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Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients???65 years with Overactive Bladder-Wet.

ABSTRACT: BACKGROUND:In older patients with overactive bladder (OAB), mirabegron, a ?3-adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile. OBJECTIVES:Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged???65 years with OAB-wet. METHODS:We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placebo. Community-dwelling patients aged???65 years with OAB-wet (one or more incontinence episode and three or more urgency episodes, and an average of eight or more micturitions/24 h over a 3-day diary) were randomized to receive placebo or mirabegron 25 mg/day (optional dose escalation to 50 mg/day at week 4 or 8). Safety analyses were performed for adverse events (AEs) and vital signs on all randomized patients who received one or more dose of study drug. RESULTS:Treatment-emergent AEs (TEAEs), the majority mild or moderate in severity, were reported in 39.4% of placebo patients and 44.2 and 49.8% of those who received mirabegron 25 mg or 50 mg, respectively. The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhea. The incidence of TEAEs was slightly higher in mirabegron patients aged???75 years than in those aged?

SUBMITTER: Herschorn S

PROVIDER: S-EPMC7473960 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients ≥ 65 years with Overactive Bladder-Wet.

Herschorn Sender S Staskin David D Schermer Carol R CR Kristy Rita M RM Wagg Adrian A

Drugs & aging 20200901 9

<h4>Background</h4>In older patients with overactive bladder (OAB), mirabegron, a β<sub>3</sub>-adrenoreceptor agonist, represents an alternative treatment that may have a favorable risk-benefit profile.<h4>Objectives</h4>Our objective was to further examine the safety and tolerability of mirabegron versus placebo treatment in patients aged ≥ 65 years with OAB-wet.<h4>Methods</h4>We conducted a 12-week, double-blind, randomized, placebo-controlled phase IV study to compare mirabegron with placeb ...[more]

PMID: 32725584

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Project description: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 ?3-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).

Project description:OnabotulinumtoxinA and mirabegron have recently gained marketing authorisation to treat symptoms of overactive bladder (OAB).To evaluate the relative efficacy of mirabegron and onabotulinumtoxinA in patients with idiopathic OAB.Network meta-analysis.A search of 9 electronic databases, review documents, guidelines and websites.Randomised trials comparing any licensed dose of onabotulinumtoxinA or mirabegron with each other, anticholinergic drugs or placebo were eligible (19 randomised trials were identified). 1 reviewer extracted data from the studies and a second reviewer checked the data. Candidate trials were assessed for similarity and networks were developed for each outcome. Bayesian network meta-analysis was conducted using both fixed-effects and random-effects models. When there were differences in mean baseline values between mirabegron and onabotulinumtoxinA trials they were adjusted for using network meta-regression (NMR).No studies directly comparing onabotulinumtoxinA to mirabegron were identified. A network was created for each of the 7 outcomes, with 3-9 studies included in each individual network. The trials included in the networks were broadly similar. Patients in the onabotulinumtoxinA trials had more urinary incontinence and urgency episodes at baseline than patients in the mirabegron trials and these differences were adjusted for using NMR. Both onabotulinumtoxinA and mirabegron were more efficacious than placebo at reducing the frequency of urinary incontinence, urgency, urination and nocturia. OnabotulinumtoxinA was more efficacious than mirabegron (50 and 25 mg) in completely resolving daily episodes of urinary incontinence and urgency and in reducing the frequency of urinary incontinence, urgency and urination. NMR supported the results of the network meta-analysis.In the absence of head-to-head trials comparing onabotulinumtoxinA to mirabegron, this indirect comparison indicates that onabotulinumtoxinA may be superior to mirabegron in improving symptoms of urinary incontinence, urgency and urinary frequency in patients with idiopathic OAB.

Project description:Introduction and hypothesisThe objective of this study was to assess the tolerability and treatment preference in patients with overactive bladder (OAB) treated with mirabegron or tolterodine.MethodsThis was a two-period, 8-week crossover, double-blind, phase IV study (PREFER; NCT02138747) in treatment-naive adults with OAB for 3 months or longer randomized to one of four treatment sequences in a 5:5:1:1 ratio (mirabegron/tolterodine, tolterodine/mirabegron, mirabegron/mirabegron, or tolterodine/tolterodine), separated by a washout period of 2 weeks. The primary endpoint was drug tolerability using the Medication Tolerability scale of the OAB Treatment Satisfaction (OAB-S) questionnaire at end of treatment (EoT). Period-by-treatment interactions were analyzed to determine any effect of drug order. Patient preference, change from baseline in OAB symptoms, and treatment-emergent adverse events (TEAEs) were assessed.ResultsA total of 358 randomized patients completed the OAB-S Medication Tolerability scale questionnaire at one or more visits after the baseline evaluation. The mean (95% CI) OAB-S Medication Tolerability scores were significantly higher (better tolerability) for mirabegron (86.29 [83.50, 89.08]) than for tolterodine (83.40 [80.59, 86.20]; p = 0.004). The period-by-treatment interaction was not significant (p = 0.955). Improvements in OAB-S Medication Tolerability scores at EoT were more evident in women, patients aged ≥65 years, and in patients without baseline incontinence, and were greater with mirabegron than with tolterodine extended release. There were no significant differences in patient preference or improvements in OAB symptoms. Significant differences in favor of mirabegron were observed for anticholinergic TEAEs (20.4% vs. 27.4%; p = 0.042) and specifically for gastrointestinal disorders (14.7% vs. 22.5%; p = 0.015).ConclusionsTolerability of mirabegron was significantly higher than that of tolterodine, and patient preference and improvements in OAB symptoms were comparable. Both treatments were well tolerated; however, anticholinergic side effects were higher with tolterodine.

Dataset Information

Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients???65 years with Overactive Bladder-Wet.

Publications

Safety and Tolerability Results from the PILLAR Study: A Phase IV, Double-Blind, Randomized, Placebo-Controlled Study of Mirabegron in Patients ≥ 65 years with Overactive Bladder-Wet.

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