INTRODUCTION: Incontinence is a bothersome symptom in patients with overactive bladder (OAB) and a main symptom for help-seeking behavior. Our analysis of three phase III studies aimed to assess the effect of darifenacin on the number of Dry Days and incontinence episodes (IEs) in participants with OAB with incontinence.
METHODS: Pooled data from three randomized, placebo-controlled, fixed-dose studies (n=1059) were analyzed. Participants with OAB received 12 weeks' treatment with once daily darifenacin 7.5 mg (n=337) or 15 mg (n=334) or placebo (n=388). The number of participants achieving ≥ 3 consecutive Dry Days was the primary analysis endpoint. Health-related quality of life (HRQoL) was assessed using the King's Health Questionnaire (KHQ).
RESULTS: Significantly more participants taking daridenacin at week 12 achieved ≥ 3 consecutive Dry Days versus placebo (52.6% versus 39.8%, respectively; P ≤ .001). Significant improvements were observed in participants with mild (< 14 IEs/week) and moderate/severe (≥ 14 IEs/week) OAB with incontinence. Participants with ≥ 3 consecutive Dry Days had statistically significantly greater improvements in IEs, IEs resulting in a change of pads/clothing, micturitions/day, episodes of urgency and KHQ scores, compared with those who did not achieve ≥ 3 consecutive Dry Days. Darifenacin was well tolerated.
CONCLUSIONS: Darifenacin treatment significantly increased the number of participants achieving ≥ 3 consecutive Dry Days and significantly reduced the number of IEs. Similar improvements were observed with long-term treatment and were associated with significant improvements in HRQoL. These findings indicate that darifenacin is an effective treatment for participants with 'wet' OAB.
Diane Newman,1 William S Aronstein,2 Yodit Seifu,3 Andrea Larson-Peters,4 Lidia Mongay3
1 Division of Urology, University of Pennsylvania, Philadelphia, PA, USA
2 CTI Clinical Trial and Consulting Services, Cincinnati, OH, USA
3 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA,
4 Procter & Gamble, Cincinnati, OH, USA
Submitted August 2, 2010 - Accepted for Publication October 27, 2010
KEYWORDS: Antimuscarinic agents; Darifenacin; Overactive bladder; Urinary incontinence.
CORRESPONDENCE: Diane Newman, Co-Director, Penn Center for Continence and Pelvic Health, Director, Clinical Trials, Division of Urology, University of Pennsylvania Medical Center, 9 Penn Tower, 34th & Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA ().
CITATION: UroToday Int J. 2010 Dec;3(6). doi:10.3834/uij.1944-5784.2010.12.11
ABBREVIATIONS AND ACRONYMS: AE, adverse event; IE, incontinence episode; HRQoL, health-related quality of life; KHQ, King's Health Questionnaire; LOCF, last-observation-carried-forward;OAB, overactive bladder.
Overactive bladder (OAB) is a chronic and debilitating syndrome that affects 16.5% of the adult population in the US . A core symptom of OAB is urgency with urge incontinence  ('wet' OAB), which affects 37% of patients with OAB, primarily in women .
Incontinence is usually the most bothersome symptom reported by patients with 'wet' OAB and has considerable negative impact on health-related quality of life (HRQoL) . In an analysis of patients with OAB in five countries, incontinence was a major factor driving patients to seek healthcare advice and/or treatment . Furthermore, the rate of help-seeking behavior may be affected by higher frequency and volume of urine leakage, and greater severity, impact and duration of symptoms [5,6]. Notably, increasing levels of urine loss are associated with escalating social and emotional consequences . In addition, containment of urine leakage is an ongoing stressor for patients and depending on the severity of leakage it can cause undue financial burden, from the cost of managing or containing urine leakage (ie, incontinence absorbent products, laundry products) .
Therefore, improvement in continence may be especially meaningful to patients with 'wet' OAB and/or their caregivers. A number of efficacy parameters are currently being used in clinical trials to complement the established measurement of reductions in number of incontinence episodes (IEs). The number of consecutive days without incontinence (ie, 'Dry Days') is an efficacy parameter that is receiving increasing recognition. This parameter may be evaluated as the number of Dry Days per week or the percentage of patients achieving consecutive Dry Days in any given time, in this case, the number of ≥ 3 consecutive Dry Days. Categorical analyses of patient response, such as reductions of > 3, > 5 and > 10 IEs per week may also be of use. Treatment for OAB and incontinence often combines behavioral interventions, such as pelvic floor muscle and bladder training with pharmacotherapy, such as antimuscarinic agents [9,10]. The M3-selective antimuscarinic agent, darifenacin, provides statistically significant improvement in the symptoms of OAB, including reductions in the number of IEs per week and number of IEs that require change of pads/clothing, as demonstrated in phase III studies [11,12].
This analysis aimed to determine the onset and duration of effect with darifenacin versus placebo in patients with 'wet' OAB (data pooled from three separate phase III studies) based on the number of consecutive Dry Days and categorical reductions in IEs. In addition, the percentage of participants achieving ≥ 3 consecutive Dry Days was also assessed in participants with mild and moderate/severe baseline incontinence.
The present analysis was conducted on pooled efficacy data from three multicenter, randomized, double-blind, placebo-controlled, 12-week studies with fixed-doses of darifenacin. Consistent methodology, inclusion/exclusion criteria, efficacy, and safety assessments between the three individual studies allowed data to be pooled and the primary outcome data have been reported in detail previously .
Each study was preceded by a screening visit, a 2-week washout period (if required) and a 2-week treatment-free or placebo run-in period. Upon completion of the placebo run-in period, participants were randomized to 12 weeks' double-blind treatment with study medication at varying doses: darifenacin 3.75 mg once daily (1 study), 7.5 mg once daily (two studies), 15 mg once daily (three studies) or 30 mg once daily (two studies). Those participants who received placebo or fixed-doses of darifenacin 7.5 or 15 mg once daily were included in this analysis. Study visits were performed after 2, 6 and 12 weeks' treatment. Daily electronic bladder diaries were completed by participants for 2 weeks (two studies) or 1 week (one study) prior to randomization (baseline) and before each subsequent study visit.
Comparable inclusion criteria were used in the three studies. In brief, men and women aged ≥ 18 years with symptoms of OAB for ≥ 6 months were eligible for inclusion if they demonstrated 5-50 IEs per week during the run-in period, along with an average of ≥ 8 micturitions per 24 hours and at least one urgency episode per 24 hours.
In this retrospective analysis, incontinence data were analyzed to determine the proportion of participants achieving ≥ 3 consecutive Dry Days and categorical reductions in IEs. A Dry Day was defined as no recorded IEs during a 24-hour period. IE responses were grouped into three categories: reductions of > 3, > 5 and > 10 IEs/week from baseline. The percentage of participants achieving ≥ 3 consecutive Dry Days was analyzed for the overall study population and for the subsets of participants with mild OAB, defined in this analysis as < 14 IEs per week at baseline, and moderate/severe OAB, defined as ≥ 14 IEs per week at baseline. These definitions were based on published literature used to validate the Patient Perception of Bladder Condition questionnaire .
Efficacy was determined from electronic daily bladder diaries completed by the participants. The diaries were used to record IEs, urgency (strong desire to void) episodes and severity of urgency, micturitions, bladder capacity (volume voided) and the number of IEs resulting in a change of absorbent pads and/or clothing. The number of micturitions per day, urgency episodes per day, IEs per week and IEs resulting in a change of pads/clothing per week were also assessed in participants with or without 3 consecutive Dry Days during the study period across treatment groups (darifenacin 7.5 or 15 mg or placebo) to ascertain the association between these efficacy parameters and differing continence levels.
To show that the percentage of participants achieving Dry Days with darifenacin in the pooled 12-week studies is maintained over long-term treatment, data from an open-label, 24-month, flexible-dose study in participants with OAB were also analyzed. All participants in the open-label, long-term study had completed one of two previous 12-week feeder darifenacin studies. One feeder study  assessed fixed-dose darifenacin and was included in the pooled analysis by Chapple et al , the other was a dose titration study . In the open-label, long-term study, the starting dose of darifenacin was 7.5 mg (irrespective of feeder-study dose) with voluntary up-titration to 15 mg after 2 weeks. Individualized dosing with darifenacin 7.5 and 15 mg was allowed thereafter.
Improvements in HRQoL were assessed using the King's Health Questionnaire (KHQ). This multidimensional questionnaire is fully validated to assess HRQoL in both women and men with lower urinary tract dysfunction, including OAB. HRQoL is assessed in 9 separate domains of the KHQ: Incontinence Impact, Severity Measures, Role Limitations, Social Limitations, Emotions, Physical Limitations, Personal Relationships, Sleep/Energy and General Health Perception. The first 6 domains address concerns of particular relevance to patients with OAB as they correspond with four areas of the generic health questionnaire, the Short-Form 36, that are associated with lower scores in patients with OAB than in the general population . The results were presented as numerical changes in domain scores from baseline to week 12; decreasing scores represent an improvement in HRQoL. KHQ scores were analyzed for participants achieving ≥ 3 consecutive Dry Days versus participants with 0-2 consecutive Dry Days. Tolerability and safety were evaluated from withdrawal rates and adverse events (AEs).
The analysis of all efficacy variables was based upon the full analysis population, defined as participants who received at least one dose of randomized study medication and had both baseline and post-baseline efficacy assessments. Where assessed, data were analyzed for the three study visits (weeks 2, 6 and 12) and at end of study, using the last-observation-carried-forward (LOCF) approach when week 12 data were missing. KHQ data were analyzed to assess the change from baseline to Week 12.
Because the 7.5 mg dose was not used in all three studies, the relevant placebo comparison for each dose used only the placebo response from the matching studies (ie, 7.5 mg darifenacin dose was compared with pooled placebo data from the two relevant studies; 15 mg with pooled placebo data from all three studies).
The proportion of participants with ≥ 3 consecutive Dry Days was calculated from the full analysis population for participants that had completed their daily diary for ≥ 3 consecutive days prior to a particular study visit. Logistic regression was used to compare proportions between darifenacin and placebo arms, adjusted for baseline IEs, study, age and gender. Similar comparisons using logistic regression analysis were performed for each category of reduction in IEs (> 3, > 5 and >10 IEs/week) for participants that had the minimum required number of IEs per week at baseline.
The differences in median changes in the electronic bladder diary variables from baseline to week 12 between participants treated with darifenacin and participants treated with the placebo were tested using the Wilcoxon rank-sum test. For each darifenacin dose, the Hodges-Lehmann estimate for the median of the difference between the darifenacin group and the corresponding placebo group along with its associated 95% confidence interval was derived.
For the KHQ scores, comparison between darifenacin and placebo was performed using a 2-sided t-test at a 5% significance level without adjustment for multiple comparisons. Differences in KHQ scores between participants who achieved ≥ 3 consecutive days and those that did not were performed using an analysis of covariance.
Of 1059 participants randomized to treatment, 1053 were included in the full analysis population evaluated here. Six participants were not included due to incomplete data in the electronic bladder diaries (4 in the 15 mg dose group and 2 in the placebo group).
In the full analysis population, age ranged from 19 to 88 years (with 30% ≥ 65 years of age), the majority of participants had idiopathic OAB and 85% of participants were women. Baseline demographics and clinical characteristics were comparable across the treatment groups (Table 1) and studies, reinforcing the validity of the comparison of data across studies, the pooling of relevant data for meta-analysis and the applicability of the trial results to the general population with OAB . In brief, more females than males were recruited into all studies, reflecting the demographics of patients seeking treatment for OAB, and patients in all treatment groups across studies were similar in age. All participants had 'wet' OAB at baseline, with < 10% of participants in any group having ≥ 3 consecutive Dry Days. In addition, 60% of the patient population was considered to have moderate/severe OAB (≥ 14 IEs per week) at baseline.
At Week 12/LOCF, statistically significantly greater numbers of participants achieved ≥ 3 consecutive Dry Days with darifenacin (7.5 and 15 mg) compared with placebo (Figure 1a). Analyses of the combined darifenacin data showed that 52.6% of participants achieved ≥ 3 consecutive Dry Days with darifenacin (7.5/15 mg) compared with 39.8% with placebo (P < .001).
The number of participants achieving ≥ 3 consecutive Dry Days on darifenacin was greater than placebo at the earliest time-point (week 2) for both darifenacin doses but was only statistically significant for darifenacin 15 mg (P < .001). The number of participants achieving ≥ 3 consecutive Dry Days increased throughout the study period, reaching statistical significance for darifenacin 7.5 mg versus placebo by week 6 (Figure 2).
At week 12/LOCF improvements were also observed in participants with mild OAB (Figure 1b) and moderate/severe OAB (Figure 1c) with a greater proportion of participants with mild OAB achieving ≥ 3 consecutive Dry Days. A similar pattern of improvement with the two doses of darifenacin was observed at weeks 2, 6, and 12, although the 7.5 mg dose was not significant until week 12 in the mild subset. For participants with ≥ 21 IEs/week at baseline, statistically significant improvements were observed at week 2 with both doses and at week 6 with the 15 mg dose.
Comparisons of reductions in urinary parameters between participants achieving ≥ 3 consecutive Dry Days and those not achieving ≥ 3 consecutive Dry Days regardless of therapy are shown in (Figure 3). In participants receiving darifenacin or placebo, statistically significantly greater reductions in the number of all parameters were observed in participants achieving ≥ 3 consecutive Dry Days, compared with those who did not achieve ≥ 3 consecutive Dry Days (Figure 3, P < .001).
The higher darifenacin dose (15 mg) produced statistically significant percent reductions compared with placebo in the number of IEs/week and IEs requiring change of pads/clothing per week for participants who achieved ≥ 3 consecutive Dry Days (P =.01 and P < .001, respectively) and participants with 0-2 consecutive Dry Days (Figure 4, both P < .001). In contrast, the percent reductions in IEs/week and IEs requiring change of pads/clothing for darifenacin 7.5 mg were only statistically significant compared with placebo, in participants with 0-2 consecutive Dry Days (Figure 4, both P < .05).
In the categorical analysis of IE reductions, statistically significantly more participants responded to 7.5 and 15 mg darifenacin with reductions from baseline of > 3, > 5 and > 10 IEs per week compared with corresponding placebo groups at week 12/LOCF (Figure 5).
A total of 716 participants entered the long-term extension study, of which, 475 participants completed 24 months of treatment . At the end of the 12-week double-blind studies/LOCF, 49% and 56.3% of participants receiving darifenacin 7.5 and 15 mg, respectively had achieved ≥ 3 consecutive Dry Days. A similar proportion of participants (49.6% to 58.5%) in the long-term extension study achieved ≥ 3 consecutive Dry Days after 2 years' treatment. The magnitude of this treatment effect was consistent over the 24-month extension period (Figure 6).
In a pooled analysis of participants receiving darifenacin or placebo, greater improvements in KHQ domains were observed in participants who had ≥ 3 consecutive Dry Days compared with those who did not (P < .001; Figure 7). Notably the improvements from baseline to week 12 in General Health and Personal Relationships were only statistically significant in participants with ≥ 3 consecutive Dry Days, all other endpoints were statistically significant in participants regardless of number of consecutive Dry Days.
In participants achieving ≥ 3 consecutive Dry Days, darifenacin treatment (7.5 or 15 mg) was associated with statistically significant improvement in KHQ scores versus placebo after 12 weeks of treatment in 5 out of 9 KHQ domains (Table 2). Participants receiving darifenacin (7.5 or 15 mg) but not achieving ≥ 3 consecutive Dry Days also showed statistically significant improvement (P < .05) in 6 of the 9 domains, of which 4 were considered of particular relevance to participants with OAB (Social Limitations, Incontinence Impact, Role Limitations and Severity Measures).
In the long-term extension study, statistically significant improvements from baseline (in the preceding feeder studies) in all KHQ domains except General Health Perceptions, were seen in both participants who achieved ≥ 3 consecutive Dry Days and those who did not (P < .05 compared with baseline after 24 months' treatment).
Tolerability and Safety
Darifenacin was well tolerated at both doses. The overall incidence of all-causality AEs was 54.0% and 65.6% in the darifenacin 7.5 mg and 15 mg groups compared with 48.7% of placebo recipients [11,17]. As expected for this class of agent, the most common all-causality AEs were dry mouth (darifenacin 7.5 mg 20.2%, 15 mg 35.3% and placebo 8.2%) and constipation (darifenacin 7.5 mg 14.8%, 15 mg 21.3% and placebo 6.2%). However, these infrequently resulted in treatment discontinuation (darifenacin 7.5 mg 0.6%, 15 mg 2.1% and placebo 3%) . The incidence of AEs was comparable in the long-term extension study where dry mouth or constipation were reported by 23.3% and 20.9% of participants, respectively .
In the overall patient population, a statistically significantly greater number of participants receiving darifenacin 7.5 mg or 15 mg achieved ≥ 3 consecutive Dry Days compared with placebo. Furthermore, darifenacin treatment effectively relieved the symptoms of OAB with incontinence (defined by the frequency of IEs) regardless of baseline severity. Greater improvements in OAB parameters were observed in participants who achieved ≥ 3 consecutive Dry Days compared to those who did not.
Early onset of effect with darifenacin treatment was indicated by the number of participants achieving ≥ 3 consecutive Dry Days and categorical reductions of IEs/week compared with placebo at the earliest time point of 2 weeks. Statistical significance was reached at week 2 for darifenacin 15 mg and at week 6 for darifenacin 7.5 mg. This efficacy was sustained over time (12-week observation period) and improvements in the number of participants achieving ≥ 3 consecutive Dry Days were maintained over long-term (additional 24 months) therapy.
Measures of Dry Days per week are likely to be an important efficacy measure for antimuscarinic agents in participants with 'wet' OAB. A decrease in urine leakage is felt to be an important outcome parameter for clinicians treating patients with OAB. However, this assessment is usually a secondary endpoint in clinical studies and/or the subject of retrospective analyses . Clinical studies often evaluate continence or 'dryness' at study end [18,19,20,21,22], yet this parameter is dependent upon multiple factors including bladder diary duration (3, 7 or 14 days), baseline frequency of urge incontinence and the population being studied. In the studies included in this analysis, the number of Dry Days was recorded in 7- or 14-day electronic diaries, longer diary recording than performed in most OAB drug studies, providing sufficient data for this analysis of Dry Days. The number of Dry Days that would be acceptable to a patient with OAB has yet to be established .
Previous studies and analyses have also identified that incontinence has a negative impact on HRQoL, mental health and quality of sleep [3,23]. Because incontinence is usually the most bothersome symptom, increases in the number of Dry Days may be more clinically relevant for participants with 'wet' OAB than other endpoints. In addition, more Dry Days may have economic benefits to participants due to less expense on incontinence containment products, such as absorbent pads and laundry-related labor and product costs. Our findings show that KHQ scores were significantly greater in participants with ≥ 3 consecutive Dry Days, regardless of treatment, which supports the importance of Dry Days to participants with OAB. Improvements in these KHQ scores were also maintained over long-term treatment, with significant improvements being shown in 8 out of 9 domains including those domains that are most important to participants with OAB. This long-term (24 month) study of participants with 'wet' OAB showed that the benefits to HRQoL associated with darifenacin were maintained throughout the study .
This analysis included a large patient population gained by pooling the three studies, which allowed the examination of subsets (participants with moderately severe and severe OAB) and may better reflect the clinical setting than smaller individual studies. In clinical practice the vast majority of patients present with symptomatic OAB, mainly of idiopathic etiology. In this analysis 95% of participants had idiopathic OAB. As the prevalence of OAB increases with age, this is also reflected in our patient population with 30% of patients ≥ 65 years of age. However, interpretation of our findings may be limited by the retrospective nature of the analysis. As for many patient-reported outcomes, the number of consecutive Dry Days or continent days is often evaluated as a secondary efficacy parameter in pooled analyses [25,26]. A prospective study designed specifically to evaluate Dry Days and its impact on participants would allow for a more detailed exploration of this outcome without being limited by the original study designs, such as fixed-dose that does not allow for an individualization of treatment per participant. Another limitation is that we did not differentiate the type of incontinence product used (eg, light absorbency product like a perineal pad versus a heavy absorbency product such as an adult brief) or the clothing that needed changing, so the actual cost savings could not be determined.
Our study highlights the clinical relevance of evaluating participants achieving consecutive Dry Days. Improvements in the number of consecutive Dry Days with darifenacin were associated with improvements in HRQoL. These findings from the overall study population are consistent with those seen in previous studies with darifenacin, which showed that efficacy and HRQoL were not affected by gender or age [11,12,24,27]. However, additional studies are warranted to further evaluate the use of Dry Days as a treatment endpoint. Future studies should aim to further investigate the impact of increased number of Dry Days on participants' lives and HRQoL.
Funding for editorial support, drafting and revising the manuscript, and for the analysis was provided by Novartis Pharmaceuticals Corporation, Novartis Pharma AG and Procter & Gamble Pharmaceuticals (currently Warner Chilcott).
The authors would like to thank Karen Boyle (Rho) for input into data analysis as well as Jessica Colon (Novartis Pharmaceuticals Corp.), and Claire Chinn and Jonathon Gibbs (professional writers with ACUMED®), for their assistance in drafting and revising this manuscript.
CONFLICT OF INTEREST
Diane Newman has served on the Advisory Board of Novartis, Astellas, GSK and Watson Pharma, and as a speaker for Procter and Gamble (now known as Warner Chilcott), Novartis, Allergan, Astellas, GSK, Pfizer, Allergan and Watson Pharma and has conducted clinical research for GSK, Allergan and Watson Pharma.
At the time of the analysis, William S Aronstein was an employee of Procter & Gamble Pharmaceuticals and received stock grants and stock options in the company. Dr. Aronstein is currently employed as a Senior Medical Director at CTI Clinical Trial and Consulting Services, Inc., Cincinnati, Ohio.
Andrea Larson-Peters is an employee of Procter & Gamble and has received stock grants and stock options in the company. Yodit Seifu and Lidia Mongay are employees of Novartis Pharmaceuticals Corp., and have received and/or own stock options in the company.
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