Dupilumab在糖皮质激素依赖性重症哮喘中的疗效和安全性
2018/11/14
摘要
背景：Dupilumab是一种人抗白细胞介素-4受体α单克隆抗体，可阻断白细胞介素-4和白细胞介素-13信号传导。在减少重症哮喘患者口服糖皮质激素剂量上具有疗效，但在用于控制哮喘的有效性尚不清楚。
方法：随机分配210名口服糖皮质激素的哮喘患者，每2周接受一次额外的dupilumab（剂量为300 mg）治疗或安慰剂，持续24周。在随机化之前进行糖皮质激素剂量调整，糖皮质激素剂量从第4周到第20周呈下降趋势，然后维持稳定剂量4周。主要节点是第24周时糖皮质激素剂量的减少百分比。关键的次要节点是第24周时糖皮质激素剂量至少减少50％患者的比例，以及糖皮质激素剂量减少至每天少于5毫克的患者比例。同时评估了在支气管扩张剂使用前的急性发作次数及FEV1。
结果：dupilumab组糖皮质激素剂量下降-70.1％，而安慰剂组为下降41.9％（P <0.001）; 80％vs50％的患者剂量减少至少50％，69％vs33％的剂量减少至5mg /天，48％vs25％完全停用口服糖皮质激素。尽管糖皮质激素剂量减少，但在总体人群中，dupilumab治疗导致急性发作频率为59％（95％可信区间37-74）低于安慰剂组，同时引起FEV1上升0.22L（95％CI，0.09-0.34）。 dupilumab的注射部位局部反应比安慰剂更常见（9％对4％）。与安慰剂组相比，dupilumab组中观察到一过性外周血嗜酸性粒细胞增多患者较多（14％对1％）。
结论：在糖皮质激素依赖重症哮喘患者中，dupilumab治疗减少口服糖皮质激素的使用，同时降低了严重急性发作的发生率并增加了FEV1。在7名Dupilumab治疗的患者中约有1人出现一过性外周嗜酸性粒细胞增多。
Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma
Rabe KF, Nair P
Abstract
BACKGROUND:Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown.
METHODS:We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed.
RESULTS:The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).
CONCLUSIONS:In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).
背景：Dupilumab是一种人抗白细胞介素-4受体α单克隆抗体，可阻断白细胞介素-4和白细胞介素-13信号传导。在减少重症哮喘患者口服糖皮质激素剂量上具有疗效，但在用于控制哮喘的有效性尚不清楚。
方法：随机分配210名口服糖皮质激素的哮喘患者，每2周接受一次额外的dupilumab（剂量为300 mg）治疗或安慰剂，持续24周。在随机化之前进行糖皮质激素剂量调整，糖皮质激素剂量从第4周到第20周呈下降趋势，然后维持稳定剂量4周。主要节点是第24周时糖皮质激素剂量的减少百分比。关键的次要节点是第24周时糖皮质激素剂量至少减少50％患者的比例，以及糖皮质激素剂量减少至每天少于5毫克的患者比例。同时评估了在支气管扩张剂使用前的急性发作次数及FEV1。
结果：dupilumab组糖皮质激素剂量下降-70.1％，而安慰剂组为下降41.9％（P <0.001）; 80％vs50％的患者剂量减少至少50％，69％vs33％的剂量减少至5mg /天，48％vs25％完全停用口服糖皮质激素。尽管糖皮质激素剂量减少，但在总体人群中，dupilumab治疗导致急性发作频率为59％（95％可信区间37-74）低于安慰剂组，同时引起FEV1上升0.22L（95％CI，0.09-0.34）。 dupilumab的注射部位局部反应比安慰剂更常见（9％对4％）。与安慰剂组相比，dupilumab组中观察到一过性外周血嗜酸性粒细胞增多患者较多（14％对1％）。
结论：在糖皮质激素依赖重症哮喘患者中，dupilumab治疗减少口服糖皮质激素的使用，同时降低了严重急性发作的发生率并增加了FEV1。在7名Dupilumab治疗的患者中约有1人出现一过性外周嗜酸性粒细胞增多。
（中日友好医院呼吸与危重症医学科 张鑫 摘译 林江涛 审校）
（1.N Engl J Med. 2018 May 21.）
（1.N Engl J Med. 2018 May 21.）
Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma
Rabe KF, Nair P
Abstract
BACKGROUND:Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown.
METHODS:We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV1) before bronchodilator use were also assessed.
RESULTS:The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV1 that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).
CONCLUSIONS:In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).
