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)

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)

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).

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.

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.