Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.
Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.
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DOI：
10.1016/s2665-9913(20)30065-5
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发表时间：
2020-05
期刊：
影响因子：
--
通讯作者：
Joosten LAB
中科院分区：
文献类型：
--
作者：
Klück V;Jansen TLTA;Janssen M;Comarniceanu A;Efdé M;Tengesdal IW;Schraa K;Cleophas MCP;Scribner CL;Skouras DB;Marchetti C;Dinarello CA;Joosten LAB
痛风发作是由白介素1β驱动的。氨苯舒可抑制NLRP3炎症体和随后的IL-1β的激活。在这项研究中，我们旨在研究口服达潘舒利治疗痛风发作的安全性和有效性。在这项开放标签、概念验证、2a阶段的试验中，在荷兰的一家门诊诊所登记了患有单关节尿酸钠结晶证实痛风发作的成年患者(年龄18-80岁)，并使用剂量适应性设计按顺序分配服用100毫克/天、300毫克/天、1000毫克/天或2000毫克/天的口服达潘脲，疗程为8天。共同的结果是患者报告的目标关节疼痛从基线到第3天以及从基线到第7天的变化，在按方案人群中进行评估(所有接受研究药物至少80%且没有重大方案偏差的患者)。安全性在意向治疗人群中进行评估。这项试验已在欧盟临床试验注册中心注册，EudraCT2016-000943-14，并已完成。在2017年5月18日至2019年1月21日期间，144名患者接受了资格评估，其中34人入选，29人纳入方案人群(3名患者因接受80%的研究药物而被排除在外，2名患者存在严重的方案偏差)：8名患者每天接受100 mg，7名患者每天接受300 mg，6名患者每天接受1000 mg，8名患者每天接受2000 mg。在基线和第3天之间，患者报告的目标关节疼痛平均减少了52.4%(SD 32.94；p=0∙016)，300 mg/d组68.4%(34·29；p=0∙016)，1000 mg/d组55.8%(44·90；p=0∙063)，以及2000 mg/d组57.6%(38·72；p=0∙016)。在第7天，与基线相比，100 mg/天组平均减少82.1%(22.68；p=0∙031)，300 mg/天组平均减少84.2%(16.33；p=0∙016)，1000 mg/天组平均减少68.9%(34.89；p=0∙031)，2000 mg/天组平均减少83.9%(15.44；p=0∙008)。34例患者中有25例(73.5%)报告了45例急诊治疗不良事件，主要为代谢和营养障碍(17例[37.8%])和胃肠道疾病(10例[22.2%])。在研究期间发生了两个严重的不良事件，在第三天因痛风发作加重而入院，以及在患者接受最后一剂药物18天后因冠状动脉狭窄入院；这些被认为是中度严重的，与研究药物无关。Dapansutrile是一种特异性的NLRP3炎性小体抑制剂，在本研究中具有令人满意的安全性和减少靶关节疼痛的疗效。还需要进一步的研究来证实达潘苏利的临床潜力。
Gout flares are driven by interleukin (IL)-1β. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1β. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare. In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18–80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed. Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) 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. 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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DOI：
10.1111/j.1365-2125.1987.tb03132.x
发表时间：
1987-07-01
影响因子：
3.4
作者：
BELLAMY, N;DOWNIE, WW;BUCHANAN, WW
通讯作者：
BUCHANAN, WW
DOI：
10.1073/pnas.1716095115
发表时间：
2018-02-13
影响因子：
11.1
作者：
Marchetti C;Swartzwelter B;Gamboni F;Neff CP;Richter K;Azam T;Carta S;Tengesdal I;Nemkov T;D'Alessandro A;Henry C;Jones GS;Goodrich SA;St Laurent JP;Jones TM;Scribner CL;Barrow RB;Altman RD;Skouras DB;Gattorno M;Grau V;Janciauskiene S;Rubartelli A;Joosten LAB;Dinarello CA
通讯作者：
Dinarello CA
影响因子：
81.5
作者：
Dalbeth, Nicola;Choi, Hyon K.;Stamp, Lisa K.
通讯作者：
Stamp, Lisa K.
影响因子：
5.5
作者：
Janssen, Carly A.;Voshaar, Martijn A. H. Oude;van de laar, Mart A. F. J.
通讯作者：
van de laar, Mart A. F. J.
影响因子：
--
作者：
Terkeltaub, Robert A.;Furst, Daniel E.;Davis, Matthew W.
通讯作者：
Davis, Matthew W.