Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
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DOI：
10.1016/s0140-6736(13)60023-9
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发表时间：
2013-06-01
期刊：
影响因子：
168.9
通讯作者：
Mandrup-Poulsen, Thomas
中科院分区：
文献类型：
--
作者：
Moran, Antoinette;Bundy, Brian;Becker, Dorothy J.;DiMeglio, Linda A.;Gitelman, Stephen E.;Goland, Robin;Greenbaum, Carla J.;Herold, Kevan C.;Marks, Jennifer B.;Raskin, Philip;Sanda, Srinath;Schatz, Desmond;Wherrett, Diane K.;Wilson, Darrell M.;Krischer, Jeffrey P.;Skyler, Jay S.;Pickersgill, Linda;de Koning, Eelco;Ziegler, Anette-G;Boeehm, Bernhard;Badenhoop, Klaus;Schloot, Nanette;Bak, Jens Friis;Pozzilli, Paolo;Mauricio, Didac;Donath, Marc Y.;Castano, Luis;Waegner, Ana;Lervang, Hans Henrik;Perrild, Hans;Mandrup-Poulsen, Thomas
先天免疫有助于自身免疫性疾病的发病机制，如1型糖尿病，但到目前为止，还没有随机对照试验的关键先天免疫介质白细胞介素-1的封锁已经完成。我们的目的是评估canakinumab（一种人单克隆抗白细胞介素-1抗体）或anakinra（一种人白细胞介素-1受体拮抗剂）是否能改善新近发作的1型糖尿病患者的β细胞功能。我们在两组新近发病的1型糖尿病患者中进行了两项随机、安慰剂对照试验，混合餐耐受试验刺激的C肽至少为0·2 nM。卡那单抗试验中的患者年龄为6-45岁，阿那白滞素试验中的患者年龄为18-35岁。canakinumab试验的患者在美国和加拿大的12个研究中心入组，而anakinra试验的患者在欧洲的14个研究中心入组。参与者通过计算机生成的区组随机分配，每月皮下注射2 mg/kg（最大300 mg）卡那单抗或安慰剂，持续12个月，或每天100 mg阿那白滞素或安慰剂，持续9个月。参与者和护理人员对治疗分配不知情。主要终点是12个月（卡那单抗试验）和9个月（阿那白滞素试验）时混合餐耐受试验的基线校正2小时曲线下面积C肽反应。这些研究在ClinicalTrials.gov上注册，编号为NCT 00947427和NCT 00711503，EudraCT编号为2007-007146-34。患者于2010年11月12日至2011年4月11日期间入组canakinumab试验，并于2009年1月26日至2011年5月25日期间入组anakinra试验。69名患者被随机分配到canakinumab（n=47）或安慰剂（n=22）每月一次，持续12个月，69名患者被随机分配到阿那白滞素（n=35）或安慰剂（n=34）每日一次，持续9个月。未进行中期分析。canakinumab试验中45例canakinumab治疗患者和21例安慰剂治疗患者以及anakinra试验中25例anakinra治疗患者和26例安慰剂治疗患者被纳入主要分析。12个月时，卡那单抗组和安慰剂组之间C肽曲线下面积的差异为0.01 nmol/L（95% CI-0.11 ~ 0.14; p= 0.86），9个月时，阿那白滞素组和安慰剂组之间的差异为0.02 nmol/L（-0.09 ~ 0.15; p= 0.71）。在canakinumab试验中，不良事件的数量和严重程度在各组之间没有差异。在阿那白滞素试验中，阿那白滞素组患者的不良事件等级明显高于安慰剂组（p= 0.018），这主要是因为阿那白滞素组的注射部位反应数量较多。Canakinumab和anakinra作为单一免疫调节药物在新发1型糖尿病中是安全的，但不是有效的。在器官特异性自身免疫性疾病中，白细胞介素-1阻断剂与靶向获得性免疫的治疗组合可能更有效。国立卫生研究院和青少年糖尿病研究基金会。
Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin-1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes. We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance-test-stimulated C peptide of at least 0·2 nM. Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0·01 nmol/L (95% CI −0·11 to 0·14; p=0·86), and between the anakinra and the placebo groups at 9 months was 0·02 nmol/L (−0·09 to 0·15; p=0·71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0·018), which was mainly because of a higher number of injection site reactions in the anakinra group. Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent-onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. National Institutes of Health and Juvenile Diabetes Research Foundation.