A Phase 4, double-blind, randomized, placebo-controlled, parallel group, multi-centre study to evaluate the efficacy, safety, and tolerability of mirabegron in older adult patients with overactive bladder syndrome (PILLAR)

Wagg A1, Staskin D2, Engel E3, Herschorn S4, Kristy R M5, Schermer C R5

Research Type

Clinical

Abstract Category

Overactive Bladder

Abstract 268
Overactive Bladder 1
Scientific Podium Short Oral Session 15
Thursday 30th August 2018
09:35 - 09:42
Hall B
Overactive Bladder Gerontology Incontinence
1. University of Alberta, Geriatric Medicine, Edmonton, Alberta, Canada, 2. St Elizabeth’s Medical Center, Division of Urology, Boston, Massachusetts, USA, 3. Bayview Research Group, Valley Village, California, USA, 4. University of Toronto, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, 5. Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA
Presenter
A

Adrian Wagg

Links

Abstract

Hypothesis / aims of study
Overactive bladder (OAB) is increasingly common amongst older people. OAB is associated with an adverse impact on quality of life and well-being in addition to well-described adverse health-related outcomes. Should lifestyle and behavioural measures fail then, until relatively recently, pharmacological options consisted of antimuscarinic therapy, the effectiveness of which may be hampered by unacceptable adverse effects which in themselves limit treatment adherence. The development of the beta-3-agonist, mirabegron, offers an alternative option for treatment of older people; however, older people make up the minority of those enrolled in prospective trials to date. The aim of this study was to assess the effect of mirabegron vs placebo in a pragmatic, prospective, randomised, placebo-controlled trial in patients aged ≥65 years, with the aim of including ≥30% patients >75 years old.
Study design, materials and methods
A 12-week, prospective, randomized, placebo-controlled trial was conducted in patients >65 years of age with OAB symptoms for ≥3 months in the United States and Canada. Patients with ≥1 incontinence episode, ≥3 urgency episodes (grade 3 or 4), and an average of 8 micturition episodes/day based on the 3-day micturition diary were included. Exclusion criteria included nursing home residence, limited life expectancy (<6 months), bladder outlet obstruction, predominant stress incontinence, elevated (>150 mL) post-void residual volume, neurogenic detrusor overactivity, acute urinary tract infection, recent (<30 days) initiation of conservative or invasive therapy for OAB, permanent or intermittent catheterization, severe renal or hepatic impairment, uncontrolled hypertension or malignancy within the last 5 years. Mental incapacity to complete the study requirements or consent procedures was the only cognitive exclusion criterion. Patients were randomized to receive mirabegron 25 mg/day with the option of dose escalation at 4 or 8 weeks depending upon individual tolerability (with no de-escalation) or placebo.
The primary analysis set was comprised of randomized patients who received ≥1 dose of study drug, had a micturition measurement at baseline, had ≥1 incontinence episode at baseline, and had ≥1 post-baseline micturition measurement. The co-primary end points were change from baseline to end-of-treatment (EOT) in mean number of micturitions/24 hour and mean number of incontinence episodes/24 hour based on a 3-day micturition diary for all mirabegron vs placebo treated patients. Secondary end points included change from baseline to EOT in mean volume voided per micturition, symptom bother and total health related quality of life scores as assessed by OAB-q questionnaire, and Patient Perception of Bladder Condition (PPBC). Cognitive function was assessed by change from baseline to EOT in the Montreal Cognitive Assessment (MoCA) score. Safety analyses were performed on the safety analysis set, defined as all patients who received ≥1 dose of study drug.
Based upon previous data from the mirabegron clinical trial program on the mean reduction in micturitions and likely response in incontinence episodes/24h in United States patients aged ≥65 years with total mirabegron vs placebo at 80% power, 400 patients per treatment arm were required. A 30% screen failure rate was anticipated and in order to randomize 800 patients, 1,150 patients were expected to be screened.
Results
In total, 888 patients were randomized (placebo, n=443; mirabegron, n=445). Of those who received mirabegron, 226 received 25 mg and 219 elected to titrate to mirabegron 50 mg by the end of the study. Demographic details and baseline characteristics are shown in Table 1. Ethnicity, race, and age categories were similar across the treatment arms. Primary outcome variables are shown in Table 2. Responder rates for zero incontinence episodes at EOT were 122/424 (28.8%) for placebo, 84/214 (39.3%) for mirabegron 25 mg, and 77/215 (35.8%) for mirabegron 50 mg. Overall, 10 placebo and 8 mirabegron patients discontinued the study due to an adverse event (AE). At least one treatment-emergent AE was reported by 39.4% of placebo patients, 44.2% of mirabegron 25 mg patients, and 49.8% of mirabegron 50 mg patients. The most common reported AEs (affecting ≥2% of patients) are shown in Table 2. Urinary retention was reported in 2/442 (0.5%) placebo patients and 2/219 (0.9%) mirabegron 50 mg patients. There was no statistically significant change in MoCA over the timescale of the study; patients on placebo experienced a mean (standard deviation) change of 0.2 (2.3) points vs -0.1 (2.3), and 0.3 (2.5) points for patients on mirabegron 25 mg and 50 mg, respectively.
Interpretation of results
In older patients with OAB and urgency incontinence, treatment with mirabegron in a flexible dosing regime was statistically superior to placebo in alleviating major OAB symptoms and associated bother. Apart from improvement in micturition frequency/24h, escalation to mirabegron 50 mg was not clearly associated with an additional benefit. The reason for this is unknown and requires further analysis. The baseline disease severity and medical complexity of patients choosing to escalate vs those who did not will be analyzed separately. Mirabegron was well tolerated overall with no unexpected AEs over those previously reported in Phase 3 trials, including no adverse cognitive effects, and low incidence of withdrawal.
Concluding message
Mirabegron treatment is effective and well tolerated for the treatment of older adults with overactive bladder. Mirabegron was not associated with any adverse cognitive effects.
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Disclosures
Funding Astellas Pharma Clinical Trial Yes Registration Number ClinicalTrials.gov Identifier: NCT02216214 RCT Yes Subjects Human Ethics Committee University of Alberta Health Research Ethics Board Helsinki Yes Informed Consent Yes