Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial
Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial
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DOI：
10.1016/s0140-6736(19)32971-x
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发表时间：
2020-01-04
期刊：
影响因子：
168.9
通讯作者：
Sieper, Joachim
中科院分区：
文献类型：
--
作者：
Deodhar, Atul;van der Heijde, Desiree;Sieper, Joachim
Ixekizumab是一种高亲和力的白细胞介素-17A（IL-17 A）单克隆抗体，先前已显示出对放射学中轴性脊柱关节炎（也称为强直性脊柱炎）的有效性。我们的目的是评估ixekizumab（一种IL-17抑制剂）治疗非放射学中轴性脊柱关节炎的疗效和安全性。在这里，我们报告的主要结果COAST-X。方法COAST-X是一个52周，随机，双盲，安慰剂对照，平行组研究在107个地点在15个国家在欧洲，亚洲，北美和南美。符合条件的参与者是患有活动性中轴脊柱关节炎的成年人（年龄≥ 18岁），没有明确的放射学骶髂关节炎（非放射学中轴脊柱关节炎），客观的炎症体征（通过MRI或C反应蛋白），以及对非甾体抗炎药（NSAID）反应不足或不耐受。患者被随机分配（1：1：1）接受皮下注射80 mg ixekizumab，每4周一次（Q4 W）或每2周一次（Q2 W），或安慰剂。第16周后，允许研究者酌情改变背景药物或转换为开放标签ixekizumab Q2 W或两者。主要终点为第16周和第52周时的国际脊柱关节炎协会评估-40（ASAS 40）应答（定义为在4个领域[患者总体、脊柱疼痛、功能和炎症]中的至少3个领域改善40%或以上，且相对于基线绝对改善2个单位或以上[范围0-10]，其余1个领域无任何恶化）。转换为开放标签ixekizumab的患者在logistic回归分析中插补为无应答者。该试验注册于ClinicalTrials.gov，编号NCT 02757352。结果在2016年8月2日至2018年1月29日期间，入组了303例患者（105例接受安慰剂，96例接受ixekizumab Q4 W，102例接受ixekizumab Q2 W）。满足两个主要终点：第16周时ASAS 40（ixekizumab Q4 W：34/96例[35%]，p=0.0094 vs安慰剂; ixekizumab Q2 W：41/102例[40%]，p=0.0016;安慰剂：20/105例[19%]）和第52周ASAS 40（ixekizumab Q4 W：29/96 [30%]，p=0.0045; ixekizumab Q2 W：32/102 [31%]，p=0.0037;安慰剂：14/105 [13%]）。安慰剂组104例患者中有60例（57%），ixekizumab Q4 W组96例患者中有63例（66%），ixekizumab Q2 W组102例患者中有79例（77%）至少发生了1起治疗后出现的不良事件。ixekizumab组中最常见的治疗后出现的不良事件是鼻咽炎和注射部位反应。在特别关注的治疗后出现的不良事件中，ixekizumab Q4 W组有1例严重感染。严重不良事件的发生率很低（302例中有4例[1%]），三组之间相似。无恶性肿瘤或死亡。没有发现新的安全性信号。解释在第16周和第52周，Ixekizumab在改善非放射学中轴性脊柱关节炎患者的体征和症状方面上级安慰剂。不良事件报告与既往ixekizumab研究相似。Ixekizumab为非放射学中轴性脊柱关节炎患者提供了一种潜在的治疗选择，这些患者对NSAID治疗反应不足或不耐受。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X.Methods COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged >= 18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352.Findings Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0.0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0.0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0.0045; ixekizumab Q2W: 32 [31%] of 102, p=0.0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified.Interpretation Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Copyright (C) 2019 Elsevier Ltd. All rights reserved.