Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.
Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial.
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DOI：
10.1136/gutjnl-2011-301668
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发表时间：
2012-12
期刊：
影响因子：
24.5
通讯作者：
Secukinumab in Crohn's Disease Study Group
中科院分区：
文献类型：
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作者：
Hueber W;Sands BE;Lewitzky S;Vandemeulebroecke M;Reinisch W;Higgins PD;Wehkamp J;Feagan BG;Yao MD;Karczewski M;Karczewski J;Pezous N;Bek S;Bruin G;Mellgard B;Berger C;Londei M;Bertolino AP;Tougas G;Travis SP;Secukinumab in Crohn's Disease Study Group
作者测试了抗白细胞介素（IL）-17A单克隆抗体Rakkinumab治疗活动性克罗恩病是否安全有效。在一项双盲、随机化、安慰剂对照概念验证研究中，59例中重度克罗恩病（克罗恩病活动指数（CDAI）≥220至≤450）患者以2：1的比例分配至2×10 mg/kg静脉注射阿基诺单抗或安慰剂组。主要终点（通过使用安慰剂历史信息增强的贝叶斯统计来解决）是在第6周时，与安慰剂相比，克林尤单抗降低CDAI ≥50分的概率。辅助分析探讨了35种候选遗传多态性与粪便钙卫蛋白反应的相关性。招募了59例患者（39例阿基诺单抗，20例安慰剂，平均基线CDAI分别为307和301）。18/59例（31%）患者提前停药（12/39例（31%）阿基诺单抗，6/20例（30%）安慰剂），10/59例（17%）患者因疗效不足而停药（8/39例（21%）阿基诺单抗，2/20例（10%）安慰剂）。10名患者发生了14起严重不良事件（7名阿基诺单抗，3名安慰剂）; 20例感染，包括4例局部真菌感染，在阿基诺单抗组中观察到，而在安慰剂组中没有观察到。主要终点分析估计了<0.1%的概率（ΔCDAI（SD）=33.9（19.7），95%可信区间为-4.9至72.9），与安慰剂相比，阿基诺单抗使CDAI降低≥50分。次要曲线下面积分析（第4-10周）显示显著差异（平均ΔCDAI=49; 95% CI（2 - 96），p=0.043），有利于安慰剂。事后亚组分析显示，炎症标志物升高的患者（CRP≥10 mg/l和/或粪便钙卫蛋白≥200 ng/ml;平均ΔCDAI=62; 95% CI（−1至125），p=0.054，有利于安慰剂）导致了对阿基诺单抗的不利反应。肿瘤坏死因子样配体1A的次要等位基因的缺失与第6周钙卫蛋白基线调整变化测量的反应缺乏密切相关（p=0.00035 Bonferroni校正）。与安慰剂相比，IL-17 A的阻断是无效的，并且注意到不良事件的发生率更高。本试验在ClinicalTrial.gov上注册，编号为NCT 01009281。
The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn’s disease. In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn’s disease (Crohn’s Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response. 59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (ΔCDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected). Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo. This trial was registered at ClinicalTrial.gov with the number NCT01009281.