Postmarketing Study of Mirabegron in Japan: Long-term Add-on Therapy With Antimuscarinics in Patients With Overactive Bladder Treated With Mirabegron
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Astellas Pharma Inc
- Enrollment
- 649
- Primary Endpoint
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 20 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Mirabegron + Solifenacin
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.
Intervention: Mirabegron tablet (Drug)
Mirabegron + Solifenacin
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.
Intervention: Solifenacin tablet (Drug)
Mirabegron + Propiverine
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.
Intervention: Mirabegron tablet (Drug)
Mirabegron + Propiverine
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.
Intervention: Propiverine tablet (Drug)
Mirabegron + Imidafenacin
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.
Intervention: Mirabegron tablet (Drug)
Mirabegron + Imidafenacin
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.
Intervention: Imidafenacin tablet (Drug)
Mirabegron + Tolterodine
Participants received mirabegron 50 mg and tolterodine 4 mg once daily after breakfast orally for 52 weeks.
Intervention: Mirabegron tablet (Drug)
Mirabegron + Tolterodine
Participants received mirabegron 50 mg and tolterodine 4 mg once daily after breakfast orally for 52 weeks.
Intervention: Tolterodine capsule (Drug)
Outcomes
Primary Outcomes
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame: From first dose of study drug up to week 52
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.
Secondary Outcomes
- Change From Baseline in Overactive Bladder Symptom Score (OABSS) Total Score(Baseline and week 4, 8, 12, 16, 28 and 52)
- Change From Baseline in the Mean Number of Urgency Episodes Per 24 Hours(Baseline and week 4, 8, 12, 16, 28, 40, 52)
- Change From Baseline in the Mean Number of Urge Incontinence Episodes Per 24 Hours(Baseline and week 4, 8, 12, 16, 28, 40, 52)
- Change From Baseline in Postvoid Residual (PVR) Volume(Baseline and week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52)
- Number of Participants Who Achieved Normalization for OABSS Total Score(Week 52 (end of treatment))
- Change From Baseline in Overactive Bladder Questionnaire Short Form (OAB-q SF) Symptom Severity Score(Baseline and week 12, 28 and 52)
- Number for Participants Who Achieved Normalization of the Mean Number of Micturitions Per 24 Hours(Week 52 (end of treatment))
- Change From Baseline in OAB-q SF Total HRQL Score(Baseline and week 12, 28 and 52)
- Number for Participants Who Achieved Normalization of the Mean Number of Urgency Episodes Per 24 Hours(Week 52 (end of treatment))
- Number for Participants Who Achieved Normalization of the Mean Number of Incontinence Episodes Per 24 Hours(Week 52 (end of treatment))
- Change From Baseline in the Mean Number of Micturitions Per 24 Hours(Baseline and week 4, 8, 12, 16, 28, 40, 52)
- Change From Baseline in the Mean Number of Incontinence Episodes Per 24 Hours(Baseline and week 4, 8, 12, 16, 28, 40, 52)
- Change From Baseline in the Mean Volume Voided Per Micturition(Baseline and week 4, 8, 12, 16, 28, 40, 52)
- Change From Baseline in the Mean Number of Nocturia Episodes Per Night(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(Week 52 (end of treatment))