背景:Dupilumab是一种人单克隆抗体,可阻断白细胞介素-4和白细胞介素-13途径,并在五种以2型炎症为标志的不同特应性疾病中显示出疗效,包括成人和青少年的嗜酸性粒细胞性食管炎。
方法:在此3期试验中,我们随机分配,以2:2:1:1的比例,1~11岁的活动性嗜酸性粒细胞性食管炎患者,对质子泵抑制剂高暴露量或低暴露量皮下dupilumab方案16周或安慰剂(两组)均无反应(A部分).在A部分的结尾,每个dupilumab组的符合条件的患者继续相同的治疗方案,安慰剂组的患者被分配到较高暴露或较低暴露的dupilumab治疗36周(B部分).在每个暴露水平,dupilumab的给药剂量是根据基线体重分层的4种剂量中的一种.主要终点为组织学缓解(食管上皮内嗜酸性粒细胞计数峰值,每个高功率场≤6个),在第16周。对关键次要终点进行分级测试。
结果:在A部分中,高暴露组37例患者中有25例(68%)出现组织学缓解,在低暴露组的31名患者中,有18名(58%),安慰剂组的34例患者中有1例(3%)(高暴露方案与安慰剂之间的差异,65个百分点[95%置信区间{CI},48至81;P<0.001];低暴露方案与安慰剂之间的差异,55个百分点[95%CI,37至73;P<0.001])。高暴露dupilumab方案导致组织学显著改善,内窥镜,和与安慰剂相比的转录组测量。组织学的改善,内窥镜,所有患者在基线和第52周之间的转录组测量结果与在A部分中接受dupilumab的患者在基线和第16周之间的改善大致相似。2019年冠状病毒病的发病率,恶心,注射部位疼痛,在接受dupilumab(任一剂量)的患者中,头痛比接受安慰剂的患者高至少10个百分点.在A部分期间接受dupilumab治疗的3例患者和B部分期间的6例患者中报告了严重不良事件。
结论:Dupilumab导致嗜酸性粒细胞性食管炎患儿的组织学缓解率明显高于安慰剂。与安慰剂相比,较高暴露的dupilumab方案还导致关键次要终点的测量有所改善。(由赛诺菲和Regeneron制药公司资助;EoEKIDSClinicalTrials.gov编号,NCT04394351。).
BACKGROUND: Dupilumab is a human monoclonal antibody that blocks interleukin-4 and interleukin-13 pathways and has shown efficacy in five different atopic diseases marked by type 2 inflammation, including eosinophilic esophagitis in adults and adolescents.
METHODS: In this phase 3 trial, we randomly assigned, in a 2:2:1:1 ratio, patients 1 to 11 years of age with active eosinophilic esophagitis who had had no response to proton-pump inhibitors to 16 weeks of a higher-exposure or lower-exposure subcutaneous dupilumab regimen or to placebo (two groups) (Part A). At the end of Part A, eligible patients in each dupilumab group continued the same regimen and those in the placebo groups were assigned to higher-exposure or lower-exposure dupilumab for 36 weeks (Part B). At each level of exposure, dupilumab was administered in one of four doses tiered according to baseline body weight. The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤6 per high-power field) at week 16. Key secondary end points were tested hierarchically.
RESULTS: In Part A, histologic remission occurred in 25 of the 37 patients (68%) in the higher-exposure group, in 18 of the 31 patients (58%) in the lower-exposure group, and in 1 of the 34 patients (3%) in the placebo group (difference between the higher-exposure regimen and placebo, 65 percentage points [95% confidence interval {CI}, 48 to 81; P<0.001]; difference between the lower-exposure regimen and placebo, 55 percentage points [95% CI, 37 to 73; P<0.001]). The higher-exposure dupilumab regimen led to significant improvements in histologic, endoscopic, and transcriptomic measures as compared with placebo. The improvements in histologic, endoscopic, and transcriptomic measures between baseline and week 52 in all the patients were generally similar to the improvements between baseline and week 16 in the patients who received dupilumab in Part A. In Part A, the incidence of coronavirus disease 2019, nausea, injection-site pain, and headache was at least 10 percentage points higher among the patients who received dupilumab (at either dose) than among those who received placebo. Serious adverse events were reported in 3 patients who received dupilumab during Part A and in 6 patients overall during Part B.
CONCLUSIONS: Dupilumab resulted in histologic remission in a significantly higher percentage of children with eosinophilic esophagitis than placebo. The higher-exposure dupilumab regimen also led to improvements in measures of key secondary end points as compared with placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; EoE KIDS ClinicalTrials.gov number, NCT04394351.).