ected in male or female rats that received lesinurad at oral doses up to 300 mg/kg/day (approximately 15 times the MRHD on a mg/m2 basis).
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies of ZURAMPIC
The efficacy of ZURAMPIC 200 mg and 400 mg once daily was studied in 3 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with hyperuricemia and gout in combination with a xanthine oxidase inhibitor, allopurinol or febuxostat. All studies were of 12 months duration and patients received prophylaxis for gout flares with colchicine or non-steroidal anti-inflammatory drugs (NSAIDs) during the first 5 months of ZURAMPIC treatment.
Although other doses have been studied, the recommended dose of ZURAMPIC is 200 mg once daily in combination with a xanthine oxidase inhibitor.
14.2 Add-on to Allopurinol in Inadequate Responders
Study 1 and Study 2 enrolled patients with gout who were on a stable dose of allopurinol of at least 300 mg (or 200 mg for moderate renal impairment) that had a serum uric acid > 6.5 mg/dL and reported at least 2 gout flares in the prior 12 months. Mean years since gout diagnosis were 12 years. More than half of the patients (61%) had mild or moderate renal impairment and 19% of the patients had tophi. Patients continued their allopurinol dose and were randomized 1:1:1 to receive ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo once daily. The average dose of allopurinol in the studies was 310 mg (range: 200-900 mg).
As shown in Table 5, ZURAMPIC 200 mg in combination with allopurinol was superior to allopurinol alone in lowering serum uric acid to less than 6 mg/dL at Month 6.
Table 5: Proportion of Patients Achieving Target Serum Uric Acid Levels (< 6 mg/dL) in Two Studies of ZURAMPIC in Combination with Allopurinol
Study
Timepoint
Patients Achieving Serum Uric Acid Target
Difference of Proportion
(95% C.I.)
Placebo + Allopurinol
ZURAMPIC 200 mg + Allopurinol
ZURAMPIC 200 mg vs Placebo
Stdy (N=603)
Month 6
28%
54%
0.26
(0.17, 0.36)
Study 2 (N=610)
Month 6
23%
55%
0.32
(0.23, 0.41)
The estimated effect of ZURAMPIC 200 mg on serum uric acid in the subgroup of patients taking thiazide diuretics at baseline was similar to the estimated effect in the overall population. The estimated effect was also similar in the subgroup of patients taking low dose aspirin at baseline.
As shown in Figure 3, reduction in average serum uric acid levels to < 6 mg/dL was noted for ZURAMPIC 200 mg in combination with allopurinol at the Month 1 visit and was maintained throughout the 12-month study.
Figure 3: Mean Serum Uric Acid Levels Over Time in Pooled Clinical Studies with ZURAMPIC in Combination with Allopurinol (Study 1 and Study 2)
Figure 3
14.3 Combination with Febuxostat in Tophaceous Gout
Study 3 enrolled gout patients with measurable tophi. Patients received febuxostat 80 mg once daily for 3 weeks and then were randomized 1:1:1 to once daily doses of ZURAMPIC 200 mg, ZURAMPIC 400 mg, or placebo in combination with febuxostat. A total of 66% of patients had mild or moderate renal impairment. Fifty percent of patients did not reach target serum uric acid < 5.0 mg/dL at Baseline after 3 weeks of febuxostat treatment.
As shown in Table 6, there was not statistical evidence of a difference in the proportion of patients treated with ZURAMPIC 200 mg in combination with febuxostat achieving a serum uric acid < 5 mg/dL by Month 6, compared with patients receiving febuxostat alone. However, the a |
