From Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville (L.B.B.); Fundación CIDEA, Buenos Aires (J.F.M.); Campbelltown Hospital, Campbelltown, NSW, and Western Sydney University, Sydney (C.H.K.) - both in Australia; Bambino Gesù Children's Hospital IRCCS, Rome (A.G.F.); Clinique Spécialisée en Allergie de la Capitale, Quebec, QC, Canada (R.G.); Hospital Vall d'Hebron, Barcelona (I.M.); Arizona Allergy and Immunology Research, Gilbert (N.J.); Peninsula Research Associates, Rolling Hills Estates, CA (L.D.S.); Sanofi, Bridgewater, NJ (X.M., U.K., P.J.R., E.L.); Sanofi, Beijing (D.L.); Regeneron Pharmaceuticals, Tarrytown, NY (Y.Z., F.A.K., Y.D., M.R., D.M.W., G.D.Y., N.A., D.J.L.); Sanofi, Chilly-Mazarin, France (A.H.K., L.P.M.); and Sanofi Genzyme, Cambridge, MA (N.P., M.H.).
N Engl J Med. 2021 Dec 9;385(24):2230-2240. doi: 10.1056/NEJMoa2106567.
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.
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 (ppFEV) 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.
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 ppFEV 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.
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. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.).
尽管接受了标准治疗，但仍有中度至重度哮喘的儿童会出现疾病并发症。单克隆抗体度普利尤单抗已获批准用于治疗哮喘以及其他 2 型炎症性疾病的成人和青少年。
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 408 名年龄在 6 至 11 岁之间、患有未控制的中度至重度哮喘的儿童随机分为两组，分别接受皮下注射度普利尤单抗（体重≤30 公斤者剂量为 100 毫克，体重＞30 公斤者剂量为 200 毫克）或匹配的安慰剂，每两周一次。所有儿童继续接受稳定剂量的标准基础治疗。主要终点是严重哮喘加重的年发生率。次要终点包括治疗 12 周时预支气管扩张后 1 秒用力呼气量（ppFEV）的百分比与基线相比的变化，以及治疗 24 周时哮喘控制问卷 7 访视者管理（ACQ-7-IA）评分的变化。在具有 2 型炎症表型（≥150 个每立方毫米血液嗜酸性粒细胞或呼气一氧化氮分数≥20 ppb）或基线时血液嗜酸性粒细胞计数至少 300 个每立方毫米的两个主要疗效人群中评估终点。
在具有 2 型炎症表型的患者中，度普利尤单抗组严重哮喘加重的年发生率为 0.31（95%置信区间 [CI]，0.22 至 0.42），安慰剂组为 0.75（95% CI，0.54 至 1.03）（度普利尤单抗组的相对风险降低率为 59.3%；95% CI，39.5 至 72.6；P<0.001）。与基线相比，度普利尤单抗组的 ppFEV 平均（±SE）变化为 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，5.2 个百分点；95% CI，2.1 至 8.3；P<0.001）。度普利尤单抗还显著改善了哮喘控制情况（P<0.001）。在基线时血液嗜酸性粒细胞计数至少为 300 个每立方毫米的患者中也观察到了类似的结果。两组严重不良事件的发生率相似。
在患有未控制的中度至重度哮喘的儿童中，与安慰剂组相比，接受度普利尤单抗附加治疗的患者哮喘发作次数更少，肺功能和哮喘控制情况更好。（由 Sanofi 和 Regeneron Pharmaceuticals 资助；Liberty Asthma VOYAGE ClinicalTrials.gov 编号，NCT02948959）。
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