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About 50–100 million people worldwide are estimated to be affected by symptoms of the overactive bladder (OAB) syndrome. It is more common than diabetes mellitus or peptic ulcer, and of similar prevalence to asthma or chronic bronchitis [1,2]. The OAB is known to adversely affect the quality of life (QoL) of sufferers, and perhaps the greatest benefits of treatment experienced by patients are improvements in QoL.
Two recent surveys, one from Europe comprising nearly 17 000 men and women, and the other from the USA comprising ≈ 5000 men and women, estimated similar overall prevalence rates of 16.6% and 16.5%, respectively [3,4]. The European survey was the first to report prevalence rates for a large population using a symptom-based definition of OAB. That analysis focused on urgency, urge incontinence and frequency as the primary symptoms of OAB, and was designed to exclude patients with possibly confounding conditions such as UTIs, pure stress incontinence or prostatic obstruction. Survey items were phrased to capture symptoms that were chronic or bothersome, and most participants reported having symptoms for >1 year . In addition, ≈ 65% of responders reported that their symptoms of OAB adversely affected their daily lives .
In the USA survey, the symptoms of OAB were associated with high depression scores and poor quality of sleep . Sleep disturbances in patients with OAB may result in daytime somnolence, interference with cognitive function, impaired concentration, and diminished physical and mental health . The incidence of anxiety and low self-esteem also appeared to be relatively high among people with OAB . Untreated OAB is associated with an increased risk of UTIs, skin infections and injury in a fall, that for the elderly is a common cause of both morbidity and mortality [7,8].
Solifenacin succinate is a once-daily oral antimuscarinic agent evaluated for treating OAB, with a suggested starting dose of 5 mg once daily. The efficacy, safety and tolerability of solifenacin were reported in four pivotal phase-3 studies conducted globally, and in a large, open-label, long-term extension study. Solifenacin 5 and 10 mg once daily were both shown to produce statistically significantly less urgency, urge incontinence and frequency than was placebo . In one phase-3 clinical trial, 51% of patients reporting urinary incontinence at baseline were continent with either solifenacin 5 or 10 mg once daily by the end of the 12-week study . There were also statistically significant increases in volume voided per void with solifenacin 5 and 10 mg once-daily . In an open-label extension study of solifenacin, the continence rate, reported as 51% after 12 weeks of treatment, rose to 60% by the end of the study.
Solifenacin was also well tolerated in these trials; 11% of patients receiving solifenacin 5 mg once daily reported dry mouth, compared with 28% of patients receiving 10 mg once daily and 4% receiving placebo. Solifenacin had no effect on vital signs, hepatic function or clinical laboratory variables, and no increased risk of serious adverse effects were associated with its use.
The ICS recommended that QoL measures be included in all studies evaluating treatments for OAB as a complement to measures of urinary symptoms. QoL questionnaires quantify the bother caused by OAB symptoms, the associated QoL impairments, and the improvements in both after successful treatment . They also provide an insight into the clinical relevance of efficacy measures and their relation to patient satisfaction, and are the only means of assessing the overall impact of OAB on a patient's life .
Several instruments have been developed to measure QoL. Generic questionnaires designed to assess large populations with many different conditions cover a broad spectrum of items, but fail to address the specific impact of OAB symptoms and are relatively insensitive outcome measures for changes in bladder symptoms. Disease-specific OAB QoL questionnaires are designed to address the impact of urinary symptoms on patients’ QoL and are more effective in identifying issues relevant to patients with OAB, and to their clinicians [6,13]. The King's Health Questionnaire (KHQ), used to measure QoL in the present report, is considered an effective disease-specific instrument and has been granted a Grade A recommendation by the WHO .
There are few published data on evaluating the impact of other OAB treatments on QoL. A study of long-term extended-release oxybutynin use assessed QoL using an incontinence impact questionnaire, a sleep impact questionnaire, and general health and bother (urinary leakage and/or bladder problem) scales . For all these tools there were statistically significant improvements over baseline values at 1 year . A study on extended-release tolterodine evaluated QoL using the KHQ [16,17]; the statistically significant improvements in QoL were sustained over 12–15 months .
In the present report we present QoL data from clinical trials evaluating solifenacin as a treatment for patients with OAB. Patient QoL data were obtained using the KHQ in two 12-week studies and a long-term extension of these studies, in which QoL served as a secondary efficacy variable.
PATIENTS AND METHODS
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- PATIENTS AND METHODS
- CONFLICT OF INTEREST
Data on QoL variables were analysed from two 12-week multinational, multicentre, double-blind randomized studies [9,19], and an open-label extension of these studies, all involving adult men and women with symptomatic OAB. In the 12-week studies, placebo or solifenacin 5 or 10 mg were administered once daily. The study by Chapple et al. treated 1077 patients and that by Cardozo et al. 907 patients. The 40-week extension study was open-label and enrolled 1637 patients from the two 12-week studies.
The KHQ is a short, sensitive, condition-specific instrument that uses patient-reported outcomes to measure the treatment effects on health-related QoL. It contains 21 questions distributed among nine domains, plus a 10th domain containing 11 questions designed to identify individual bladder problems and their effects on the patient (Table 1) . Because the KHQ has several validated language translations it is ideal for multinational clinical trials .
Table 1. The 10 domains of the KHQ , and the changes in the domain scores from baseline to study end in the two 12-week placebo comparator studies (1033 and 857 patients)
|QoL domain||N questions||Study 1||Study 2|
|Placebo||5 mg||10 mg||Placebo||5 mg||10 mg|
|General health perception|| 1||−1.7||−4.3||−3.5||−2.3||−5.8||−4.5|
|Incontinence impact|| 1||−17.8||−22.4||−23.6*||−20.1||−27.0†||−30.3‡|
|Role limitations|| 2||−14.7||−20.6*||−21.5†||−15.9||−21.9†||−24.4‡|
|Physical limitations|| 2|| −11.9||−18.2*||−17.8*||−15.4||−19.2||−22.3‡|
|Social limitations|| 2||−7.0|| −11.9||−10.9||−9.0||−12.1|| −11.7|
|Personal relationships|| 3||−9.7||−9.2||−10.0||−9.4||−8.5||−8.3|
|Sleep/energy|| 2||−9.3||−12.8||−12.7|| −11.4||−15.4*||−15.9*|
|Severity measures|| 5||−6.9||−12.4‡||−13.2‡||−7.2||−9.6|| −11.8†|
|Symptom severity|| 11||−2.2||−3.3†||−3.2†||−2.4||−3.4†||−3.4†|
The KHQ offers a rapid appraisal in various clinical settings and contains questions about the bother and effects of specific bladder symptoms on QoL . In a multinational clinical trial conducted over 12 weeks and involving 1284 patients, psychometric testing supported the reliability and validity of the questionnaire as an OAB-specific measure of health-related QoL .
Patients in the two 12-week studies evaluated in this report were supplied with the questionnaire at visit 2 (the start of double-blind treatment), visit 3 (after 4 weeks of double-blind treatment), and visit 5A (at the end-of-study visit after 12 weeks of treatment). At visit 2, patients were instructed on the completion of the questionnaire. To avoid potential bias, patients completed the questionnaire in the absence of the investigating staff. If required, e.g. with elderly patients, an independent nurse could assist with the completion. Subsequently, the questionnaire was reviewed by the investigator or research nurse to ensure completion.
Patients in the extension study were supplied with the questionnaire at visit 5B (the start of open-label treatment), visit 6 (after 4 weeks of treatment with solifenacin 5 mg), and at visits 7, 8 and 9 (each 12 weeks after additional treatment with solifenacin 5 or 10 mg once daily). Visit 9 was the end-of-study assessment, conducted 40 weeks after the start of the open-label extension.
The results of the KHQ are usually presented as the individual QoL domain scores, but can be presented as overall scores. Scores for each domain are scored on a 0–100-point scale; an exception is the symptom severity domain, which is scored on a 0–30-point scale . A higher domain score corresponds to a greater impairment of QoL for that domain [13,16].
Changes from baseline to end of study in domain scores, derived from the answers to the individual questions, were analysed. In the two 12-week studies, changes from baseline were assessed by anova, including treatment as a fixed factor. A hierarchic (step-down) test procedure was used, with comparison of solifenacin 10 mg once daily with placebo tested at the two-sided 0.05 significance level using the corresponding contrast. If there was a statistically significant difference the comparison of solifenacin 5 mg once daily with placebo was similarly tested. The extension study used descriptive statistics.
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Results from the KHQ assessments indicated that patients receiving once-daily solifenacin had statistically significant improvements in many disease-specific aspects of QoL. In one of the 12-week studies, 1033 patients provided QoL data; the change from baseline to study end (with baseline included as a covariate) was statistically better than with placebo for both solifenacin 5 and 10 mg once daily for five of the 10 domains (role limitations, physical limitations, emotions, severity measures and symptom severity; Table 1). For the incontinence impact domain, solifenacin 10 mg once-daily was significantly better than placebo.
In the other 12-week study, 857 patients provided QoL data; the change from baseline to study end (with baseline included as a covariate) was statistically significantly different from placebo for the incontinence impact, role limitations, emotions, sleep/energy, and symptom severity domains for both solifenacin 5 and 10 mg once daily. Solifenacin 10 mg was also significantly different for the physical limitations and severity measures (Table 1).
Pooling of data from the two 12-week studies showed statistically significant differences against placebo for solifenacin once daily at both doses for all domains except personal relationships (Table 1). Table 2 shows that there were many fewer patients included in the analysis of the personal relationships domain than in the other domains. Many (≈ 40%) patients in each study did not answer the two questions related to sex life, which were required to calculate the personal relationships domain score. This is a common problem with questionnaires that address this aspect of QoL.
Table 2. Pooled changes from baseline in the KHQ domain scores for the 12-week placebo comparator studies, and to the end point of the open-label extension study, by original treatment group
|QoL domain||Treatment||N||Change, baseline to endpoint||P||Change, baseline to endpoint, open-label|
|General health perception||Placebo||499||−2.3|| ||−7.8|
|Incontinence impact||Placebo||498||−18.2|| ||−32.9|
|Role limitations||Placebo||498||−15.4|| ||−30.8|
|Physical limitations||Placebo||497||−13.7|| ||−26.0|
|Social limitations||Placebo||489||−7.8|| ||−15.7|
|5 mg||514|| −11.3||0.003||−15.6|
|10 mg||523|| −11.7||0.015||−18.1|
|Personal relationships||Placebo||319||−9.7|| ||−13.2|
|Severity measures||Placebo||493||−7.3|| ||−14.7|
|Symptom severity||Placebo||500||−2.6|| ||−4.7|
Estimated differences from placebo were similar for all active treatment groups when the results from the two 12-week studies were combined. The findings from the primary analysis of both studies were confirmed after adjusting for multiple comparisons in almost all cases. Regression analyses confirmed the validity of the statistical model used for all domains.
Results from 1347 patients from the extension study indicated that both solifenacin 5 and 10 mg provided an improvement in all QoL domains from baseline (start of 12-week studies) to the end of the extension study, which was 17% for the general health perception and 35–48% for all the other domains. Incremental improvements during the extension study were 28–35% of the total effect obtained from the baseline of the 12-week studies to the endpoint of the extension study. Based on all the QoL domain scores, patients continued to improve throughout the 40 weeks of the extension period (Fig. 1).
Figure 1. (A) KHQ individual domain scores with time for the original double-blind studies (solifenacin treatment only) and 40-week extension study. A, incontinence impact (light red open circle), role limitations (light green open square), physical limitations (red closed square) and social limitations (green closed circle); B, personal relationships (light red open circle), emotions (light green open square), sleep/energy (red close square) and severity measures (green open circle); C, general health (green open circle) and symptom severity (red closed square).
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At the start of the 12-week studies, patients randomized to placebo had QoL domain scores comparable with those randomized to solifenacin. At the end of the 12-week studies (beginning of the extension study), QoL domain scores for placebo recipients had not improved to the extent they had among solifenacin recipients (Table 2). However, after placebo recipients changed to solifenacin in the extension study, they had improvements in QoL similar to those of patients who had been taking solifenacin during the double-blind studies (Table 2).
- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
As a chronic, debilitating condition, OAB has a profound negative impact on QoL, including social, physical, psychological, occupational and sexual domains [1,2,20,21]. Many people with OAB stop pursuing the social and physical activities they once enjoyed, and experience seclusion and psychological stress. Embarrassment, frustration, anxiety and depression are common responses to symptomatic OAB . Understanding QoL in patients with OAB is essential to conducting appropriate investigations and to evaluating new interventions, including pharmacological agents . It is desirable that patients have improvements in QoL in parallel with those in efficacy variables.
Based on data from nearly 2000 patients who provided QoL scores from the two double-blind studies and from 1347 patients in the long-term open-label extension study, solifenacin treatment improved the ability of patients to perform daily activities. The lack of statistically significant improvement at the end of the 12-week studies on the personal relationships domain can be explained by the fewer patients completing the questions in this domain. However, it could also be explained by the short duration of treatment, which is interesting because this domain showed an incremental benefit during long-term treatment. This domain particularly might be subject to the effects of adaptive changes over time, as patients become more confident in the improvement in their bladder symptoms, and this confidence is reflected in their interpersonal relations.
The statistically significant improvements in QoL with solifenacin 5 and 10 mg once daily in the double-blind studies were commensurate with those in OAB symptoms. In both 12-week studies, there were significantly fewer urgency episodes, incontinence episodes and voids per 24 h with solifenacin 5 and 10 mg than with placebo. There were also statistically significantly greater mean volumes voided per void in patients receiving solifenacin [9,19]. In addition, the improvements in the incontinence impact domain would appear to correlate with the fewer incontinence episodes per 24 h. A notable finding of the KHQ analysis is the improvement in the sleep/energy domain, which appears to correlate with the improvements in nocturia symptoms seen in patients treated with solifenacin .
In the solifenacin extension study, all patients were asked to rate the efficacy and tolerability at each drug-dose assessment visit (weeks 4, 16 and 28). The ratings for efficacy increased at each assessment, from 48% at 4 weeks to 68% at 16 weeks, and to 74% at 28 weeks. These increases in efficacy ratings paralleled the improvements in QoL over time in the extension study.
Tolerability was rated as acceptable or satisfactory for >99% of all patients at all three assessment visits. The favourable tolerability ratings are further supported by the high continuation rates (83% of patients randomized to solifenacin in the double-blind studies elected to participate in the extension study) and high persistence rates (81% of patients entering the extension study completed the full 40 weeks of treatment). The statistically significant improvement in QoL and high rate of persistence with solifenacin suggest that patients were very satisfied with this antimuscarinic agent.
The OAB is a chronic, debilitating condition requiring long-term therapy that maintains a positive QoL. Combined data from two 12-week clinical trials supported the use of solifenacin as a safe and effective option for treating OAB symptoms that also statistically significantly enhanced the QoL of the patient being treated. Improvements in QoL with solifenacin continued in the long-term, open-label extension study. The favourable balance of efficacy and tolerability offered by solifenacin for managing the OAB is further supported by the positive findings in health-related QoL reported here, and by the long-term patient satisfaction and persistence.