Dapansutrile,口服选择性NLRP3 inflammasome抑制剂,用于治疗痛风耀斑:一个非盲、dose-adaptive概念,第二阶段试验。

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Kluck V,詹森TLTA,詹森M, Comarniceanu, Efde M, Tengesdal信息战,Schraa K, Cleophas MCP,斯克里布纳尔出版社CL, Skouras DB,马尔凯蒂C, Dinarello CA, Joosten实验室

Dapansutrile,口服选择性NLRP3 inflammasome抑制剂,用于治疗痛风耀斑:一个非盲、dose-adaptive概念,第二阶段试验。

柳叶刀Rheumatol。2020; 2 (5): e270-e280。doi: 10.1016 / s2665 - 9913 (20) 30065 - 5。Epub 2020年4月8日。

PubMed ID
33005902 (在PubMed
]
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摘要:背景:痛风耀斑是由白介素(IL) 1β。Dapansutrile抑制了NLRP3 inflammasome IL-1beta和随后的激活。在这项研究中,我们旨在调查口头管理的安全性和有效性dapansutrile患者痛风耀斑。方法:在这个非盲、概念,第二阶段审判,成人患者(18 - 80岁)单钠尿酸盐单关节crystal-proven痛风耀斑在门诊登记顺序在荷兰和分配使用dose-adaptive设计接受100毫克/天,300毫克/天,1000毫克/天,或2000毫克/天口服dapansutrile 8天。patient-reported coprimary结果改变目标关节疼痛从基线到第三天,从基线到7天,按方案进行评估人口(所有病人至少80%的研究药物和没有重大协议的偏差)。安全评估的意向处理人口。这个试验是在欧盟临床试验登记注册,EudraCT 2016-000943-14,完成。之间发现:2017年5月18日和1月21日,2019年,144名患者评估资格,其中34个登记,29日按方案中包括人口(三个患者被排除由于接受< 80%的研究药物和两个主要协议偏差):8名患者接受100毫克/天,7收到300毫克/天,6收到1000毫克/天,和八个收到2000毫克/天。基线和第三天之间,意味着patient-reported减少目标52.4%的关节疼痛(SD 32.94;p = 0016) 100毫克/天组,68.4% (34.29; p=0016) for the 300 mg/day group, 55.8% (44.90; p=0063) for the 1000 mg/day group, and 57.6% (38.72; p=0016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82.1% (22.68; p=0031) for the 100 mg/day group, 84.2% (16.33; p=0016) for the 300 mg/day group, 68.9% (34.89; p=0031) for the 1000 mg/day group, and 83.9% (15.44; p=0008) for the 2000 mg/day group, compared to baseline. 25 (73.5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37.8%]) and gastrointestinal disorders (ten [22.2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug. Interpretation: Dapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.

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