administration. Subject agrees not to participate in another interventional study while on treatment. Inclusion Criteria assessed at Visit 2 (Baseline) based on the 3-day diary: Subject continues to meet all inclusion criteria of Visit 1 (Screening). Subject must experience an average of 8 or more micturitions per day over the 3-day diary period. Subject must experience an average of 2 episodes of urgency per day (grade 3 or 4) over the 3-diary period Exclusion Criteria assessed at Visit 1 (Screening): Subject has post-void residual volume (PVR) >200 mL. Subject has maximum urinary flow (Qmax) <5.0 mL/second with a minimum voided volume of 125 mL. Subject has hematuria >3 rbc/hpf that has not been fully evaluated. Subject has evidence of Urinary Tract Infection (UTI). Urine culture and sensitivity will be performed for positive leukocytes, nitrites, or turbidity and will be confirmed with a culture greater than 100,000 cfu/mL. If a subject has a UTI, at Screening (Visit 1) the subject may be rescreened after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). Subject has neurogenic bladder (spinal cord injury, multiple sclerosis, Parkinson's, etc.). Subject has diabetic neuropathy. Previous open, robotic or minimally invasive prostate surgery (including transurethral procedures). Planned (scheduled) pelvic or prostate surgery during the study period. Planned (scheduled) cataract surgery. Subject with significant stress incontinence Subject with clinically significant bladder outlet obstruction. Subject has an indwelling catheter or practices intermittent self-catheterization. Subject has experienced 3 or more episodes of recurrent urinary tract infection within the last 12 months. Subject has a symptomatic urinary tract infection, prostatitis, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs (i.e., within the confines of the pelvis including the bladder, prostate and rectum; organs of the lower gastrointestinal tract are not necessarily considered pelvic organs such as the distal ascending colon, the full transverse colon and proximal portion of the descending colon are in the abdomen). Subject has received intravesical injection in the past 12 months with botulinum toxin, resiniferatoxin, or capsaicin. Subject has ever received electro-stimulation therapy for OAB (e.g. sacral nerve stimulation or Percutaneous Tibial Nerve Stimulation [PTNS]). Subject began or has changed a bladder training program or pelvic floor exercises less than 30 days prior to Screening. Subject has postural hypotension or syncope or postural orthostatic tachycardia. Subject has moderate or severe hepatic impairment defined as Child-Pugh Class B or C. Subject has severe renal impairment defined as estimated creatinine clearance less than 29 mL/min/1.73 m2 as determined by hospital laboratory calculation of eGFR. A subject with End Stage Renal Disease (ESRD) or undergoing dialysis is also not a candidate for the study. Subject has severe uncontrolled hypertension, which is defined as a sitting systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg. Subject has baseline resting pulse rate <60 BPM or >90 BPM. Subject has evidence of QT prolongation on Screening (Visit 1) or Baseline (Visit 2) electrocardiogram (ECG) defined as QTcF >450 msec. Subject has any clinically significant ECG abnormality. Subject has AST or ALT >2x upper limit of normal (ULN), or γ-GT >3x ULN and considered clinically significant. Subject has a hypersensitivity to any components of mirabegron, tamsulosin hydrochloride, or any of the inactive ingredients. Subject has a history of angioedema. Subject has any clinical significant condition which makes the subject unsuitable for study participation. Subject has been treated with an experimental device within 28 days or received an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Screening. Subject has a concurrent malignancy or history of any malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully. Subject has ongoing alcohol and/or drug abuse. Subject is using prohibited medications within 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6). Subject has stopped, started or changed the dose of a restricted medication within the 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6) Subject has participated in an interventional trial within 30 days prior to Screening (Visit 1). Subject is involved in the conduct of the study as an employee of the Astellas group, third party associated with the study, or the study site team. Subject has previously received mirabegron in the 6 months prior to Screening (Visit 1). Exclusion Criteria assessed at Visit 2 (Baseline): Subject was non-compliant during the 4-week tamsulosin hydrochloride run-in period, defined as taking less than 80% or greater than 120% of study medication. Subject had an average total daily urine volume >3000 mL as recorded in the 3-day 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<br>Participants received initial dose of 25 mg of mirabegron which was increased to 50 mg after 4 weeks. In addition to mirabegron participants received 0.4 mg of oral tamsulosin hydrochloride daily throughout the study. | Drug: Mirabegron<br>* Participants received initial dose of 25 mg of mirabegron (oral tablet) which was increased to 50 mg after 4 weeks.<br>* Other names: YM178;Drug: Tamsulosin Hydrochloride<br>* Participants received once daily treatment with tamsulosin hydrochloride 0.4 mg (oral tablet) throughout the study.<br>* Other names: Omnic;|
| Placebo Comparator: Placebo<br>Participants received matching placebo in addition to oral tamsulosin hydrochloride daily throughout the study. | Drug: Placebo<br>* Participants received initial dose of 25 mg of matching placebo (oral tablet) which was increased to 50 mg after 4 weeks.<br>Drug: Tamsulosin Hydrochloride<br>* Participants received once daily treatment with tamsulosin hydrochloride 0.4 mg (oral tablet) throughout the study.<br>* Other names: Omnic;|

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 Day | Participants recorded micturitions in the e-diary during three days. The mean number of micturitions was calculated as the average number of times a participant recorded a micturition per day during the 3-day period. Only voluntary micturitions were counted and the episodes of incontinence were not included. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 4, Week 8, and Week 12 in Mean Number of Micturitions Per Day | Participants recorded micturitions in the e-diary during three days. The mean number of micturitions was calculated as the average number of times a participant recorded a micturition per day during the 3-day period. Only voluntary micturitions were counted and the episodes of incontinence were not included. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Volume Voided Per Micturition | The mean volume voided per micturition during 3 days of the 3-day micturition diary period. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Incontinence Episodes Per Day | 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 as the average number of times a participant recorded an incontinence episode per day during the 3-day micturition diary period. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Episodes (Grade 3 or 4) Per Day | Urgency was defined as a complaint of a sudden, compelling desire to pass urine, which is difficult to defer. An urgency episode was defined as any micturition or incontinence episode with a severity of grade 3 or 4, assessed by participants based on the Patient Perception of Intensity of Urgency Scale (PPIUS), where 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. The mean number of urgency episodes (grade 3 and/or 4) per day was calculated as the average number of times a participant recorded an urgency episode (grade 3 and/or 4) with or without incontinence per day during the 3-day micturition diary period. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in International Prostate Symptom Score (IPSS) Total Score | The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). The IPSS total score classification ranges from mild (0 to 7) to moderate (8 to 19) or severe (20 to 35). Higher IPSS scored indicated more severe symptoms. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Voiding Score | The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). Each question is assigned points from 0 to 5 indicating increasing severity of the particular symptom. The subscale voiding score is the sum of the responses to 4 voiding symptoms questions (incomplete emptying, intermittency, weak stream, and straining). The lowest and highest possible scores range from 0 to 20 (mildly symptomatic to severely symptomatic). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12, and EoT in IPSS Subscale Storage Score | The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). Each question is assigned points from 0 to 5 indicating increasing severity of the particular symptom. The subscale storage score is the sum of the responses to 3 storage symptoms questions (frequency, urgency, and nocturia). The lowest and highest possible scores range from 0 to 15 (mildly symptomatic to severely symptomatic). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Quality of Life (QoL) Score | The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). The QoL assessment was a single question asking the participant how he would feel about tolerating his current level of symptoms for the rest of his life. The lowest and highest possible score ranges from 0 to 6 (very pleased to terrible). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Incontinence Episodes Per Day | Urgency Incontinence was defined as the complaint of involuntary leakage accompanied by or immediately proceeded by urgency. The mean number of urgency incontinence episodes was calculated as the average number of times a participant recorded an urgency incontinence episode per day during the 3-day micturition diary period. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Symptom Bother Score | Overactive bladder symptoms were assessed using the Symptom Bother Scale of the Overactive Bladder questionnaire (OAB-q). The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The symptom bother portion consists of 8 questions, rated on a 6-point Likert scale (1 through 6). The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 (least severity) to 100 (worst severity). Lower scores on OAB-q symptom bother indicate a better response. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Total Health Related Quality of Life (HRQL) Score | The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The HRQoL portion consists of 25 HRQoL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. The total score was calculated by adding the 4 HRQoL subscale scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A higher score on OAB-q HRQL indicated a better response. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Coping Score | The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQL). The HRQL portion consists of 25 HRQL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. A higher score on OAB-q HRQL indicated a better response. The lowest and highest possible scores for the Coping subscale ranges from 8 to 48. The Coping score was calculated by adding the 8 response scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from baseline indicated an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Concern Score | The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQL). The HRQL portion consists of 25 HRQL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. A higher score on OAB-q HRQL indicated a better response. The lowest and highest possible scores for the Concern subscale ranges from 7 to 42. The Concern score was calculated by adding the 7 response scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from baseline indicated an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Sleep Score | The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQL). The HRQL portion consists of 25 HRQL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. A higher score on OAB-q HRQL indicated a better response. The lowest and highest possible scores for the Sleep subscale ranges from 5 to 30. The Sleep score was calculated by adding the 5 response scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from baseline indicated an improvement. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Social Interaction Score | The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQL). The HRQL portion consists of 25 HRQL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. A higher score on OAB-q HRQL indicated a better response. The lowest and highest possible scores for the Social Interaction subscale ranges from 5 to 30. The Social Interaction score was calculated by adding the 5 response scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A positive change from baseline indicated an improvement. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in European Quality of Life in 5 Dimensions and 5 Levels (EQ-5D-5L Questionnaire) Utilities | The EQ-5D-5L is an international standardized non-disease specific generic instrument for describing and valuing health status. It has a multidimensional measure of health-related QoL, capable of being expressed as a single index value and specifically designed to complement other health status measures. The EQ-5D-5L has five dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension has 5 response levels (e.g., 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems/unable to perform the activity). Health-state utility (HSU) data are estimates of the preference for a given state of health on a cardinal numeric scale, where a value of 1.0 represents full health, 0.0 represents dead, and negative values represent states worse than death. Missing EoT values were imputed using LOCF method. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Patient Perception of Bladder Condition (PPBC) | The PPBC is a validated, global assessment tool using a 6-point Likert scale that asks participants to rate their subjective impression of their current bladder condition. Participants assessed their bladder condition using this scale: 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; 6. Causes me many severe problems. A higher score indicated a worse perception of bladder condition. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Total Urgency and Frequency Score (TUFS) | The TUFS was calculated by adding the PPIUS scores of every void in a participant's 3-day diary, and dividing this by the number of days recorded in the diary. Due to a programming failure in the e-diary data for the number of pads used was not collected. | Baseline and Weeks 4, 8 and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Nocturia Episodes Per 24 Hours | A nocturia episode was defined as waking at night one or more time to void (i.e., any voiding associated with sleep disturbance between the date/time the participant goes to bed with the intention to sleep until the date/time the participant gets up in the morning with the intention to stay awake). A night time episode of incontinence is not considered a nocturia episode. The mean number of nocturia episodes per day (24 hours) was calculated as the average number of times a participant recorded a nocturia episode per day during the 3-day micturition diary period. | Baseline and Weeks 4, 8, and 12 | 
| Change From Baseline to Week 4, Week 8, Week 12 and EoT in Treatment Satisfaction Visual Analog Scale (TS-VAS) | The TS-VAS is a visual analog scale that asks participants to rate their satisfaction with the treatment by placing a vertical mark on a line that runs from 0 (No, not at all) to 100 (Yes, completely). | Baseline and Weeks 4, 8, and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myrbetriq, Lower Urinary Tract Symptoms, Benign Prostatic Hyperplasia, Overactive Bladder, Betmiga, Mirabegron, Tamsulosin Hydrochloride