Dupilumab治疗中到大剂量吸入糖皮质激素加长效β2受体激动剂仍未能控制持续性哮喘成年患者的疗效和安全性:一项随机双
2016/07/07
摘要
背景：Dupilumab，一种全人源化抗白细胞介素4受体α的单克隆抗体，可抑制白介素-4和白细胞介素-13信号（Th2型气道炎症关键驱动因子）。入选对象为正在接受中到大剂量吸入糖皮质激素（ICS）加长效β2受体激动剂（LABA）治疗仍然未能控制的持续性成年哮喘患者，这些患者需要额外治疗。本研究旨在不考虑基线嗜酸粒细胞计数情况下，评估中到大剂量ICS+LABA治疗仍未控制的持续性哮喘患者添加dupilumab治疗的疗效和安全性。
方法：这是一项随机、双盲、安慰剂对照、平行组设计的的2b阶段临床试验，共计16个国家或地区的174个研究中心参加。参与者为根据2009年全球哮喘防治指南被诊断为哮喘有12个月或以上的成年患者（年龄≥18岁），这些患者正接受中到大剂量ICS+LABA治疗。患者被随机分配（1：1：1：1：1）接收每2周或4周皮下注射dupilumab 200毫克或300毫克，或安慰剂治疗，治疗期共24周。主要研究终点是在意向性治疗人群，即基线外周血嗜酸性粒细胞每微升至少300个，从基线到12周第1秒用力呼气容积（FEV1）的变化。在所有接受至少一个剂量或一种研究药物部分剂量的患者进行安全性评估。该试验在ClinicalTrials.gov注册，编号NCT01854047，同时也在欧盟临床试验登记注册，注册号2013-000856-16。
结果：共有769例患者（安慰剂组158例，dupilumab组611例）接受至少一个剂量研究药物。在外周血每微升至少300个嗜酸性粒细胞的亚组分析中，与安慰剂组相比，在12周时FEV1有最大的增加（每2周200毫克，p=0.0008; 每2周300毫克，p=0.0063），与安慰剂组（0.18 L [SE 0.05]）相比，每2周300毫克组平均变化0.39 L [SE 0.05]，平均差异0.21 [95％CI 0.06-0.36; p=0.0063]），每2周200毫克组平均变化0.43 L [SE 0.05]，平均差异0.26 [0.11-0.40，p=0.0008]。在总人群和每微升少于300个嗜酸性粒细胞的亚组中，也同样观察到类似的增加效果（总人群中：每2周200毫克，P<0.0001; 每2周300毫克，P<0.0001；每微升<300嗜酸性粒细胞：每2周200毫克，p=0.0034; 每2周300毫克，p=0.0086），并分别持续到24周。同样研究发现，每2周一次的dupilumab治疗组，在总人群（70-70.5％），每微升至少300嗜酸性粒细胞的亚组（71.2-80.7％）以及每微升少于300个嗜酸性粒细胞的亚组（59.9-67.6％）中，每年的哮喘急性加重率都有最大程度的减少。与安慰剂组相比，dupilumab组最常见的不良反应为上呼吸道感染（33-41％ vs 35％）和注射部位反应（13-26％ vs 13％）。
解释：在未控制的持续性哮喘患者中，无论基线嗜酸性粒细胞计数如何，Dupilumab都可以改善肺功能和减少哮喘急性加重，并具有良好的安全性，因此，与单独的标准治疗相比，将其加入到ICS+LABA治疗中能改善未控制持续性哮喘患者的生活。
Wenzel S, Castro M, Corren J,et al. Louis-Tisserand M5, Teper A5. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet.
2016 April 26. pii: S0140-6736(16)30307-5. doi: 10.1016/S0140-6736(16)30307-5. [Epub ahead of print]
Abstract
BACKGROUND:Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count.
METHODS:We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.
FINDINGS:769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks), p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).
INTERPRETATION:Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.
FUNDING:Sanofi-Genzyme and Regeneron Pharmaceuticals.
背景：Dupilumab，一种全人源化抗白细胞介素4受体α的单克隆抗体，可抑制白介素-4和白细胞介素-13信号（Th2型气道炎症关键驱动因子）。入选对象为正在接受中到大剂量吸入糖皮质激素（ICS）加长效β2受体激动剂（LABA）治疗仍然未能控制的持续性成年哮喘患者，这些患者需要额外治疗。本研究旨在不考虑基线嗜酸粒细胞计数情况下，评估中到大剂量ICS+LABA治疗仍未控制的持续性哮喘患者添加dupilumab治疗的疗效和安全性。
方法：这是一项随机、双盲、安慰剂对照、平行组设计的的2b阶段临床试验，共计16个国家或地区的174个研究中心参加。参与者为根据2009年全球哮喘防治指南被诊断为哮喘有12个月或以上的成年患者（年龄≥18岁），这些患者正接受中到大剂量ICS+LABA治疗。患者被随机分配（1：1：1：1：1）接收每2周或4周皮下注射dupilumab 200毫克或300毫克，或安慰剂治疗，治疗期共24周。主要研究终点是在意向性治疗人群，即基线外周血嗜酸性粒细胞每微升至少300个，从基线到12周第1秒用力呼气容积（FEV1）的变化。在所有接受至少一个剂量或一种研究药物部分剂量的患者进行安全性评估。该试验在ClinicalTrials.gov注册，编号NCT01854047，同时也在欧盟临床试验登记注册，注册号2013-000856-16。
结果：共有769例患者（安慰剂组158例，dupilumab组611例）接受至少一个剂量研究药物。在外周血每微升至少300个嗜酸性粒细胞的亚组分析中，与安慰剂组相比，在12周时FEV1有最大的增加（每2周200毫克，p=0.0008; 每2周300毫克，p=0.0063），与安慰剂组（0.18 L [SE 0.05]）相比，每2周300毫克组平均变化0.39 L [SE 0.05]，平均差异0.21 [95％CI 0.06-0.36; p=0.0063]），每2周200毫克组平均变化0.43 L [SE 0.05]，平均差异0.26 [0.11-0.40，p=0.0008]。在总人群和每微升少于300个嗜酸性粒细胞的亚组中，也同样观察到类似的增加效果（总人群中：每2周200毫克，P<0.0001; 每2周300毫克，P<0.0001；每微升<300嗜酸性粒细胞：每2周200毫克，p=0.0034; 每2周300毫克，p=0.0086），并分别持续到24周。同样研究发现，每2周一次的dupilumab治疗组，在总人群（70-70.5％），每微升至少300嗜酸性粒细胞的亚组（71.2-80.7％）以及每微升少于300个嗜酸性粒细胞的亚组（59.9-67.6％）中，每年的哮喘急性加重率都有最大程度的减少。与安慰剂组相比，dupilumab组最常见的不良反应为上呼吸道感染（33-41％ vs 35％）和注射部位反应（13-26％ vs 13％）。
解释：在未控制的持续性哮喘患者中，无论基线嗜酸性粒细胞计数如何，Dupilumab都可以改善肺功能和减少哮喘急性加重，并具有良好的安全性，因此，与单独的标准治疗相比，将其加入到ICS+LABA治疗中能改善未控制持续性哮喘患者的生活。
（南方医科大学南方医院 彭显如 赵海金）
2016 April 26. pii: S0140-6736(16)30307-5. doi: 10.1016/S0140-6736(16)30307-5. [Epub ahead of print]
2016 April 26. pii: S0140-6736(16)30307-5. doi: 10.1016/S0140-6736(16)30307-5. [Epub ahead of print]
Wenzel S, Castro M, Corren J,et al. Louis-Tisserand M5, Teper A5. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial.Lancet.
2016 April 26. pii: S0140-6736(16)30307-5. doi: 10.1016/S0140-6736(16)30307-5. [Epub ahead of print]
Abstract
BACKGROUND:Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count.
METHODS:We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.
FINDINGS:769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks), p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).
INTERPRETATION:Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.
FUNDING:Sanofi-Genzyme and Regeneron Pharmaceuticals.
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