Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial
Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial
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DOI：
10.1016/s0140-6736(17)31191-1
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发表时间：
2017-06-10
期刊：
影响因子：
168.9
通讯作者：
Shumel, Brad
中科院分区：
文献类型：
--
作者：
Blauvelt, Andrew;de Bruin-Weller, Marjolein;Shumel, Brad
背景Dupilumab（一种抗白细胞介素4受体α单克隆抗体）阻断白细胞介素4和白细胞介素13的信号传导，2型/Th 2细胞因子与从哮喘到特应性皮炎的许多过敏性疾病有关。既往16周单药治疗研究显示，dupilumab可显著改善中重度特应性皮炎的体征和症状，安全性可接受，验证了白细胞介素4和白细胞介素13在特应性皮炎发病机制中的关键作用。我们的目的是评估dupilumab与中等效力局部皮质类固醇相比，安慰剂与局部皮质类固醇在成人中重度特应性皮炎患者中的长期疗效和安全性。（LIBERTY AD CHRONOS），在161家医院招募了患有中度至重度特应性皮炎和对局部皮质类固醇反应不足的成人，在欧洲、亚太和北美的14个国家的诊所和学术机构。通过中央交互式语音/网络响应系统将患者随机分配（3：1：3）至皮下注射dupilumab 300 mg每周一次（qw）、dupilumab 300 mg每2周一次（q2 w）或安慰剂组，并按严重程度和全球地区分层。所有三组均同时给予局部皮质类固醇，在不适合局部皮质类固醇的情况下，联合或不联合局部钙调磷酸酶抑制剂。局部皮质类固醇可根据疾病活动度逐渐减少、停止或重新开始。共同主要终点为第16周时达到研究者总体评估（伊加）0/1和2分或更高改善的患者（%），以及自基线的晕厥面积和严重程度指数改善75%（EASI-75）。第16周疗效和第52周安全性分析包括所有随机化患者;第52周疗效包括截至美国监管提交截止日期完成治疗的患者。本研究注册于ClinicalTrials.gov，NCT 02260986。结果2014年10月3日至2015年7月31日期间，入组了740例患者：319例随机分配至dupilumab qw+外用皮质类固醇组，106例随机分配至dupilumab q2 w+外用皮质类固醇组，315例随机分配至安慰剂+外用皮质类固醇组。623例（分别为270、89和264例）可评价第52周疗效。在第16周，接受dupilumab+外用皮质类固醇治疗的患者中，更多患者达到了共同主要终点伊加0/1（39% [125例患者]接受dupilumab+局部皮质类固醇qw，39% [41例患者]接受dupilumab q2 w+局部皮质类固醇vs 12% [39例患者]接受安慰剂+局部皮质类固醇; p < 0.0001）和EASI-75（64% [204]和69% [73] vs 23% [73]; p < 0.0001）。第52周结果相似。261例（83%）接受dupilumab qw+外用皮质类固醇的患者、97例（88%）接受dupilumab q2 w的患者和266例（84%）接受安慰剂的患者报告了不良事件，分别有9例（3%）、4例（4%）和16例（5%）患者报告了严重不良事件。未观察到dupilumab诱导的显著实验室异常。注射部位反应和结膜炎在接受dupilumab加外用皮质类固醇治疗的患者中比在接受安慰剂加外用皮质类固醇治疗的患者中更常见。解释Dupilumab加用标准外用皮质类固醇治疗1年，可改善特应性皮炎体征和症状，安全性可接受。
Background Dupilumab (an anti-interleukin-4-receptor-alpha monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis.Methods In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3: 1: 3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986.Findings Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p < 0.0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p < 0.0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids.Interpretation Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety.