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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2401304

摘要内容如下：

背景

Dupilumab是一种全人源单克隆抗体，可阻断白细胞介素-4和白细胞介素-13的共享受体成分，而白细胞介素-4和白细胞介素-13是2型炎症的关键和核心驱动因素。Dupilumab已在一项3期临床试验中显示出疗效和安全性，该试验涉及患有慢性阻塞性肺病（COPD）和2型炎症且恶化风险升高的患者。目前还不清楚这些发现是否会在第二个第三阶段试验中得到证实。

方法

在一项3期、双盲、随机试验中，我们将血液嗜酸性粒细胞计数为每微升300个细胞或更高的COPD患者分配接受皮下注射dupilumab（300 mg）或安慰剂，每2周一次。主要终点是中度或重度急性发作的年发生率。以分层方式进行分析以调整多重性的关键次要终点包括第12周和第52周使用支气管扩张剂前1秒钟用力呼气容积（FEV1）与基线相比的变化，以及圣乔治呼吸问卷（SGRQ；分数范围从0到100，分数越低表示生活质量越好）第52周的总分。

结果

共有935名患者接受了随机分组:470名患者被分配到dupilumab组，465名患者被分配到安慰剂组。根据预先规定，主要分析在阳性中期分析后进行，并纳入935名参与者的所有可用数据，其中721名参与者在第52周纳入分析。dupilumab组中度或重度恶化的年发生率为0.86（95%置信区间[CI]，0.70至1.06），安慰剂组为1.30（95%CI，1.05至1.60）；与安慰剂相比，比率为0.66（95%CI，0.54至0.82；P<0.001）。从基线到第12周，使用dupilumab（最小二乘均数变化，139 mL[95%CI，105-173]）与使用安慰剂（最小二乘均数变化，57 mL[95%CI，23-91]）相比，使用前支气管扩张剂的FEV1增加，第12周的显著最小二乘均数差异为82 mL（P<0.001），第52周的显著最小二乘均数差异为62 mL（P=0.02）。从基线到52周，SGRQ评分的变化没有观察到显著的组间差异。两组的不良事件发生率相似，与已建立的dupilumab特征一致。

结论

在血液嗜酸性粒细胞计数升高的COPD和2型炎症患者中，与安慰剂相比，dupilumab与更少的急性加重和更好的肺功能相关。（由赛诺菲（Sanofi）和Regeneron Pharmaceuticals资助；Notus ClinicalTrials.gov编号，NCT04456673。）

英文原文如下：

Abstracts

BACKGROUND  Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear.

METHODS  In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52.

RESULTS  A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchiodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab.

CONCLUSIONS  In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).

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