Dupilumab单抗治疗未控制的中重度哮喘儿童
2021/12/24
摘要
背景：尽管接受了标准的治疗，患有中重度哮喘的儿童仍然存在疾病并发症。单克隆抗体dupilumab已被批准用于治疗成人和青少年哮喘以及其他2型炎症性疾病。
方法：在这项为期52周的3期随机、双盲、安慰剂对照试验中，我们将年龄在6岁至11岁之间、患有未控制的中重度哮喘的408名儿童分配到皮下注射dupilumab单抗（体重≤30 kg的患者为100毫克，体重> 30 kg的患者为200 mg）或每2周服用一次匹配的安慰剂。所有儿童继续接受稳定剂量的标准背景治疗。主要终点是严重哮喘发作的年化发生率。次要终点包括第12周时预测的支气管扩张剂前1秒用力呼气量百分比（ppFEV1）和第24周时哮喘控制问卷7受试者管理（ACQ-7-IA）得分与基线相比的变化。对具有2型炎症性哮喘表型的两个主要疗效人群的终点进行评估(每立方毫米≥150个血液嗜酸性粒细胞或呼出的一氧化氮≥20 ppb）或血液嗜酸性粒细胞计数至少为每立方毫米300个细胞。
结果：在具有2型炎症表型的患者中，使用dupilumab单抗的严重哮喘发作的年化率为0.31（95%可信区间[CI]，0.22至0.42），使用安慰剂的年化率为0.75（95%可信区间，0.54至1.03）（dupilumab单抗组的相对风险降低，59.3%；95%可信区间，39.5至72.6；P<0.001）。ppFEV1与基线检查时相比的平均（±SE）变化，dupilumab单抗组为10.5±1.0个百分点，安慰剂组为5.3±1.4个百分点（平均差异为5.2个百分点；95%可信区间为2.1至8.3；P<0.001）。Dupilumab的哮喘控制效果也明显优于安慰剂（P<0.001）。在基线检查时嗜酸性粒细胞计数至少为每立方毫米300个细胞的患者中观察到类似结果。两组严重不良事件的发生率相似。
结论：在未控制的中重度哮喘患儿中，与安慰剂组相比，服用附加dupilumab单抗的患儿哮喘发作较少，肺功能和哮喘控制更好。
Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma.
Leonard B Bacharier, Jorge F Maspero, Constance H Katelaris, Alessandro G Fiocchi, Remi Gagnon, Ines de Mir, Neal Jain, Lawrence D Sher, Xuezhou Mao, Dongfang Liu, Yi Zhang, Asif H Khan, Upender Kapoor, Faisal A Khokhar, Paul J Rowe, Yamo Deniz, Marcella Ruddy, Elizabeth Laws, Naimish Patel, David M Weinreich, George D Yancopoulos, Nikhil Amin, Leda P Mannent, David J Lederer, Megan Hardin, Liberty Asthma VOYAGE Investigators
Abstract
Background: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases.
Methods: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline.
Results: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups.
Conclusions: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo.
背景：尽管接受了标准的治疗，患有中重度哮喘的儿童仍然存在疾病并发症。单克隆抗体dupilumab已被批准用于治疗成人和青少年哮喘以及其他2型炎症性疾病。
方法：在这项为期52周的3期随机、双盲、安慰剂对照试验中，我们将年龄在6岁至11岁之间、患有未控制的中重度哮喘的408名儿童分配到皮下注射dupilumab单抗（体重≤30 kg的患者为100毫克，体重> 30 kg的患者为200 mg）或每2周服用一次匹配的安慰剂。所有儿童继续接受稳定剂量的标准背景治疗。主要终点是严重哮喘发作的年化发生率。次要终点包括第12周时预测的支气管扩张剂前1秒用力呼气量百分比（ppFEV1）和第24周时哮喘控制问卷7受试者管理（ACQ-7-IA）得分与基线相比的变化。对具有2型炎症性哮喘表型的两个主要疗效人群的终点进行评估(每立方毫米≥150个血液嗜酸性粒细胞或呼出的一氧化氮≥20 ppb）或血液嗜酸性粒细胞计数至少为每立方毫米300个细胞。
结果：在具有2型炎症表型的患者中，使用dupilumab单抗的严重哮喘发作的年化率为0.31（95%可信区间[CI]，0.22至0.42），使用安慰剂的年化率为0.75（95%可信区间，0.54至1.03）（dupilumab单抗组的相对风险降低，59.3%；95%可信区间，39.5至72.6；P<0.001）。ppFEV1与基线检查时相比的平均（±SE）变化，dupilumab单抗组为10.5±1.0个百分点，安慰剂组为5.3±1.4个百分点（平均差异为5.2个百分点；95%可信区间为2.1至8.3；P<0.001）。Dupilumab的哮喘控制效果也明显优于安慰剂（P<0.001）。在基线检查时嗜酸性粒细胞计数至少为每立方毫米300个细胞的患者中观察到类似结果。两组严重不良事件的发生率相似。
结论：在未控制的中重度哮喘患儿中，与安慰剂组相比，服用附加dupilumab单抗的患儿哮喘发作较少，肺功能和哮喘控制更好。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(N Engl J Med. 2021 Dec 9;385(24):2230-2240. doi: 10.1056/NEJMoa2106567.)
(N Engl J Med. 2021 Dec 9;385(24):2230-2240. doi: 10.1056/NEJMoa2106567.)
Dupilumab in Children with Uncontrolled Moderate-to-Severe Asthma.
Leonard B Bacharier, Jorge F Maspero, Constance H Katelaris, Alessandro G Fiocchi, Remi Gagnon, Ines de Mir, Neal Jain, Lawrence D Sher, Xuezhou Mao, Dongfang Liu, Yi Zhang, Asif H Khan, Upender Kapoor, Faisal A Khokhar, Paul J Rowe, Yamo Deniz, Marcella Ruddy, Elizabeth Laws, Naimish Patel, David M Weinreich, George D Yancopoulos, Nikhil Amin, Leda P Mannent, David J Lederer, Megan Hardin, Liberty Asthma VOYAGE Investigators
Abstract
Background: Children with moderate-to-severe asthma continue to have disease complications despite the receipt of standard-of-care therapy. The monoclonal antibody dupilumab has been approved for the treatment of adults and adolescents with asthma as well as with other type 2 inflammatory diseases.
Methods: In this 52-week phase 3, randomized, double-blind, placebo-controlled trial, we assigned 408 children between the ages of 6 and 11 years who had uncontrolled moderate-to-severe asthma to receive a subcutaneous injection of dupilumab (at a dose of 100 mg for those weighing ≤30 kg and 200 mg for those weighing >30 kg) or matched placebo every 2 weeks. All the children continued to receive a stable dose of standard background therapy. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included the change from baseline in the percentage of predicted prebronchodilator forced expiratory volume in 1 second (ppFEV1) at week 12 and in the score on the Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) at week 24. End points were evaluated in the two primary efficacy populations who had either a type 2 inflammatory asthma phenotype (≥150 blood eosinophils per cubic millimeter or a fraction of exhaled nitric oxide of ≥20 ppb at baseline) or a blood eosinophil count of at least 300 cells per cubic millimeter at baseline.
Results: In patients with the type 2 inflammatory phenotype, the annualized rate of severe asthma exacerbations was 0.31 (95% confidence interval [CI], 0.22 to 0.42) with dupilumab and 0.75 (95% CI, 0.54 to 1.03) with placebo (relative risk reduction in the dupilumab group, 59.3%; 95% CI, 39.5 to 72.6; P<0.001). The mean (±SE) change from baseline in the ppFEV1 was 10.5±1.0 percentage points with dupilumab and 5.3±1.4 percentage points with placebo (mean difference, 5.2 percentage points; 95% CI, 2.1 to 8.3; P<0.001). Dupilumab also resulted in significantly better asthma control than placebo (P<0.001). Similar results were observed in the patients with an eosinophil count of at least 300 cells per cubic millimeter at baseline. The incidence of serious adverse events was similar in the two groups.
Conclusions: Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo.
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三联吸入器与双联吸入器治疗中至重度哮喘的成本效用比较
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