Severity of overactive bladder symptoms and response to dose escalation in a randomized, double-blind trial of solifenacin (SUNRISE)

Authors


Correspondence: Professor Linda Cardozo, Department of Urogynaecology, King's College Hospital, Denmark Hill, London SE5 9RS, UK.

e-mail: linda@lindacardozo.co.uk

Abstract

What's known on the subject? and What does the study add?

  • Antimuscarinics are effective and well tolerated for treatment of OAB. Studies have found that a flexible dosing strategy can be effective in improving OAB symptoms with minimal impact on tolerability.
  • This study confirms these findings with two doses of solifenacin, and shows that improved outcomes can be achieved by increasing solifenacin dose (from 5 to 10 mg) in patients with more severe symptoms.

Objective

  • To determine the relationship between severity of baseline overactive bladder (OAB) symptoms and requests for solifenacin dose increases, and the efficacy of 5 and 10 mg solifenacin doses in relieving OAB symptoms in patients who requested a dose increase.

Patients and Methods

  • In a 16-week clinical study, patients with OAB were randomized to double-blind treatment with solifenacin or placebo once daily.
  • At week 8, all patients could request a dose increase; these patients entered a second phase of 8 weeks in which those in the solifenacin group were randomized to either 5 or 10 mg doses.
  • The primary efficacy variable was mean change in the number of urgency episodes with or without incontinence per 24 h, measured using the Patient Perception of Intensity of Urgency Scale (PPIUS; grades 3 and 4).

Results

  • Of 591 patients receiving solifenacin at 8 weeks, 275 (46.5%) requested a dose increase to 10 mg, and were further randomized to receive 10 mg (n = 140) or to remain on 5 mg (n = 135).
  • Patients who requested a dose increase at week 8 generally had more severe OAB symptoms at baseline and a smaller response at week 8 to the initial solifenacin 5 mg dosage than those who did not.
  • Greater reductions in the mean number of severe urgency episodes (PPIUS grades 3 and 4) were observed from week 8 to the end of treatment for patients requesting a dose increase and randomized to 10 mg solifenacin compared with those randomized to remain on 5 mg (mean reductions –0.9 vs –0.4, respectively), although these did not reach statistical significance.
  • Statistically significant reductions were observed in mean total urgency score (TUS; –2.7 vs –0.6; P = 0.010), mean maximum PPIUS urgency rating (–0.3 vs –0.1; P = 0.034) and mean micturition frequency (–0.8 vs –0.1; P = 0.037). For all other OAB variables, greater changes were observed in the solifenacin 10 mg group but these did not reach statistical significance.
  • Of those who requested a dose increase, eight (5.7%) patients randomized to receive 10 mg and one (0.7%) patient randomized to remain on 5 mg reported new or worsening cases of dry mouth.

Conclusions

  • Increasing the solifenacin dose to 10 mg further improved OAB symptoms in patients who requested a dose increase after 8 weeks' treatment with 5 mg solifenacin.
  • The present study supports the view that patients with severe OAB symptoms benefit from a higher antimuscarinic dose.
Abbreviations
OAB

overactive bladder

PPIUS

Patient Perception of Intensity of Urgency Scale

TUS

total urgency score

Introduction

Overactive bladder (OAB) syndrome is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection or other obvious pathology [1, 2]. Symptoms of OAB can have a significant impact on the health-related quality of life of patients with OAB, and can be associated with additional burden from an increased risk of falls and fractures, urinary tract and skin infections, sleep disturbances and depression [3]. Population-based surveys indicate that OAB occurs in about 12–17% of people, and prevalence increases with age [4-6].

The first line of treatment is normally to offer advice on fluid management, bladder training and pelvic floor muscle exercises. In many patients, drug treatment will also be needed at some stage, with antimuscarinics being the usual treatment of choice. These agents are generally regarded as efficacious, but are associated with a relatively high incidence of anticholinergic-type adverse events, such as dry mouth [7]. Where antimuscarinics are available in two or more dose strengths, a flexible dosing strategy could help to achieve the desired efficacy/tolerability ratio [8]. Several randomized controlled trials using flexible dosing with antimuscarinics have demonstrated that this strategy can be effective in improving subjective and objective outcome measures in patients with OAB [9-14]. However, there is a relative lack of data that directly compare the potential benefits of dose escalation vs non-escalation in matched groups of patients in randomized studies. There is also little information from controlled studies about which types of patients are most likely to request, or benefit from, dose increases.

We previously reported the primary results of the SUNRISE trial [9]. This was a 16-week study of solifenacin vs placebo in which patients with OAB randomized to solifenacin were initiated on a 5 mg dose, then given the opportunity to request a dose increase to 10 mg after 8 weeks. The original report presented data on pooled results of flexible dosing with 5/10 mg solifenacin vs placebo, and showed that solifenacin 5/10 mg was significantly more effective than placebo in reducing the mean number of urgency episodes with or without incontinence per 24 h from baseline to the end of treatment (P < 0.001), and that there were also statistically significant differences in favour of solifenacin 5/10 mg over placebo for all secondary variables measured at the end of treatment, including patient-reported outcomes.

In addition to these pooled flexible dosing results, the protocol of the SUNRISE trial was also designed to provide data from patients who requested dose increases at week 8, who were randomized to receive 10 mg solifenacin or to continue receiving the 5 mg dose. The objectives of the present analysis were to determine whether requests for dose increases were related to the severity of OAB symptoms at baseline, and to compare the effects of solifenacin in patients requesting dose increases who received a dose increase to 10 mg with those who remained on the 5 mg dose.

Patients and Methods

SUNRISE was a 16-week, prospective, double-blind, double-randomized, parallel-group, multicentre study [9]. Eligible patients had ≥ three severe urgency episodes with or without incontinence during the 3-day voiding diary period, defined as Patient Perception of Intensity of Urgency Scale (PPIUS) grades 3 and 4 (Table 1), and ≥ eight micturitions/24 h. After a single-blind, placebo-controlled, 2-week run-in period, patients were randomized (3:1) at baseline (i.e. week 0) to receive 16 weeks of double-blind treatment with solifenacin or placebo once daily. During the first 8 weeks, the patients received solifenacin 5 mg or placebo. At week 8, all patients were given the opportunity to request a dose increase, based on a consideration of efficacy and tolerability discussed jointly between the patient and doctor. Patients were aware from the informed consent form that they could request a dose increase.

Table 1. The PPIUS. The rating was documented at each void during the diary period. In the present study, the primary variable was change from baseline in the number of severe urgency episodes (PPIUS grades 3 and 4).
ScoreDescription
  1. *Equating to the ICS definition of urgency [1]. Equating to urgency incontinence.
0I felt no need to empty my bladder but did so for other reasons
1I could postpone voiding as long as necessary without fear of wetting myself
2I could postpone voiding for a short while without fear of wetting myself
3I could not postpone voiding but had to rush to the toilet in order not to wet myself*
4I leaked before arriving at the toilet

Those who requested a dose increase entered a second randomization phase in which patients in the solifenacin group received either 10 mg (two × 5 mg solifenacin tablets once daily) or 5 mg (one × 5 mg solifenacin tablet and one placebo tablet once daily). Patients originally randomized to placebo continued on this treatment in a double-blind manner regardless of their dose increase request. Patients who did not request a dose increase continued for the rest of the treatment period as before. Patients and investigators were blinded as to whether a dose increase was received or not. Throughout the study, all patients received two tablets daily, and this was not altered by the dose decision. As the main aim of this analysis was to determine whether a dose–response relationship could be demonstrated with solifenacin, data for placebo groups are not presented here.

The primary endpoint was the mean change in the number of severe urgency episodes with or without incontinence per 24 h measured using the PPIUS, grades 3 and 4 (Table 1). Secondary efficacy variables included number of urgency episodes (PPIUS grades 1–4) per 24 h, maximum urgency intensity per 24 h, total urgency score (TUS) per 24 h (a measure of both frequency and urgency, calculated as the mean of daily totals for all recorded PPIUS urgency gradings [from 0 to 4] for each diary day [15]), micturition frequency per 24 h, number of incontinence episodes, number of urgency incontinence episodes, Patient Perception of Bladder Condition (PPBC), urgency bother visual analogue scale (UB-VAS), and treatment satisfaction visual analogue scale (TS-VAS). Safety and tolerability, including the nature, frequency and intensity of adverse events, and withdrawals due to adverse events, were also assessed as secondary endpoints.

Mixed model analyses were used to compare estimated differences between the 5 and 10 mg solifenacin groups in subjects who requested dose increases at week 8, with 95% CIs and P values for superiority testing. Baseline values at week 8 were included as a covariate; ‘country’ was included as a random factor; treatment group and previous treatment for OAB were fixed factors.

The full analysis set included all randomized patients who had taken at least one dose of double-blind study medication, who had the number of severe urgency episodes (PPIUS grades 3 and 4) recorded at baseline, and who provided data on PPIUS during double-blind treatment. Patients who were included in the full analysis set for changes from week 8 were required to have a PPIUS value at week 8 and at least one other value thereafter. The safety population included all randomized patients who received at least one dose of double-blind study medication. Patients who were still receiving treatment and who received at least one dose of double-blind study medication at week 8 (dose increase) were included in a second safety population.

Results

A total of 973 patients entered the placebo run-in phase; 865 were randomized and 863 were treated. At week 8, 790 patients (591 in the solifenacin group and 199 in the placebo group) were still receiving treatment. Dose increases at week 8 were requested by 275/591 (46.5%) patients in the solifenacin group. Of these, 135 were randomized to remain on solifenacin 5 mg, and 140 on solifenacin 10 mg. Dose increases were requested by 131 (65.8%) patients on placebo, but all continued to receive placebo.

Patient demographics and disease characteristics at the initial study baseline (week 0) were similar across all groups and have been reported previously [9]. Overall, most patients were female (87.3%) and Caucasian (98.5%), with a mean (sd) age of 57.4 (13.0) years. Approximately 45% of patients had received prior therapy for OAB symptoms within 1 year of the start of the study, the most common being urinary antispasmodics (32.5% of solifenacin-treated patients), primarily oxybutynin (17.8%) and tolterodine (13.9%). Solifenacin-treated patients requesting a dose increase at week 8 were more likely to have failed previous treatment than those not requesting a dose increase (24.4% vs 15.8%) (Table 2), and had more severe OAB symptoms (Table 3). Patients requesting a dose increase had higher numbers of severe urgency episodes (PPIUS grades 3 and 4), higher TUS, greater micturition frequencies, more incontinence and urgency incontinence episodes per 24 h, and worse perceived bladder condition, urgency bother and treatment satisfaction at week 8 than those not requesting a dose increase, with similar values for those randomized to 10 mg solifenacin and those randomized to remain on 5 mg (Table 3).

Table 2. Patient demographics at week 8 for solifenacin-treated patients (safety population). Data are percentages unless noted otherwise.
 5 mg NRD (n = 316)5 mg RD (n = 135)10 mg RD (n = 140)
  1. NRD, patients who did not request a dose increase and who were not randomized at 8 weeks; RD, patients who requested a dose increase and underwent a second randomization to 5 or 10 mg solifenacin.
Age   
Mean, years58.855.855.7
≤65 years66.574.875.0
>65 years33.525.225.0
>75 years5.47.45.0
Sex   
Male10.117.011.4
Female89.983.088.6
Incontinence   
Urgency49.754.150.7
Mixed16.517.820.0
None25.919.320.0
Other7.98.89.3
Median (range) time since start of symptoms, years4.08 (0.3–50.1)5.00 (0.4–28.9)4.38 (0.3–54.8)
Prior OAB drug therapy within 1 year of study start   
Any40.553.052.1
≥ One effective24.726.130.0
None effective15.826.922.1
No59.547.047.9
Table 3. Disease characteristics at week 8 for solifenacin-treated patients (full analysis set). All values are means (± sd).
 5 mg NRD (n = 315)5 mg RD (n = 135)10 mg RD (n = 140)
  1. *Per 24 h during the 3 days before baseline.
  2. NRD, patients who did not request a dose increase and who were not randomized at 8 weeks; RD, patients who requested a dose increase and underwent a second randomization to 5 or 10 mg solifenacin; PPBC, Patient Perception of Bladder Condition; UB-VAS, urgency bother visual analogue scale; TS-VAS, treatment satisfaction visual analogue scale.
OAB variable   
PPIUS grades 3 and 4*2.6 (3.3)4.5 (3.7)4.7 (4.0)
Total urgency score*15.5 (7.7)23.4 (11.5)24.5 (12.2)
Micturition frequency*10.0 (2.0)11.3 (3.5)11.8 (4.9)
Incontinence episodes*1.3 (1.4)1.8 (1.6)2.1 (2.4)
Urgency incontinence episodes*1.2 (1.5)1.7 (1.6)2.1 (2.4)
PPBC3.1 (1.0)4.1 (1.0)4.1 (1.0)
UB-VAS27.5 (20.9)51.6 (25.6)54.6 (24.2)
TS-VAS73.9 (21.2)48.7 (29.3)51.0 (26.1)

Greater improvements in the number of severe urgency episodes of PPIUS grades 3 and 4 were observed from week 8 to the end of treatment in patients who requested a dose increase and were randomized to receive solifenacin 10 mg compared with those who were randomized to remain on 5 mg (–0.9 vs –0.4, respectively; Fig. 1).

Figure 1.

Mean changes in OAB variables from week 8 to end of treatment in solifenacin-treated patients who requested a dose increase at week 8 (full analysis set, descriptive statistics). RD, patients who requested a dose increase and underwent a second randomization; *P < 0.05 vs solifenacin 5 mg RD.

Numerical improvements were also observed in all other assessed OAB efficacy variables from week 8 to the end of treatment for all patients who requested a dose increase, with greater improvements observed for patients randomized to solifenacin 10 mg compared with those randomized to remain on the 5 mg dose. These reached statistical significance for the maximum PPIUS urgency rating (decreases of –0.3 vs –0.1; P = 0.034), TUS (decreases of –2.7 vs –0.6; P = 0.010) and micturition frequency (decreases of –0.8 vs –0.1; P = 0.037) (Fig. 1).

Improvements in PPBC scores were similar in both solifenacin dose groups, decreasing from 4.1 at week 8 to 3.7 at end of treatment in the 5 mg group and from 4.1 to 3.6 in the 10 mg group. Urgency Bother visual analogue scale scores decreased by 12.8 points, from 54.57 at week 8 to 41.79 at the end of treatment, indicating an improvement in patients who were randomized to solifenacin 10 mg, whereas there was a smaller improvement in those who remained on solifenacin 5 mg during the same period (decrease of 7.4 points, from 51.57 to 44.13) (Fig. 2A). Treatment satisfaction scores improved in all groups. Patients who received a dose increase at week 8 reported greater improvements in Treatment Satisfaction visual analogue scale scores from week 8 to the end of treatment (from 51.01 to 61.04) than patients who remained on solifenacin 5 mg (from 48.70 to 55.48) (Fig. 2B).

Figure 2.

Mean change from week 8 to end of treatment in urgency bother (UB-VAS) (A) and treatment satisfaction visual analogue scale (TS-VAS) scores (B) for patients receiving solifenacin who requested a dose increase. Differences between the solifenacin 5 and 10 mg groups were not statistically significant at week 8 or at the end of treatment. RD, patients who requested a dose increase and underwent a second randomization.

Treatment-emergent adverse events that either started or worsened after week 8 were more frequent in patients randomized to 10 mg solifenacin than those who remained on the 5 mg dose (Table 4). More patients reported dry mouth with the 10 mg dose than with the 5 mg dose (8 [5.7%] vs 1 [0.7%]), but the absolute numbers were low and similar to or lower than previously reported rates with solifenacin [8]. Treatment-emergent adverse events in the randomized groups led to discontinuation in two patients on 10 mg (urinary retention and peripheral oedema) and no patients on 5 mg solifenacin. Another patient who had not requested a dose increase also had a treatment-emergent adverse event between weeks 8 and 16 that led to discontinuation (cerebral haemorrhage).

Table 4. Number of patients reporting treatment-emergent adverse events (TEAEs) starting or worsening between week 8 (when a dose increase could be requested) and week 16 (end of treatment).
 5 mg RD (n = 135) (n [%])10 mg RD (n = 140) (n [%])
  1. *Occurring in ≥2% of patients in any group.
  2. RD, patients who requested a dose increase and underwent a second randomization to 5 or 10 mg solifenacin.
Any TEAE10 (7.4)31 (22.1)
Mild5 (3.7)16 (11.4)
Moderate5 (3.7)8 (5.7)
Severe07 (5.0)
Any drug-related TEAE5 (3.7)19 (13.6)
Frequently reported drug-related TEAEs*  
Gastrointestinal disorders3 (2.2)12 (8.6)
Dry mouth1 (0.7)8 (5.7)
Constipation1 (0.7)3 (2.1)
Nervous system disorders1 (0.7)4 (2.9)
Skin and subcutaneous tissue disorders3 (2.2)0
Serious TEAEs01 (0.7)
Discontinued due to TEAEs02 (1.4)
Deaths due to TEAEs00

Discussion

Data from several studies with solifenacin, darifenacin, fesoterodine and oxybutynin extended-release concluded that a strategy based on patient-requested dose increases can be effective in improving the symptoms of OAB [8-14]. The present results extend these observations, as assessed using the PPIUS and several subjective and objective tools for measuring secondary variables.

In the present study, patients who requested a dose increase at week 8 generally had more episodes of urgency, frequency, incontinence and urgency incontinence per 24 h compared with those who did not request a dose increase. Furthermore, patients requesting a dose increase were more likely to have received – and failed – previous treatment for OAB than patients who did not request a dose increase. This is consistent with data from the STAR study by Chapple et al. [16], which also reported that patients requesting a dose increase at 4 weeks with either solifenacin or tolterodine tended to have more severe and troublesome OAB. Although a marked benefit from treatment with solifenacin has been observed as early as week 4 [17], week 8 was considered a suitable time at which to allow a dose change to ensure patients had sufficient time to reach maximum efficacy and to stabilize on this dose. However, a similar proportion of patients randomized to solifenacin requested a dose increase at 4 weeks in STAR as at 8 weeks in the present study, suggesting that either time point could be used to consider a dose increase.

The estimated differences in effect between the 5 and 10 mg doses on the number of severe urgency episodes (PPIUS grades 3 and 4) in the second randomization phase were not statistically significant (P = 0.12, based on mixed model analysis), which might reflect the relatively small patient numbers in those groups. Nevertheless, the numerical observations were based on several objective and subjective outcome measures, and greater improvements were observed in secondary efficacy variables in patients randomized to the 10 mg dose than those who remained on the 5 mg dose, reaching statistical significance for maximum urgency intensity, TUS and micturition frequency.

The present study shows that although approximately half of patients respond well and are satisfied on the 5 mg dose, the availability of a higher dose for those requesting it had therapeutic benefit. While, in practice, it would be important to allow a sufficiently long initial treatment period and ensure patient compliance with prescribed therapy before deciding whether to increase the dose, flexible dosing using a self-selection process has the potential to improve outcomes for those with more severe symptoms.

Acknowledgements

All authors had full access to all the data in the study and the primary author (LC) had final responsibility for the decision to submit this manuscript for publication. The study received ethical committee approval at all sites. Writing and editorial assistance was provided by Steve Sharpe, Sophie Berry, and David Hallett.

Conflict of Interest

Source of Funding: Research grant from Astellas Pharma Europe Ltd. LC carries out research, consultancy and/or advisory work for Astellas, Advamed, Ethicon, Merck, Pfizer and Teva; TD, MW and GC are employees of Astellas.

Appendix: Appendix 1

SUNRISE Study Group

Belgium: D. De Ridder; R. Opsomer; T. Quackels; K. Vekemans; L. Dewilde; P. Vossaert; J. Ampe; J. De Leval; P. Van Erps; M. Dhont. Czech Republic: I. Pavlik; J. Feyereisl; J. Mokris; Z. Adamik; J. Krut. Egypt: B. Wadie. France: F. Haab; B. Deval; G. Amarenco; P. Costa; J-J. Labat; J-P. Ansieau; J. Biserte; B. Mauroy. Germany: T. Benusch; W. Hechelmann; M. Hentschel; E. Hessdörfer; F.P. Kaesler; R. Klammert; K-U Laval; D. Mertins; S. Mühlich; R. Ostwald; P. Sawaya; P.Schmidt; D. Spelmeyer; W. Vilmar; J. Willgerodt. Greece: N. Sofikitis; F. Sofras; Ch. Theodorou. Hungary: L. Farkas; L. Kiss; G. Nagy; L. Pajor; Z. Tóth. Italy: B. Adile; R. Carone; R. Damiano; P. Di Benedetto; P. Ferrari; M. Meschia; R. Milani; L. Selvaggi; Poland: J. Lorenz; Z. Wolski. Portugal: L. Costa; M. Guimarães; A. Matos Ferreira; P. Vasco; Russian Federation: V. Abashin; S.H. Al-Shukri; I. Apolikhina; V. Avdoshin; V. Gomberg; O.B. Loran; E.B. Mazo; S. Petrov; D. Pushkar; M.F. Trapeznikova; Y.M. Zakhmatov. Slovak Republic: V. Baláz; J. Kliment; J. Mikulas; Spain: P. Arañó Bertran; D. Castro Diaz; E. Duenas; E. Garcia Sastre; M. Leva; C. Llorente Abarca; J.L. Parra; J.A. Romero; M. Sánchez Chapado. United Kingdom: Z. Almallah; J. Barrington; R. Beard; J.P. Britton; L.D. Cardozo; D. Greene; J. Hetherington; A. Leather; S. Lui; A. Monga; I. Pearce; M. Slack; L. Stewart; R. Thakar; J. Vanwaeyenbergh; A. Wagg; R. Webb. Study Team: T. Drogendijk; P. Leunissen; D. Macfarlane; H. Mollee; E. Vink; D.M. Wright.

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