A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder
Authors: Chapple Christopher , Steers William , Norton Peggy , Millard Richard , Kralidis Georg , Glavind Karin , Abrams Paul 
Published: April 2005

An international group of authors present a pooled analysis of data from their phase III multicentre double‐blind clinical trials in patients with overactive bladder, which evaluated the efficacy, tolerability and safety of darifenacin. They found the drug, a muscarinic M3 selective receptor antagonist, to be effective in the treatment of this condition, with excellent tolerability and safety.

A paper from Denmark compares the efficacy and safety of alfuzosin and tamsulosin in a large randomized, double‐blind, placebo‐controlled, multicentre study. There were similar improvements in urinary symptoms and maximum urinary flow with the two drugs compared to placebo, but the incidence of sexual function adverse events was higher with tamsulosin than placebo.

OBJECTIVE

To evaluate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist (M3 SRA), from an analysis of pooled data from three phase III, multicentre, double‐blind clinical trials in patients with overactive bladder (OAB).

PATIENTS AND METHODS

After a 4‐week washout/run‐in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for ≥ 6 months were randomized to once‐daily oral treatment with darifenacin (7.5 mg, 337; or 15 mg, 334) or matching placebo (388) for 12 weeks. Efficacy was evaluated using electronic patient diaries that recorded incontinence episodes (including those resulting in a change of clothing or pads), frequency and severity of urgency, voiding frequency, and bladder capacity (volume voided). Safety was evaluated by analysis of adverse events (AEs), withdrawal rates and laboratory tests.

RESULTS

Relative to baseline, 12 weeks of treatment with darifenacin resulted in a significant reduction in the median (% change, interquartile range) number of incontinence episodes per week; 7.5 mg (−8.8, −68.4%, −15.1 to −4.4); 15 mg; (−10.6, −76.8%, −17.3 to −5.8: both P < 0.01 vs placebo). There was a significant dose–response trend in each study for which darifenacin 7.5 and 15 mg were evaluated (P < 0.01). There were also significant decreases in the frequency and severity of urgency, voiding frequency, and number of significant leaks (incontinence episodes resulting in a change of clothing or pads; both P ≤ 0.001 vs placebo), together with an increase in bladder capacity (both P < 0.01 vs placebo). Darifenacin was well tolerated; the most common AEs were dry mouth and constipation, although together these resulted in few discontinuations (darifenacin 7.5 mg 0.6% of patients; 15 mg 2.1%; placebo 0.3%). The incidence of peripheral/central nervous system and cardiovascular AEs were comparable with those on placebo.

CONCLUSIONS

Darifenacin (7.5 and 15 mg once daily) is effective in the treatment of patients with OAB. As predicted by its M3 selectivity and associated M1/M2‐sparing profile, darifenacin was well tolerated with no central nervous system or cardiovascular safety concerns.