Objectives: To evaluate the efficacy, tolerability and safety of darifenacin, a once-daily M3) selective receptor antagonist (M3 SRA), in patients with overactive bladder (OAB).
Methods: This multicentre, double-blind, placebo-controlled, parallel-group study enrolled 561 patients (19-88 years; 85% female) with OAB symptoms for >6 months, and included some patients with prior exposure to antimuscarinic agents. After washout and a 2-week placebo run-in, patients were randomised (1:4:2:3) to once-daily oral darifenacin controlled-release tablets (3.75 mg [n=53], 7.5 mg [229] or 15 mg [n=115]) or matching placebo (n=164) for 12 weeks. Patients recorded daily incontinence episodes, micturition frequency, bladder capacity (mean volume voided), frequency of urgency, severity of urgency, incontinence episodes resulting in change of clothing or pads and nocturnal awakenings due to OAB using an electronic diary during weeks 2, 6 and 12 (directly preceding clinic visits). Tolerability data were evaluated from adverse event reports.
Results: Darifenacin 7.5 mg and 15 mg had a rapid onset of effect, with significant improvement compared with placebo being seen for most parameters at the first clinic visit (week 2). This effect was sustained through week 12. At this time the number of incontinence episodes per week was reduced from baseline by 67.7% with darifenacin 7.5 mg and 72.8% with darifenacin 15 mg compared with 55.9% with placebo (p=0.010 and p=0.017, respectively, versus placebo). The 3.75 mg group (null dose arm) was included for proof of concept of dose flexibility, therefore formal sample sizing and statistical analysis were not performed for this group. Darifenacin 7.5 mg and 15 mg, respectively, were significantly superior to placebo for improvements in micturition frequency (p<0.001, p<0.001), bladder capacity (p<0.040, p<0.001), frequency of urgency (p<0.001, p=0.005), severity of urgency (p<0.001, p=0.002) and number of incontinence episodes leading to a change in clothing or pads (p<0.001, p=0.002). There was no significant reduction in nocturnal awakenings due to OAB. The most common adverse events were mild-to-moderate dry mouth and constipation. However, no patients withdrew from the study as a result of dry mouth and discontinuation related to constipation was rare (0.6% placebo versus 0.9% darifenacin). In addition, there was a low need for laxative use, with no difference between the darifenacin groups and those taking placebo. There were no reports of blurred vision and the CNS and cardiac safety profile was comparable to placebo.
Conclusions: Darifenacin significantly improves the major symptoms of OAB. No significant CNS (primarily M1-receptor mediated) adverse events or cardiac (primarily M2-receptor mediated) adverse events were identified in this study, as may be predicted from the M3 selective receptor profile of darifenacin.