Department of Medicine, University of Auckland, 85 Park Road, Grafton, Auckland, 1, New Zealand.
University of Tasmania, Hobart, TAS, Australia.
Arthritis Res Ther. 2019 Jan 7;21(1):8. doi: 10.1186/s13075-018-1788-4.
In gout, long-term urate-lowering therapy (ULT) promotes dissolution of tissue urate crystal deposits. However, no studies using combined xanthine oxidase inhibition and uricosuric ULT have focused on clinical outcomes or adverse events (AEs) beyond 12 months of therapy. Our objective in the present study was to examine efficacy and long-term safety in patients with tophaceous gout receiving febuxostat plus lesinurad as combination therapy.
Patients receiving combined lesinurad and febuxostat in the 12-month core CRYSTAL study continued at the same doses in the extension study ("200CONT", "400CONT"), whereas those receiving only febuxostat 80 mg were randomized to lesinurad 200 or 400 mg with febuxostat ("200CROSS", "400CROSS"). The primary endpoint was the proportion of patients experiencing complete resolution (CR) of at least one target tophus by extension month (EM) 12. The key secondary endpoint was mean rate of gout flares requiring treatment from the end of EM 2 to the end of EM 12. Secondary endpoints included reduction in the sum of areas for all target tophi. Safety assessments included AEs and laboratory data for the entire extension study (median length of lesinurad exposure, 800 days).
Of 235 patients completing the core study, 196 (83.4%) enrolled in the extension: 200CONT (n = 64), 200CROSS (n = 33), 400CONT (n = 65), and 400CROSS (n = 34). At EM 12, 59.6%, 43.5%, 66.7%, and 50.0% of patients, respectively, had CR of at least one target tophus. The sum of areas for all target tophi was reduced by 76.4%, 58.1%, 77.5%, and 62.8%, respectively. The adjusted mean (SE) rates of gout flares requiring treatment from the end of EM 2 to the end of EM 12 were 0.6 (0.19), 1.3 (0.48), 0.2 (0.08), and 1.9 (0.93), respectively. Target sUA < 5.0 mg/dl was achieved by 77.1%, 79.2%, 88.5%, and 71.4% of patients, respectively. Exposure-adjusted incidence rates of treatment-emergent adverse events (TEAEs) and renal-related TEAEs in the core study were not increased with prolonged lesinurad exposure in the extension study.
Patients receiving lesinurad plus febuxostat therapy for 2 years continued to be at sUA target. Patients exhibited a progressive increase in CR of at least one target tophus, progressive reduction in tophus size, and reduction of gout flares requiring treatment over the second year, with AEs consistent with those observed in the core study.
ClinicalTrials.gov , NCT01510769 . Registered on 13 January 2012.
在痛风中，长期的尿酸降低治疗（ULT）可促进组织尿酸晶体沉积物的溶解。然而，在使用联合黄嘌呤氧化酶抑制和尿酸排泄 ULT 的研究中，没有研究关注治疗 12 个月后超过 12 个月的临床结局或不良事件（AE）。本研究的目的是在接受非布司他联合利昔那普治疗的痛风石性痛风患者中检查疗效和长期安全性。
在为期 12 个月的核心 CRYSTAL 研究中接受联合利昔那普和非布司他治疗的患者在扩展研究中继续以相同剂量治疗（“200CONT”，“400CONT”），而仅接受非布司他 80mg 的患者则随机接受利昔那普 200 或 400mg 联合非布司他（“200CROSS”，“400CROSS”）。主要终点是扩展月（EM）12 时至少有一个靶痛风石完全缓解（CR）的患者比例。关键次要终点是从 EM2 结束到 EM12 结束期间需要治疗的痛风发作的平均发生率。次要终点包括所有靶痛风石面积总和的减少。安全性评估包括整个扩展研究的 AE 和实验室数据（利昔那普的暴露中位数，800 天）。
在完成核心研究的 235 名患者中，196 名（83.4%）患者入组了扩展研究：200CONT（n=64）、200CROSS（n=33）、400CONT（n=65）和 400CROSS（n=34）。在 EM12 时，分别有 59.6%、43.5%、66.7%和 50.0%的患者至少有一个靶痛风石达到 CR。所有靶痛风石面积总和分别减少了 76.4%、58.1%、77.5%和 62.8%。从 EM2 结束到 EM12 结束期间需要治疗的痛风发作的调整平均（SE）率分别为 0.6（0.19）、1.3（0.48）、0.2（0.08）和 1.9（0.93）。分别有 77.1%、79.2%、88.5%和 71.4%的患者达到了目标血清尿酸（sUA）<5.0mg/dl。在核心研究中，与延长利昔那普暴露相关的治疗中出现的不良事件（TEAE）和肾脏相关 TEAE 的发生率在扩展研究中并未增加。
接受利昔那普联合非布司他治疗 2 年的患者继续达到 sUA 目标。患者在第二年表现出至少一个靶痛风石 CR 的逐渐增加、痛风石大小的逐渐减少以及需要治疗的痛风发作的减少，AE 与核心研究中观察到的一致。
ClinicalTrials.gov，NCT01510769。于 2012 年 1 月 13 日注册。
