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

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

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

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.

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