Abstract
Objective:
To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy.
Patients and methods:
This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > −0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance.
Results:
For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was −0.18 (−0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron.
Conclusions:
Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.
Keywords: mirabegron, noninferiority, overactive bladder, solifenacin
Trial registration: ClinicalTrials.gov identifier NCT01638000
Introduction
Overactive bladder (OAB) is a chronic symptom syndrome characterized by urgency with or without urgency incontinence, often with increased daytime frequency and nocturia, in the absence of an underlying pathologic or metabolic condition that may cause or mimic the symptoms [Abrams et al. 2009].
Antimuscarinic drugs are still the mainstay of oral pharmacological treatment for OAB, relaxing the detrusor muscle and reducing sensory symptoms during the storage phase of the micturition cycle by inhibiting muscarinic receptor subtypes, M2 and M3. Both subtypes are expressed in multiple tissues, increasing the risk of bothersome, anticholinergic adverse events (AEs) such as dry mouth, which along with lack of efficacy, is the most frequently cited reason for discontinuation of antimuscarinic treatment [Benner et al. 2010].
The β3-adrenoceptor agonist, mirabegron, which acts via a different mechanism of action to antimuscarinics, could potentially improve the efficacy/tolerability balance over current standard of care in the management of OAB. In four 12-week phase III studies [Herschorn et al. 2013; Khullar et al. 2013a; Nitti et al. 2013a; Yamaguchi et al. 2014], a pooled analysis [Nitti et al. 2013b] and 12-month study [Chapple et al. 2013], mirabegron (25–100 mg) consistently demonstrated superiority over placebo with respect to reductions in incontinence episodes and micturition frequency, with a similar incidence of AEs as placebo.
Patients refractory to antimuscarinics due to lack of efficacy and/or tolerability require an alternative that is well tolerated and clinically effective to ensure patient satisfaction and long-term treatment success. Prescribing an alternative antimuscarinic, such as solifenacin or darifenacin, has improved symptoms in patients previously dissatisfied with efficacy [Karram and Chancellor, 2006; Zinner et al. 2008; Chancellor et al. 2008]; however, the potential for bothersome anticholinergic AEs may hinder long-term persistence. A post hoc subgroup analysis of phase III clinical trial data suggested that patients who discontinued at least one prior antimuscarinic due to insufficient efficacy benefited from mirabegron (50 and 100 mg), whereas patients receiving tolterodine extended-release (ER) 4 mg demonstrated a placebo-like effect [Khullar et al. 2013b].
The primary objective was to assess the efficacy of mirabegron 50 mg compared with solifenacin 5 mg (primary efficacy endpoint assessed by noninferiority) in the treatment of OAB in patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. Secondary objectives were to assess safety and tolerability between mirabegron and solifenacin.
Given the historic data available that demonstrate the effectiveness and superiority of solifenacin and mirabegron to placebo in OAB patients, a placebo arm was not included in this study. In clinical practice, solifenacin 5 mg is the most commonly prescribed dose, constituting approximately three-quarters of the solifenacin prescriptions in Europe [IMS Health National Prescription Audit, May 2014–October 2014]. Furthermore, when a patient switches from one antimuscarinic to solifenacin, the Summary of Product Characteristics recommendation is to start from 5 mg [Astellas Pharma, 2013].
Subjects and methods
Study design and patient population
This randomized, double-blind, multinational, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who had expressed dissatisfaction, using the Treatment Satisfaction-Likert questionnaire (see Table S1), with the efficacy of their last antimuscarinic. Patients who were dissatisfied with their last antimuscarinic, primarily due to tolerability, or patients who were prescribed solifenacin as their last antimuscarinic prior to study entry, were not eligible.
After initial screening to ascertain eligibility, patients entered a 2-week, single-blind, placebo run-in period to wash out previous medications and to establish daily baseline data using a patient-recorded electronic micturition diary (DiaryPRO®, eResearch Technology, Pittsburgh, USA). Patients who fulfilled all inclusion criteria (see Table S2) at baseline (Visit 2) were randomized 1:1 to receive double-blind mirabegron 50 mg or solifenacin 5 mg once daily for 12 weeks (Figure 1; see Table S3 for randomization and blinding).
Figure 1.
Study design.
Efficacy assessment
The primary efficacy variable was the change from baseline to the end of treatment (EoT; Visit 5) in the mean number of micturitions/24 h, based on an electronic 3-day micturition diary. Secondary efficacy variables included change from baseline to EoT in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes/24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and nocturia episodes/24 h.
A total of three efficacy responder analyses were performed at EoT: (1) normalization of micturition (⩾8 micturitions/24 h at baseline and <8 micturitions/24 h post baseline); (2) zero incontinence episodes (incontinent at baseline and 0 incontinence episodes post baseline); and (3) ⩾50% reduction in incontinence episodes/24 h (incontinent at baseline and ⩾50% decrease from baseline).
Safety assessment
Safety variables included the incidence and severity of treatment-emergent AEs (TEAEs), change from baseline in vital signs (blood pressure and pulse rate), electrocardiogram (ECG) and laboratory parameters. AEs of special interest included antimuscarinic AEs (dry mouth, blurred vision, constipation and dyspepsia) and urinary retention. Vital signs were assessed at each study visit, 12-lead ECG and laboratory parameters were assessed at screening and EoT (see Table S4 for vital sign assessment).
Patient-reported outcomes
Patient-reported outcomes included measures of quality of life (QoL) [symptom bother and total health-related QoL (HRQoL) based on the OAB-q, assessed at visits 2, 3, 4 and 5 (EoT)] and treatment satisfaction [Treatment Satisfaction-Likert questionnaire, assessed at screening and EoT, Treatment Satisfaction-Visual Analogue Scale (TS-VAS), assessed at visits 2 and EoT, and Patient Perception of Bladder Condition (PPBC) questionnaire, assessed at visits 2, 3, 4, and EoT: see Table S1]. Responder analyses assessed the proportion of patients who achieved a minimally important difference of ⩾1 or 2 points in PPBC, and ⩾10 points in the OAB-q (symptom bother and/or HRQoL).
Statistical analyses
The primary endpoint was analyzed in the Per Protocol Set (PPS), that is, all randomized patients who took ⩾1 dose of double-blind study drug with ⩾1 micturition measurement in the baseline and post baseline diary (Full Analysis Set; FAS) who completed the study with no major protocol violations, in accordance with regulatory guidance on noninferiority testing and was repeated for the FAS. The noninferiority margin was determined following regulatory guidance [Committee for Medicinal Products for Human Use, 2014; Committee for Proprietary Medicinal Products, 2014; US Food and Drug Administration, 2010] and based on unpublished pooled data from two placebo-controlled studies [Cardozo et al. 2004; Chapple et al. 2004], which showed the 95% confidence interval (CI) for the difference between solifenacin 5 mg and placebo to be (−1.28, −0.61). The selected noninferiority margin of −0.20 is one third of the upper limit and was not considered a clinically relevant difference. Based on the assumption that the difference between solifenacin 5 mg and mirabegron 50 mg for patients dissatisfied with previous OAB treatment due to lack of efficacy was 0.20 [standard deviation (SD) 2.7], a sample size of 1436 eligible patients was required to show noninferiority of mirabegron 50 mg, with a power of 80% based on a one-sided test and α = 0.025. Assuming dropout rates of 15% during double-blind treatment, 1692 patients were to be randomized.
If the lower limit of the two-sided 95% CI for the difference between solifenacin and mirabegron was > −0.20, noninferiority was concluded (Figure 2). An analysis of covariance (ANCOVA) model, including treatment group, randomization stratification factors [gender, age group (<65, ⩾65), number of prior antimuscarinics (1, ⩾2) and geographic region] as fixed factors, and baseline micturitions/24 h as a covariate, was used to analyze the primary endpoint. Treatment differences were summarized using least squares means and two-sided 95% CIs for mean changes from baseline within treatment group and between treatment groups.
Figure 2.
Possible scenarios for demonstrating noninferiority and superiority between mirabegron and solifenacin.
CI, confidence interval.
For all other efficacy endpoints, the superiority of mirabegron versus solifenacin was assessed using the FAS or FAS-I (FAS-Incontinence; all FAS patients with ⩾1 incontinence episode at baseline).
An ANCOVA model similar to that used for the primary endpoint analyzed urgency episodes and continuous patient-reported outcomes. The primary method for analyzing count data (i.e. incontinence episodes, urgency incontinence episodes, nocturia episodes) used a mixed effects Poisson regression model. As a sensitivity analysis, mean changes from baseline for these endpoints were analyzed using an ANCOVA model. The ANCOVA results are summarized here to facilitate comparisons with previous published data. Responder analyses were analyzed using a logistic regression model with treatment group, randomization factors (gender, age group, number of prior antimuscarinics and geographic region) and baseline measurement. Treatment differences were summarized using point estimates and two-sided 95% CIs based on normal approximation. The p value and 95% CI for odds ratio (OR) were also presented.
Descriptive statistics were presented for the Safety Analysis Set (SAF; all randomized patients who received ⩾1 dose of double-blind study drug). No formal statistical testing was performed on the incidence of individual TEAEs. Change from baseline to EoT for vital signs were analyzed using the ANCOVA model described above.
Results
Demographic and baseline characteristics
A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944); discontinuation rates and reasons for discontinuation of previous antimuscarinic therapy were similar between the treatment groups (Figure 3). The majority of patients were female (76%) and mean age was 57 years; 57.1% of patients had used one antimuscarinic and 42.9% had used >1 antimuscarinic prior to study entry. Approximately 25% of patients had used solifenacin in the past, but not as the most recent antimuscarinic with which the patient was dissatisfied prior to study entry. Demographic and baseline characteristics were similar in both groups (Table 1).
Figure 3.
Patient disposition.
Table 1.
Patient demographics and baseline characteristics (SAF).
| Mirabegron 50 mg |
Solifenacin 5 mg |
Total |
|
|---|---|---|---|
| (n = 936) | (n = 934) | (n = 1870) | |
| Females, n (%) | 712 (76.1) | 709 (75.9) | 1421 (76.0) |
| Mean age, years (SD) | 56.7 (14.3) | 57.4 (13.6) | 57.0 (13.9) |
| ⩾65 years, n (%) | 315 (33.7) | 314 (33.6) | 629 (33.6) |
| Type of OAB*, n (%) | |||
| Urgency incontinence | 383 (40.9) | 387 (41.4) | 770 (41.2) |
| Mixed stress/urgency incontinence | 131 (14.0) | 162 (17.3) | 293 (15.7) |
| Frequency/urgency without incontinence | 422 (45.1) | 385 (41.2) | 807 (43.2) |
| Mean duration of OAB, months (SD) | 63.4 (79.8) | 58.9 (68.8) | 61.1 (74.6) |
| Number of prior antimuscarinics, n (%) | |||
| 1 | 529 (56.5) | 539 (57.7) | 1068 (57.1) |
| 2 | 269 (28.7) | 253 (27.1) | 522 (27.9) |
| >2 | 138 (14.7) | 142 (15.2) | 280 (15.0) |
| Hypertensive patients (medical history and use of antihypertensives at baseline), n (%) | 329 (35.1) | 346 (37.0) | 675 (36.1) |
| Micturitions/24 h, mean (SD) [n] | 11.6 (3.3) [933] | 11.4 (2.9) [932] | 11.5 (3.1) [1865] |
| Incontinence episodes/24 h, mean (SD) [n] | 2.1 (2.3) [410] | 2.1 (2.1) [424] | 2.1 (2.2) [834] |
| Urgency incontinence episodes/24 h, mean (SD) [n] | 1.9 (2.0) [401] | 2.0 (1.9) [413] | 2.0 (2.0) [814] |
| Urgency episodes (grade 3 or 4)/24 h, mean (SD) [n] | 7.7 (4.8) [931] | 7.8 (4.5) [931] | 7.8 (4.6) [1862] |
| Nocturia episodes/24 h, mean (SD) [n] | 2.3 (1.4) [890] | 2.3 (1.4) [895] | 2.3 (1.4) [1785] |
Summaries for incontinence episodes, urgency incontinence episodes, urgency episode, and nocturia episodes are only for patients with baseline value >0.
Type of OAB as assessed by investigator.
OAB, overactive bladder; SAF, safety analysis set; SD, standard deviation.
Efficacy results
Adjusted mean decrease (SE) from baseline to EoT in mean number of micturitions/24 h was 2.95 (0.09) and 3.13 (0.09) in the mirabegron 50 mg and solifenacin 5 mg groups, respectively, with an adjusted mean (95% CI) difference of −0.18 (−0.42, 0.06) (Figure 4). Non-inferiority of mirabegron was not demonstrated since the lower limit of the 95% CI was not > −0.20. Secondary analyses of noninferiority in the FAS demonstrated similar results as in the PPS (Figure 5).
Figure 4.
(a) Adjusted change from baseline to EoT in primary efficacy variable (mean number of micturitions/24 h [PPS]). (b) Treatment difference for change from baseline to EoT in mean number of micturitions/24 h.
CI, confidence interval; EoT, end of treatment; PPS, Per Protocol Set.
Figure 5.
Adjusted change from baseline to EoT in the primary efficacy variable (secondary analysis in FAS) and secondary efficacy variables [mean number of incontinence episodes/24 h (FAS-I), urgency incontinence episodes/24 h (FAS-I), urgency (grade 3 or 4)/24 h and nocturia episodes/24 h (both FAS)].
ANCOVA, analysis of covariance; EoT, end of treatment; FAS, Full Analysis Set; FAS-I, Full Analysis Set-Incontinence.
Clinically meaningful improvements from baseline to EoT in secondary efficacy variables were observed in both treatment groups. None of the treatment differences were statistically significant (Figure 5). Mirabegron and solifenacin also demonstrated improvements in key OAB symptoms in patients aged <65 and ⩾65 years (see Table S5).
Micturition normalization at EoT was achieved in: 43.6% and 47.2% of mirabegron and solifenacin patients, respectively, with a corresponding OR versus mirabegron (95% CI) of 1.14 (0.93, 1.39); 85.1% and 88.1% of patients, respectively, achieved a ⩾50% decrease in incontinence episodes/24 h at EoT with a corresponding OR (95% CI) versus mirabegron of 1.25 (0.82, 1.90); and 67.3% and 68.5% of patients, respectively, achieved zero incontinence episodes at EoT, OR (95% CI) versus mirabegron 1.02 (0.73, 1.42). None of the treatment differences were statistically significant.
Safety results
The incidence of TEAEs was similar between mirabegron 50 mg (29.3%) and solifenacin 5 mg (30.2%). There was no difference in the rate of discontinuation due to AEs in the mirabegron 50 mg [n = 13 (1.4%)] and solifenacin 5 mg [n = 17 (1.8%)] groups. The majority of AEs were of mild or moderate severity with both treatments. TEAEs reported by ⩾2% of patients in the mirabegron 50 mg and solifenacin 5 mg groups, respectively, were dry mouth (3.1% and 5.8%), constipation (2.2% and 2.5%) and headache (3.0% and 2.4%). Two patients experienced urinary retention, one in each treatment group, which resolved spontaneously in both cases. There were no cases of acute urinary retention (Table 2).
Table 2.
Summary of the number of patients who reported TEAEs, the most common TEAEs (⩾2.0% in either treatment group) and AEs of special interest (SAF).
| Mirabegron 50 mg |
Solifenacin 5 mg |
|
|---|---|---|
| (n = 936) | (n = 934) | |
| TEAEs, n (%) | 274 (29.3) | 282 (30.2) |
| Treatment-related* TEAEs, n (%) | 104 (11.1) | 135 (14.5) |
| Death, n (%) | 0 | 0 |
| Serious TEAEs, n (%) | 14 (1.5) | 13 (1.4) |
| Treatment-related* serious TEAEs, n (%) | 4 (0.4) | 4 (0.4) |
| Discontinued due to TEAE, n (%) | 13 (1.4) | 17 (1.8) |
| Discontinued due to treatment-related* TEAE, n (%) | 9 (1.0) | 14 (1.5) |
| Severity of TEAE, n (%) | ||
| Mild | 166 (17.7) | 172 (18.4) |
| Moderate | 87 (9.3) | 93 (10.0) |
| Severe | 21 (2.2) | 17 (1.8) |
| TEAEs in ⩾2.0% of patients in either treatment group, n (%) | ||
| Dry mouth | 29 (3.1) | 54 (5.8) |
| Constipation | 21 (2.2) | 23 (2.5) |
| Headache | 28 (3.0) | 22 (2.4) |
| AEs of special interest, n (%) | ||
| Vision blurred | 6 (0.6) | 4 (0.4) |
| Dyspepsia | 5 (0.5) | 5 (0.5) |
| Hypertension | 10 (1.1) | 14 (1.5) |
| QT prolongation | 2 (0.2) | 0 |
| Cardiac arrhythmia | 13 (1.4) | 10 (1.1) |
| Cardiac failure | 5 (0.5) | 1 (0.1) |
| Tachycardia (reported as AE) | 1 (0.1) | 2 (0.2) |
| Tachycardia (as AE or pulse rate ⩾100 bpm) | 16 (1.7) | 17 (1.8) |
| Atrial fibrillation | 1 (0.1) | 1 (0.1) |
| AEs suggestive of urinary tract infection | 22 (2.4) | 24 (2.6) |
| Urinary retention | 1 (0.1) | 1 (0.1) |
| Acute urinary retention | 0 | 0 |
| Seizure | 0 | 0 |
| Syncope/falls/postural hypotension | 9 (1.0) | 9 (1.0) |
| Hypersensitivity | 32 (3.4) | 35 (3.7) |
| Neoplasm | 5 (0.5) | 4 (0.4) |
| Glaucoma | 7 (0.7) | 7 (0.7) |
| Hepatotoxicity | 4 (0.4) | 2 (0.2) |
No formal statistical testing was performed on the incidence of individual TEAEs.
All potential neoplasm and serious cardiovascular events were adjudicated by an Independent Adjudication Committee.
Drug-related TEAEs were reported if the investigator suspected a possible or probable relationship to study treatment.
AE, adverse event; SAF, safety analysis set; TEAE, treatment emergent adverse event.
Adjusted change from baseline to EoT in vital signs was small in both groups with a mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) <1 mm Hg, and a mean increase in pulse rate <0.5 beats per minute (bpm); treatment differences were not statistically significant (Table 3). There were no clinically relevant treatment differences between hypertensive and nonhypertensive patients (see Table S6). A total of 6 patients [mirabegron 50 mg (n = 2) and solifenacin 5 mg (n = 4)] had treatment-emergent clinically significant ECG findings at EoT; none of the patients discontinued the study (see Table S7).
Table 3.
Change from baseline to final visit in vital signs (SAF).
| Mirabegron 50 mg | Solifenacin 5 mg | |
|---|---|---|
| SBP (mm Hg) | n = 916 | n = 911 |
| Baseline, mean (SE) | 127.06 (0.458) | 127.15 (0.460) |
| Final visit, mean (SE) | 127.81 (0.449) | 127.66 (0.462) |
| Adjusted change from baseline, mean (SE) (95% CI) | 0.74 (0.331) | 0.52 (0.331) |
| (0.09, 1.39) | (−0.13, 1.17) | |
| Difference versus mirabegron, mean (SE) (95% CI) | −0.22 (0.468) (−1.14, 0.70) | |
| DBP (mm Hg) | n = 916 | n = 911 |
| Baseline, mean (SE) | 77.08 (0.265) | 76.85 (0.268) |
| Final visit, mean (SE) | 77.69 (0.272) | 77.74 (0.274) |
| Adjusted change from baseline, mean (SE) (95% CI) | 0.66 (0.219) | 0.85 (0.219) |
| (0.23, 1.09) | (0.42, 1.28) | |
| Difference versus mirabegron, mean (SE) (95% CI) | 0.19 (0.310) (−0.42, 0.80) | |
| Pulse rate (bpm) | n = 915 | n = 910 |
| Baseline, mean (SE) | 72.36 (0.294) | 72.67 (0.297) |
| Final visit, mean (SE) | 72.87 (0.295) | 72.71 (0.317) |
| Adjusted change from baseline, mean (SE) (95% CI) | 0.45 (0.240) | 0.11 (0.240) |
| (−0.02, 0.92) | (−0.36, 0.58) | |
| Difference versus mirabegron, mean (SE) (95% CI) | −0.34 (0.339) (−1.00, 0.33) | |
At each visit, triplicate readings were measured. The average of the second and third readings was used for all visits.
Adjusted change from baseline values were generated from the ANCOVA model. Difference of the adjusted mean was calculated by subtracting the adjusted mean of mirabegron 50 mg from the adjusted mean of solifenacin 5 mg. All 95% CIs are two-sided.
ANCOVA, analysis of covariance; bpm, beats per minute; CI, confidence interval; DBP, diastolic blood pressure; SAF, safety analysis set; SBP, systolic blood pressure; SE, standard error.
Patient-reported outcomes
Both treatments demonstrated clinically meaningful improvements in symptom bother and total HRQoL (OAB-q), treatment satisfaction (TS-Likert questionnaire and TS-VAS) and perception of bladder condition (PPBC; Table 4). With the exception of total HRQoL, treatment differences for each patient-reported outcome were statistically significantly in favor of solifenacin. The high percentage of responders (⩾10 point improvement in symptom bother or total HRQoL; ⩾1 or 2 point improvement in PPBC) in both groups reflected the magnitude of change in these patient-reported outcomes (see Table S8).
Table 4.
Adjusted change from baseline to EoT in OAB-q, PPBC, TS-VAS and TS-Questionnaire Likert Scale (FAS).
| Mirabegron 50 mg | Solifenacin 5 mg | |
|---|---|---|
| OAB-q – Symptom bother | n = 906 | n = 897 |
| Baseline, mean (SE) | 60.36 (0.623) | 60.86 (0.605) |
| Final visit, mean (SE) | 31.77 (0.752) | 29.80 (0.716) |
| Adjusted change, mean (SE) (95% CI) | −28.89 (0.652) | −30.76 (0.655) |
| (−30.17, −27.61) | (−32.04, −29.48) | |
| Difference versus mirabegron, mean (SE) (95% CI) [p value] | −1.87 (0.924) (−3.68, −0.06) [0.043] | |
| OAB-q total HRQoL | n = 906 | n = 897 |
| Baseline, mean (SE) | 49.91 (0.716) | 50.47 (0.730) |
| Final visit, mean (SE) | 74.50 (0.722) | 76.36 (0.694) |
| Adjusted change, mean (SE) (95% CI) | 24.53 (0.616) | 25.94 (0.619) |
| (23.32, 25.74) | (24.73, 27.16) | |
| Difference versus mirabegron, mean (SE) (95% CI) [p value] | 1.41 (0.873) (−0.30, 3.12) [0.11] | |
| PPBC | n = 906 | n = 897 |
| Baseline, mean (SE) | 4.78 (0.032) | 4.81 (0.030) |
| Final visit, mean (SE) | 3.26 (0.047) | 3.12 (0.046) |
| Adjusted change, mean (SE) (95% CI) | −1.53 (0.042) | −1.67 (0.042) |
| (−1.62, −1.45) | (−1.75, −1.59) | |
| Difference versus mirabegron, mean (SE) (95% CI) [p value] | −0.14 (0.059) (−0.25, −0.02) [0.021] | |
| TS-VAS | n = 891 | n = 876 |
| Baseline, mean (SE) | 3.25 (0.11) | 3.01 (0.11) |
| Final visit, mean (SE) | 6.58 (0.11) | 6.97 (0.10) |
| Adjusted change, mean (SE) (95% CI) | 3.44 (0.10) | 3.86 (0.10) |
| (3.24, 3.63) | (3.66, 4.05) | |
| Difference versus mirabegron, mean (SE) (95% CI) [p value] | 0.42 (0.14) (0.14, 0.70) [0.003] | |
| TS-Questionnaire – Likert scale | n = 897 | n = 889 |
| Baseline, mean (SE) | 2.11 (0.023) | 2.12 (0.023) |
| Final visit, mean (SE) | 4.99 (0.054) | 5.15 (0.052) |
| Adjusted change, mean (SE) (95% CI) | 2.88 (0.050) | 3.03 (0.050) |
| (2.78, 2.97) | (2.93, 3.12) | |
| Difference versus mirabegron, mean (SE) (95% CI) [p value] | 0.15 (0.071) (0.01, 0.29) [0.034] | |
Symptom bother score ranges from 0 (least severity) to 100 (worst severity); Total HRQoL score ranges from 0 (worst quality of life) to 100 (best quality of life); PPBC is a Likert scale question asking patients their impression of their current bladder condition: 1 = causes no problems; 6 = causes many severe problems; TS-VAS scale ranges from 0 (no satisfaction with treatment) to 10 (complete satisfaction with treatment); TS Questionnaire-Likert scale ranges from 1 (extremely dissatisfied) to 7 (extremely satisfied).
Adjusted change from baseline values were generated from the ANCOVA model. Difference of the adjusted mean was calculated by subtracting the adjusted mean of mirabegron 50 mg from the adjusted mean of solifenacin 5 mg. All 95% confidence intervals are two-sided.
ANCOVA, analysis of covariance; CI, confidence interval; EoT, end of treatment; FAS, full analysis set; HRQoL, health-related quality of life; OAB-q, overactive bladder-questionnaire; PPBC, Patient Perception of Bladder Condition; SE, standard error; TS-VAS, Treatment Satisfaction-Visual Analogue Scale.
Discussion
Antimuscarinic agents are known to have poor rates of persistence due to bothersome AEs and/or lack of efficacy [Shaya et al. 2005; D’Souza et al. 2008; Wagg et al. 2012], with discontinuation rates as high as 50% and 75% after 6 months and 1 year, respectively [Brostrom and Hallas, 2009; Benner et al. 2010]. Identifying an agent with the optimum balance of efficacy and tolerability remains a major challenge in the management of OAB. A recent meta-analysis and a phase III study suggest that mirabegron has comparable efficacy and improved tolerability compared with antimuscarinics [Khullar et al. 2013a; Maman et al. 2014], making it an attractive therapeutic option in patients who discontinue antimuscarinic therapy. Noninferiority trials are used to demonstrate a potential clinical advantage of a new treatment over a well-established therapy, when no difference in efficacy is expected [Schumi and Wittes, 2011].
Solifenacin 5 mg and 10 mg is licensed for the treatment of OAB. Phase IIIa clinical studies have demonstrated solifenacin also to be an effective treatment for patients who are dissatisfied with their prior antimuscarinic treatment (unpublished pooled data from two placebo-controlled studies) [Cardozo et al. 2004; Chapple et al. 2004]. Solifenacin not only reduced OAB symptoms but also improved HRQoL in OAB patients who were switched from tolterodine ER 4 mg [Karram and Chancellor, 2006; Chancellor et al. 2008]. Mirabegron has been approved for treatment of OAB in several regions in the world, including the USA, Europe, Japan, Canada and Australia. Phase IIIa clinical studies with mirabegron have demonstrated superiority to placebo in patients with OAB [Herschorn et al. 2013; Khullar et al. 2013a; Nitti et al. 2013a,b; Yamaguchi et al. 2014]. Additionally, post hoc subgroup analyses suggest that patients who have previously been exposed to antimuscarinic therapy and discontinued treatment of at least one prior antimuscarinic due to insufficient efficacy did benefit from mirabegron, whereas patients in the group who received tolterodine ER 4 mg demonstrated a placebo-like effect [Khullar et al. 2013b].
In this study the treatment effect with mirabegron 50 mg was similar to solifenacin 5 mg and there were no clinically significant differences between the two treatments for any of the key OAB symptoms. Noninferiority of mirabegron, however, was not confirmed since the resulting lower limit of the two-sided 95% CI for the primary endpoint of micturition frequency was not > −0.20.
Clinically significant reductions of a similar magnitude in key symptoms of OAB were seen in both treatment groups and were reflected by a high percentage of patients becoming asymptomatic (micturition normalization and zero incontinence). The magnitude of reduction in urgency episodes, micturition frequency, and the proportion of responders with mirabegron and solifenacin was higher than that reported in pooled analyses of previous phase III studies [Chapple et al. 2006; Nitti et al. 2013b]; baseline urgency was more severe in this study than in the pooled analyses which could explain the larger magnitude of treatment effect for these endpoints. Improvements in OAB symptoms were observed regardless of age (< or ⩾65 years), confirming a benefit in elderly patients, a significant proportion of the OAB population.
Mirabegron 50 mg and solifenacin 5 mg were well tolerated. The low incidence of AEs with mirabegron including antimuscarinic-associated AEs – dry mouth, constipation and blurred vision – is very consistent with phase III trials where mirabegron demonstrated rates similar to placebo [Herschorn et al. 2013; Khullar et al. 2013a; Nitti et al. 2013a]. Despite a lower incidence of antimuscarinic AEs and lower than expected rates of discontinuation with solifenacin compared with previous studies [Chapple et al. 2006], which was presumably due to the exclusion of treatment-naive patients and patients dissatisfied with previous antimuscarinics solely or primarily due to poor tolerability, the incidence of dry mouth was lower with mirabegron compared with solifenacin. There were no reports of acute urinary retention in this study, which included a relatively high population of male patients (~24%). Small changes in vital signs in both groups were not considered clinically significant and were of a similar magnitude regardless of pre-existing hypertension.
Patients’ perception of efficacy is equally as important as demonstrating objective improvements in OAB symptoms since this predominantly determines persistence. Clinically relevant improvements in QoL, treatment satisfaction and perception of bladder condition were observed in both groups, and were reflected by a high percentage of responders. Although the treatment difference in each case (with the exception of total HRQoL) was statistically significantly in favor of solifenacin, these differences were small in magnitude and not considered to be clinically significant.
The lack of a placebo arm in this study could preclude the inference that mirabegron or solifenacin were associated with any clinically meaningful improvements in OAB symptoms. However, previous placebo-controlled trials in OAB patients, including a post hoc analysis in patients who discontinued prior antimuscarinic therapy due to insufficient efficacy, have demonstrated treatment responses with mirabegron 50 mg and solifenacin 5 mg of a similar or lower magnitude than reported here that were statistically significantly superior compared with placebo [Chapple et al. 2006; Herschorn et al. 2013; Khullar et al. 2013a,b; Nitti et al. 2013a,b]. Other potential study limitations relate to the patient population and the study duration. Patients were excluded if they were dissatisfied with their previous antimuscarinic solely or primarily due to tolerability issues. As a result, it is unclear whether mirabegron would have improved OAB symptoms in patients who responded to previous antimuscarinic agents in addition to those who showed lack of tolerability. This cohort of refractory OAB patients may share certain characteristics or attitudes/beliefs that contribute to a perceived lack of efficacy such as unrealistic expectations of their treatment or poor adherence, which may predispose patients to less favorable efficacy outcomes or delay treatment success. Interestingly, mean baseline TS-VAS was lower among patients randomized to solifenacin, suggesting a higher level of treatment dissatisfaction and a greater potential for symptom improvement following treatment. Direct comparisons between mirabegron and solifenacin in this study and comparisons with previous phase III studies should take account of the antimuscarinic-refractory population in this study, which may have reduced the size of the treatment effect with solifenacin. Urgency, a key OAB symptom, was not selected as a primary endpoint in this study due to the subjectivity of its definition. As a consequence, OAB trials usually include urgency as a secondary efficacy endpoint.
Despite these limitations, there is the opportunity to conduct a larger head-to-head trial between mirabegron and solifenacin with a longer study duration that may benefit from the inclusion of newly diagnosed patients and a crossover design to allow nonresponders to switch treatment arms. This may identify potential patient characteristics that are predictive of treatment response with solifenacin or mirabegron. As a result, new insights into the natural history of OAB could be detected which may help improve treatment and QoL in refractory and treatment-naïve OAB patients.
Conclusion
Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency was not demonstrated in this study of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Nevertheless, clinically relevant improvements were observed with both mirabegron and solifenacin in micturition frequency, incontinence and urgency after 12 weeks’ treatment with no statistically significant differences observed between the two treatments. Both monotherapies were well tolerated, with a numerically lower incidence of dry mouth with mirabegron.
Supplementary Material
Acknowledgments
A full list of study investigators can be found in Table S9.
Footnotes
Funding: The study was funded by Astellas, and designed and analyzed by Astellas in collaboration with the authors. Editorial assistance was funded by Astellas Pharma Inc. Astellas had a role in the design and conduct of the study; management, analysis and interpretation of the data; and the preparation, review, and approval of the manuscript. The authors received editorial assistance from Stuart Murray (Envision Scientific Solutions) in preparing the initial and final drafts of the manuscript.
Conflict of interest statement: M. Huang, E.S. and M.K. are paid employees of Astellas. A.C. is employed as a contractor for Astellas and received consultancy fees from Astellas for his contribution to the study. S.H. received grants from Sunnybrook Research Institute during the conduct of the study, and grants and personal fees from Astellas, Pfizer and Allergan outside the submitted work. J.E.B. and J.C. received fees from Astellas for their roles as study investigators. T.R. received consultancy fees and payment for his role as study investigator from Astellas. H.K. and M. Halaska report no conflicts of interest in preparing this article.
Contributor Information
Jose E. Batista, Urodynamics Unit, URD Hospital Quiron Teknon, Barcelona, Spain
Heinz Kölbl, Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Austria.
Sender Herschorn, Department of Surgery/Urology, University of Toronto, Toronto, Ontario, Canada.
Tomasz Rechberger, II Department of Gynaecology, Medical University, Lublin, Poland.
Javier Cambronero, Department of Urology, Infanta Leonor Hospital, Madrid, Spain.
Michael Halaska, Department of Obstetrics and Gynaecology, Charles University in Prague, Prague, Czech Republic.
Alex Coppell, Astellas Pharma Europe Ltd, Chertsey, Surrey.
Mathilde Kaper, Department of Biostatistics, Astellas Pharma Global Development, Leiden, Netherlands.
Moses Huang, Astellas Pharma Europe Ltd, Chertsey, Surrey.
Emad Siddiqui, Astellas Pharma Europe Ltd, Chertsey, Surrey.
References
- Abrams P., Artibani W., Cardozo L., Dmochowski R., Van Kerrebroeck P., Sand P. (2009) Reviewing the ICS 2002 terminology report: the ongoing debate. Neurourol Urodyn 28: 287. [DOI] [PubMed] [Google Scholar]
- Astellas Pharma Ltd (2013) Vesicare 5mg & 10mg film-coated tablets. London: electronic Medicines Compendium (eMC) Available at: https://www.medicines.org.uk/emc/medicine/14900/SPC/Vesicare+5mg+%26+10mg+film-coated+tablets/ (accessed January 2015). [Google Scholar]
- Benner J., Nichol M., Rovner E., Jumadilova Z., Alvir J., Hussein M., et al. (2010) Patient-reported reasons for discontinuing overactive bladder medication. BJU Int 105: 1276–1282. [DOI] [PubMed] [Google Scholar]
- Brostrom S., Hallas J. (2009) Persistence of antimuscarinic drug use. Eur J Clin Pharmacol 65: 309–314. [DOI] [PubMed] [Google Scholar]
- Cardozo L., Lisec M., Millard R., Van Vierssen Trip O., Kuzmin I., Drogendijk T., et al. (2004) Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 172: 1919–1924. [DOI] [PubMed] [Google Scholar]
- Chancellor M., Zinner N., Whitmore K., Kobashi K., Snyder J., Siami P., et al. (2008) Efficacy of solifenacin in patients previously treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study. Clin Ther 30: 1766–1781. [DOI] [PubMed] [Google Scholar]
- Chapple C., Cardozo L., Steers W., Govier F. (2006) Solifenacin significantly improves all symptoms of overactive bladder syndrome. Int J Clin Pract 60: 959–966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chapple C., Kaplan S., Mitcheson D., Klecka J., Cummings J., Drogendijk T., et al. (2013) Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 63: 296–305. [DOI] [PubMed] [Google Scholar]
- Chapple C., Rechberger T., Al-Shukri S., Meffan P., Everaert K., Huang M., et al. (2004) Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 93: 303–310. [DOI] [PubMed] [Google Scholar]
- Committee for Medicinal Products for Human Use (2014). Guideline on the choice of the non-inferiority margin. London: European Medicines Agency; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003636.pdf (accessed July 2014). [DOI] [PubMed] [Google Scholar]
- Committee for Proprietary Medicinal Products (2014) Points to consider on switching between superiority and non-inferiority. London: European Medicines Agency; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003658.pdf (accessed July 2014). [Google Scholar]
- IMS Health National Prescription Audit, May 2014. –October 2014.
- D’Souza A., Smith M., Miller L., Doyle J., Ariely R. (2008) Persistence, adherence, and switch rates among extended-release and immediate-release overactive bladder medications in a regional managed care plan. J Manag Care Pharm 14: 291–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herschorn S., Barkin J., Castro-Diaz D., Frankel J., Espuna-Pons M., Gousse A., et al. (2013) A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 82: 313–320. [DOI] [PubMed] [Google Scholar]
- Karram M., Chancellor M. (2006) Solifenacin treatment reduces symptoms of overactive bladder in patients with residual urgency on tolterodine treatment: results of the VERSUS study. Int Urogynecol J 17(Suppl. 3): S441. [Google Scholar]
- Khullar V., Amarenco G., Angulo J., Cambronero J., Hoye K., Milsom I., et al. (2013a) Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European–Australian phase 3 trial. Eur Urol 63: 283–295. [DOI] [PubMed] [Google Scholar]
- Khullar V., Cambronero J., Angulo J., Wooning M., Blauwet M., Dorrepaal C., et al. (2013b) Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European–Australian phase 3 trial. BMC Urol 13: 45. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maman K., Aballea S., Nazir J., Desroziers K., Neine M., Siddiqui E., et al. (2014) Comparative efficacy and safety of medical treatments for the management of overactive bladder: a systematic literature review and mixed treatment comparison. Eur Urol 65: 755–765. [DOI] [PubMed] [Google Scholar]
- Nitti V., Auerbach S., Martin N., Calhoun A., Lee M., Herschorn S. (2013a) Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 189: 1388–1395. [DOI] [PubMed] [Google Scholar]
- Nitti V., Khullar V., Van Kerrebroeck P., Herschorn S., Cambronero J., Angulo J., et al. (2013b) Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract 67: 619–632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schumi J., Wittes J. (2011) Through the looking glass: understanding non-inferiority. Trials 12: 106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shaya F., Blume S., Gu A., Zyczynski T., Jumadilova Z. (2005) Persistence with overactive bladder pharmacotherapy in a medicaid population. Am J Manag Care 11: S121–S129. [PubMed] [Google Scholar]
- US Food and Drug Administration (2010) Guidance for industry: non-inferiority clinical trials. Draft guidance. Silver Spring, MD: Center for Drug Evaluation and Research; http://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf (accessed July 2014). [Google Scholar]
- Wagg A., Compion G., Fahey A., Siddiqui E. (2012) Persistence with prescribed antimuscarinic therapy for overactive bladder: a UK experience. BJU Int 110: 1767–1774. [DOI] [PubMed] [Google Scholar]
- Yamaguchi O., Marui E., Kakizaki H., Homma Y., Igawa Y., Takeda M., et al. (2014) Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 113: 951–960. [DOI] [PubMed] [Google Scholar]
- Zinner N., Kobashi K., Ebinger U., Viegas A., Egermark M., Quebe-Fehling E., et al. (2008) Darifenacin treatment for overactive bladder in patients who expressed dissatisfaction with prior extended-release antimuscarinic therapy. Int J Clin Pract 62: 1664–1674. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.