lls in the intimal lining of the aorta. In the adrenal gland, vacuoles were located within cortical cells in the zona reticularis and zona fasciculata. The clinical significance of these findings and the functional consequences are unknown.
14 CLINICAL STUDIES
The efficacy of KRYSTEXXA was studied in adult patients with chronic gout refractory to conventional therapy in two replicate, multicenter, randomized, double-blind, placebo-controlled studies of six months duration: Trial1 and Trial2. Patients were randomized to receive KRYSTEXXA 8mg every 2weeks or every 4weeks or placebo in a 2:2:1ratio. Studies were stratified for the presence of tophi. Seventy-one percent (71%) of patients had baseline tophi. All patients were prophylaxed with an oral antihistamine, intravenous corticosteroid and acetaminophen. Patients also received prophylaxis for gout flares with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine, or both, beginning at least one week before KRYSTEXXA treatment unless medically contraindicated or not tolerated. Patients who completed the randomized clinical trials were eligible to enroll in a 2-year open label extension study.
Entry criteria for patients to be eligible for the trials were: baseline serum uric acid (SUA) of at least 8mg/dL; had symptomatic gout with at least 3gout flares in the previous 18months or at least 1gout tophus or gouty arthritis; and had a self-reported medical contraindication to allopurinol or medical history of failure to normalize uric acid (to less than 6mg/dL) with at least 3months of allopurinol treatment at the maximum medically appropriate dose.
The mean age of study subjects was 55years (23-89); 82% were male, mean body mass index (BMI) was 33kg/m2, mean duration of gout was 15years, and mean baseline SUA was 10mg/dL.
To assess the efficacy of KRYSTEXXA in lowering uric acid, the primary endpoint in both trials was the proportion of patients who achieved plasma uric acid (PUA) less than 6mg/dL for at least 80% of the time during Month3 and Month6. As shown in Table2, a greater proportion of patients treated with KRYSTEXXA every 2weeks achieved urate lowering to below 6mg/dL than patients receiving placebo. Although the 4week regimen also demonstrated efficacy for the primary endpoint, this regimen was associated with increased frequency of anaphylaxis and infusion reactions and less efficacy with respect to tophi.
Table 2 Plasma Uric Acid <6mg/dL for at Least 80% of the Time During Months3 and 6 Treatment Group N Number (%) of Subjects Who Met Response Criteria 95% Confidence Interval1 P-Value2
1 95% confidence interval for differences in responder rate between pegloticase group vs. placebo
2 P-value using Fisher's exact test to compare pegloticase group vs. placebo
Note: Based on post-hoc analyses of the clinical trial data, if KRYSTEXXA had been stopped when a patient's uric acid level rose to greater than 6mg/dL on a single occasion, the incidence of infusion reactions would have been reduced by approximately 67%, but the success rates for the primary efficacy endpoint would have been reduced by approximately 20%. If KRYSTEXXA had been stopped after 2consecutive uric acid levels greater than 6mg/dL, the incidence of infusion reactions would have been half, and there would have been little change in the efficacy outcome.
Trial 1
Pegloticase 8mg every 2weeks 43 20 (47%) [32%, 61%] <0.001
Pegloticase 8mg every 4weeks 41 8 (20%) [7% |
