Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Older Adult Subjects With Overactive Bladder (OAB)

Study Overview
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Brief Summary
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The purpose of this study was to assess the efficacy, safety and tolerability of mirabegron versus placebo in the treatment of older adult subjects with OAB.

Official Title
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A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Parallel Group, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Older Adult Subjects With Overactive Bladder (OAB)

Conditions
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Overactive Bladder (OAB)

Intervention / Treatment
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* Drug: Mirabegron
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria assessed at Visit 1 (Screening): Subject is willing and able to complete the micturition diary and questionnaires correctly. Subject has symptoms of wet overactive bladder (OAB) (urinary frequency and urgency with incontinence) for greater than or equal to 3 months prior to Screening. Subject agrees not to participate in another interventional study from the time of screening until the final study visit. Inclusion Criteria assessed after placebo run-in period at Visit 3 (Baseline): Subject continues to meet all inclusion criteria of Visit 1. Subjects must experience at least one incontinence episode in the placebo run-in period based on the 3-day micturition diary. Subject must experience at least 3 episodes of urgency (grade 3 or 4) based on the 3-day micturition diary. Subject must experience an average of greater than or equal to 8 micturitions/day based on the 3-day micturition diary. Exclusion Criteria assessed at Visit 1 (Screening): Subject has ongoing symptoms suggestive of bladder outlet obstruction (BOO) or history of BOO that is currently not well controlled. Subject has Post-Void Residual Volume (PVR) greater than 150 mL. Subject has neurogenic bladder or neurological dysfunction or injury which could affect the lower urinary tract or nerve supply. Subject has significant stress incontinence or mixed stress/urgency incontinence where stress is the predominant factor as determined by the Investigator (for female subjects confirmed by a cough provocation test). Subjects with a history of stress incontinence that is currently treated (e.g. remote history of surgery for stress incontinence) may be included as long as they pass cough provocation test. Subject has an indwelling catheter or practices intermittent self-catheterization. Subject has evidence of Urinary Tract Infection (UTI). Urine culture and sensitivity will be performed for positive leukocytes, or nitrites, or turbidity, or at the investigator's discretion 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 can be rescreened after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture). Subject has a chronic inflammatory condition 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 and rectum in both sexes and the uterus, ovaries, and fallopian tubes in females; organs of the lower gastrointestinal tract are not necessarily considered pelvic organs as the distal ascending colon, the full transverse colon and proximal portion of the descending colon are in the abdomen). Subject resides in a nursing home. Subject is likely to enter a hospital or nursing home due to medical instability within the next 6 months in the opinion of the Investigator. Subject has received intravesical injection in the past 12 months with botulinum toxin, resiniferatoxin, or capsaicin. Subject has 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 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 determined by Estimated Glomerular Filtration Rate (eGFR, Cockroft-Gault, or MDRD formulae). A subject with end stage renal disease 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 greater than or equal to 180 mmHg and/or diastolic blood pressure greater than or equal to 110 mmHg. Subject has evidence of QT prolongation on electrocardiogram (ECG) defined as QTc greater than 450 msec for males, QTc greater than 470 msec for females or a known history of QT prolongation. Subject has a clinically significant ECG abnormality, as determined by the Investigator. Subject has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 2x upper limit of normal (ULN), or γ-GT greater than 3x ULN and considered clinically significant by the Investigator. Subject has a hypersensitivity to any components of mirabegron, other β-AR agonists, or any of the inactive ingredients. Subject has any clinically significant condition, which in the opinion of the Investigator 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 with current history of alcohol and/or drug abuse. Subject is using prohibited medications which cannot be stopped safely during the period. Subject has stopped, started or changed the dose of a restricted medication within the last 30 days prior to Screening. 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. Exclusion Criteria assessed after placebo run-in period at Visit 3 (Baseline): Subject fulfills any exclusion criteria of Visit 1 (subject does not need to repeat screening assessments [PVR, cough provocation test, chemistry/hematology/urinalysis]). Subject was non-compliant during 2-week placebo run-in period, defined as taking less than 80% or greater than 120% of study medication. Subject has any systolic blood pressure measurement > 180 mmHg or diastolic blood pressure measurement > 110 in the 3-day diary or during the baseline visit.

Ages Eligible for Study
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Minimum Age: 65 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 placebo to match mirabegron at an initial dose of 25 mg and may have been increased to 50 mg of matching placebo based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug. | Drug: Placebo<br>* oral tablet<br>|
| Experimental: Mirabegron<br>Participants received mirabegron at an initial dose of 25 mg and may have been increased to 50 mg mirabegron after 4 weeks or 8 weeks based on individual participant efficacy, tolerability and investigator discretion. Once a participant had increased dose, they remained on that dose for the remainder of the study unless there were safety reasons that required discontinuation of study drug. | Drug: Mirabegron<br>* oral tablet<br>* Other names: Myrbetriq;|

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 act of passing urine (excluding incontinence only episodes). The mean number of micturitions per 24 hours was calculated as the average number of times a participant urinated per day during the 3-day micturition diary period. | 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 as the average number of times a participant recorded an incontinence episode per day during the 3-day micturition diary period. | Baseline and EOT (up to 12 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 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 EOT (up to 12 weeks) | 
| Change From Baseline to EOT in Overactive Bladder Questionnaire (OAB-q): Symptom Bother Score | 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). A negative change from baseline indicated an improvement. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline to EOT in OAB-q: Health Related Quality of Life (HRQL) Total 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 positive change from baseline indicated an improvement. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline to 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 EOT (up to 12 weeks) | 
| Change From Baseline to EOT in Mean Number of Urgency Episodes (Grade 3 and/or 4) Per 24 Hours | 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 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 24 hours 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 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 the involuntary leakage of urine accompanied by or immediately preceded by urgency. The mean number of urgency 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 EOT (up to 12 weeks) | 
| Change From to 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 only is not considered a nocturia episode. The mean number of nocturia episodes per 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 EOT (up to 12 weeks) | 
| Change From Baseline to EOT in Barthel Index of Daily Living Score | The Barthel Index consists of 10 items that measure a person's daily functioning; specifically the activities of daily living and mobility. The total possible score ranges from 0 to 20, with lower scores indicating increased disability. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline to EOT in Vulnerable Elder Survey-13 (VES-13) Score | The VES-13 is a simple function-based tool for screening community-dwelling populations to identify older persons at risk for health deterioration. The VES-13 considers age, self-related health, limitation in physical function, and functional disabilities. The total possible score ranges from 0 to 10, with higher scores indicating increased disability. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline to EOT in PPIUS | The PPIUS is a 5-point categorical scale used by participants to rate the degree of associated urgency for each micturition and/or incontinence episode they experienced. categories include: 0 - No urgency, I felt no need to empty my bladder, but did so for other reasons; 1 - Mild urgency, I could postpone voiding as long as necessary, without fear of wetting myself; 2 - Moderate urgency, I could postpone voiding for a short while, without fear of wetting myself; 3 - Severe urgency, I could not postpone voiding, but had to rush to the toilet in order not to wet myself; 4 - Urge incontinence, I leaked before arriving at the toilet. Scores were recorded in the micturition diary. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline to EOT in OAB-q HRQL Subscale Scores | 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 Coping score has 8 items, the Concern score has 7 items, the Sleep and Social score has 5 items each. Each subscale score was calculated by adding each score's items 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 EOT (up to 12 weeks) | 
| Change From Baseline to 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 EOT (up to 12 weeks) | 
| Change From Baseline to EOT in University of Alabama, Birmingham - Life Space Assessment (UAB-LSA) | The UAB-LSA measures mobility in terms of the spatial extent of a person's life. Life space is defined based upon the distance a person routinely travels to perform activities over this time frame. The UAB-LSA includes determining how far and how often the person leaves his or her place of residence and the degree of independence the person has. Each level of life space represents a distance further from the room where one sleeps: 0 - Mobility limited to the room where one sleeps; 1 - Mobility limited to within one's dwelling; 2 - Mobility limited to the space just proximal to one's personal living space (for instance, a porch, patio, or yard just outside the home or hallway outside of an apartment); 3 - Mobility limited to one's neighborhood; 4 - Mobility limited to one's town; 5 - Mobility outside one's town. The total scores ranges from 0-120, where a higher score indicates greater mobility. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline in Number of Incontinence Episodes Reported During 3-Day Diary Prior to Each Visit | An incontinence episode was defined as the complaint of any involuntary leakage of urine. The number of incontinence episodes were calculated as the total number of the incontinence episodes recorded during the 3-day micturition diary period. | Baseline and Weeks 4, 8 and EOT (up to 12 weeks) | 
| Change From Baseline in Number of Pads During 3-Day Diary Prior to Each Visit | The number of pads were calculated as the number of times a participant records a new pad used during the 3-day micturition diary period. No data were collected for the number of pads used due to a failure in the programming of the diary used for data collection. | Baseline and EOT (up to 12 weeks) | 
| Percentage of Participants Who Achieved Micturition Frequency Normalization | Participants who achieved micturition frequency normalization were defined as participants who had at least 8 micturitions per 24 hours at baseline and less than 8 micturitions per 24 hours post-baseline. | End of treatment (up to 12 weeks) | 
| Percentage of Participants With 50% Reduction in Mean Number of Incontinence Episodes Per 24 Hours | An incontinence episode was defined as the complaint of any involuntary leakage of urine. Participants with 50% reduction in mean number of incontinence episodes per 24 hours were defined as participants with at least 50% decrease from baseline in mean number of incontinence episodes per 24 hours during the treatment period at each visit. | End of treatment (up to 12 weeks) | 
| Percentage of Participants With Zero Incontinence Episodes Per 24 Hours | An incontinence episode was defined as the complaint of any involuntary leakage of urine. Participants with zero incontinence episodes per 24 hours were defined as participants who had no incontinence episodes per 24 hours during the treatment period at each visit. | End of treatment (up to 12 weeks) | 
| Percentage of Participants With ≥ 10-Point Improvement From Baseline in OAB-q HRQL Subscales | 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 Coping score has 8 items, the Concern score has 7 items, the Sleep and Social score has 5 items each. Each subscale score was calculated by adding each score's items and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. Participants with ≥ 10-point improvement from baseline in OAB-q HRQL subscales were defined as participants with at least 10-point improvement from baseline in OAB-q Subscales at each visit. | End of treatment (up to 12 weeks) | 
| Percentage of Participants With ≥ 1-Point Improvement From Baseline in 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. Participants with ≥ 1-point improvement from baseline in PPBC were defined as participants with at least 1-point improvement from baseline in PPBC at each visit. | End of treatment (up to 12 weeks) | 
| Percentage of Participants Major (≥ 2-Point) Improvement From Baseline in 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. Participants with ≥ 2-point improvement from baseline in PPBC were defined as participants with at least 1-point improvement from baseline in PPBC at each visit. | End of treatment (up to 12 weeks) | 
| Number of Participants With Adverse Events (AEs) | Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events. | From first dose of study drug up to 30 days after last dose of study drug (up to 13 weeks) | 
| Change From Baseline to EOT in Montreal Cognitive Assessment (MoCA) Score | The MoCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points, with lower scores indicating worse cognitive function. | Baseline and EOT (up to 12 weeks) | 
| Change From Baseline in Post-void Residual Volume (PVR) | PVR was assessed by ultrasonography or bladder scan. | 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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Urinary Incontinence, Mirabegron, Overactive Bladder