美泊利单抗治疗重度嗜酸性粒细胞型哮喘
2015/02/25
摘要
背景: 尽管连续使用大剂量吸入型糖皮质激素（加或不加口服糖皮质激素），一些重度哮喘患者仍频繁发生与持续的嗜酸粒细胞性炎症相关的急性发作。
方法: 这项随机、双盲、双模拟研究共纳入了576例在使用大剂量吸入型糖皮质激素后仍然反复急性发作的哮喘受试者，这些受试者同时伴有嗜酸性气道炎症。所有受试者被分到三个研究组，分别予静脉注射美泊利单抗75 mg（一种人源化抗白介素-5单克隆抗体）、皮下注射美泊利单抗100 mg或予安慰剂。每4周随访1次，共随访32周。主要结局指标为哮喘急性发作率。其它结局指标包括第1秒用力呼气量（FEV1），圣乔治呼吸问卷评分（St. George’s Respiratory Questionnaire，SGRQ）和哮喘控制问卷评分（Asthma Control Questionnaire ，ACQ-5）。同时评价美泊利单抗的安全性。
结果: 静脉注射美泊利单抗的受试者急性发作率较安慰剂组降低了47%（P＜0.001；95%CI:29-61），皮下注射美泊利单抗的受试者较安慰剂组降低了53%（P＜0.001；95%CI:37-65）。需要到急诊科就诊或住院的急性发作，静脉注射和皮下注射美泊利单抗的急性发作率较安慰剂组分别降低了32%和61%。32周时，相对于安慰剂组，静脉注射和皮下注射美泊利单抗的受试者，其FEV1较安慰剂组分别增加平均100ml（P=0.02）和98ml（P=0.03）。静脉注射和皮下注射美泊利单抗均能使受试者SGRQ得分较基线增加，分别较安慰剂组增加6.4分和7.0分（P＜0.001，具临床意义的最小值为4分）。静脉和皮下注射美泊利单抗能增加受试者ACQ-5得分，分别较安慰剂组增加0.42分和0.44分（P＜0.001，具临床意义的最小值为0.5分）。而美泊利单抗与安慰剂安全性相近。
结论: 无论静脉或皮下注射美泊利单抗均能显著降低哮喘急性发作率，且与哮喘控制的相关标志物改善相关。（本研究得到GlaxoSmithKline资助，试验名称：Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA)，试验注册机构：ClinicalTrials.gov，注册号：NCT01691521）。
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
Hector G. Ortega, Mark C. Liu, Ian D. Pavord, Guy G. Brusselle, J. Mark FitzGerald, Alfredo Chetta ,Marc Humbert, Lynn E. Katz, Oliver N. Keene, Steven W. Yancey, and Pascal Chanez, for the MENSA Investigators*
* A complete list of investigators in the Mepolizumab as Adjunctive Therapy in
Patients with Severe Asthma (MENSA) study is provided in the Supplementary Appendix, available at NEJM.org.
ABSTRACT
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids.
METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George’s Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed.
RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous
mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo
(P = 0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo.
CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number,NCT01691521.)
N Engl J Med;2014;371;1198-207
背景: 尽管连续使用大剂量吸入型糖皮质激素（加或不加口服糖皮质激素），一些重度哮喘患者仍频繁发生与持续的嗜酸粒细胞性炎症相关的急性发作。
方法: 这项随机、双盲、双模拟研究共纳入了576例在使用大剂量吸入型糖皮质激素后仍然反复急性发作的哮喘受试者，这些受试者同时伴有嗜酸性气道炎症。所有受试者被分到三个研究组，分别予静脉注射美泊利单抗75 mg（一种人源化抗白介素-5单克隆抗体）、皮下注射美泊利单抗100 mg或予安慰剂。每4周随访1次，共随访32周。主要结局指标为哮喘急性发作率。其它结局指标包括第1秒用力呼气量（FEV1），圣乔治呼吸问卷评分（St. George’s Respiratory Questionnaire，SGRQ）和哮喘控制问卷评分（Asthma Control Questionnaire ，ACQ-5）。同时评价美泊利单抗的安全性。
结果: 静脉注射美泊利单抗的受试者急性发作率较安慰剂组降低了47%（P＜0.001；95%CI:29-61），皮下注射美泊利单抗的受试者较安慰剂组降低了53%（P＜0.001；95%CI:37-65）。需要到急诊科就诊或住院的急性发作，静脉注射和皮下注射美泊利单抗的急性发作率较安慰剂组分别降低了32%和61%。32周时，相对于安慰剂组，静脉注射和皮下注射美泊利单抗的受试者，其FEV1较安慰剂组分别增加平均100ml（P=0.02）和98ml（P=0.03）。静脉注射和皮下注射美泊利单抗均能使受试者SGRQ得分较基线增加，分别较安慰剂组增加6.4分和7.0分（P＜0.001，具临床意义的最小值为4分）。静脉和皮下注射美泊利单抗能增加受试者ACQ-5得分，分别较安慰剂组增加0.42分和0.44分（P＜0.001，具临床意义的最小值为0.5分）。而美泊利单抗与安慰剂安全性相近。
结论: 无论静脉或皮下注射美泊利单抗均能显著降低哮喘急性发作率，且与哮喘控制的相关标志物改善相关。（本研究得到GlaxoSmithKline资助，试验名称：Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma (MENSA)，试验注册机构：ClinicalTrials.gov，注册号：NCT01691521）。
(张欣1 张红萍1 王刚1 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（N Engl J Med;2014;371;1198-207)
（N Engl J Med;2014;371;1198-207)
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma
Hector G. Ortega, Mark C. Liu, Ian D. Pavord, Guy G. Brusselle, J. Mark FitzGerald, Alfredo Chetta ,Marc Humbert, Lynn E. Katz, Oliver N. Keene, Steven W. Yancey, and Pascal Chanez, for the MENSA Investigators*
* A complete list of investigators in the Mepolizumab as Adjunctive Therapy in
Patients with Severe Asthma (MENSA) study is provided in the Supplementary Appendix, available at NEJM.org.
ABSTRACT
BACKGROUND: Some patients with severe asthma have frequent exacerbations associated with persistent eosinophilic inflammation despite continuous treatment with high-dose inhaled glucocorticoids with or without oral glucocorticoids.
METHODS: In this randomized, double-blind, double-dummy study, we assigned 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high doses of inhaled glucocorticoids to one of three study groups. Patients were assigned to receive mepolizumab, a humanized monoclonal antibody against interleukin-5, which was administered as either a 75-mg intravenous dose or a 100-mg subcutaneous dose, or placebo every 4 weeks for 32 weeks. The primary outcome was the rate of exacerbations. Other outcomes included the forced expiratory volume in 1 second (FEV1) and scores on the St. George’s Respiratory Questionnaire (SGRQ) and the 5-item Asthma Control Questionnaire (ACQ-5). Safety was also assessed.
RESULTS: The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Exacerbations necessitating an emergency department visit or hospitalization were reduced by 32% in the group receiving intravenous mepolizumab and by 61% in the group receiving subcutaneous
mepolizumab. At week 32, the mean increase from baseline in FEV1 was 100 ml greater in patients receiving intravenous mepolizumab than in those receiving placebo
(P = 0.02) and 98 ml greater in patients receiving subcutaneous mepolizumab than in those receiving placebo (P=0.03). The improvement from baseline in the SGRQ score was 6.4 points and 7.0 points greater in the intravenous and subcutaneous mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 4 points), and the improvement in the ACQ-5 score was 0.42 points and 0.44 points greater in the two mepolizumab groups, respectively, than in the placebo group (minimal clinically important change, 0.5 points) (P<0.001 for all comparisons). The safety profile of mepolizumab was similar to that of placebo.
CONCLUSIONS: Mepolizumab administered either intravenously or subcutaneously significantly reduced asthma exacerbations and was associated with improvements in markers of asthma control. (Funded by GlaxoSmithKline; MENSA ClinicalTrials.gov number,NCT01691521.)
N Engl J Med;2014;371;1198-207
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