Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications.

Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan-Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV 1.5 block and to support the observed clinical safety of lamotrigine. We used HEK-293 cells stably expressing the hNaV 1.5 channel and voltage clamp electrophysiology to quantify the potency (half-maximal inhibitory concentration) against peak and late channel current, on-/off-rate binding kinetics, voltage-dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV 1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV 1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Albiglutide efficacy and safety in the Latino/Hispanic subpopulation for the integrated phase III program.

OBJECTIVE: to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin. METHODS: Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator. RESULTS: At baseline in the Latino/Hispanic subpopulation, the mean HbA1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m2, and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p < 0.001) for the overall phase III population. Changes in fasting plasma glucose mirrored those of HbA1c. Weight loss with albiglutide was numerically greater than with OADs and insulin in both populations, but it was smaller than with liraglutide. Within the Latino/Hispanic subpopulation, more injection-site reactions were reported with albiglutide vs all comparators, while gastrointestinal and hypoglycemic adverse events were comparable between the two groups, and the latter was uncommon when used without insulin and/or a sulfonylurea. CONCLUSIONS: In the Latino/Hispanic population, albiglutide resulted in effective lowering of glucose and modest weight loss, and it was generally well tolerated.

Efficacy of solifenacin for overactive bladder symptoms, symptom bother, and health-related quality of life in patients by duration of self-reported symptoms: a secondary analysis of the VIBRANT study.

In this post-hoc analysis of data from patients with overactive bladder (OAB) in VIBRANT patients receiving solifenacin showed statistically significantly greater improvement versus placebo in most outcome measures regardless of OAB symptom duration (less than five years and five years or longer).

Efficacy and tolerability of solifenacin in patients aged ≥ 65 years with overactive bladder: post-hoc analysis of 2 open-label studies.

BACKGROUND: Antimuscarinics have proven efficacy as first-line therapy in overactive bladder (OAB); however, data on their use in older adults are needed. OBJECTIVE: To assess the efficacy and tolerability of solifenacin in patients aged ≥ 65 years, we conducted post-hoc analyses of data from VESIcare® Open-Label Trial (VOLT) and VESIcare® Efficacy and Research Study US (VERSUS). METHODS: In both of these 12-week, open-label, flexible-dosing studies involving 2645 patients with OAB for ≥ 3 months, patients received 5 mg solifenacin daily for 4 weeks, with an option to increase to 10 mg at week 4 (both studies) and week 8 (VOLT). VERSUS patients had received tolterodine extended release 4 mg for ≥ 4 weeks without sufficient subjective improvement in urgency (mean ≥ 3 urgency episodes/24 h). Baseline values 14 days after tolterodine washout were used for comparison with VOLT. Common study endpoints were the Patient Perception of Bladder Condition (PPBC) scale and the Overactive Bladder Questionnaire (OAB-q). VOLT used a horizontal visual analog scale (VAS), and diary-recorded symptom data were captured in VERSUS. RESULTS: In the full analysis sets (FAS), 40% of VOLT and 44% of VERSUS patients were aged ≥ 65 years. After 12 weeks of solifenacin, older patients experienced decreases in OAB symptoms, and improvements from baseline on the PPBC, OAB-q, and VAS. In total, 59% of older VOLT and 62% of older VERSUS patients reported ≥ 1 treatment-emergent adverse event (AE); the AEs were mostly anticholinergic and of mild-to-moderate severity. Results were consistent with younger patients and the FAS. CONCLUSIONS: In this large group of older patients, flexibly dosed solifenacin was associated with reductions in diary-documented OAB symptoms (VERSUS). In both studies, solifenacin was associated with improvements in measures assessing patients' perception of their bladder problems, symptom bother, and aspects of health-related quality of life. Adverse event rates in older patients were comparable to those in younger patients and the FAS.

Efficacy of Solifenacin on Overactive Bladder Symptoms, Symptom Bother, and Other Patient-Reported Outcomes in Subjects With or Without Incontinence: A Post Hoc Analysis of Data From VIBRANT.

OBJECTIVE: : To evaluate the efficacy of solifenacin versus placebo by baseline continence status using post hoc analysis. METHODS: : Patients with overactive bladder (OAB) were randomized to solifenacin or placebo for 12 weeks; patient-reported outcome (PRO) measures and bladder diaries were completed at prespecified time points. VESIcare Investigation of Bother and Quality of Life in Subjects with OAB (VIBRANT) was not designed to show treatment differences within continence status subgroups. RESULTS: : In the full analysis set (n = 750), 73% of patients were incontinent (n = 545) at baseline. After 12 weeks, incontinent patients receiving solifenacin showed significant improvements versus placebo on PRO measures and most diary-based end points; continent patients (n = 205) showed smaller but similar treatment-related changes. Tolerability was similar in both subgroups and by treatment; most frequent adverse events were dry mouth and constipation. CONCLUSIONS: : In the VIBRANT study, solifenacin significantly improved OAB symptom bother, health-related quality of life, and most symptoms versus placebo in incontinent patients. Continent patients showed smaller but similar trends. Solifenacin was well tolerated in both subgroups.

Impact of solifenacin on diary-recorded and patient-reported urgency in patients with severe overactive bladder (OAB) symptoms.

OBJECTIVE: It is widely recognized that patient perception of overactive bladder (OAB) symptoms can vary considerably from mild to severe bother. This post hoc analysis reports outcomes in patients with severe OAB symptoms at baseline taken from the VESIcare Efficacy and Safety in PatieNts with Urgency Study (VENUS). METHODS: VENUS was a 12-week, randomized, double-blind, placebo-controlled trial of solifenacin (5 or 10 mg/day, flexibly dosed) in OAB patients. The primary endpoint in VENUS was mean change from baseline to study end in urgency episodes/day using 3-day bladder diaries. Secondary endpoints included other diary endpoints (frequency, incontinence, and nocturia), warning time (WT; time between first sensation of urgency to voiding), and patient-reported outcome (PRO) measures of urgency (the Indevus Urgency Severity Scale [IUSS] and Urgency Perception Scale [UPS]) and of symptom bother and health-related quality of life (HRQL) (the Patient Perception of Bladder Condition [PPBC] and Overactive Bladder Questionnaire). For this analysis, severe OAB was defined as baseline PPBC score ≥5 (1 = no problems, 6 = many severe problems). TRIAL REGISTRATION: NCT00454896. RESULTS: In total, 158/707 (22.3%) patients in the full analysis set (FAS) reported severe OAB symptoms. Solifenacin reduced mean urgency episodes/day versus placebo in the severe subgroup (-4.6 vs. -3.1, p = 0.1150), similar to the significant reduction observed in the FAS (-3.9 vs. -2.7, p < 0.0001). Solifenacin also improved the other diary endpoints and PRO measures in the severe subgroup; these changes were consistent with the significant solifenacin- versus placebo-related improvements for the FAS. Treatment-emergent adverse events were mostly mild/moderate, and few patients taking solifenacin or placebo discontinued treatment in the severe subgroup (4.5% vs. 6.5%) or FAS (6.5% vs. 4.6%). Key limitations are that VENUS was not powered to detect treatment differences in subgroups, and that the lack of a standardized definition of OAB symptom severity may limit the generalizability of the findings. CONCLUSIONS: Patients with severe OAB symptoms showed objective and subjective improvements in symptoms, symptom bother, HRQL, and urgency severity with solifenacin similar to the FAS. Solifenacin was also well-tolerated in this subgroup.

Efficacy of Solifenacin on Symptom Bother and Health-Related Quality of Life in Patients With Acute, Early Chronic, and Late Chronic Overactive Bladder: Secondary Analysis of Data From the VOLT Study.

OBJECTIVES: : In many clinical trials of pharmacotherapy for overactive bladder (OAB), the duration of symptoms is reported as a baseline characteristic; none has investigated this as a prognostic variable. We evaluated the efficacy of solifenacin by patient-reported OAB duration. METHODS: : In this post hoc analysis, patients from a 12-week, open-label study of solifenacin were grouped into 3 OAB duration categories: 3 months to 1 year, 1 to 5 years, and more than 5 years. Changes from baseline to end point on the Patient Perception of Bladder Condition (PPBC), Overactive Bladder Questionnaire (OAB-q), and visual analog scale (VAS) are summarized for each duration cohort. In addition, analysis of covariance was used to compare baseline characteristics and treatment-related changes from baseline among the 3 duration cohorts. RESULTS: : After 12 weeks, all 3 duration cohorts showed numeric improvements in the PPBC, VAS, and OAB-q. Approximately 75% of patients in each group showed improvement on the PPBC. All 3 cohorts showed a 36- to 45-point improvement in the level of bother on the symptom-specific VAS. The magnitude of score improvements (14-31 points) on the OAB-q exceeded the minimally important within group difference of 10 points in all 3 groups. Although results from the analysis of covariance model indicated statistically significant differences between the 3 cohorts for some end points, these differences were numerically small and may not be clinically relevant. Tolerability was similar among the cohorts and compared with the safety population. The most frequently reported adverse events were dry mouth, constipation, headache, and blurred vision. CONCLUSIONS: : These findings showed that irrespective of OAB symptom duration, patients who received 12 weeks of solifenacin perceived meaningful improvements in symptom-specific bother, health-related quality of life, and their overall bladder condition.

Solifenacin treatment in men with overactive bladder: effects on symptoms and patient-reported outcomes.

OBJECTIVE: In the few studies to evaluate antimuscarinics for overactive bladder (OAB) in men, safety has been the primary focus. In OAB efficacy trials, subject populations have been predominantly female and patient-reported outcomes (PROs) have been assessed only recently. We present a post hoc analysis of PRO-based findings from the subset of men (without presumed bladder outlet obstruction [BOO]) from two large, independent, open-label trials of solifenacin. METHODS: Subjects with OAB for > or =3 months received flexibly dosed solifenacin for 12 weeks. At baseline and 4-week intervals, subjects completed the Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q). In one study, subjects also completed 3-day bladder diaries. At baseline, mean PPBC scores were similar in both studies and indicative of moderate-to-severe problems. RESULTS: After 12 weeks of solifenacin, mean PPBC scores improved significantly (p < 0.0001); values were suggestive of minor-to-moderate problems. Mean scores on the OAB-q were also significantly improved after solifenacin (p values < or =0.001). In men without presumed BOO, solifenacin significantly improved PRO measures of symptom bother, health-related quality of life, and overall perception of bladder problems. CONCLUSION: Results from these two studies support the use of solifenacin as a well-tolerated and efficacious treatment option for providing symptom relief in men with OAB without BOO.

Solifenacin for overactive bladder: patient-reported outcomes from a large placebo-controlled trial.

OBJECTIVE: Overactive bladder (OAB) is a prevalent, chronic condition that can negatively affect health-related quality of life (HRQL). Treatment goals are to improve symptoms and HRQL. We assessed the efficacy of solifenacin in OAB patients using several patient-reported outcome (PRO) measures, with a focus on urgency severity. Results for the primary endpoint, reductions in daily urgency episodes, and other bladder-diary variables have been recently reported. MATERIALS AND METHODS: In this 12-week multicenter trial, 739 patients (aged >or= 18 years) were randomized to flexibly dosed solifenacin (5/10 mg) or placebo. Prespecified secondary PRO measures included the Indevus Urgency Severity Scale (IUSS), Urgency Perception Scale (UPS), Patient Perception of Bladder Condition (PPBC), and Overactive Bladder Questionnaire (OAB-q). Appropriate statistical tests compared treatment-group differences in continuous and categorical data. RESULTS: In the full analysis set, patients who received solifenacin (n = 357) versus placebo (n = 350) showed significant improvements on the IUSS and UPS; treatment-group differences were 0.4 (P < 0.0001) and 0.2 (P = 0.0018), respectively. On the PPBC, significantly more patients taking solifenacin (66%) than placebo (48%) perceived fewer bladder-related problems (P < 0.0001) by week 12. On the OAB-q, solifenacin was superior to placebo for the Symptom Bother and total HRQL scales and for 3 of the 4 HRQL domains at study end (P

Patient-reported most bothersome symptoms in OAB: post hoc analysis of data from a large, open-label trial of solifenacin.

INTRODUCTION AND HYPOTHESIS: In overactive bladder (OAB), subjects' most bothersome symptom (MBS) may influence treatment-related outcomes. We evaluated effects of solifenacin on patient-reported outcomes (PROs) in subjects stratified by their MBS at baseline. METHODS: In a 12-week, open-label study, the effects of solifenacin on PROs were assessed using visual analog scales (VAS), the OAB questionnaire (OAB-q), and the patient perception of bladder condition (PPBC). Statistics were descriptive. RESULTS: Subjects' baseline MBS were frequency (27%), urge urinary incontinence (UUI; 26%), urgency (23%), and nocturia (15%); VAS scores were worse for MBS. By study end, participants' MBS showed the largest solifenacin-related VAS improvements. The UUI subgroup showed the largest VAS, OAB-q, and PPBC improvements. CONCLUSIONS: Solifenacin improved overall and symptom-specific bother, HRQL, and perception of their bladder condition in MBS subgroups, with larger improvements in subjects' MBS. Those with UUI as MBS showed greater improvement in most outcomes.

Diary and patient-reported outcomes in patients with severe overactive bladder switching from tolterodine extended release 4 mg/day to solifenacin treatment: An open-label, flexible-dosing, multicentre study.

OBJECTIVE: We report outcomes from the VERSUS (VESIcare Efficacy and Research Study US) study in a cohort with severe overactive bladder (OAB), defined as patients with a score >or=5 on the Patient Perception of Bladder Condition (PPBC) scale at baseline (on tolterodine extended release [ER] 4 mg/day) who remained severe at post-washout (on no drug). METHODS: VERSUS was a 12-week, open-label, flexible-dosing study assessing the efficacy, tolerability and effects on health-related quality of life (HRQOL) of solifenacin in patients with OAB. The current study is a post hoc analysis of a severely affected subgroup, as self-defined using the PPBC scale. Patients had received tolterodine ER 4 mg/day for >or=4 weeks but wished to switch therapy because of a lack of sufficient subjective improvement in urgency. They had to have continued to have three or more urgency episodes/24 hours at baseline (pre-washout, i.e. while taking tolterodine ER 4 mg/day). After >or=14 days' washout, patients received oral solifenacin 5 mg/day, with the option of continuing/adjusting the dose to 5 or 10 mg/day at weeks 4 and 8. Diary-documented improvements in urgency, urge incontinence, frequency, nocturia and nocturnal voids were compared with pre-washout (on tolterodine) and post-washout (on no drug) diary entries. The PPBC scale and Overactive Bladder Questionnaire (OAB-q) assessed patient-reported outcomes. Tolerability was evaluated based on the nature, frequency and severity of observed or reported adverse events (AEs). RESULTS: In this severe OAB cohort, the mean number of urgency episodes/24 hours decreased by 3.95 (95% CI -4.81, -3.08; p < 0.0001) from pre-washout (7.38) to study end (3.26). All other diary variables were also significantly reduced (p < 0.0001). Patients had a mean PPBC score of 5.3 at pre-washout and 3.6 at study end, representing an improvement of 1.7 (95% CI -2.0, -1.5; p < 0.0001). Patients also reported significant improvements for all OAB-q scales and domains (p < 0.0001). Treatment-emergent AEs were mostly mild/moderate, and resulted in few discontinuations (5/116, 4.3%). CONCLUSION: In patients with severe OAB symptoms, solifenacin was effective and well tolerated. Solifenacin improved urgency, incontinence, micturition frequency, nocturia and nocturnal voids in patients continuing to experience urgency episodes on tolterodine ER 4 mg/day. Patients experienced improvements in HRQOL and perceived bother from OAB.

Treatment with solifenacin increases warning time and improves symptoms of overactive bladder: results from VENUS, a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: In this double-blind, placebo-controlled trial, we assessed the efficacy and tolerability of solifenacin treatment for overactive bladder (OAB) with a focus on urgency-related endpoints. Changes in number of urgency episodes were evaluated as the primary endpoint; secondary endpoints included changes in conventional diary-based OAB symptoms. We also measured warning time (defined as the time from first sensation of urgency to voiding). METHODS: We randomized patients (n = 739) to once-daily solifenacin or placebo for 12 weeks. Solifenacin 5 mg or matching placebo was administered for 4 weeks; dose could be maintained or adjusted at weeks 4 and 8. Participants completed 3-day micturition diaries at multiple study visits; warning time was recorded at baseline and week 12. RESULTS: At study end, the mean number of urgency episodes per 24 hours decreased by 3.91 (from 6.15 to 2.24) with solifenacin and by 2.73 (from 6.03 to 3.30) with placebo (P < .0001 between groups). Other diary-recorded symptoms (incontinence and micturition frequency) were also significantly more reduced with solifenacin compared with placebo. Median warning time increased 31.5 seconds (baseline, 67.8 seconds) with solifenacin, significantly longer (P = .008) than the median increase of 12.0 seconds (baseline, 65.0 seconds) observed with placebo. CONCLUSIONS: Solifenacin treatment significantly reduced episodes of urgency and other key symptoms of OAB. Solifenacin is the first antimuscarinic to demonstrate significant warning time improvement at approved dosing, as shown in a large OAB study population. This is the largest OAB clinical trial yet conducted to evaluate warning time and diary variables in the same study population.

Efficacy of solifenacin in patients previously treated with tolterodine extended release 4 mg: results of a 12-week, multicenter, open-label, flexible-dose study.

OBJECTIVE: This study evaluated the use of solifenacin in patients experiencing residual urgency symptoms during treatment with tolterodine extended release (ER) 4 mg for overactive bladder (OAB). METHODS: This was a 12-week, multicenter, openlabel, flexible-dose study of the efficacy, tolerability, and effects on health-related quality of life (HRQL) of solifenacin in patients aged >or=18 years who had symptoms of OAB for >or=3 months, had been treated with tolterodine ER 4 mg for >or=4 weeks, and wished to switch therapy because of a lack of sufficient subjective improvement in urgency. At baseline (before washout of tolterodine), patients had to have >or=3 urgency episodes/24 hours. After >or=14 days' washout of tolterodine, all patients received oral solifenacin 5 mg/d, with the option of a dose increase to 10 mg at weeks 4 and 8. On 3 consecutive days before the prewashout, postwashout (no drug treatment for OAB), and week 4, 8, and 12 visits (during and at the end of treatment with solifenacin), patients used a bladder diary to document daily symptoms of urgency, urge incontinence, frequency, nocturia, and nocturnal voids. Changes in these measures at study end were compared with prewashout and postwashout values. The Patient Perception of Bladder Condition (PPBC) and Overactive Bladder Questionnaire (OAB-q) were used to assess patient-reported outcomes at prewashout, postwashout, and week 12. Tolerability was evaluated based on the nature, frequency, and severity of observed or reported adverse events (AEs). RESULTS: Of 606 patients screened, 441 received study medication (mean [SD] age, 61.4 [13.8] years; 88.9% white; 88.2% female). Diary-documented urgency changed from a mean of 6.0 episodes/24 hours at prewashout to 2.6 episodes/24 hours at study end, a mean decrease of 3.4 episodes/24 hours (95% CI, -3.8 to -3.0; P < 0.001). The frequency of all other diary variables was also significantly reduced from prewashout to study end (P < 0.001). The mean PPBC score changed from 4.2 points at prewashout to 3.0 points at study end, a mean improvement of 1.2 points (95% CI, -1.3 to -1.1; P < 0.001). Changes in all OAB-q scales and domains (symptom bother, coping, concern, sleep, social interaction, and total HRQL) from prewashout and postwashout to study end were also statistically significant (P < 0.001). Treatment-emergent AEs were mainly mild or moderate (237/261 [90.8%]) and led to few discontinuations (16/441 [3.6%]). Treatment-emergent AEs included anticholinergic AEs such as dry mouth (77 [17.5%]), constipation (51 [11.6%]), and blurred vision (10 [2.3%]). CONCLUSIONS: Among these patients with residual urgency after treatment with tolterodine ER 4 mg, solifenacin was associated with significant improvements in urgency and other diary-documented symptoms of OAB. Patients receiving solifenacin also had significant improvements in HRQL and the perceived bother of OAB.

Solifenacin at 3 years: a review of efficacy and safety.

Now on the market in the United States for almost 3 years and available in 48 countries worldwide, solifenacin 5 mg or 10 mg once daily continues to demonstrate a profile of safety and efficacy as a treatment for incontinence, urgency, and other symptoms of OAB. More than 2.2 million patients have been treated worldwide with solifenacin. Safety and efficacy data across numerous studies in several thousand patients, along with flexible dosing, support the use of this agent as a first-line antimuscarinic treatment for OAB. Data from large randomized controlled trials such as VENUS and STAR show statistically significant superiority compared with placebo and improved outcomes over those achieved with tolterodine ER 4 mg. Solifenacin is an agent of choice for OAB-related incontinence, with more than 50% of incontinent patients reporting no incontinence episodes after 12 weeks of solifenacin therapy. In addition to improved efficacy, solifenacin offers good tolerability with a low incidence of side effects. Once-daily, flexible dosing with this agent provides 24-hour control of OAB symptoms and significantly increases warning time (the period from onset of urgency to voiding), which may also increase a patient's chance of avoiding episodes of incontinence.