Two randomized, placebo-controlled, double-blind studies were performed. In a dose-finding study, 242 patients were randomized to
AZD3582 375, 750, 1500, or 2250 mg (n = 41, 37, 42, and 41, respectively);
naproxen 500 mg (n = 39); or placebo (n = 42). In a comparator study, 282 patients were randomized to
AZD3582 500 mg (n = 78) or 750 mg (n = 83),
rofecoxib 50 mg (n = 80), or placebo (n = 41). Primary outcomes included time to rescue medication, time to
pain relief, and mean
pain intensity difference (MPID), as well as safety profile.
Pain was rated on a visual analog scale.
RESULTS: In the dose-finding study, 52% (126/242) were women; the mean (SD) age was 25.1 (4) years, mean weight was 69.0 kg, and the mean (SD) body mass index (BMI) was 23.7 (3) kg/m2. In the comparator study, 58% (164/282) were women; the mean (SD) age was 27 (6.4) years, mean weight was 71 kg, and mean (SD) BMI was 24.2 (3) kg/m2. In the dose-finding study, the
AZD3582 750-, 1500-, and 2250-mg groups were superior to placebo in the primary variables "time to rescue medication (0-8 hours)" (hazard ratios [HRs] [95% CIs], 0.17 [0.07-0.42], P < 0.003; 0.23 [0.11-0.50], P < 0.001; and 0.15 [0.06-0.36], P < 0.001, respectively), "time to meaningful
pain relief" (HRs [95% CIs], 3.42 [1.87-6.25], P < 0.003; 2.49 [1.37-4.50], P < 0.003; and 3.07 [1.70-5.55], P < 0.001, respectively), and MPID (analysis of covariance [ANCOVA] least squares mean [LSM] differences [95% CIs], 25.8 [17.3-34.4], P < 0.003; 20.4 [12.1-28.7], P < 0.003; and 29.3 [20.9-37.6], P < 0.001, respectively).
AZD3582 and
naproxen did not show any statistically significant differences for the 3 primary variables, except that
naproxen was superior to the
AZD3582 375-mg dose for the variables time to meaningful
pain relief (HR difference, 0.48 [95% CI, 0.29-0.78], P < 0.004) and MPID (difference in ANCOVA LSM, -10.2, [95% CI, -18.2 to -2.2], P < 0.012). The median times to meaningful
pain relief were 115 minutes for
AZD3582 375 mg, 66 minutes for 750 mg, 85 minutes for 1500 mg, 81 minutes for 2250 mg, and 162 minutes for placebo (P = NS, P = 0.003, P < 0.003, and P < 0.001, respectively). The median time to first rescue medication was 144 minutes for placebo, and <50% of the subjects on any of the
AZD3582 doses or
naproxen took rescue medication within 8 hours after dosing. In the comparator study,
AZD3582 750 mg was superior to placebo in "time to rescue medication (0-24 hours)" (HR [95% CI], 0.4 [0.3-0.6], P < 0.001), "time to confirmed perceptible
pain relief" (2.1 [1.1-3.8], P = 0.02), and MPID (11.9 [4.2-19.5], P = 0.002). However, inferiority of
AZD3582 to
rofecoxib for MPID could not be excluded (tolerance limit of 10 mm; P = NS for noninferiority testing). The median times to confirmed perceptible
pain relief were 45 minutes for
AZD3582 500 mg, 40 minutes for 750 mg, and 37 minutes for
rofecoxib. The median times to first rescue medication were 218 minutes for
AZD3582 500 mg, 365 minutes for 750 mg, 635 minutes for
rofecoxib, and 90 minutes for placebo. Overall,
AZD3582 was well tolerated. However, an effect on orthostatic blood pressure could not be excluded because there seemed to be more subjects with
dizziness and orthostatic blood pressure reduction who were administered
AZD3582 > or =750 mg. The proportions of patients with
vertigo and decreased orthostatic blood pressure each group were as follows:
AZD3582 500 mg, 6%;
AZD3582 750 mg, 12%;
rofecoxib, 3%; and placebo, 5%.
CONCLUSIONS: