Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial
Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial
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DOI：
10.1016/s0140-6736(15)00388-8
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发表时间：
2016-01-02
期刊：
影响因子：
168.9
通讯作者：
Ardeleanu, Marius
中科院分区：
文献类型：
--
作者：
Thaci, Diamant;Simpson, Eric L.;Ardeleanu, Marius
早期研究的背景数据表明，白细胞介素（IL）-4和IL-13是特应性皮炎的必要驱动因素，dupilumab（一种阻断两种途径的全人单克隆抗体）治疗后的显著改善证明了这一点。我们的目的是评估dupilumab的几种剂量方案在局部治疗控制不佳的中重度特应性皮炎成人中的疗效和安全性。我们招募了18岁或以上的患者，他们在筛选时的湿疹面积和严重程度指数（EASI）评分为12或更高（基线时>= 16）和对局部治疗反应不足，来自加拿大、捷克共和国、德国、匈牙利、日本、波兰和美国的91个研究中心，包括医院、诊所和学术机构。患者被随机分配（1：1：1：1：1：1），按严重程度分层（中度或重度，根据研究者的总体评估）和地区（日本vs世界其他地区）接受dupilumab皮下给药：300 mg每周一次、300 mg每2周一次、200 mg每2周一次、300 mg每4周一次、100 mg每4周一次或安慰剂每周一次持续16周。我们使用了一个中央随机化方案，提供了一个互动的语音应答系统。对药盒进行编码，对治疗分配进行掩蔽，并隐藏分配。每2周一次和每4周一次治疗的患者在未给予dupilumab时每周接受体积匹配的安慰剂，以确保双盲。主要结局为dupilumab给药方案的疗效，基于EASI评分最小二乘均值百分比变化（SE），自基线至第16周。分析包括所有随机分配的接受一剂或多剂研究药物的患者。该试验在ClinicalTrials.gov注册，编号NCT 01859988。结果在2013年5月15日至2014年1月27日期间，对452名患者进行了资格评估，并随机分配了380名患者。379例患者接受了一剂或多剂研究药物（300 mg每周一次[n=63]、300 mg每2周一次[n=64]、200 mg每2周一次[n=61]、300 mg每4周一次[n=65]、100 mg每4周一次[n =65];安慰剂[n=61]）。与安慰剂相比，EASI评分改善有利于所有dupilumab方案（p
Background Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.Methods In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (>= 16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1: 1: 1: 1: 1: 1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988.Findings Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p