雷西纳德与别嘌醇联合使用：一项针对对标准治疗反应不足的痛风患者的随机、双盲、安慰剂对照研究（多国CLEAR 2研究）
Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).
作者信息
Bardin Thomas, Keenan Robert T, Khanna Puja P, Kopicko Jeff, Fung Maple, Bhakta Nihar, Adler Scott, Storgard Chris, Baumgartner Scott, So Alexander
机构信息
Rhumatologie, Lariboisière Hospital, and Université Paris Diderot Sorbonne Cité, Paris, France.
Division of Rheumatology, Duke University School of Medicine, Durham, North Carolina, USA.
出版信息
Ann Rheum Dis. 2017 May;76(5):811-820. doi: 10.1136/annrheumdis-2016-209213. Epub 2016 Nov 7.
OBJECTIVES
Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial.
METHODS
Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data.
RESULTS
Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively.
CONCLUSION
Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.
TRIAL REGISTRATION NUMBER
NCT01493531.
目的
在一项为期12个月的随机III期试验中，确定在血清尿酸（sUA）未达标的患者中，每日口服200或400mg雷西纳德联合别嘌醇的疗效和安全性。
方法
服用别嘌醇≥300mg（中度肾功能损害患者≥200mg）的患者，在筛查时sUA水平≥6.5mg/dL（≥387µmol/L），且在前一年有两次或更多次痛风发作。主要终点是达到sUA水平<6.0mg/dL（<357µmol/L）（第6个月）的患者比例。关键次要终点是需要治疗的平均痛风发作率（第7至12个月）以及一个或多个目标痛风石完全消退的患者比例（第12个月）。安全性评估包括不良事件和实验室数据。
结果
患者（n = 610）以男性为主，平均（±标准差）年龄51.2±10.90岁，痛风病程11.5±9.26年，基线sUA为6.9±1.2mg/dL（410±71µmol/L）。与单独使用别嘌醇治疗相比，在别嘌醇基础上加用200mg和400mg剂量的雷西纳德，到第6个月时达到sUA目标的患者比例显著增加（分别为55.4%、66.5%和23.3%，两种雷西纳德联合别嘌醇治疗组p均<0.0001）。在关键次要终点方面，治疗组之间没有统计学上显著有利于雷西纳德的差异。雷西纳德总体耐受性良好；200mg剂量的安全性与单独使用别嘌醇治疗相当。200mg雷西纳德联合别嘌醇组发生肾脏相关不良事件的比例为5.9%，400mg雷西纳德联合别嘌醇组为15.0%，单独使用别嘌醇组为4.9%，血清肌酐升高≥1.5倍基线的比例分别为5.9%、15.0%和3.4%。严重的治疗中出现的不良事件分别发生在200mg雷西纳德联合别嘌醇组的4.4%、400mg雷西纳德联合别嘌醇组的9.5%和单独使用别嘌醇组的3.9%。
结论
在别嘌醇基础上加用雷西纳德在降低sUA方面优于单独使用别嘌醇治疗，对于需要额外治疗的痛风患者，200mg雷西纳德总体耐受性良好。
试验注册号
NCT01493531。
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