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Efficacy, safety, and tolerability of mirabegron in patients aged ≥65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR)
EURURO-8599; No. of Pages 10 E U R O P E A N U RO L O GY X X X ( 2 019 ) X X X – X X X
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Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR) Adrian Wagg a,*, David Staskin b, Eli Engel c, Sender Herschorn d, Rita M. Kristy e, Carol R. Schermer e a
Geriatric Medicine, University of Alberta, Edmonton, Alberta, Canada;
b
Division of Urology, St Elizabeth’s Medical Center, Boston, MA, USA; c Bayview
Research Group, LLC, Valley Village, CA, USA; d Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; e Astellas Pharma Global Development, Inc., Northbrook, IL, USA
Article info
Abstract
Article history: Accepted October 4, 2019
Background: The majority of patients with overactive bladder (OAB) are aged >65 yr. There has been no prospectively designed study assessing treatment efficacy with the b3-adrenoreceptor agonist, mirabegron, specifically in this age group. Objective: A phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence. Design, setting, and participants: Community-dwelling patients aged 65 yr with OAB for 3 mo. Intervention: Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/ 24 h were randomised 1:1 to double-blind 25 mg/d mirabegron or matched placebo, for 12 wk. After week 4 or 8, the dose could be increased to 50 mg/d mirabegron/matched placebo based on patient and investigator discretion. Outcome measurements and statistical analysis: Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h. Results and limitations: Statistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Safety and tolerability were consistent with the known mirabegron safety profile. Conclusions: Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged 65 yr with OAB and incontinence.
Associate Editor: J.-N. Cornu Keywords: Aged Clinical trial phase IV Cognition Lower urinary tract symptoms Urinary bladder Overactive
* Corresponding author. Department of Medicine, 1-198 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada. Tel. +1-780-492-5338; Fax: +1-780-492-2874. E-mail address: [email protected] (A. Wagg).
https://doi.org/10.1016/j.eururo.2019.10.002 0302-2838/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Patient summary: We examined the effect of mirabegron compared with placebo in people aged 65 yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron.
1.
Introduction
Overactive bladder (OAB) syndrome is characterised by urinary urgency, with or without urgency incontinence [1,2], with the prevalence increasing with age [3,4]. The burden of OAB wet extends beyond symptom bother and health-related quality of life. Elderly patients with OAB commonly have high levels of comorbidity and concomitant medication use, are more likely to have impairment in activities of daily living, and are at increased risks of falls and fractures [5–7]. Although effective in older people [8], treatment with antimuscarinics may lead to intolerable adverse events (AEs) and contribute to problematic anticholinergic burden [5,9–12]. Exposure to drugs with anticholinergic properties has been associated with adverse cognitive effects, particularly in people aged >65 yr [10–14]. Mirabegron, a b3adrenoreceptor agonist, represents an alternative to antimuscarinics for OAB pharmacotherapy, with a potentially more favourable benefit-to-risk ratio in older patients [11,12,15,16]. The primary results of PILLAR, the first prospectively designed randomised controlled trial (RCT) of mirabegron efficacy, safety, and tolerability in patients aged 65 yr, are reported herein. 2.
Patients and methods
PILLAR was a phase IV, double-blind, randomised, placebocontrolled, parallel-group, multicentre, 12-wk study (NCT02216214) conducted between October 2014 and December 2017 in 103 sites in the USA and Canada. The study was designed to compare mirabegron in a flexible dosing regimen with placebo. 2.1.
Patients
Community-dwelling patients aged 65 yr with one or more incontinence episodes, three or more urgency episodes (Patient Perception of Intensity of Urgency Scale [PPIUS] grade 3 or 4 [severe urgency or urgency incontinence]), and an average of eight or more micturition episodes per day based on a 3-d micturition diary were included. Exclusion criteria were nursing home residence, bladder outlet obstruction, predominant stress incontinence, postvoid residual volume (PVR) >150 ml, neurogenic detrusor overactivity, acute urinary tract infection, recent initiation of conservative/invasive therapy for OAB, permanent or intermittent catheterisation, severe renal or hepatic impairment, or uncontrolled hypertension. Mental incapacity to complete the study or consent procedures was
the only cognitive exclusion criterion (Supplementary Table 1 shows all the inclusion/exclusion criteria). Institutional review board/independent ethics committee–approved written informed consent was obtained from all participants or their legally authorised representative prior to any study-related procedures. 2.2.
Study overview
After screening, eligible patients entered a 2-wk placebo run-in period and completed a 3-d electronic diary to record micturition data (Fig. 1). Patients were randomised 1:1 to receive mirabegron or matched placebo, stratified by age <75/75 yr. Randomisation was undertaken via a phone- or web-based platform according to a computer-generated randomisation schedule prepared by the sponsor. Patients, investigators, and the sponsor were blinded to treatment allocation. Enrolled patients initially received 25 mg/d mirabegron or placebo equivalent, but could increase to 50 mg/d mirabegron or placebo equivalent after week 4 or 8 based on individual efficacy/tolerability and investigator discretion. Patients completed 3-d micturition diaries immediately before study visits at weeks 4, 8, and 12. 2.3.
Assessments
The coprimary endpoints were change from baseline to end of treatment (EOT; week 12) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Other endpoints included change from baseline to EOT in the mean volume voided/micturition, and in the mean numbers of urgency episodes/24 h (PPIUS grade 3 or 4) and urgency incontinence episodes/24 h. AEs were collected throughout the study until a followup phone call at week 16 (4 wk after EOT). Patients reported AEs in response to an open-ended question rather than to questions about specific events. A treatment-emergent adverse event (TEAE) was one that started or worsened from the intake of first study medication until 4 wk after EOT. TEAE severity and causal relationship with the study drug were determined by the study investigator according to the protocol. Vital signs (blood pressure and pulse rate) were measured, and electrocardiograms were recorded at every study visit. Patients recorded blood pressure and pulse rate in their electronic diary for 3 d prior to each study visit. Physical examinations were conducted, laboratory parameters were obtained, and PVR was assessed by an ultrasonography/bladder scan at screening and EOT. The Montreal Cognitive Assessment (MoCA), a rapid screening instrument for mild cognitive impairment [17], was conducted at baseline and EOT.
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 1 – Study flow diagram. EOT = end of treatment (week 12).
2.4.
Analyses
Based on previous study data, the probability that a patient receiving mirabegron would have a greater change in the mean number of incontinence episodes/24 h than a patient receiving placebo was 56% [18,19]. Based on a Wilcoxon (Mann-Whitney) rank-sum test, 340 patients per treatment group would yield 82% power, with a two-sided test at a significance level of 0.05. For the change from baseline in the mean number of micturitions/24 h, it was estimated that 340 patients per treatment group would yield 97% power to detect a reduction of 0.8 assuming a standard deviation of 2.7 using a two-sided t test at a significance level of 0.05 [18,19]. Assuming that the changes in the numbers of micturitions and incontinence episodes were independent, the overall power was 80%. The study was designed and powered to detect a difference between the placebo and total mirabegron groups (patients remaining on 25 mg for 12 wk and those who increased to 50 mg at week 4 or 8) and not for each individual dosing group. Data are displayed as placebo versus total and according to the last mirabegron treatment received (ie, 25 or 50 mg). The safety analysis set (SAF) included all randomised patients who received one or more doses of study medication. Baseline characteristics and AEs were summarised descriptively on the SAF. The full analysis set— incontinence (FAS-I) included all patients who received one or more doses of study medication, reported one or more micturition episodes at baseline and after baseline, and one or more incontinence episodes at baseline. Baseline OAB characteristics were summarised descriptively, and all efficacy analyses were conducted on the FAS-I. To control for the possible effect of testing multiple related items, hypotheses were tested in the following order: mean number of incontinence episodes/24 h, mean number of micturitions/24 h, and mean volume voided/micturition. Change from baseline to EOT in the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h were analysed using analysis of covariance (ANCOVA) models, with treatment group, sex, age group (<75/75 yr), and country as fixed factors and the baseline value as a covariate. Change
from baseline to EOT in the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h was analysed using stratified rank ANCOVA models with the same factors. In addition to the overall FAS-I, the coprimary endpoints were also examined in patients aged <75/75 yr. Responder analyses (percentage of patients achieving a 50% decrease in the number of incontinence episodes/24 h, number of zero incontinence episodes/24 h, and normalisation of micturition frequency [<8/24 h] at EOT) were performed using a logistic regression model including the same factors as the ANCOVA models, with odds ratios (ORs) and 95% confidence intervals (CIs) comparing treatment effect between the mirabegron total and placebo groups. 3.
Results
3.1.
Patients
There were 103 study sites, 86 in the USA and 16 in Canada. Data from one US site were removed prior to database lock and unblinding due to data irregularities; these data were not analysed and are not represented in the manuscript. Out of 2380 patients screened, 443 were randomised to receive placebo and 445 mirabegron (Fig. 2). The majority who discontinued during placebo run-in failed to meet the inclusion/exclusion criteria or diary criteria at the end of the run-in period (baseline) or withdrew consent. The SAF comprised 887 patients (Table 1). The majority of patients were female and white, with 28% aged 75 yr. Patients had a mean (standard deviation [SD]) of 8.2 (5.7) comorbid conditions at baseline, with the history of hypertension (57%) and osteoarthritis (36%) being most frequent. The Charlson Comorbidity Index score (mean SD) was 2.3 1.2 for both the mirabegron group and the placebo group [20]. A mean (SD) of 6.5 (4.7) concomitant medications was recorded at baseline. Among 883 patients with baseline MoCA data, the majority (70%) had a normal score, with approximately 25% having mild impairment and <1% having moderate or worse impairment. There were no notable differences between the mirabegron total and placebo groups in baseline demographic characteristics (Table 1 and Supplementary Table 2).
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 2 – Patient disposition. AE = adverse event.
A total of 868 patients comprised the FAS-I. At baseline, the mean OAB duration was approximately 10 yr, with 60% of patients having 10 voids/24 h and 56% having two or more incontinence episodes/24 h. Information concerning OAB medications received before the start of the study was collected only for 30 d prior to enrolment. Oxybutynin was the most common OAB medication used, followed by solifenacin and tolterodine (Supplementary Table 3). As this 30-d window does not adequately represent treatmentnaïve versus experienced patients, these data were not included in the analysis. OAB characteristics were similar between the mirabegron total and placebo groups. Nearly half (219/445 [49%]) of patients who received mirabegron at randomisation were up-titrated from 25 to 50 mg. 3.2.
Efficacy
Statistically significant adjusted mean improvements were observed for the mirabegron group versus the placebo group for the coprimary endpoints of change from baseline to EOT in the mean number of micturitions/24 h (difference [standard error {SE}]: –0.7 [0.2]; 95% CI –1.0, –0.3) and mean
number of incontinence episodes/24 h (difference [SE]: –0.6 [0.1]; 95% CI –0.8, –0.3; Fig. 3A and 3B). Changes in secondary endpoints by mirabegron dose titration are shown in Fig. 4. Statistically significant adjusted mean improvements from baseline to EOT were observed for the mirabegron total group versus the placebo group in the mean volume voided/micturition (difference [SE]: 13.7 [4.5]; 95% CI 5.0, 22.4), mean number of urgency episodes/24 h (difference [SE]: –0.94 [0.22]; 95% CI –1.37, –0.51), and mean number of urgency incontinence episodes/24 h (difference [SE]: –0.56 [0.14]; 95% CI –0.83, –0.29; Fig. 4C, 4D, and 4E, respectively). Despite similar numbers of incontinence episodes/24 h at baseline (Supplementary Table 4), the adjusted mean change at EOT (SE) was lower in patients aged 75 versus <75 yr (total mirabegron group 75 yr: –1.98 [0.20], 95% CI –2.37, –1.60; total mirabegron group <75 yr: –2.09 [0.14], 95% CI –2.36, –1.81; placebo group 75 yr: –1.13 [0.21], 95% CI –1.54, –0.73; placebo group <75 yr: –1.66 [0.14], 95% CI –1.94, –1.38), although the change in the number of micturitions/24 h was similar between the age groups (total mirabegron group 75 yr: –2.33 [0.26], 95% CI –2.84,
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Table 1 – Baseline demographic and OAB characteristics. Demographic characteristics (safety analysis set)
Placebo (n = 442)
Mirabegron 25 mga (n = 226)
Mirabegron 50 mga (n = 219)
Mirabegron total (n = 445)
Female sex, n (%) Age, mean SD Age 75 yr, n (%) BMI category, n (%) <25 25–<30 30 Race, n (%) White Asian Black or African American Other MoCA total score category, n (%)b Normal (26) Mild (18–25) Moderate (10–17) Severe (<10) Missing Medical history, most frequent conditions, n (%)c Hypertension Osteoarthritis Hypertonic bladderd Gastro-oesophageal reflux disease
324 (73) 71.9 6.0 124 (28)
168 (74) 71.6 5.8 66 (29)
149 (68) 71.7 5.2 59 (27)
317 (71) 71.7 5.5 125 (28)
91 (21) 150 (34) 201 (46)
60 (27) 84 (37) 82 (36)
48 (22) 73 (33) 98 (45)
108 (24) 157 (35) 180 (40)
357 (81) 54 (12) 25 (5.7) 6 (1.4)
151 (67) 58 (26) 16 (7.1) 1 (0.4)
197 (90) 1 (0.46) 17 (7.8) 4 (1.8)
348 (78) 59 (13.3) 33 (7.4) 5 (1.1)
305 (69) 103 (23) 3 (0.68) 0 29 (6.6)
168 (74) 44 (20) 1 (0.44) 0 13 (5.8)
142 (65) 68 (31) 2 (0.91) 0 5 (2.3)
310 (70) 112 (25) 3 (0.67) 0 18 (4.1)
243 (55.0) 173 (39.1) 145 (32.8) 135 (30.5)
134 (59.3) 60 (26.5) 86 (38.1) 54 (23.9)
125 (57.1) 87 (39.7) 72 (32.9) 77 (35.2)
259 (58.2) 147 (33.0) 158 (35.5) 131 (29.4)
OAB characteristics (full analysis set—incontinence)
Placebo (n = 431)
Mirabegron 25 mga (n = 220)
Mirabegron 50 mga (n = 217)
Mirabegron total (n = 437)
Duration of symptoms (mo), mean SD Number of micturitions/24 h, mean SDe Number of incontinence episodes/24 h, mean SDe Number of urgency episodes/24 h, mean SDe,f Number of urgency incontinence episodes/24 h, mean SDe Mean volume voided/micturition (ml), mean SD
120 112 10.5 3.1 3.4 3.2 5.8 3.9 3.4 3.1 185 75.2
119 119 10.7 2.3 3.2 3.1 6.7 3.9 3.2 3.1 175 59.2
123 113 10.5 2.5 3.7 3.1 5.0 3.0 3.7 3.1 199 90.1
121 116 10.6 2.4 3.5 3.1 5.9 3.6 3.4 3.1 186 76.3
BMI = body mass index; MoCA = Montreal Cognitive Assessment; OAB = overactive bladder; SD = standard deviation. Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes at and after baseline, and one or more incontinence episodes at baseline. Safety analysis set: all randomised patients who received one or more doses of study medication. a Dose at the end of treatment. b Placebo (n = 440); mirabegron 25 mg (n = 226); mirabegron 50 mg (n = 217); mirabegron total (n = 443). c By preferred term. d Worsening OAB. e Placebo (n = 430). f Patient Perception of Intensity of Urgency Scale grade 3–4.
–1.81; total mirabegron group <75 yr: –2.30 [0.19], 95% CI –2.67, –1.93; placebo group 75 yr: –1.58 [0.27], 95% CI –2.11, –1.05; placebo group <75 yr: –1.77 [0.19], 95% CI –2.14, –1.40; Fig. 3A and B, and Supplementary Table 4). Statistically significantly greater proportions of patients in the mirabegron group versus the placebo group achieved a 50% decrease in incontinence episodes/24 h (72% vs 60%; OR 1.78, 95% CI 1.32, 2.38), zero incontinence episodes/24 h (38% vs 30%; OR 1.50; 95% CI 1.09, 2.06), and normalisation of micturition frequency (45% vs 36%; OR 1.50; 95% CI 1.13, 2.00) at EOT (all p < 0.05; Supplementary Table 5). 3.3.
(2.7%) placebo patients and 15 (3.4%) mirabegron patients. Two patients in the placebo group (0.5%) experienced serious TEAEs (cerebrovascular accident and transient ischaemic attack) that were deemed by the investigator possibly or probably related to study drug. Cardiac disorders were reported in five (1.1%) placebo patients and nine (2.0%) mirabegron patients. No TEAEs resulted in death. There was no statistically significant change in MoCA score from baseline to EOT, with adjusted mean (standard error) changes of 0.1 (0.1) points for placebo and 0.2 (0.1) for mirabegron.
Safety
4. TEAEs were reported by 174 (39%) placebo patients and 209 (47%) mirabegron patients, with 57 (13%) and 84 (19%) deemed possibly or probably related to study drug, respectively (Table 2). The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhoea. Serious TEAEs were reported in 12
Discussion
PILLAR is the first prospectively designed investigation of mirabegron specifically in patients aged 65 yr. The high numbers of comorbid conditions and concomitant medications observed were consistent with those in the general older US population [5].
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 3 – Adjusted mean change from baseline to end of treatment (week 12) in the numbers of (A) micturitions/24 h and (B) incontinence episodes/24 h in all age groups and those aged <75 and 75 yr (full analysis set—incontinence). Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes in the baseline diary and after baseline, and reported one or more incontinence episodes at baseline. Adjusted mean changes were generated from ANCOVA models with treatment group, sex, age group (<75 or 75 yr), and country as fixed factors and baseline value as a covariate. ANCOVA = analysis of covariance; CI = confidence interval; SE = standard error. * Baseline: placebo (n = 430); mirabegron total (n = 437). EOT: placebo (n = 427); mirabegron 25 mg (n = 220), mirabegron 50 mg (n = 215); mirabegron total (n = 435).
Mirabegron treatment resulted in statistically significant reductions in the mean numbers of micturitions/24 h and incontinence episodes/24 h versus placebo over 12 wk. In addition, greater improvements in the mean volume voided/micturition, number of urgency episodes/24 h, and number of urgency incontinence episodes/24 h were also observed. This study was not designed to detect a difference between individual mirabegron doses and placebo, because patients were not randomly allocated to individual doses.
Up-titration to 50 mg was based on individual subject efficacy, tolerability, and patient and investigator discretion, which could have led to the observed differences between the individual mirabegron dose groups. Patients remaining on 25 mg had different baseline demographic and disease characteristics from those electing to increase their dose to 50 mg mirabegron at week 4 or 8, including more women, more Asians, a leaner body mass index (BMI), a higher micturition frequency (10–15 episodes/24 h), and fewer incontinence episodes. Differences in OAB prevalence and
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 4 – Adjusted mean change from baseline over time in the (A) number of micturitions/24 h, (B) number of incontinence episodes/24 h, (C) mean volume voided/micturition, (D) number of urgency episodes/24 h, and (E) number of urgency incontinence episodes/24 h (full analysis set— incontinence). Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes in the baseline diary and post-baseline, and reported one or more incontinence episodes at baseline. Adjusted mean changes were generated from ANCOVA models with treatment group, sex, age group (<75 or 75 yr), and country as fixed factors and baseline value as a covariate. There was no correction for alpha inflation for the mirabegron 25 and 50 mg groups. ANCOVA = analysis of covariance; CI = confidence interval; EOT = end of treatment; SE = standard error. a Baseline: placebo (n = 430), mirabegron total (n = 437); EOT: placebo (n = 427), mirabegron 25 mg (n = 220), mirabegron 50 mg (n = 215), mirabegron total (n = 435). b The study was powered to detect a difference between the placebo and mirabegron total groups. c Baseline: placebo (n = 322), mirabegron total (n = 330); EOT: placebo (n = 319), mirabegron 25 mg (n = 171), mirabegron 50 mg (n = 155), mirabegron total (n = 326).
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
<75 yr
All ages
75 yr
Placebo (n = 442)
Mirabegron 25 mg (n = 226)
Mirabegron 50 mg (n = 219)
Placebo (n = 318)
Mirabegron 25 mg (n = 160)
Mirabegron 50 mg (n = 160)
Placebo (n = 124)
Mirabegron 25 mg (n = 66)
Mirabegron 50 mg (n = 59)
1 TEAEs Drug-related TEAEsb Serious TEAEs Serious drug-related TEAEsb TEAEs leading to discontinuation Drug-related TEAEs leading to discontinuationb Cardiac disorders Most frequent TEAEsc Urinary tract infectiond Headache Diarrhoea Fatigue Upper respiratory tract infection Nausea Dizziness Nasopharyngitis
174 (39) 57 (13) 12 (2.7) 2 (0.45) 14 (3.2) 7 (1.6) 5 (1.1)
100 (44) 47 (21) 7 (3.1) 0 8 (3.5) 6 (2.7) 2 (0.88)
109 (50) 37 (17) 8 (3.7) 0 6 (2.7) 4 (1.8) 7 (3.2)
125 (39) 43 (14) 9 (2.8) 2 (0.63) 6 (1.9) 5 (1.6) 3 (0.94)
65 (41) 30 (19) 5 (3.1) 0 6 (3.8) 4 (2.5) 2 (1.3)
80 (50) 29 (18) 7 (4.4) 0 4 (2.5) 2 (1.3) 7 (4.4)
49 (40) 14 (11) 3 (2.4) 0 8 (6.5) 2 (1.6) 2 (1.6)
35 (53) 17 (26) 2 (3.0) 0 2 (3.0) 2 (3.0) 0
29 (49) 8 (14) 1 (1.7) 0 2 (3.4) 2 (3.4) 0
31 (7.0) 12 (2.7) 6 (1.4) 14 (3.2) 10 (2.3) 6 (1.4) 7 (1.6) 10 (2.3)
16 (7.1) 15 (6.6) 11 (4.9) 6 (2.7) 3 (1.3) 7 (3.1) 1 (0.44) 3 (1.3)
9 8 2 4 7 1 5 2
21 (6.6) 8 (2.5) 2 (0.63) 8 (2.5) 6 (1.9) 5 (1.6) 7 (2.2) 7 (2.2)
11 (6.9) 12 (7.5) 8 (5.0) 3 (1.9) 3 (1.9) 4 (2.5) 1 (0.63) 2 (1.3)
5 4 2 3 5 1 5 2
10 (8.1) 4 (3.2) 4 (3.2) 6 (4.8) 4 (3.2) 1 (0.8) 0 3 (2.4)
5 3 3 3 0 3 0 1
4 4 0 1 2 0 0 0
(4.1) (3.7) (0.91) (1.8) (3.2) (0.46) (2.3) (0.91)
(3.1) (2.5) (1.3) (1.9) (3.1) (0.63) (3.1) (1.3)
(7.6) (4.5) (4.5) (4.5) (4.5) (1.5)
(6.8) (6.8) (1.7) (3.4)
TEAE = treatment emergent adverse event. MedDRA version 20.1. Safety analysis set: all randomised patients who received one or more doses of study medication. a TEAE — an adverse event that started or worsened in the period from first double-blind medication intake until 30 d after the last double-blind medication intake. The number of patients reporting an event is presented. b Possible or probable, as assessed by the investigator, or where relationship was missing. c Preferred term; affecting 2% of any treatment group. d Escherichia urinary tract infection, streptococcal urinary tract infection, urinary tract infection, or bacterial urinary tract infection.
E U RO P E A N U R O L O GY X X X ( 2 019 ) X X X – X X X
TEAEs, n (%)a
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Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
Table 2 – Treatment emergent adverse events (safety analysis set).
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characteristics between race/ethnic groups have been observed in previous studies [21,22], with higher a BMI noted as a potential risk factor for OAB [23]. As a lack of treatment effect was likely to be a key reason for a dose increase, it seems plausible, given the higher level of incontinence and longer duration of OAB, that the group that titrated to 50 mg contained more severely affected patients than the 25 mg group. Ultimately, the impact of the lack of power for individual dosing groups and the elective titration study design on treatment efficacy warrant caution in the interpretation of the dose-specific mirabegron results. A further confounding factor occurs with improvements from baseline in the placebo group, a well-recognised observation in OAB clinical trials [24,25]. Importantly, however, the data within the PILLAR study are consistent with mirabegron efficacy demonstrated previously in a subanalysis of patients aged 65 yr enrolled in three phase III studies [26] and a post hoc analysis of patients aged 75 yr from a Japanese postmarketing study [27]. Mirabegron was well tolerated. The overall frequency of mirabegron TEAEs in this study (47%) was slightly lower than in patients aged 65 yr enrolled in the phase III studies (mirabegron 25 mg, 55%; mirabegron 50 mg, 50%) [26]. The most frequent TEAEs were consistent with the known safety profile of the drug [28]. When classified by baseline MoCA scores, 24% of mirabegron and 25% of placebo group patients had mild cognitive impairment. There was no evidence of change in cognitive function as measured by the MoCA over the 12-wk course of the study, which is of particular relevance given that the potential for cognitive AEs is of concern to older patients receiving treatment for OAB [29]. Despite the increasing prevalence of OAB with age [3,4], those aged 65 yr are often under-represented in clinical trials [30]; as such, the results from this age-group–specific study population, including a significant proportion aged 75 yr, are clinically relevant. The patient eligibility criteria were designed to be simple, although they remain a limitation of any RCT. A relatively high number of patients failed to meet the trial criteria after the placebo run-in period, where their diary data and updated clinical history were re-evaluated. From the diary variables, the majority failed on the urgency episode criterion. Medication persistence and adherence are greater in treatmentexperienced versus treatment-naïve patients [31], and some patients may be refractory to treatment. Since the study recorded OAB medication use only for 30 d prior to the placebo run-in period, we do not know the true proportion of treatment-experienced patients and hence were unable to determine the potential impact on outcomes reported here. The impact of frailty on elderly patients with OAB is complex [32], and a formal frailty assessment may have been a useful addition to determine the generalisability of the data.
9
65 yr, with tolerability consistent with the known safety profile of the drug over 12 wk. Despite the increasing prevalence of OAB with age [3,4], those aged 65 yr are often under-represented in clinical trials [30]; as such, the results from this study population, including a significant proportion aged 75 yr, are clinically relevant.
Author contributions: Adrian Wagg had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Schermer. Acquisition of data: Kristy, Schermer. Analysis and interpretation of data: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Drafting of the manuscript: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Critical revision of the manuscript for important intellectual content: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Statistical analysis: Kristy. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: None. Other: None.
Financial disclosures: Adrian Wagg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Adrian Wagg has received grants, personal fees, and other nonfinancial support from Astellas, Essity, Pfizer, and Pierre Fabre. David Staskin has received grants and personal fees for services as an investigator, consultant, and speaker for Astellas. Eli Engel has received payment for services as an investigator from Astellas. Sender Herschorn has received grants from Allergan, Astellas, Ipsen, and Ixaltis, and personal fees from Allergan, Astellas, and Pfizer. Rita M. Kristy and Carol R. Schermer are employees of Astellas Pharma Global Development, Inc.
Funding/Support and role of the sponsor: This study was funded by Astellas Pharma Global Development, Inc. Medical writing support was provided by Emily Howard, CMPP, of Envision Scientific Solutions and funded by Astellas Pharma Global Development, Inc.
Acknowledgements: The authors would like to thank the PILLAR study investigators, and all patients and their legal representatives who took part in the study. Access to anonymised individual participant level data collected during the trial, in addition to supporting clinical documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com. Study-related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan,
5.
Conclusions
and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable)
These findings demonstrate the efficacy of mirabegron for the treatment of OAB-wet symptoms in patients aged
and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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analysis of the study data. The research proposal is reviewed by an
[16] Chapple CR, Siddiqui E. Mirabegron for the treatment of overactive
Independent Research Panel. If the proposal is approved, access to the
bladder: a review of efficacy, safety and tolerability with a focus on
study data is provided in a secure data sharing environment after receipt
male, elderly and antimuscarinic poor-responder populations, and
of a signed data sharing agreement.
patients with OAB in Asia. Expert Rev Clin Pharmacol 2017;10:131– 51.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. eururo.2019.10.002.
[17] Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9. [18] Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013;189:1388–95. [19] Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized,
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Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Incontinence Editorial by XXX on pp. x-y of this issue.
Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR) Adrian Wagg a,*, David Staskin b, Eli Engel c, Sender Herschorn d, Rita M. Kristy e, Carol R. Schermer e a
Geriatric Medicine, University of Alberta, Edmonton, Alberta, Canada;
b
Division of Urology, St Elizabeth’s Medical Center, Boston, MA, USA; c Bayview
Research Group, LLC, Valley Village, CA, USA; d Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; e Astellas Pharma Global Development, Inc., Northbrook, IL, USA
Article info
Abstract
Article history: Accepted October 4, 2019
Background: The majority of patients with overactive bladder (OAB) are aged >65 yr. There has been no prospectively designed study assessing treatment efficacy with the b3-adrenoreceptor agonist, mirabegron, specifically in this age group. Objective: A phase IV study comparing flexibly dosed mirabegron versus placebo in elderly patients with OAB and urgency incontinence. Design, setting, and participants: Community-dwelling patients aged 65 yr with OAB for 3 mo. Intervention: Following a 2-wk placebo run in, patients with one or more incontinence episodes, three or more urgency episodes, and an average of eight or more micturitions/ 24 h were randomised 1:1 to double-blind 25 mg/d mirabegron or matched placebo, for 12 wk. After week 4 or 8, the dose could be increased to 50 mg/d mirabegron/matched placebo based on patient and investigator discretion. Outcome measurements and statistical analysis: Coprimary endpoints: change from baseline to end of treatment (EOT) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Secondary endpoints: change from baseline to EOT in the mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Analysis of covariance (ANCOVA) was used for the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h. Stratified rank ANCOVA was used for the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h. Results and limitations: Statistically significant improvements were observed for mirabegron versus placebo in change from baseline to EOT in the mean number of micturitions/24 h, mean number of incontinence episodes/24 h, mean volume voided/micturition, mean number of urgency episodes/24 h, and mean number of urgency incontinence episodes/24 h. Safety and tolerability were consistent with the known mirabegron safety profile. Conclusions: Mirabegron efficacy, safety, and tolerability over 12 wk were confirmed in patients aged 65 yr with OAB and incontinence.
Associate Editor: J.-N. Cornu Keywords: Aged Clinical trial phase IV Cognition Lower urinary tract symptoms Urinary bladder Overactive
* Corresponding author. Department of Medicine, 1-198 Clinical Sciences Building, University of Alberta, Edmonton, Alberta, Canada. Tel. +1-780-492-5338; Fax: +1-780-492-2874. E-mail address: [email protected] (A. Wagg).
https://doi.org/10.1016/j.eururo.2019.10.002 0302-2838/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Patient summary: We examined the effect of mirabegron compared with placebo in people aged 65 yr or older with overactive bladder and incontinence. Mirabegron improved the symptoms of overactive bladder compared with placebo. Side effects were similar to those already known for mirabegron.
1.
Introduction
Overactive bladder (OAB) syndrome is characterised by urinary urgency, with or without urgency incontinence [1,2], with the prevalence increasing with age [3,4]. The burden of OAB wet extends beyond symptom bother and health-related quality of life. Elderly patients with OAB commonly have high levels of comorbidity and concomitant medication use, are more likely to have impairment in activities of daily living, and are at increased risks of falls and fractures [5–7]. Although effective in older people [8], treatment with antimuscarinics may lead to intolerable adverse events (AEs) and contribute to problematic anticholinergic burden [5,9–12]. Exposure to drugs with anticholinergic properties has been associated with adverse cognitive effects, particularly in people aged >65 yr [10–14]. Mirabegron, a b3adrenoreceptor agonist, represents an alternative to antimuscarinics for OAB pharmacotherapy, with a potentially more favourable benefit-to-risk ratio in older patients [11,12,15,16]. The primary results of PILLAR, the first prospectively designed randomised controlled trial (RCT) of mirabegron efficacy, safety, and tolerability in patients aged 65 yr, are reported herein. 2.
Patients and methods
PILLAR was a phase IV, double-blind, randomised, placebocontrolled, parallel-group, multicentre, 12-wk study (NCT02216214) conducted between October 2014 and December 2017 in 103 sites in the USA and Canada. The study was designed to compare mirabegron in a flexible dosing regimen with placebo. 2.1.
Patients
Community-dwelling patients aged 65 yr with one or more incontinence episodes, three or more urgency episodes (Patient Perception of Intensity of Urgency Scale [PPIUS] grade 3 or 4 [severe urgency or urgency incontinence]), and an average of eight or more micturition episodes per day based on a 3-d micturition diary were included. Exclusion criteria were nursing home residence, bladder outlet obstruction, predominant stress incontinence, postvoid residual volume (PVR) >150 ml, neurogenic detrusor overactivity, acute urinary tract infection, recent initiation of conservative/invasive therapy for OAB, permanent or intermittent catheterisation, severe renal or hepatic impairment, or uncontrolled hypertension. Mental incapacity to complete the study or consent procedures was
the only cognitive exclusion criterion (Supplementary Table 1 shows all the inclusion/exclusion criteria). Institutional review board/independent ethics committee–approved written informed consent was obtained from all participants or their legally authorised representative prior to any study-related procedures. 2.2.
Study overview
After screening, eligible patients entered a 2-wk placebo run-in period and completed a 3-d electronic diary to record micturition data (Fig. 1). Patients were randomised 1:1 to receive mirabegron or matched placebo, stratified by age <75/75 yr. Randomisation was undertaken via a phone- or web-based platform according to a computer-generated randomisation schedule prepared by the sponsor. Patients, investigators, and the sponsor were blinded to treatment allocation. Enrolled patients initially received 25 mg/d mirabegron or placebo equivalent, but could increase to 50 mg/d mirabegron or placebo equivalent after week 4 or 8 based on individual efficacy/tolerability and investigator discretion. Patients completed 3-d micturition diaries immediately before study visits at weeks 4, 8, and 12. 2.3.
Assessments
The coprimary endpoints were change from baseline to end of treatment (EOT; week 12) in the mean numbers of micturitions/24 h and incontinence episodes/24 h. Other endpoints included change from baseline to EOT in the mean volume voided/micturition, and in the mean numbers of urgency episodes/24 h (PPIUS grade 3 or 4) and urgency incontinence episodes/24 h. AEs were collected throughout the study until a followup phone call at week 16 (4 wk after EOT). Patients reported AEs in response to an open-ended question rather than to questions about specific events. A treatment-emergent adverse event (TEAE) was one that started or worsened from the intake of first study medication until 4 wk after EOT. TEAE severity and causal relationship with the study drug were determined by the study investigator according to the protocol. Vital signs (blood pressure and pulse rate) were measured, and electrocardiograms were recorded at every study visit. Patients recorded blood pressure and pulse rate in their electronic diary for 3 d prior to each study visit. Physical examinations were conducted, laboratory parameters were obtained, and PVR was assessed by an ultrasonography/bladder scan at screening and EOT. The Montreal Cognitive Assessment (MoCA), a rapid screening instrument for mild cognitive impairment [17], was conducted at baseline and EOT.
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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3
Fig. 1 – Study flow diagram. EOT = end of treatment (week 12).
2.4.
Analyses
Based on previous study data, the probability that a patient receiving mirabegron would have a greater change in the mean number of incontinence episodes/24 h than a patient receiving placebo was 56% [18,19]. Based on a Wilcoxon (Mann-Whitney) rank-sum test, 340 patients per treatment group would yield 82% power, with a two-sided test at a significance level of 0.05. For the change from baseline in the mean number of micturitions/24 h, it was estimated that 340 patients per treatment group would yield 97% power to detect a reduction of 0.8 assuming a standard deviation of 2.7 using a two-sided t test at a significance level of 0.05 [18,19]. Assuming that the changes in the numbers of micturitions and incontinence episodes were independent, the overall power was 80%. The study was designed and powered to detect a difference between the placebo and total mirabegron groups (patients remaining on 25 mg for 12 wk and those who increased to 50 mg at week 4 or 8) and not for each individual dosing group. Data are displayed as placebo versus total and according to the last mirabegron treatment received (ie, 25 or 50 mg). The safety analysis set (SAF) included all randomised patients who received one or more doses of study medication. Baseline characteristics and AEs were summarised descriptively on the SAF. The full analysis set— incontinence (FAS-I) included all patients who received one or more doses of study medication, reported one or more micturition episodes at baseline and after baseline, and one or more incontinence episodes at baseline. Baseline OAB characteristics were summarised descriptively, and all efficacy analyses were conducted on the FAS-I. To control for the possible effect of testing multiple related items, hypotheses were tested in the following order: mean number of incontinence episodes/24 h, mean number of micturitions/24 h, and mean volume voided/micturition. Change from baseline to EOT in the mean number of micturitions/24 h, mean volume voided/micturition, and mean number of urgency episodes/24 h were analysed using analysis of covariance (ANCOVA) models, with treatment group, sex, age group (<75/75 yr), and country as fixed factors and the baseline value as a covariate. Change
from baseline to EOT in the mean numbers of incontinence episodes/24 h and urgency incontinence episodes/24 h was analysed using stratified rank ANCOVA models with the same factors. In addition to the overall FAS-I, the coprimary endpoints were also examined in patients aged <75/75 yr. Responder analyses (percentage of patients achieving a 50% decrease in the number of incontinence episodes/24 h, number of zero incontinence episodes/24 h, and normalisation of micturition frequency [<8/24 h] at EOT) were performed using a logistic regression model including the same factors as the ANCOVA models, with odds ratios (ORs) and 95% confidence intervals (CIs) comparing treatment effect between the mirabegron total and placebo groups. 3.
Results
3.1.
Patients
There were 103 study sites, 86 in the USA and 16 in Canada. Data from one US site were removed prior to database lock and unblinding due to data irregularities; these data were not analysed and are not represented in the manuscript. Out of 2380 patients screened, 443 were randomised to receive placebo and 445 mirabegron (Fig. 2). The majority who discontinued during placebo run-in failed to meet the inclusion/exclusion criteria or diary criteria at the end of the run-in period (baseline) or withdrew consent. The SAF comprised 887 patients (Table 1). The majority of patients were female and white, with 28% aged 75 yr. Patients had a mean (standard deviation [SD]) of 8.2 (5.7) comorbid conditions at baseline, with the history of hypertension (57%) and osteoarthritis (36%) being most frequent. The Charlson Comorbidity Index score (mean SD) was 2.3 1.2 for both the mirabegron group and the placebo group [20]. A mean (SD) of 6.5 (4.7) concomitant medications was recorded at baseline. Among 883 patients with baseline MoCA data, the majority (70%) had a normal score, with approximately 25% having mild impairment and <1% having moderate or worse impairment. There were no notable differences between the mirabegron total and placebo groups in baseline demographic characteristics (Table 1 and Supplementary Table 2).
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 2 – Patient disposition. AE = adverse event.
A total of 868 patients comprised the FAS-I. At baseline, the mean OAB duration was approximately 10 yr, with 60% of patients having 10 voids/24 h and 56% having two or more incontinence episodes/24 h. Information concerning OAB medications received before the start of the study was collected only for 30 d prior to enrolment. Oxybutynin was the most common OAB medication used, followed by solifenacin and tolterodine (Supplementary Table 3). As this 30-d window does not adequately represent treatmentnaïve versus experienced patients, these data were not included in the analysis. OAB characteristics were similar between the mirabegron total and placebo groups. Nearly half (219/445 [49%]) of patients who received mirabegron at randomisation were up-titrated from 25 to 50 mg. 3.2.
Efficacy
Statistically significant adjusted mean improvements were observed for the mirabegron group versus the placebo group for the coprimary endpoints of change from baseline to EOT in the mean number of micturitions/24 h (difference [standard error {SE}]: –0.7 [0.2]; 95% CI –1.0, –0.3) and mean
number of incontinence episodes/24 h (difference [SE]: –0.6 [0.1]; 95% CI –0.8, –0.3; Fig. 3A and 3B). Changes in secondary endpoints by mirabegron dose titration are shown in Fig. 4. Statistically significant adjusted mean improvements from baseline to EOT were observed for the mirabegron total group versus the placebo group in the mean volume voided/micturition (difference [SE]: 13.7 [4.5]; 95% CI 5.0, 22.4), mean number of urgency episodes/24 h (difference [SE]: –0.94 [0.22]; 95% CI –1.37, –0.51), and mean number of urgency incontinence episodes/24 h (difference [SE]: –0.56 [0.14]; 95% CI –0.83, –0.29; Fig. 4C, 4D, and 4E, respectively). Despite similar numbers of incontinence episodes/24 h at baseline (Supplementary Table 4), the adjusted mean change at EOT (SE) was lower in patients aged 75 versus <75 yr (total mirabegron group 75 yr: –1.98 [0.20], 95% CI –2.37, –1.60; total mirabegron group <75 yr: –2.09 [0.14], 95% CI –2.36, –1.81; placebo group 75 yr: –1.13 [0.21], 95% CI –1.54, –0.73; placebo group <75 yr: –1.66 [0.14], 95% CI –1.94, –1.38), although the change in the number of micturitions/24 h was similar between the age groups (total mirabegron group 75 yr: –2.33 [0.26], 95% CI –2.84,
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Table 1 – Baseline demographic and OAB characteristics. Demographic characteristics (safety analysis set)
Placebo (n = 442)
Mirabegron 25 mga (n = 226)
Mirabegron 50 mga (n = 219)
Mirabegron total (n = 445)
Female sex, n (%) Age, mean SD Age 75 yr, n (%) BMI category, n (%) <25 25–<30 30 Race, n (%) White Asian Black or African American Other MoCA total score category, n (%)b Normal (26) Mild (18–25) Moderate (10–17) Severe (<10) Missing Medical history, most frequent conditions, n (%)c Hypertension Osteoarthritis Hypertonic bladderd Gastro-oesophageal reflux disease
324 (73) 71.9 6.0 124 (28)
168 (74) 71.6 5.8 66 (29)
149 (68) 71.7 5.2 59 (27)
317 (71) 71.7 5.5 125 (28)
91 (21) 150 (34) 201 (46)
60 (27) 84 (37) 82 (36)
48 (22) 73 (33) 98 (45)
108 (24) 157 (35) 180 (40)
357 (81) 54 (12) 25 (5.7) 6 (1.4)
151 (67) 58 (26) 16 (7.1) 1 (0.4)
197 (90) 1 (0.46) 17 (7.8) 4 (1.8)
348 (78) 59 (13.3) 33 (7.4) 5 (1.1)
305 (69) 103 (23) 3 (0.68) 0 29 (6.6)
168 (74) 44 (20) 1 (0.44) 0 13 (5.8)
142 (65) 68 (31) 2 (0.91) 0 5 (2.3)
310 (70) 112 (25) 3 (0.67) 0 18 (4.1)
243 (55.0) 173 (39.1) 145 (32.8) 135 (30.5)
134 (59.3) 60 (26.5) 86 (38.1) 54 (23.9)
125 (57.1) 87 (39.7) 72 (32.9) 77 (35.2)
259 (58.2) 147 (33.0) 158 (35.5) 131 (29.4)
OAB characteristics (full analysis set—incontinence)
Placebo (n = 431)
Mirabegron 25 mga (n = 220)
Mirabegron 50 mga (n = 217)
Mirabegron total (n = 437)
Duration of symptoms (mo), mean SD Number of micturitions/24 h, mean SDe Number of incontinence episodes/24 h, mean SDe Number of urgency episodes/24 h, mean SDe,f Number of urgency incontinence episodes/24 h, mean SDe Mean volume voided/micturition (ml), mean SD
120 112 10.5 3.1 3.4 3.2 5.8 3.9 3.4 3.1 185 75.2
119 119 10.7 2.3 3.2 3.1 6.7 3.9 3.2 3.1 175 59.2
123 113 10.5 2.5 3.7 3.1 5.0 3.0 3.7 3.1 199 90.1
121 116 10.6 2.4 3.5 3.1 5.9 3.6 3.4 3.1 186 76.3
BMI = body mass index; MoCA = Montreal Cognitive Assessment; OAB = overactive bladder; SD = standard deviation. Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes at and after baseline, and one or more incontinence episodes at baseline. Safety analysis set: all randomised patients who received one or more doses of study medication. a Dose at the end of treatment. b Placebo (n = 440); mirabegron 25 mg (n = 226); mirabegron 50 mg (n = 217); mirabegron total (n = 443). c By preferred term. d Worsening OAB. e Placebo (n = 430). f Patient Perception of Intensity of Urgency Scale grade 3–4.
–1.81; total mirabegron group <75 yr: –2.30 [0.19], 95% CI –2.67, –1.93; placebo group 75 yr: –1.58 [0.27], 95% CI –2.11, –1.05; placebo group <75 yr: –1.77 [0.19], 95% CI –2.14, –1.40; Fig. 3A and B, and Supplementary Table 4). Statistically significantly greater proportions of patients in the mirabegron group versus the placebo group achieved a 50% decrease in incontinence episodes/24 h (72% vs 60%; OR 1.78, 95% CI 1.32, 2.38), zero incontinence episodes/24 h (38% vs 30%; OR 1.50; 95% CI 1.09, 2.06), and normalisation of micturition frequency (45% vs 36%; OR 1.50; 95% CI 1.13, 2.00) at EOT (all p < 0.05; Supplementary Table 5). 3.3.
(2.7%) placebo patients and 15 (3.4%) mirabegron patients. Two patients in the placebo group (0.5%) experienced serious TEAEs (cerebrovascular accident and transient ischaemic attack) that were deemed by the investigator possibly or probably related to study drug. Cardiac disorders were reported in five (1.1%) placebo patients and nine (2.0%) mirabegron patients. No TEAEs resulted in death. There was no statistically significant change in MoCA score from baseline to EOT, with adjusted mean (standard error) changes of 0.1 (0.1) points for placebo and 0.2 (0.1) for mirabegron.
Safety
4. TEAEs were reported by 174 (39%) placebo patients and 209 (47%) mirabegron patients, with 57 (13%) and 84 (19%) deemed possibly or probably related to study drug, respectively (Table 2). The most common TEAEs in mirabegron-treated patients were urinary tract infection, headache, and diarrhoea. Serious TEAEs were reported in 12
Discussion
PILLAR is the first prospectively designed investigation of mirabegron specifically in patients aged 65 yr. The high numbers of comorbid conditions and concomitant medications observed were consistent with those in the general older US population [5].
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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Fig. 3 – Adjusted mean change from baseline to end of treatment (week 12) in the numbers of (A) micturitions/24 h and (B) incontinence episodes/24 h in all age groups and those aged <75 and 75 yr (full analysis set—incontinence). Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes in the baseline diary and after baseline, and reported one or more incontinence episodes at baseline. Adjusted mean changes were generated from ANCOVA models with treatment group, sex, age group (<75 or 75 yr), and country as fixed factors and baseline value as a covariate. ANCOVA = analysis of covariance; CI = confidence interval; SE = standard error. * Baseline: placebo (n = 430); mirabegron total (n = 437). EOT: placebo (n = 427); mirabegron 25 mg (n = 220), mirabegron 50 mg (n = 215); mirabegron total (n = 435).
Mirabegron treatment resulted in statistically significant reductions in the mean numbers of micturitions/24 h and incontinence episodes/24 h versus placebo over 12 wk. In addition, greater improvements in the mean volume voided/micturition, number of urgency episodes/24 h, and number of urgency incontinence episodes/24 h were also observed. This study was not designed to detect a difference between individual mirabegron doses and placebo, because patients were not randomly allocated to individual doses.
Up-titration to 50 mg was based on individual subject efficacy, tolerability, and patient and investigator discretion, which could have led to the observed differences between the individual mirabegron dose groups. Patients remaining on 25 mg had different baseline demographic and disease characteristics from those electing to increase their dose to 50 mg mirabegron at week 4 or 8, including more women, more Asians, a leaner body mass index (BMI), a higher micturition frequency (10–15 episodes/24 h), and fewer incontinence episodes. Differences in OAB prevalence and
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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7
Fig. 4 – Adjusted mean change from baseline over time in the (A) number of micturitions/24 h, (B) number of incontinence episodes/24 h, (C) mean volume voided/micturition, (D) number of urgency episodes/24 h, and (E) number of urgency incontinence episodes/24 h (full analysis set— incontinence). Full analysis set—incontinence: all patients who received one or more doses of study medication after randomisation, reported one or more micturition episodes in the baseline diary and post-baseline, and reported one or more incontinence episodes at baseline. Adjusted mean changes were generated from ANCOVA models with treatment group, sex, age group (<75 or 75 yr), and country as fixed factors and baseline value as a covariate. There was no correction for alpha inflation for the mirabegron 25 and 50 mg groups. ANCOVA = analysis of covariance; CI = confidence interval; EOT = end of treatment; SE = standard error. a Baseline: placebo (n = 430), mirabegron total (n = 437); EOT: placebo (n = 427), mirabegron 25 mg (n = 220), mirabegron 50 mg (n = 215), mirabegron total (n = 435). b The study was powered to detect a difference between the placebo and mirabegron total groups. c Baseline: placebo (n = 322), mirabegron total (n = 330); EOT: placebo (n = 319), mirabegron 25 mg (n = 171), mirabegron 50 mg (n = 155), mirabegron total (n = 326).
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
<75 yr
All ages
75 yr
Placebo (n = 442)
Mirabegron 25 mg (n = 226)
Mirabegron 50 mg (n = 219)
Placebo (n = 318)
Mirabegron 25 mg (n = 160)
Mirabegron 50 mg (n = 160)
Placebo (n = 124)
Mirabegron 25 mg (n = 66)
Mirabegron 50 mg (n = 59)
1 TEAEs Drug-related TEAEsb Serious TEAEs Serious drug-related TEAEsb TEAEs leading to discontinuation Drug-related TEAEs leading to discontinuationb Cardiac disorders Most frequent TEAEsc Urinary tract infectiond Headache Diarrhoea Fatigue Upper respiratory tract infection Nausea Dizziness Nasopharyngitis
174 (39) 57 (13) 12 (2.7) 2 (0.45) 14 (3.2) 7 (1.6) 5 (1.1)
100 (44) 47 (21) 7 (3.1) 0 8 (3.5) 6 (2.7) 2 (0.88)
109 (50) 37 (17) 8 (3.7) 0 6 (2.7) 4 (1.8) 7 (3.2)
125 (39) 43 (14) 9 (2.8) 2 (0.63) 6 (1.9) 5 (1.6) 3 (0.94)
65 (41) 30 (19) 5 (3.1) 0 6 (3.8) 4 (2.5) 2 (1.3)
80 (50) 29 (18) 7 (4.4) 0 4 (2.5) 2 (1.3) 7 (4.4)
49 (40) 14 (11) 3 (2.4) 0 8 (6.5) 2 (1.6) 2 (1.6)
35 (53) 17 (26) 2 (3.0) 0 2 (3.0) 2 (3.0) 0
29 (49) 8 (14) 1 (1.7) 0 2 (3.4) 2 (3.4) 0
31 (7.0) 12 (2.7) 6 (1.4) 14 (3.2) 10 (2.3) 6 (1.4) 7 (1.6) 10 (2.3)
16 (7.1) 15 (6.6) 11 (4.9) 6 (2.7) 3 (1.3) 7 (3.1) 1 (0.44) 3 (1.3)
9 8 2 4 7 1 5 2
21 (6.6) 8 (2.5) 2 (0.63) 8 (2.5) 6 (1.9) 5 (1.6) 7 (2.2) 7 (2.2)
11 (6.9) 12 (7.5) 8 (5.0) 3 (1.9) 3 (1.9) 4 (2.5) 1 (0.63) 2 (1.3)
5 4 2 3 5 1 5 2
10 (8.1) 4 (3.2) 4 (3.2) 6 (4.8) 4 (3.2) 1 (0.8) 0 3 (2.4)
5 3 3 3 0 3 0 1
4 4 0 1 2 0 0 0
(4.1) (3.7) (0.91) (1.8) (3.2) (0.46) (2.3) (0.91)
(3.1) (2.5) (1.3) (1.9) (3.1) (0.63) (3.1) (1.3)
(7.6) (4.5) (4.5) (4.5) (4.5) (1.5)
(6.8) (6.8) (1.7) (3.4)
TEAE = treatment emergent adverse event. MedDRA version 20.1. Safety analysis set: all randomised patients who received one or more doses of study medication. a TEAE — an adverse event that started or worsened in the period from first double-blind medication intake until 30 d after the last double-blind medication intake. The number of patients reporting an event is presented. b Possible or probable, as assessed by the investigator, or where relationship was missing. c Preferred term; affecting 2% of any treatment group. d Escherichia urinary tract infection, streptococcal urinary tract infection, urinary tract infection, or bacterial urinary tract infection.
E U RO P E A N U R O L O GY X X X ( 2 019 ) X X X – X X X
TEAEs, n (%)a
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Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
Table 2 – Treatment emergent adverse events (safety analysis set).
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characteristics between race/ethnic groups have been observed in previous studies [21,22], with higher a BMI noted as a potential risk factor for OAB [23]. As a lack of treatment effect was likely to be a key reason for a dose increase, it seems plausible, given the higher level of incontinence and longer duration of OAB, that the group that titrated to 50 mg contained more severely affected patients than the 25 mg group. Ultimately, the impact of the lack of power for individual dosing groups and the elective titration study design on treatment efficacy warrant caution in the interpretation of the dose-specific mirabegron results. A further confounding factor occurs with improvements from baseline in the placebo group, a well-recognised observation in OAB clinical trials [24,25]. Importantly, however, the data within the PILLAR study are consistent with mirabegron efficacy demonstrated previously in a subanalysis of patients aged 65 yr enrolled in three phase III studies [26] and a post hoc analysis of patients aged 75 yr from a Japanese postmarketing study [27]. Mirabegron was well tolerated. The overall frequency of mirabegron TEAEs in this study (47%) was slightly lower than in patients aged 65 yr enrolled in the phase III studies (mirabegron 25 mg, 55%; mirabegron 50 mg, 50%) [26]. The most frequent TEAEs were consistent with the known safety profile of the drug [28]. When classified by baseline MoCA scores, 24% of mirabegron and 25% of placebo group patients had mild cognitive impairment. There was no evidence of change in cognitive function as measured by the MoCA over the 12-wk course of the study, which is of particular relevance given that the potential for cognitive AEs is of concern to older patients receiving treatment for OAB [29]. Despite the increasing prevalence of OAB with age [3,4], those aged 65 yr are often under-represented in clinical trials [30]; as such, the results from this age-group–specific study population, including a significant proportion aged 75 yr, are clinically relevant. The patient eligibility criteria were designed to be simple, although they remain a limitation of any RCT. A relatively high number of patients failed to meet the trial criteria after the placebo run-in period, where their diary data and updated clinical history were re-evaluated. From the diary variables, the majority failed on the urgency episode criterion. Medication persistence and adherence are greater in treatmentexperienced versus treatment-naïve patients [31], and some patients may be refractory to treatment. Since the study recorded OAB medication use only for 30 d prior to the placebo run-in period, we do not know the true proportion of treatment-experienced patients and hence were unable to determine the potential impact on outcomes reported here. The impact of frailty on elderly patients with OAB is complex [32], and a formal frailty assessment may have been a useful addition to determine the generalisability of the data.
9
65 yr, with tolerability consistent with the known safety profile of the drug over 12 wk. Despite the increasing prevalence of OAB with age [3,4], those aged 65 yr are often under-represented in clinical trials [30]; as such, the results from this study population, including a significant proportion aged 75 yr, are clinically relevant.
Author contributions: Adrian Wagg had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Schermer. Acquisition of data: Kristy, Schermer. Analysis and interpretation of data: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Drafting of the manuscript: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Critical revision of the manuscript for important intellectual content: Wagg, Staskin, Engel, Herschorn, Kristy, Schermer. Statistical analysis: Kristy. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: None. Other: None.
Financial disclosures: Adrian Wagg certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Adrian Wagg has received grants, personal fees, and other nonfinancial support from Astellas, Essity, Pfizer, and Pierre Fabre. David Staskin has received grants and personal fees for services as an investigator, consultant, and speaker for Astellas. Eli Engel has received payment for services as an investigator from Astellas. Sender Herschorn has received grants from Allergan, Astellas, Ipsen, and Ixaltis, and personal fees from Allergan, Astellas, and Pfizer. Rita M. Kristy and Carol R. Schermer are employees of Astellas Pharma Global Development, Inc.
Funding/Support and role of the sponsor: This study was funded by Astellas Pharma Global Development, Inc. Medical writing support was provided by Emily Howard, CMPP, of Envision Scientific Solutions and funded by Astellas Pharma Global Development, Inc.
Acknowledgements: The authors would like to thank the PILLAR study investigators, and all patients and their legal representatives who took part in the study. Access to anonymised individual participant level data collected during the trial, in addition to supporting clinical documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com. Study-related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan,
5.
Conclusions
and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable)
These findings demonstrate the efficacy of mirabegron for the treatment of OAB-wet symptoms in patients aged
and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant
Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002
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analysis of the study data. The research proposal is reviewed by an
[16] Chapple CR, Siddiqui E. Mirabegron for the treatment of overactive
Independent Research Panel. If the proposal is approved, access to the
bladder: a review of efficacy, safety and tolerability with a focus on
study data is provided in a secure data sharing environment after receipt
male, elderly and antimuscarinic poor-responder populations, and
of a signed data sharing agreement.
patients with OAB in Asia. Expert Rev Clin Pharmacol 2017;10:131– 51.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j. eururo.2019.10.002.
[17] Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9. [18] Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013;189:1388–95. [19] Herschorn S, Barkin J, Castro-Diaz D, et al. A phase III, randomized,
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Please cite this article in press as: Wagg A, et al. Efficacy, safety, and tolerability of mirabegron in patients aged 65 yr with overactive bladder wet: a phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol (2019), https://doi.org/ 10.1016/j.eururo.2019.10.002