ORIGINAL CLINICAL ARTICLE

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1 Received: 20 January 2017 Accepted: 25 April 2017 DOI: /nau ORIGINAL CLINICAL ARTICLE Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients Dudley Robinson 1 Con Kelleher 2 David Staskin 3 Elizabeth R. Mueller 4 Christian Falconer 5 Jianye Wang 6 Arwin Ridder 7 Matthias Stoelzel 7 Asha Paireddy 7 Rob van Maanen 7 Zalmai Hakimi 8 Sender Herschorn 9 1 King s College Hospital, London, UK 2 Guy s and St Thomas Hospital, London, UK 3 Tufts University School of Medicine, Boston, Massachusetts 4 Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois 5 Karolinska Institute, Stockholm, Sweden 6 Beijing Hospital, Beijing, China 7 Astellas Pharma Global Development, Leiden, Netherlands 8 Astellas Pharma Europe Ltd, Surrey, UK 9 Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada Correspondence Dudley Robinson, Department of Urogynaecology, King s College NHS, Foundation Trust, Denmark Hill, London SE5 9RS, UK. dudley.robinson@nhs.net Funding information Astellas Pharma Europe B.V Aims: To evaluate patient-reported outcomes (PROs) of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo in patients with overactive bladder (OAB) from the SYNERGY trial. Methods: Following a 4-week placebo run-in, period patients ( 18 years) with OAB were randomized 2:2:1:1:1:1 to receive solifenacin 5 mg + mirabegron 25 mg (combination mg), solifenacin 5 mg + mirabegron 50 mg (combination mg), solifenacin 5 mg, mirabegron 25 mg, mirabegron 50 mg, or placebo for 12 weeks, followed by a 2-week washout period. At each visit, PROs related to quality of life, symptom bother, and treatment satisfaction were assessed, including OAB-q Symptom Bother score, health-related quality of life (HRQOL), Total score, treatment satisfaction-visual analogue scale (TS-VAS), and patient perception of bladder condition (PPBC) questionnaires. Results: Overall, 3527 patients were randomized into the study, with 3494 receiving double-blind treatment. At end of treatment (EoT), both combination groups showed greater improvements in OAB-q Symptom Bother score compared with the monotherapy groups (nominal P < 0.001). Statistically significant improvements in HRQOL Total scores were observed in the combination groups versus Alan Wein led the peer-review process as the Associate Editor responsible for the paper Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/nau Neurourology and Urodynamics. 2018;37:

2 ROBINSON ET AL. 395 monotherapy groups (P 0.002). For both combination groups, the OAB-q Symptom Bother score responder rates at EoT were statistically significantly higher versus mirabegron monotherapy (P < 0.05). The mean adjusted changes from baseline to EoT for PPBC were greater in the combination groups compared with monotherapy groups. Conclusions: PROs showed that combination therapy provided clear improvements and an additive effect for many HRQOL parameters, including OAB-q Symptom Bother score, HRQOL Total score, and PPBC. KEYWORDS β 3 -adrenoceptor agonist, add-on, combination therapy, mirabegron, overactive bladder, solifenacin 1 INTRODUCTION The prevalence of overactive bladder (OAB), with or without urgency urinary incontinence (UUI) and lower urinary tract symptoms (LUTS), is substantial in both men and women and has a considerable impact on health-related quality of life (HRQOL). 1 4 The objective of treatment is to reduce these troublesome symptoms and provide meaningful clinical benefits for patients. 5 Until recently the pharmacological treatment of OAB has primarily involved the use of antimuscarinic agents, despite their limited tolerability and the poor persistence of patients with treatment. 6 8 In patients where urinary incontinence persists after antimuscarinic therapy, changing antimuscarinic agents may not provide further benefit. 9 Mirabegron is the first in a new class of β 3 - adrenoceptor agonists and offers an alternative pharmacotherapy option for the treatment of OAB. 10 As mirabegron has a different mechanism of action from antimuscarinic agents, combining mirabegron with an antimuscarinic agent such as solifenacin may improve tolerability while maintaining efficacy compared with an escalating dose of antimuscarinic monotherapy. 11,12 The concept of combining two oral pharmacotherapies with different modes of action is intended to improve OAB symptoms and persistence with treatment without adding to antimuscarinic side effects. This approach may potentially alleviate the need for antimuscarinic medication dose escalation or more invasive procedures. OAB symptoms can have a negative impact on HRQOL and increase the economic healthcare burden. 13 Patient satisfaction with treatment and improvement in HRQOL are the main factors in patient persistence with treatment. Patient-reported outcomes (PROs) have been used to complement objective efficacy assessments in clinical trials and to measure patient satisfaction with treatment and subsequent improvement in HRQOL. 14 There are a number of instruments designed to assess OAB symptom severity, HRQOL and patient well-being, which include the OABquestionnaire (OAB-q), patient perception of bladder condition (PPBC), patient global impression of change (PGIC), and treatment satisfaction-visual analogue scale (TS-VAS). These instruments are robust and validated for assessing disease severity, continence and incontinence, treatment outcomes, and responsiveness to change in severity of OAB symptoms in both clinical trial and real-life settings Collectively, these PRO instruments provide patient relevant insights into the level and degree of improvement in bothersome symptoms and HRQOL of patients. The primary objective of the SYNERGY trial was to evaluate the efficacy and safety of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy by assessing incontinence and micturition frequency in patients with OAB. The primary objective was not met as the mg combination showed superiority versus solifenacin 5 mg, whereas statistical significance versus mirabegron 50 mg was not demonstrated (P = 0.052). 20 A secondary objective was to evaluate PROs of combinations of solifenacin and mirabegron compared with solifenacin and mirabegron monotherapy and with placebo, which are reported here. 2 METHODS 2.1 Study design SYNERGY (ClinicalTrials.gov NCT ) was a multinational, multicenter, randomized, double-blind, parallelgroup, placebo, and active-controlled phase III trial conducted at 435 sites in 42 countries globally. The primary findings of this trial together with methodology and patient eligibility criteria have been reported elsewhere. 20 Briefly, patients aged 18 years with symptoms of OAB for 3 months who recorded on average 8 micturition

3 396 ROBINSON ET AL. episodes/24 h, 1 urgency episode/24 h, and 3 incontinence episodes over a 7-day period prior to randomization were eligible for inclusion. Exclusion criteria included: the presence of an indwelling catheter; chronic inflammation due to bladder pain syndrome or interstitial cystitis; intravesical treatment in the previous 12 months; urinary or gastric retention; severe ulcerative colitis; any contraindication against antimuscarinic agents; significant cardiovascular or cerebrovascular diseases within 6 months of screening; QT prolongation; severe hypertension (defined as a systolic blood pressure 180 mmhg and/or average diastolic blood pressure 110 mmhg when sitting); moderate-to-severe hepatic impairment; severe renal impairment; known hypersensitivity to solifenacin or mirabegron; post-void residual volume >150 ml; significant mixed-urinary incontinence where stress urinary incontinence was the predominant feature. Following a 4-week single-blind placebo run-in period, patients were randomized in a 2:2:1:1:1:1 ratio to receive: solifenacin 5 mg + mirabegron 25 mg (combination mg); solifenacin 5 mg + mirabegron 50 mg (combination mg); solifenacin 5 mg; mirabegron 25 mg; or mirabegron 50 mg or placebo for a 12-week double-blind treatment period, followed by a follow-up visit after a 2-week single-blind washout period (Fig. 1). Randomization was stratified by sex, age group (<65 years, 65 years), geographic region, and previous OAB treatment (yes/no defined as having received any pharmacological OAB treatment at any time in the past). Independent ethics committees or institutional review boards at participating sites approved the protocol and all amendments. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice. For all sites, approval of the protocol was obtained from the government authorities. 2.2 Patient-reported outcomes and assessments All assessments on efficacy and PROs were carried out on the Full Analysis Set (FAS), which comprised all randomized FIGURE 1 Study design. Reprinted from Herschorn et al 20 patients who took 1 dose of double-blind treatment after randomization, reported 1 micturition in the baseline diary and 1 micturition post-baseline, and reported 1 incontinence episode in the baseline diary. Key secondary PROs included changes from baseline to end of treatment (EoT) in OAB-q Symptom Bother score and TS-VAS; other secondary outcomes included OAB-q Total score, PPBC, PGIC scale, and Work Productivity and Activity Impairment: Specific Health Problem (WPAI: SHP) questionnaire scores. (Supplementary Table S1). Responder analyses explored the frequency of patients who showed a 10-point improvement in OAB-q Symptom Bother score, 10-point improvement in HRQOL Total score, and a 1- or 2-point improvement in PPBC, which corresponds to an improvement by the minimally important difference. 15,17 Double-responder analyses included those who had at least a 50% reduction in the mean number of incontinence episodes/24 h and either a: 10-point improvement in the OAB-q Symptom Bother score from baseline or 10-point improvement in HRQOL Total score, or 1-point improvement in PPBC. Triple-responder analyses included those with at least a 50% reduction in the mean number of incontinence episodes/ 24 h plus and either a: 10-point improvement in the OAB-q Symptom Bother score and a 1-point improvement in PPBC from baseline to EoT, or 10-point improvement in HRQOL Total score and a 1- point improvement in PPBC from baseline to EoT. 2.3 Statistical analyses With 762 evaluable patients in a combination therapy group and 381 in each monotherapy or placebo group, the study had a power of 83% to detect an odds ratio (OR) of 1.6 or higher in the number of responders on the Symptom Bother score of the OAB-q between combination and monotherapy groups (assuming a responder rate of 75% in the monotherapy arms). For continuous variables, descriptive statistics included the number of patients (mean, median, minimum, and maximum). Percentages (based on the number of patients with no missing data, ie, add up to 100%) were used to summarize categorical data descriptively. All statistical comparisons were made using two-sided tests at the 0.05 significance level without multiplicity correction. A last observation carried forward (LOCF) approach was applied for the analysis at EoT for patients who withdrew before week 12 and did not have efficacy

4 ROBINSON ET AL. 397 measurements available for that visit. Change from baseline in OAB-q Symptom Bother, HRQOL, and PPBC was analyzed using an ANCOVA model with treatment group, sex, age group (<65, 65 years), previous OAB treatment (yes/no), and geographic region as fixed factors and baseline value as covariate. LS means and two-sided 95% confidence intervals (CIs) for mean changes from baseline within each treatment group as well as differences between treatment groups and P values were derived. Responder analyses were performed using a logistic regression model with treatment, age group (<65, 65 years), sex, previous OAB treatment (yes/no), and baseline value(s) as covariate(s) (if applicable). Odds ratios between combination therapy, monotherapies, and placebo were calculated with two-sided 95% CIs and P values. 3 RESULTS A total of 6991 patients were screened of which 6275 received the placebo run-in medication and 3527 patients were randomized into the study with 3494 receiving double-blind treatment (Fig. 2). In total, 3185 (90.3%) patients completed the study. There were no relevant differences between groups in early discontinuations from double-blind treatment. 3.1 OAB-q symptom bother score There were no major differences among treatment groups in mean OAB-q Symptom Bother scores at baseline, which ranged from 60.6 for the mirabegron 25 mg group to 64.5 for the solifenacin 5 mg treatment group. The mean adjusted change from baseline to EoT in OAB-q Symptom Bother score was greater in the combination groups compared with the monotherapy and placebo groups (Fig. 3A). Both combination groups showed greater improvements in OAB-q Symptom Bother score compared with the monotherapy groups with mean adjusted differences ranging from 4.6, 95%CI ( 7.0, 2.3) for the mg combination group versus solifenacin 5 mg to 7.1, 95%CI ( 9.5, 4.8) for the mg group versus mirabegron 25 mg (nominal P < for both combination groups vs monotherapy groups). At EoT all active treatment groups had a statistically significantly greater improvement in mean OAB-q Symptom Bother score compared with placebo (nominal P for all active treatment groups). For both OAB treatment naïve and previously treated patients the effect size was greater in the combination treatment groups compared with monotherapy groups. The effect size was larger in the previously treated population than in the treatment-naïve population (Supplementary Table S2). 4 HRQOL Statistically significant improvements in HRQOL Total scores were observed in the combination groups versus monotherapy groups (combination mg vs solifenacin 5 mg mean adjusted difference 3.8, 95%CI [1.7, 5.9] and mirabegron 25 mg mean adjusted difference 5.0, 95%CI [2.9, 7.2], P < for both assessments; combination mg vs FIGURE 2 Patient disposition *Excludes one patient who entered placebo run-in period but did not take placebo run-in medication. Excludes four patients who did not have end of run-in data. Includes one patient who entered the placebo run-in period but did not take placebo run-in medication, but was randomized. Patients from one site were excluded from the SAF and FAS due to non-compliance with the protocol. Randomized/registered but never received/dispensed study drug. In the study 3494 patients received double-blind treatment. Reprinted from Herschorn et al 20

5 398 ROBINSON ET AL. FIGURE 3 Adjusted change from baseline to EoT in (A) OAB-q Symptom Bother score and (B) HRQOL Total score (FAS) solifenacin 5 mg mean adjusted difference 4.2, 95%CI [2.0, 6.3], P < and mirabegron 50 mg, mean adjusted difference 3.3, 95%CI [1.2, 5.4], P = 0.002). Statistically significant improvements in HRQOL Total and sub-scale scores from baseline to EoT were observed in all active treatment groups compared with placebo (Fig. 3B, Table 1). For the HRQOL Total scores the effect sizes of combination therapy were roughly the sum of those of the respective monotherapy groups, which is indicative of an additive effect for the combination groups. Both combination groups statistically significantly improved the concern, coping, sleep, and social sub-scale scores from baseline to EoT versus the monotherapy groups (P < 0.05) apart from combination mg versus mirabegron 50 mg on the social sub-scale, which did not reach statistical significance (Table 1). 4.1 Other PRO assessments The mean TS-VAS at baseline was similar across all treatment groups (range 5.2 in solifenacin 5 mg, mirabegron 50 mg and placebo to 5.4 in combination mg). In all groups there was an improvement in TS-VAS at week 4 with a continued improvement over time. Both combination groups provided greater improvements in TS-VAS compared with mirabegron monotherapy (adjusted mean difference for both combinations versus mirabegron monotherapy 0.4, 95%CI: [0.1, 0.7], nominal P < 0.01). Both combination groups provided greater improvements in TS-VAS compared with solifenacin monotherapy (Table 1). The effect size is larger in previously treated patients (in terms of difference vs placebo) compared with the treatment-naïve group (Supplementary Table S2). ThemeanadjustedchangesfrombaselinetoEoTforPPBC were greater in the combination groups compared with monotherapy groups and indicative of an additive effect (Table 1). For the PGIC, more patients in the combination groups reported their bladder very much improved at EoT compared with the monotherapy groups (combination mg 20%; combination mg 27%; solifenacin 5 mg 14%; mirabegron 25 mg 14%; mirabegron 50 mg 15%; and placebo 8%).

6 ROBINSON ET AL. 399 TABLE 1 Mean changes from baseline to EoT in HRQOL sub-scale, TS-VAS, and PPBC scores Placebo (n = 400) Mirabegron 25 mg (n = 392) Mirabegron 50 mg (n = 398) Solifenacin 5 mg (n = 399) Combination mg (n = 800) Combination mg (n = 795) HRQOL concern adjusted mean change, 17.0 (15.0, 18.9) 21.6 (19.6, 23.5) 23.1 (21.1, 25.0) 22.7 (20.7, 24.6) 26.9 (25.5, 28.3) 27.5 (26.1, 28.9) P = 0.001* P < 0.001* P < 0.001* P < 0.001* P < 0.001* HRQOL concern combination vs mirabegron (at same dose) mean difference, NA NA NA NA 5.3 (2.9, 7.8) 4.4 (2.0, 6.8) P < P < HRQOL concern combination vs solifenacin mean difference, NA NA NA NA 4.2 (1.8, 6.6) 4.8 (2.4, 7.2) P = P < HRQOL coping adjusted mean change, 17.7 (15.7, 19.8) 21.3 (19.2, 23.4) 24.3 (22.3, 26.4) 23.3 (21.2, 25.3) 27.4 (25.9, 28.8) 28.1 (26.7, 29.6) P = 0.017* P < 0.001* P < 0.001* P < 0.001* P < 0.001* HRQOL coping combination vs mirabegron (at same dose) mean difference, NA NA NA NA 6.1 (3.6, 8.6) 3.8 (1.3, 6.3) P < P = HRQOL coping combination vs solifenacin mean difference, NA NA NA NA 4.1 (1.6, 6.7) 4.9 (2.3, 7.4) P = P < HRQOL sleep adjusted mean change, 14.2 (12.2, 16.2) 17.5 (15.5, 19.5) 19.1 (17.1, 21.1) 18.0 (16.0, 20.0) 22.4 (21.0, 23.8) 22.4 (21.0, 23.8) P = 0.020* P = 0.001* P = 0.008* P < 0.001* P < 0.001* HRQOL sleep combination vs mirabegron (at same dose) mean difference, NA NA NA NA 4.9 (2.4, 7.3) 3.3 (0.8, 5.7) P < P = HRQOL sleep combination vs solifenacin mean difference, NA NA NA NA 4.4 (2.0, 6.9) 4.4 (2.0, 6.9) P < P < HRQOL social adjusted mean change, 10.6 (9.0, 12.1) 13.0 (11.5, 14.6) 14.9 (13.3, 16.5) 13.6 (12.0, 15.2) 15.8 (14.7, 17.0) 15.8 (14.7, 16.9) P = 0.030* P < 0.001* P = 0.008* P < 0.001* P < 0.001* HRQOL social combination vs mirabegron (at same dose) mean difference, NA NA NA NA 2.8 (0.9, 4.7) 1.0 ( 1.0, 2.9) P = P = HRQOL social combination vs solifenacin mean difference, NA NA NA NA 2.3 (0.3, 4.2) 2.3 (0.3, 4.2) P = P = TS-VAS adjusted mean change, 1.4 (1.2, 1.6) 2.2 (1.9, 2.4) 2.2 (2.0, 2.4) 2.3 (2.1, 2.5) 2.5 (2.4, 2.7) 2.6 (2.4, 2.7) P < 0.001* P < 0.001* P < 0.001* P < 0.001* P < 0.001* (Continues)

7 400 ROBINSON ET AL. TABLE 1 (Continued) Placebo (n = 400) Mirabegron 25 mg (n = 392) Mirabegron 50 mg (n = 398) Solifenacin 5 mg (n = 399) Combination mg (n = 800) Combination mg (n = 795) n = 399 n = 391 n = 398 n = 399 n = 798 n = 794 TS-VAS combination vs mirabegron (at same dose) mean difference, TS-VAS combination vs solifenacin mean difference, PPBC adjusted mean change, PPBC combination vs mirabegron (at same dose) mean difference, PPBC combination vs solifenacin mean difference, NA NA NA NA 0.4 (0.1, 0.7) 0.4 (0.1, 0.7) P = P = NA NA NA NA 0.3 ( 0.0,0.5) 0.3 (0.0, 0.6) P = P = ( 1.0, 0.8) 1.2 a ( 1.3, 1.1) 1.3 ( 1.4, 1.2) 1.3 ( 1.4, 1.2) 1.5 b ( 1.6, 1.4) 1.7 ( 1.8, 1.6) P = 0.002* P < 0.001* P < 0.001* P < 0.001* P < 0.001* NA NA NA NA 0.4 ( 0.5, 0.2) 0.4 ( 0.5, 0.2) P < P < NA NA NA NA 0.3 ( 0.4, 0.1) 0.4 ( 0.5, 0.3) P < P < EoT, end of treatment; HRQOL, health-related quality of life; NA, not applicable; OAB-q, overactive bladder questionnaire; SD, standard deviation. a n = 393. b n = 801. *P-value for differences in mean adjusted values for active treatment group versus placebo. Changes from baseline to EoT in the WPAI:SHP scores showed no clear trends between treatment groups in absence from work, impairment during work, and in overall work impairment (Fig. 4). 4.2 Treatment responders For both combination groups the OAB-q Symptom Bother score responder rates ( 10-point improvement from baseline to EoT) at EoT were statistically significantly higher versus mirabegron monotherapy (combination mg vs mirabegron 25 mg, P < 0.001; combination mg vs mirabegron 50 mg, P = 0.002), and the combination mg was statistically significant versus solifenacin monotherapy (P = 0.037) (Table 2). The OR for HRQOL Total score at EoT for the combination mg versus mirabegron 25 mg reached statistical significance (P < 0.001). For the HRQOL Total score at EoT the OR for responders in all active treatment groups except mirabegron 25 mg were statistically significant compared with placebo. The odds of achieving a 1- or 2-point improvement in PPBC from baseline to EoT were statistically significantly higher for each combination group versus the mirabegron monotherapy groups at the same dosage and for combination mg combination group versus solifenacin 5 mg and effect sizes of combination therapy groups versus monotherapy groups appeared indicative of an additive effect (Table 2). At EoT, the highest proportion of double responders were observed in the combination groups (Fig. 5). For the 50% reduction in incontinence and 10-point improvement in the OAB-q Symptom Bother score group there were statistically significant ORs for the combination mg versus mirabegron 25 mg and for the combination mg group versus both monotherapies. All active treatment groups for each double responder group had statistically significant OR versus placebo. For the 50% reduction in incontinence and 10-point improvement in the HRQOL Total score there was a statistically significant OR for the combination mg group versus mirabegron 25 mg at EoT. For the 50% reduction in incontinence and 1-point improvement in the PPBC there were statistically significant ORs for the combination mg versus mirabegron 25 mg and for combination mg versus both monotherapies. At EoT, the highest proportion of triple responders were observed in the combination groups (Fig. 6). For the first group of triple responders (50% reduction in mean number of incontinence episodes/24 h plus a 10-point improvement in the OAB-q Symptom Bother score from baseline and 1-point improvement in PPBC), the combination mg had a statistically significant OR versus mirabegron 25 mg, and the combination mg had a statistically significant OR versus both monotherapies. For the second group of triple responders

8 ROBINSON ET AL. 401 FIGURE 4 Mean changes from baseline to EoT in WPAI.SHP scores for (A) absence from work; (B) impairment during work; (C) overall work impairment (negative score indicates improvement) (50% reduction in mean number of incontinence episodes/24 h plus a 10-point improvement in HRQOL Total score and 1- point improvement in PPBC), both combinations had a statistically significant OR versus mirabegron but neither combination showed statistical significance against solifenacin. All active treatment groups for each triple responder group had a statistically significant OR versus placebo. 5 DISCUSSION PRO variables generally demonstrated that combination therapy had a positive impact in improving HRQOL of patients with OAB. Improvements in the HRQOL Total score and subscales scores with both combinations exceeded those for the monotherapy components at EoT with the exception of the social subscale. There were also statistically significant differences in favor of both combination therapies versus monotherapies in PPBC score. A higher proportion of patients reported that their bladder symptoms had much improved or very much improved score on the PGIC scale in the combination treatment groups compared with the monotherapy groups. At EoT, there were statistically significant ORs in favor of combination compared with monotherapy in the proportion of responders with a 10-point improvement in OAB-q Symptom Bother score, and in the proportion of patients with 1-point improvement from baseline in PPBC (except for the combination mg vs solifenacin 5 mg). Double- and triple-responder analyses demonstrated statistically significant improvements for the combination mg versus both monotherapies for three out of five variables (double responders of 50% reduction in

9 402 ROBINSON ET AL. TABLE 2 Proportion of responders at EoT for each HRQOL parameter OAB-q symptom bother score responders a n/n (%) Placebo Mirabegron 25 mg Mirabegron 50 mg Solifenacin 5 mg Combination mg Combination mg 261/400 (65.3) 279/392 (71.2) 307/398 (77.1) 324/399 (81.2) 662/800 (82.8) 670/795 (84.3) P = 0.043* P < 0.001* P < 0.001* P < 0.001* P < 0.001* OAB-q symptom bother score responders a Combination vs mirabegron (at same dose) OR NA NA NA NA 2.0 (1.5, 2.7) 1.7 (1.2, 2.3) P < P = OAB-q symptom bother score responders a combination vs solifenacin OR NA NA NA NA 1.2 (0.9, 1.7) 1.4 (1.0, 2.0) P = P = HRQOL Total score responders b n/n, (%) 227/400 (56.8) 239/392 (61.0) 272/398 (68.3) 284/399 (71.2) 596/800 (74.5) 565/795 (71.1) P = 0.185* P < 0.001* P < 0.001* P < 0.001* P < 0.001* HRQOL Total score responders b combination vs mirabegron (at same dose) OR NA NA NA NA 1.9 (1.5, 2.5) 1.2 (0.9, 1.5) P < P = HRQOL Total score responders b Combination vs solifenacin OR NA NA NA NA 1.3 (1.0, 1.7) 1.2 (0.9, 1.5) P = P = PPBC 1-point improvement n/n (%) 239/400 (59.8) 257/393 (65.4) 288/398 (72.4) 287/399 (71.9) 606/801 (75.7) 623/795 (78.4) P = 0.027* P < 0.001* P < 0.001* P < 0.001* P < 0.001* PPBC 1-point improvement combination vs mirabegron (at same dose) OR NA NA NA NA 1.8 (1.3, 2.4) 1.5 (1.1, 2.0) P < P = PPBC 1-point improvement combination vs solifenacin OR NA NA NA NA 1.3 (1.0, 1.8) 1.7 (1.2, 2.3) P = P = PPBC 2-point improvement n/n (%) 118/400 (29.5) 146/393 (37.2) 162/398 (40.7) 170/399 (42.6) 398/801 (49.7) 407/795 (51.2) P = 0.008* P < 0.001* P < 0.001* P < 0.001* P < 0.001* PPBC 2-point improvement combination vs mirabegron (at same dose) OR NA NA NA NA 1.8 (1.3, 2.3) 1.7 (1.3, 2.2) P < P < PPBC 2-point improvement combination vs solifenacin OR NA NA NA NA 1.4 (1.1, 1.9) 1.7 (1.3, 2.2) P = P < EoT, end of treatment; HRQOL, health-related quality of life; NA, not applicable; OAB-q, overactive bladder questionnaire; OR, odds ratio; PPBC, patient perception bladder condition. a Responders defined as 10-point improvement from baseline to EoT in OAB-q Symptom Bother score. b Responders defined as 10-point improvement from baseline to EoT in HRQOL Total score. *P-value for odds ratio for active treatment group versus placebo.

10 ROBINSON ET AL. 403 FIGURE 5 Proportion of double responders at EoT with at least a 50% reduction in incontinence/24 h and (A) 10-point improvement in OAB-q Symptom Bother score, (B) 10-point improvement in HRQOL Total score, (C) 1-point improvement in PPBC score incontinence episodes/24 h and 10-point improvement in OAB-q Symptom Bother score; double responders 50% reduction in incontinence episodes/24 h plus 1-point improvement in PPBC; triple responder 50% reduction in incontinence episodes/24 h plus 10-point improvement in OAB-q Symptom Bother score plus 1-point improvement in PPBC) and for the combination mg for all five variables versus mirabegron 25 mg monotherapy. Collectively, these results show that combination treatment provided patient-relevant improvements, mostly suggestive of an additive effect of combination therapy in the HRQOL of patients compared with monotherapies. However, there were no adjustments for multiplicity beyond the primary and key secondary efficacy endpoints in the SYNERGY trial so it cannot be excluded that some of the improvements in PROs may be due to chance findings.

11 404 ROBINSON ET AL. FIGURE 6 Proportion of triple responders at EoT with at least a 50% reduction in incontinence/24 h and (A) 10-point improvement in OAB-q Symptom Bother score and a 1-point improvement in PPBC or (B) 10-point improvement in HRQOL Total score and a 1-point improvement in PPBC In comparison, the BESIDE study showed the benefit of combination treatment when mirabegron was added to solifenacin 5 mg. 12 However, the patient population in the BESIDE study differed from the present study in that only treatment-experienced patients were recruited and combination therapy was only given to those whose incontinence persisted after 4 weeks of monotherapy with solifenacin 5 mg and who therefore may represent a group of patients with more severe OAB. Consequently, combination therapy with solifenacin 5 mg and mirabegron 50 mg for 12 weeks significantly reduced mean daily incontinence episodes and micturition frequency in this population of antimuscarinic treatment-experienced patients. 12 In SYNERGY, combination treatment was offered to both treatment-naïve and previously treated patients. Previously treated patients tended to respond better to combination treatment. The difference between the two studies in the recruitment of patients may be clinically relevant in considering how to select patients for combination therapy and may partially explain the differences in the primary outcomes between the two studies. One consideration from the SYNERGY trial is that only patients with incontinence were recruited, but two-thirds of patients with OAB do not suffer from incontinence. 21 Therefore, it may be of interest to see if the clinical benefit and HRQOL improvements seen in this study are reflected in real-life clinical practice. A further consideration is that our study used 7-day electronic diaries, which had previously been reported as having a higher reliability and accuracy for measuring micturition and incontinence in OAB patients compared with traditional 3-day paper diaries. 22 However, previous combination studies, including BESIDE and SYM- PHONY, used 3-day electronic diaries; therefore differences in the use of patient diaries may partially have contributed to differences in the efficacy outcomes between the studies. 12,23 6 CONCLUSION PROs showed that solifenacin and mirabegron combination therapy provided clear improvements and a generally additive effect for many HRQOL parameters, including OAB-q Symptom Bother score, HRQOL Total score, PPBC, and double and triple responders compared with solifenacin and mirabegron monotherapy.

12 ROBINSON ET AL. 405 ACKNOWLEDGMENTS The authors would like to thank the SYNERGY study investigators, and all patients and their parents/legal representatives who took part in the study. This study was funded by Astellas Pharma Europe B.V. Medical writing support was provided by John Clarke of Envision Scientific Solutions and funded by Astellas Pharma, Inc. DISCLOSURES This study was funded by Astellas Pharma, Inc. Dudley Robinson is a consultant for Astellas, Pfizer, Allergan, and Ferring and a speaker for Astellas,Pfizer,and Allergan.Con Kelleher is a consultant for Astellas and has received travel sponsorship from Astellas. David Staskin is a speaker, consultant, and investigator for Astellas, speaker and consultant for Allergan, consultant for Outpost Medical Ltd., Juniper Pharma, and NewUro. Elizabeth R. Mueller is a member of Astellas Advisory Board and PeriCoach Advisory Board. Christian Falconer has received non-financial support from Astellas. 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13 406 ROBINSON ET AL. 25. Khullar V, Amarenco G, Angulo JC, et al. Efficacy and tolerability of mirabegron, a beta(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol. 2013;63: SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article. How to cite this article: Robinson D, Kelleher C, Staskin D, et al. Patient-reported outcomes from SYNERGY, a randomized, double-blind, multicenter study evaluating combinations of mirabegron and solifenacin compared with monotherapy and placebo in OAB patients. Neurourology and Urodynamics. 2018;37: