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Overactive bladder symptom score to evaluate efficacy of solifenacin for the treatment of overactive bladder symptoms

Liu, Ming; Wang, Jianye; Yang, Yong; An, Ruihua; Wen, Jianguo; Guan, Zhichen; Zheng, Shaobin; Wang, Dongwen; Song, Bo; Liao, Limin; Guo, Hongqian; Xiao, Jiaquan; Sun, Yinghao; Shen, Zhoujun; Kong, Chuize; He, Dalin; Huang, Yiran; Wang, Xiaofeng; Zhang, Xu; Li, Hanzhong; Huang, Jian; Zhao, Xiaokun; Zeng, Puqing; Song, Xishuang; Ye, Zhangqun

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doi: 10.3760/cma.j.issn.0366-6999.20131349
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Abstract

Overactive bladder (OAB) is a common symptom complex that is defined as urgency with or without urge incontinence, usually accompanied by daytime frequency and/or nocturia, in the absence of infection or other obvious pathology.1,2 The prevalence of OAB was 11.8% according to the expanded prostate cancer index composite (EPIC) study.2 This was the first study to evaluate lower urinary tract symptoms in five western countries using the 2002 International Continence Society (ICS) definitions.2 Another similar large survey, epidemiology of lower urinary tract symptoms (EpiLUTS), reported a relatively high rate of storage symptoms in adults from the USA, UK, and Sweden, including urgency, the cardinal symptom of OAB (35.7%) and nocturia (two or more voids per night, 33.7%).3

Diagnosis and evaluation of OAB rely, to a large extent, on the symptoms. Multi-item questionnaires have been introduced to evaluate the impact of OAB and the treatment outcomes. However, most of the questionnaires focus on the influence of OAB on the quality of life (QOL) rather than the symptoms. One major concern for physicians who provide OAB treatment is the lack of a widely accepted questionnaire for OAB assessment. This makes comparison among studies difficult.

Homma et al4 developed a single symptom score in 2006 that uses a self-report questionnaire to quantify OAB symptoms using a 1-week recall period, which is called overactive bladder symptom score (OABSS). The authors selected four symptoms: daytime frequency (score 0-2), nocturia (0-3), urgency (0-5), and urge incontinence (0-5).

The score collectively expresses the OAB symptoms in a single score ranging from 0 to 15, with greater scores indicating increasing symptom severity. The OABSS is derived from self-reports of patients rather than the 3-day voiding diary, which makes it a more convenient tool for OAB evaluation. The original OABSS was validated in a Japanese OAB patient group with high reproducibility (weighted κ coefficients 0.804-1.000 for each item and 0.861 for OABSS).4 Recently, the Chinese version of OABSS has been developed linguistically and psychometrically. It is a validated tool with good test-retest reliability (internal correlation coefficient 0.9172; weighted κ coefficients of individual scores in OABSS 0.5902-0.9274).5 Both validation studies indicated that in Japanese and Chinese patients, OABSS could match the severity of symptoms and infer patient perception of bladder condition or bother from the symptoms.4,5 Another important aspect of OABSS is that it shows good responsiveness to symptom changes.6 In a recent study, the minimal clinically important change (MCIC) in the OABSS (0-15) was estimated to be −3, meaning that a change of 3 points is considered the minimal threshold for allowing differentiation between the “no change” and “minor improvement” groups.6

However, most research concerning the treatment of OAB is evaluated using numeric changes in the frequency of each symptom.7,8 OABSS has not been widely used as an evaluation tool in research, which limits its clinical application. Also, this questionnaire needs to be tested in languages other than Japanese and Chinese.

The present trial used the validated Chinese version of OABSS to evaluate the efficacy of solifenacin succinate, a competitive muscarinic receptor antagonist, for the treatment of OAB. The consistency of OABSS with symptoms and PPBC score before and after treatment were also evaluated.

METHODS

Study design

This was a prospective, single arm, 12-week study of solifenacin for alleviating symptoms of OAB. The study was conducted from December 2009 to May 2011, and was performed in 24 medical centers in China. The study protocol and informed consent forms were reviewed and approved by the ethics committee of each center. The clinical study design is available at http://www.chictr.org/cn/ (Unique ID ChiCTR-TNC-10000948). To be eligible for inclusion, patients had to fulfill all the following criteria: male or female aged >18 years who gave signed informed consent and were willing to record 3-day voiding diaries; OAB symptoms for >3 months and ≥3 episodes of urgency, with or without incontinence, in the past 3 days. Exclusion criteria included: pregnancy or child-bearing potential; stress incontinence or mixed incontinence; indwelling urethral catheter or intermittent self-catheterization; urinary tract infection, interstitial cystitis, or bladder stone; history of pelvic malignancy or pelvic radiation; conditions contraindicating use of anticholinergic medication; or neurological disease caused by diabetes mellitus. Any treatment for OAB including anticholinergic drugs, drugs that inhibit cytochrome P450 3A4 isoenzymes, or investigational drugs were not permitted during the study.

The study plan is shown in Figure 1. All patients were informed of the nature and purpose of the study, and written informed consent was obtained from each patient. During the screening, the inclusion and exclusion criteria were verified. Patients were also instructed on how to fill in the voiding diary during this period. Then, the patients had a 2-week washout period. When washout was finished, baseline variables were recorded and patients were administered 5 mg/d solifenacin at the baseline visit. After 4 weeks treatment, patients were given the option of either continuing the original dose or increasing the dose to 10 mg/d. Patients were asked to complete the 3-day voiding diary prior to each scheduled visit at Weeks 0, 4, and 12. During these visits, they were asked to report pad usage and fill in the OABSS, PPBC score, international prostate symptoms score (IPSS) and QOL.

Figure 1.
Figure 1.:
Study plan.

The primary assessment was the efficacy of solifenacin for the treatment of OAB by comparing OABSS at week 12 with that at week 0. Other efficacy variables included changes in micturition frequency, episodes of urgency and urge incontinence, nocturia, and PPBC score. The secondary assessment was the relationship between OABSS and PPBC score or voiding diary parameters. Before this study, we performed a small test on the consistency of OABSS in 5 hospitals. The researchers in each center of this study were given training on all the questionnaires involved in the study.

Safety and tolerability were also evaluated within the study protocol, including the nature, frequency, and intensity of adverse events, and withdrawals due to adverse events. At each visit any adverse event reported by the patient was recorded in the Case Report Form. Adverse events were defined as occurring after the first dose of solifenacin, or an exacerbation of a pre-existing symptom that was present before the first dose. The severity of adverse events was determined by the investigator, according to the following guidelines: a mild adverse event caused discomfort but no disruption of normal daily activity; a moderate adverse event caused discomfort sufficient to reduce or affect normal daily activity; and a severe adverse event was one that resulted in an inability to work or perform daily activities.

Statistical analysis

Patients who took at least 1 dose of medication and had a baseline assessment and at least 1 on-treatment efficacy assessment were included in the full analysis set (FAS). A broad set of descriptive statistics relating to demographics, characteristics, and variables was recorded during the study. To evaluate the efficacy of solifenacin, results at weeks 4 and 12 were compared with those at week 0 using a signedrank test. Spearman correlation coefficient (r) was used to describe the association between OABSS and PPBC score or voiding diary variables. For interpreting correlation coefficients, the guidelines proposed by Cohen were used, with a coefficient of 0.1 being weak, 0.3 moderate, and 0.5 strong.9 SPSS 17.0 (SPSS Inc., USA) was used for the statistical analysis and P value of less than 0.05 was considered statistically significant.

RESULTS

Patient characteristics

A total of 241 patients were enrolled in the study, and the FAS population included 221 patients, with 47 (21.27%) men and 174 (78.73%) women. Mean age was (48±18) years. The number of cases with a history of OAB of 3 months-1 year, 1-5 years and >5 years was 40 (18.10%), 116 (52.49%), and 65 (29.41%), respectively. Ninety patients (40.72%) had accepted previous medical therapy for OAB; among which 36 had toterodine and the rest had flavoxate. With regard to baseline symptoms, 58 (26.24%) cases had 3-5 urgency episodes per 24 hours, whereas 58 (26.24%) and 105 (47.51%) had 6-8 and ≥9 episodes, respectively. At week 4, 38 patients (17.19%) chose to increase the dosage of solifenacin from 5 to 10 mg/d. The final assessment was performed at week 12. The study was not completed for nine cases: two because of adverse events, three due to insufficient response, and four were lost to follow-up.

Efficacy of solifenacin

At baseline, the mean OABSS for all patients was 9.41±2.40 (Table 1), suggesting that they were suffering from persistent OAB symptoms (OABSS ≥6). The primary efficacy variable was the change in OABSS at week 12, and OABSS was reduced significantly (-3.76 points; 61.21%) when compared with baseline (P<0.0001). There was also a significant reduction in each OABSS subscore at week 12 after solifenacin treatment. The parameters from the 3-day voiding dairy proved the effectiveness of solifenacin in improving OAB symptoms. There were improvements in all four symptoms including frequency, nocturia, urgency episodes, and urge incontinence episodes. This improvement was progressive, both at weeks 4 and 12. The self-reported PPBC score, IPSS, and QOL also significantly decreased during the study (P<0.0001, Table 1).

Table 1
Table 1:
OABSS, OABSS subscore, main variables from 3-day voiding diary and PPBC score at baseline and weeks 4 and 12

Adverse events of solifenacin

The overall incidence of adverse events was 19.91% (44 cases). The most commonly affected site was the gastrointestinal system (11.31%). There were 20 cases of dry mouth (9.05%) and eight of constipation (3.62%). Eleven (5.88%) patients had adverse events related to the genitourinary system. Five cases (2.26%) had blurred vision. No patient reported urinary retention, and most of the adverse events were mild or moderate in severity.

Consistency of OABSS with other parameters

There was a strong correlation between OABSS and urge incontinence in the voiding diary at baseline assessment (r=0.70), whereas the correlation decreased continuously in weeks 4 and 12 (r=0.50 and 0.48, respectively). On the contrary, the correlations between OABSS and other symptoms (micturition frequency, urgency episode, and nocturia) increased during treatment when compared with baseline. The relationship between OABSS and PPBC score was weak at baseline (r<0.3), but became strongly associated (r>0.5) at week 12 (Table 2).

Table 2
Table 2:
Spearman rank correlation coefficient (r) between OABSS and variables from voiding diary or PPBC score (r (P))

DISCUSSION

Solifenacin succinate is a bladder-selective antimuscarinic receptor antagonist approved for daily once treatment of OAB. Solifenacin significantly reduces urgency and urge incontinence episodes and is associated with reduced micturition frequency and nocturia compared with placebo.10 The recommended starting dose of solifenacin is 5 mg (can be increased to 10 mg if well tolerated), which may allow physicians to individualize therapy to help achieve a balance between efficacy and tolerability. This kind of flexible dosing was also used in some international trials, such as STAR8 and SUNRISE,11 in which 48% and 46.5% of patients chose to increase solifenacin dose, respectively. This change in dose was also adopted in the present study and 17.19% of patients chose to increase their dose.

One of the distinctive features of this study was using OABSS as the primary assessment tool to evaluate drug efficacy. There are many different tools available for assessing treatment success of OAB.11-13 Most trials have tended to use voiding diary as the device to measure changes in micturition frequency in daytime and nocturia, as well as the episodes of urgency or urge incontinence. For instance, the VENUS study, a randomized placebo-controlled study analyzing the efficacy of solifenacin for OAB, adopted a 3-day micturition diary to record changes in urgency episodes (primary efficacy variable) and warning time (secondary efficacy variable, defined as time from first sensation of urgency to voiding).13 Solifenacin significantly reduced key symptoms of OAB and improved warning time. Although voiding diaries can accurately reflect symptoms, they are complicated in clinical practice and difficult to use in comparing the effects of different treatment options because all the symptoms contribute to problems caused by OAB.

Besides voiding diaries, some other patient-reported multi-item questionnaires were developed to assess the severity of OAB symptoms. In particular, the SUNRISE study applied the patient perception of intensity of urgency scale (PPIUS) as the primary efficacy variable.11 Secondary efficacy variables included PPBC and patient-completed voiding diary. Solifenacin significantly reduced the number of urgency episodes and the extent of urgency bother. Other assessment tools for OAB symptoms include the primary overactive bladder symptom questionnaire, overactive bladder questionnaire (OAB-q), and overactive bladder symptom composite score (OAB-SCS).14,15 Most of the aforementioned measures are reliable, but they mostly focus on the influence of OAB on QOL instead of the symptoms themselves. OAB-SCS can quantify symptoms in a single score, but it requires recording in a voiding diary, which reduces its applicability in clinical practice.15

In order to reflect the authenticity of OAB symptoms and have better comparability a new tool has been developed in recent years. The OABSS is a single symptom score derived from four questions to express collectively all the OAB symptoms, and might be useful as a brief assessment tool for symptom severity as well as bother. The simplicity of this tool might be especially useful and feasible for clinical practice. The present study used OABSS to evaluate the efficacy of solifenacin for the treatment of OAB. OABSS was significantly reduced after treatment with solifenacin, from 9.41 at baseline to 7.07 at week 4 and 5.65 at week 12. With an MCIC of -3 for OABSS, the improvement seen at week 12 (-3.76) could be considered meaningful. It is also noteworthy that the improvement was present in all four subscores of OABSS. The data from the voiding diary demonstrated similar results, which found that at week 12, mean daily episodes of micturition, urgency, urge incontinence, and nocturia significantly decreased by 4.24, 4.96, 0.73, and 1.08 from baseline, respectively. Although the effect of placebo was not investigated in the current study, solifenacin appeared to be effective in improving all four OAB symptoms.

In a previous study, the relationship between OABSS and patient perceptions of the disease was assessed.16 OABSS was negatively correlated with patient perceptions, which were measured by OAB-q, PPBC score, and medical outcomes study short-form 36. In the present study, urge incontinence had the strongest correlation with OABSS at baseline (r=0.70). Urgency episodes and nocturia had moderate correlation with OABSS, whereas micturition frequency had a relatively weak correlation. After drug treatment (at weeks 4 and 12), the correlation between OABSS and urge incontinence became weaker, whereas OABSS became increasingly correlated with other symptoms. At baseline, there was fairly weak correlation between OABSS and PPBC score, whereas the correlation at week 12 became stronger. The reason for these trends needs further evaluation.

Solifenacin is well tolerated and severe side effects are rare. In the present study, the overall incidence of adverse events was 19.91%, and most of them were considered mild or moderate. The most common events included dry mouth and constipation, and only two patients discontinued treatment because of adverse events. The number of adverse events in the present study was in line with previous clinical trials, indicating that solifenacin is well tolerated.17,18

In conclusion, OABSS integrates four OAB symptoms into a single score and may be a useful tool for research and clinical practice. The limitation of this study was that it was an open-label single arm study. As a result, the placebo effect in OABSS was not taken into consideration, and the study results cannot be easily compared with those from pivotal studies such as SUNRISE or VENUS. Another limitation was that we did not measure the effect of slifenacin on residual urine. Nonetheless, the current study showed that solifenacin appeared to be clinically effective for relieving OAB symptoms, considering the balance between efficacy, well-being, and tolerability.

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Keywords:

overactive bladder; muscarinic antagonists; symptom score

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