Effect of mirabegron on cognitive function in elderly patients with overactive bladder: MoCA results from a phase 4 randomized, placebo-controlled study (PILLAR)

Tomas L Griebling, Noll L Campbell, Jeffrey Mangel, David Staskin, Sender Herschorn, Dina Elsouda, Carol R Schermer, Tomas L Griebling, Noll L Campbell, Jeffrey Mangel, David Staskin, Sender Herschorn, Dina Elsouda, Carol R Schermer

Abstract

Background: Antimuscarinics are often used for treatment of overactive bladder (OAB), but exposure to medications such as antimuscarinics that have anticholinergic properties has been linked to adverse cognitive effects. A phase 4 placebo-controlled study (PILLAR; NCT02216214) described the efficacy and safety of mirabegron, a β3-adrenoreceptor agonist, for treatment of wet OAB in patients aged ≥65 years. This pre-planned analysis aimed to measure differences in cognitive function between mirabegron and placebo, using a rapid screening instrument for mild cognitive impairment: the Montreal Cognitive Assessment (MoCA).

Methods: Outpatients aged ≥65 years with wet OAB were randomized 1:1 to mirabegron or placebo, stratified by age (<75/≥75 years). There were no exclusion criteria regarding cognitive status. Patients randomized to mirabegron initially received 25 mg/day with an optional increase to 50 mg/day after week 4/8 based on patient/investigator discretion. The MoCA was administered at baseline and end of treatment (EoT, week 12). The study protocol was Independent Ethics Committee/Institutional Review Board-approved.

Results: Of the 887 randomized patients who received ≥1 dose of study drug, 72.3% were female, 79.5% were white, and 28.1% were aged ≥75 years. All patients had ≥1 comorbidity and 94.3% were receiving ≥1 concomitant medication. One third of patients had a history of psychiatric disorders, the most common being depression (17.2%), insomnia (15.7%), and anxiety (11.4%). Baseline mean (standard error, SE) MoCA total scores were 26.9 (0.1) and 26.8 (0.1) in the mirabegron and placebo groups, respectively. Among patients with MoCA data available at baseline/EoT, 27.1% (115/425) and 25.8% (106/411) of mirabegron and placebo group patients, respectively, had impaired cognitive function at baseline (MoCA total score <26). There was no statistically significant change in adjusted mean (SE) MoCA total score from baseline to EoT in the mirabegron group (-0.2 [0.1]) or the placebo group (-0.1 [0.1]).

Conclusions: Treatment with mirabegron for 12 weeks did not contribute to drug-related cognitive side effects in patients aged ≥65 years, as measured by the MoCA. Furthermore, the pattern of change in cognition over time in an older OAB trial population does not appear to differ from that of subjects receiving placebo.

Trial registration: NCT02216214 (prospectively registered August 13, 2014).

Keywords: Aged; Clinical trial; Cognition; Elderly; Geriatric; Lower urinary tract symptoms; Overactive; Phase 4; Urinary bladder.

Conflict of interest statement

TLG is a consultant for Astellas, and has received grants from the National Institute on Aging and the National Institutes of Health. NLC is a consultant for Astellas. JM has received grants from Astellas. DS has received grants and personal fees for services as an investigator, consultant, and speaker for Astellas. SH has received grants from Allergan, Astellas, Ipsen, and Ixaltis, and personal fees from Allergan, Astellas, and Pfizer. DE and CRS are employees of Astellas Pharma Global Development, Inc.

Figures

Fig. 1
Fig. 1
MoCA score at baseline and week 12/EoT. EoT end of treatment, MoCA Montreal Cognitive Assessment. Impaired cognitive function = MoCA total score <26 [19]
Fig. 2
Fig. 2
Percentage of patients with indicated MoCA score change at week 12/EoT. EoT end of treatment, MoCA Montreal Cognitive Assessment
Fig. 3
Fig. 3
Forest plot for MCD of at least −4 points in total MoCA score. CL confidence limit, EoT end of treatment, LCL lower confidence limit, MCD minimally clinically important difference, MoCA Montreal Cognitive Assessment, N number of observations, RR relative risk ratio, UCL upper confidence limit

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