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.
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).


METHODS
After a 4-week washout/run-in period, 1059 adults (85% women) with symptoms of OAB (frequency and urgency with urge incontinence) for > or = 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 < or = 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.
Chapple
Christopher
C
Urology Research, Royal Hallamshire Hospital, Sheffield, UK. c.r.chapple@shef.ac.uk
Steers
William
W
Norton
Peggy
P
Millard
Richard
R
Kralidis
Georg
G
Glavind
Karin
K
Abrams
Paul
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001572:Benzofurans / Q000008:administration & dosage* / Q000009:adverse effects; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014549:Urinary Incontinence / Q000188:drug therapy*
D001572:Benzofurans; D011759:Pyrrolidines; D043587:Receptor, Muscarinic M3; C101207:darifenacin