Benralizumab在重症哮喘治疗中的激素节减效应
2017/07/12
摘要
背景：许多重症哮喘患者依赖口服糖皮质激素来控制其疾病。我们研究Benralizumab单克隆抗体是否可以直接抑制IL-5的α亚基受体来显著减少哮喘急性加重的发生率，是否对于嗜酸性粒细胞增高的激素依赖型重症哮喘患者是一种有效的激节减疗法。
方法：在为期28周的随机对照试验中，我们评估与安慰剂相比，Benralizumab（30mg每4周或每8周[在前3次每4周一次]皮下注射）对哮喘控制稳定的成年重症哮喘患者口服糖皮质激素的减量效应。主要终点是从基线到第28周口服糖皮质激素剂量的变化百分比。并评估哮喘的急性发作率、肺功能、症状及安全性。
结果：369例患者中，220例接受了随机分组，并接受Benralizumab或安慰剂治疗。2种Benralizumab给药方案均显著减少糖皮质激素服用剂量，剂量从基线下降75%，而安慰剂组仅下降25%（P＜0.001，两种给药方案均是）。使用Benralizumab降低糖皮质激素用量的可能性是安慰剂的4倍。在次要结果中，每4周给Benralizumab一次，哮喘患者平均急性发作率为55%，低于安慰剂组（边界率 0.83 vs. 1.83 P=0.003），每8周予Benralizumab一次，急性发作率为70%，也低于安慰剂组（边界率 0.54 vs.1.83 P＜0.001）。在第28周，与安慰剂相比，2种Benralizumab给药方案对FEV1改善均无显著效应。Benralizumab对哮喘症状的各种影响是复杂的，一些显示有显著影响，一些则没有。不良事件的发生频率在Benralizumab组和安慰剂组无显著性差异。
结论：Benralizumab在糖皮质激素使用和哮喘急性加重方面与安慰剂相比，有显著地临床获益，但在FEV1改善方面没有持续效应。
Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma
Parameswaran Nair, M.D., Ph.D., Sally Wenzel, M.D., Klaus F. Rabe, M.D., Ph.D.,Arnaud Bourdin, M.D., Ph.D., Njira L. Lugogo, M.D., Piotr Kuna, M.D., Ph.D.,Peter Barker, Ph.D., Stephanie Sproule, M.Math., Sandhia Ponnarambil, M.D.,and Mitchell Goldman, M.D., for the ZONDA Trial Investigators*
Abstract
BACKGROUND：Many patients with severe asthma rely on oral glucocorticoids to manage their disease.We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid–sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.
METHODS：In a 28-week randomized, controlled trial, we assessed the effects of benralizumab(at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks[with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates,lung function, symptoms, and safety were assessed.
RESULTS：Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes,benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P = 0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.
CONCLUSIONS：Benralizumab showed significant, clinically relevant benefits, as compared with placebo,on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255.)
背景：许多重症哮喘患者依赖口服糖皮质激素来控制其疾病。我们研究Benralizumab单克隆抗体是否可以直接抑制IL-5的α亚基受体来显著减少哮喘急性加重的发生率，是否对于嗜酸性粒细胞增高的激素依赖型重症哮喘患者是一种有效的激节减疗法。
方法：在为期28周的随机对照试验中，我们评估与安慰剂相比，Benralizumab（30mg每4周或每8周[在前3次每4周一次]皮下注射）对哮喘控制稳定的成年重症哮喘患者口服糖皮质激素的减量效应。主要终点是从基线到第28周口服糖皮质激素剂量的变化百分比。并评估哮喘的急性发作率、肺功能、症状及安全性。
结果：369例患者中，220例接受了随机分组，并接受Benralizumab或安慰剂治疗。2种Benralizumab给药方案均显著减少糖皮质激素服用剂量，剂量从基线下降75%，而安慰剂组仅下降25%（P＜0.001，两种给药方案均是）。使用Benralizumab降低糖皮质激素用量的可能性是安慰剂的4倍。在次要结果中，每4周给Benralizumab一次，哮喘患者平均急性发作率为55%，低于安慰剂组（边界率 0.83 vs. 1.83 P=0.003），每8周予Benralizumab一次，急性发作率为70%，也低于安慰剂组（边界率 0.54 vs.1.83 P＜0.001）。在第28周，与安慰剂相比，2种Benralizumab给药方案对FEV1改善均无显著效应。Benralizumab对哮喘症状的各种影响是复杂的，一些显示有显著影响，一些则没有。不良事件的发生频率在Benralizumab组和安慰剂组无显著性差异。
结论：Benralizumab在糖皮质激素使用和哮喘急性加重方面与安慰剂相比，有显著地临床获益，但在FEV1改善方面没有持续效应。
(中日友好医院医院呼吸与危重症医学科 李红雯摘译 林江涛审校)
（N ENJL J Med 376;25 NEJM.ORG JUNE 22, 2017）
（N ENJL J Med 376;25 NEJM.ORG JUNE 22, 2017）
Oral Glucocorticoid–Sparing Effect of Benralizumab in Severe Asthma
Parameswaran Nair, M.D., Ph.D., Sally Wenzel, M.D., Klaus F. Rabe, M.D., Ph.D.,Arnaud Bourdin, M.D., Ph.D., Njira L. Lugogo, M.D., Piotr Kuna, M.D., Ph.D.,Peter Barker, Ph.D., Stephanie Sproule, M.Math., Sandhia Ponnarambil, M.D.,and Mitchell Goldman, M.D., for the ZONDA Trial Investigators*
Abstract
BACKGROUND：Many patients with severe asthma rely on oral glucocorticoids to manage their disease.We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid–sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia.
METHODS：In a 28-week randomized, controlled trial, we assessed the effects of benralizumab(at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks[with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates,lung function, symptoms, and safety were assessed.
RESULTS：Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes,benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P = 0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group.
CONCLUSIONS：Benralizumab showed significant, clinically relevant benefits, as compared with placebo,on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255.)
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