Novartis Institutes for BioMedical Research, Basel, Switzerland.
Gut. 2012 Dec;61(12):1693-700. doi: 10.1136/gutjnl-2011-301668. Epub 2012 May 17.
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 (CDAI (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.
作者检测了抗白细胞介素（IL）-17A 单克隆抗体司库奴单抗治疗活动期克罗恩病的安全性和有效性。
在一项双盲、随机、安慰剂对照的概念验证研究中，59 例中重度克罗恩病患者（克罗恩病活动指数（CDAI）≥220 至≤450）以 2:1 的比例随机分配至 2×10mg/kg 静脉注射司库奴单抗或安慰剂。主要终点采用贝叶斯统计方法，结合历史安慰剂信息进行评估，即司库奴单抗组在第 6 周时 CDAI 降低≥50 分的概率高于安慰剂组。辅助分析探索了 35 个候选遗传多态性和粪便钙卫蛋白反应的相关性。
共纳入 59 例患者（39 例司库奴单抗，20 例安慰剂，基线 CDAI 分别为 307 和 301）。18/59（31%）例患者提前停药（12/39（31%）司库奴单抗，6/20（30%）安慰剂），10/59（17%）例因治疗效果不佳（8/39（21%）司库奴单抗，2/20（10%）安慰剂）。10 例患者发生 14 例严重不良事件（7 例司库奴单抗，3 例安慰剂）；20 例感染，包括 4 例局部真菌感染，在司库奴单抗组中发生，而安慰剂组中未发生。主要终点分析估计司库奴单抗组 CDAI 降低≥50 分的概率<0.1%（CDAI（SD）=33.9（19.7），95%可信区间（-4.9 至 72.9））。次要的曲线下面积分析（第 4-10 周）显示安慰剂组具有显著差异（平均ΔCDAI=49；95%CI（2 至 96），p=0.043）。事后亚组分析显示，在炎症标志物升高的患者中（CRP≥10mg/l 和/或粪便钙卫蛋白≥200ng/ml），司库奴单抗治疗的不良反应更明显（平均ΔCDAI=62；95%CI（-1 至 125），p=0.054 有利于安慰剂）。肿瘤坏死因子样配体 1A 的次要等位基因缺失与第 6 周时粪便钙卫蛋白的基线校正变化测量的无反应强烈相关（p=0.00035 Bonferroni 校正）。
与安慰剂相比，阻断白细胞介素-17A 无效，且不良反应发生率更高。
本研究在 ClinicalTrials.gov 上注册，编号为 NCT01009281。
