Postmarketing Study to Evaluate add-on Therapy With Anticholinergics in Patients With Overactive Bladder (OAB) on Mirabegron.

Study Overview
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Brief Summary
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The objective of the study was to evaluate the safety and efficacy of add-on therapy with anticholinergics in patients with OAB on mirabegron.

Detailed Description
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This was a multicenter, open-label study to evaluate the safety and efficacy of add-on therapy with antimuscarinics in patients with OAB treated with mirabegron. The total duration of the study period was 54 weeks in total, comprising a 2-week screening period and a 52-week treatment period. Patients who met the eligibility criteria for provisional enrollment received orally the study drug for the screening period (mirabegron 50 mg) once daily after breakfast for 2 weeks. Patients who met the eligibility criteria after the screening period were randomized to solifenacin 5 mg, propiverine 20 mg, imidafenacin 0.2 mg or tolterodine 4 mg in a 1:1:1:1 ratio, and received orally mirabegron 50 mg and antimuscarinics for 52 weeks. At week 8 visit, the dose of all antimuscarinics except for tolterodine could be increased by 2-fold (solifenacin 10 mg, propiverine 40 mg or imidafenacin 0.4 mg) if a patient met the following criteria: (1) had no response to the study drugs; (2) was considered by the investigator to have no safety concerns; and (3) agreed to increase the dose. However, in the event of AEs after the dose was increased, it could be reduced to the level before the increase. A dose increase for a second time after dose reduction was not permitted.

Official Title
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Postmarketing Study of Mirabegron in Japan: Long-term Add-on Therapy With Antimuscarinics in Patients With Overactive Bladder Treated With Mirabegron

Conditions
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Overactive Bladder (OAB)

Intervention / Treatment
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* Drug: Mirabegron tablet
* Drug: Solifenacin tablet
* Drug: Propiverine tablet
* Drug: Imidafenacin tablet
* Drug: Tolterodine capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female: OAB outpatient who had been postmenopausal for at least 1 year Male: OAB outpatient who had no wish to have children in the future Patient had been under treatment with mirabegron at a stable dose of 50 mg once daily for at least 6 weeks before the start of the screening period Patient capable of walking to the bathroom without assistance Patient had a total Overactive Bladder Symptom Score (OABSS) of ≥3 points and a Question 3 score of ≥2 points Exclusion Criteria: Patient had an established diagnosis of stress urinary incontinence (patient had no symptom other than stress urinary incontinence) Patient had urinary tract infection (cystitis, prostatitis, etc.), urinary calculus (ureteric calculus, urethral calculus, bladder calculus, etc.), interstitial cystitis, or a history of recurrent urinary tract infection (at least 3 episodes within 24 weeks before the start of the screening period) Patient had a residual urine volume of ≥100 mL at week -2 visit or patient with benign prostatic hyperplasia or lower urinary tract obstruction Patient had uncontrolled hypertension (sitting systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg at week -2 visit) Patient had a pulse rate of ≥110 bpm or <50 bpm at week -2 visit Patient had a contraindication to antimuscarinics (urinary retention; obstruction in thepylorus, duodenum, or intestine; paralytic ileus; gastric/intestinal atony; myasthenia gravis; and decreased gastrointestinal motility/tone, etc.) Patient had glaucoma, ulcerative colitis, hyperthyroidism, dementia, cognitive dysfunction, parkinsonism symptoms, or clinically significant cerebrovascular disorder Patient had serious heart disease (myocardial infarction, cardiac failure, uncontrolled angina pectoris, serious arrhythmia, use of pacemaker, etc.), liver disease, kidney disease, immunological disease, lung disease, etc. or patient had a history of malignant tumor (except for malignant tumor that had not been treated for at least 5 years before the start of the screening period with no risk of recurrence) Patient had drug hypersensitivity to β-agonists or anticholinergics Patient was under treatment with flecainide acetate or propafenone hydrochloride Patient had long QT syndrome, patient was vulnerable to arrhythmia such as bradycardia or acute myocardial ischemia, patient had hypokalemia, and patient had ischemic heart disease such as angina pectoris Patient had used any prohibited concomitant medication within 4 weeks before the start of the screening period Patient was under catheterization or intermittent self-catheterization or patient had pelvic organ prolapse that affected the urinary tract function Patient had received radiotherapy that affected the urinary tract function Patient had received surgical therapy that may have affected the urinary tract function within 24 weeks before the start of the screening period Patient had received nonpharmacological therapy for OAB such as electric stimulation therapy (interferential low frequency therapy, magnetic stimulation therapy, etc.), biofeedback therapy, bladder training, or pelvic floor muscle exercise within 2 weeks before the start of the screening period Patient had or had a history of mood disorder, neurotic disorder, and schizophrenia

Ages Eligible for Study
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Minimum Age: 20 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirabegron + Solifenacin<br>Participants received mirabegron 50 mg and solifenacin 5 mg once daily after breakfast orally for 8 weeks. In the next 44 weeks, participants continued to receive mirabegron 50 mg, but received an increased dose of solifenacin 10 mg, if the treatment was not effective. | Drug: Mirabegron tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast<br>* Other names: YM178;Drug: Solifenacin tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast (could be increased to 2 tablets)<br>|
| Experimental: Mirabegron + Propiverine<br>Participants received mirabegron 50 mg and propiverine 20 mg once daily after breakfast orally for 8 weeks. In the next 44 weeks, participants continued to receive mirabegron 50 mg, but received an increased dose of propiverine 40 mg, if the treatment was not effective. | Drug: Mirabegron tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast<br>* Other names: YM178;Drug: Propiverine tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast (could be increased to 1 tablet twice daily after breakfast and after dinner)<br>|
| Experimental: Mirabegron + Imidafenacin<br>Participants received mirabegron 50 mg and imidafenacin 0.2 mg once daily after breakfast orally for 8 weeks. In the next 44 weeks, participants continued to receive mirabegron 50 mg, but received an increased dose of imidafenacin 0.4 mg, if the treatment was not effective. | Drug: Mirabegron tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast<br>* Other names: YM178;Drug: Imidafenacin tablet<br>* orally administered at a dose of 1 tablet (0.1 mg tablet) twice daily after breakfast and after dinner (could be increased to 2 tablets twice daily after breakfast and after dinner)<br>|
| Experimental: Mirabegron + Tolterodine<br>Participants received mirabegron 50 mg and tolterodine 4 mg once daily after breakfast orally for 52 weeks. | Drug: Mirabegron tablet<br>* orally administered at a dose of 1 tablet once daily after breakfast<br>* Other names: YM178;Drug: Tolterodine capsule<br>* orally administered at a dose of 1 capsule once daily after breakfast (could not be increased)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs were defined as AEs observed after the first administration of the study drugs for the treatment period. The investigator assessed the severity of AEs, including abnormal clinical laboratory values, electrocardiogram (ECG), vital signs, 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. | From first dose of study drug up to week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Overactive Bladder Symptom Score (OABSS) Total Score | The OABSS questionnaire was a questionnaire completed by participants with 4 questions regarding their OAB symptoms. For each participant, the OABSS total score was calculated from the sum total of the score of each question. The total score ranges from 0 to 15 with higher score indicating more symptoms. The OABSS data obtained at week 0 were used as baseline. | Baseline and week 4, 8, 12, 16, 28 and 52 | 
| Number of Participants Who Achieved Normalization for OABSS Total Score | Normalization for OABSS Total Score was defined as OABSS total score ≤ 2 or OABSS Question 3 score ≤ 1. | Week 52 (end of treatment) | 
| Change From Baseline in Overactive Bladder Questionnaire Short Form (OAB-q SF) Symptom Severity Score | The OAB-q SF questionnaire was a questionnaire completed by participants composed of 2 sections: Symptom Severity and the Health-related Quality of Life (HRQL). The Symptom Severity section included 6 questions. For each participant, the symptom severity score was derived as a sum of scores for Questions 1 to 6. The total score ranges from 6 to 36 with higher symptom severity score indicating greater symptom bother. OAB-q SF data obtained at week 0 visit were used as baseline. | Baseline and week 12, 28 and 52 | 
| Change From Baseline in OAB-q SF Total HRQL Score | The OAB-q SF questionnaire was a questionnaire completed by participants composed of 2 sections: Severity Symptom and the HRQL. The HRQL section included 13 questions. For each participant, the total HRQL score was derived as a sum of scores for Questions 7 to 19. The total score ranges from 13 to 78 with higher total HRQL score indicating greater HRQL. OAB-q SF data obtained at week 0 visit were used as baseline. | Baseline and week 12, 28 and 52 | 
| Change From Baseline in the Mean Number of Micturitions Per 24 Hours | Participants completed the patient diary (paper document) for 3 days immediately before each visit. The mean number of micturitions per 24 hours was calculated by taking the sum of all marked episodes in the patient diary where the variable urinated was indicated, divided by the number of days on which episodes were recorded. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Number for Participants Who Achieved Normalization of the Mean Number of Micturitions Per 24 Hours | Normalization for the mean number of micturitions per 24 hours was defined as < 8 micturitions per 24 hours. | Week 52 (end of treatment) | 
| Change From Baseline in the Mean Number of Urgency Episodes Per 24 Hours | Participants completed the patient diary (paper document) for 3 days immediately before each visit. 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 by taking the sum of all marked episodes in the patient diary where the variable urgency was indicated, divided by the number of days on which episodes were recorded. Only participants who had an urgency episode at baseline was included in the analysis. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Number for Participants Who Achieved Normalization of the Mean Number of Urgency Episodes Per 24 Hours | Normalization for the mean number of urgency episodes per 24 hours was defined as no urgency episode per 24 hours. | Week 52 (end of treatment) | 
| Change From Baseline in the Mean Number of Incontinence Episodes Per 24 Hours | Participants completed the patient diary (paper document) for 3 days immediately before each visit. 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 by taking the sum of all marked episodes in the patient diary where the variable urinary incontinence' was indicated, divided by the number of days on which episodes were recorded. Only participants who had an incontinence episode at baseline was included in the analysis. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Number for Participants Who Achieved Normalization of the Mean Number of Incontinence Episodes Per 24 Hours | Normalization for the mean number of incontinence episodes per 24 hours was defined as no incontinence episode per 24 hours. | Week 52 (end of treatment) | 
| Change From Baseline in the Mean Number of Urge Incontinence Episodes Per 24 Hours | Participants completed the patient diary (paper document) for 3 days immediately before each visit. An urge incontinence episode was defined as any episode when both urgency and incontinence occurred concurrently. The mean number of incontinence episodes per 24 hours was calculated by taking the sum of all marked episodes in the patient diary where the variable urgency and urinary incontinence' were indicated, divided by the number of days on which episodes were recorded. Only participants who had an urge incontinence episode at baseline was included in the analysis. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Change From Baseline in the Mean Volume Voided Per Micturition | Participants completed the patient diary (paper document) for 3 days immediately before each visit. The mean volume per micturition was calculated by taking the sum of the urinary volumes where the volume voided was > 0 and where urinary incontinence was not indicated in the patient diary, divided by the number of micturitions where the volume voided was > 0 and where urinary incontinence was not indicated. Only participants who had volume voided was > 0 at baseline was included in the analysis. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Change From Baseline in the Mean Number of Nocturia Episodes Per Night | Participants completed the patient diary (paper document) for 3 days immediately before each visit. A nocturia episode was defined as waking at night 1 or more times to void. Night time was defined as the period between bedtime 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 night was calculated by taking the sum of nocturia episodes in the patient diary where the variable urinated was indicated during the night time, divided by the number of nights. Only participants who had a nocturia episode at baseline was included in the analysis. | Baseline and week 4, 8, 12, 16, 28, 40, 52 | 
| Number of Participants Who Achieved Normalization of the Mean Number of Nocturia Episodes Per 24 Hours | Normalization for the mean number of nocturia episodes per 24 hours was defined as no nocturia episode per 24 hours. | Week 52 (end of treatment) | 
| Change From Baseline in Postvoid Residual (PVR) Volume | Measurement of PVR volume was made using either ultrasonography or urethral catheterization, provided that the same method was used for the same participant throughout the study. | Baseline and week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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YM178, Anticholinergic, Overactive Bladder (OAB), Mirabegron