Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA.
Lancet. 2022 Aug 13;400(10351):502-511. doi: 10.1016/S0140-6736(22)01198-9.
Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone.
This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588.
Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab.
Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.
US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.
美国城市环境中生活的黑人和西班牙裔儿童哮喘发病率和死亡率过高。针对嗜酸性粒细胞表型的治疗可减少成人哮喘恶化，但儿童和不同人群的数据很少。此外，对于免疫治疗预防或持续存在的恶化的分子机制仍了解甚少。我们旨在确定美泊利珠单抗联合基于指南的护理是否比单独基于指南的护理在 52 周期间减少哮喘恶化的次数。
这是一项在美国 9 个城市医疗中心进行的随机、双盲、安慰剂对照、平行组试验。年龄在 6-17 岁之间、居住在社会经济弱势社区、过去一年有过两次以上哮喘恶化（定义为血液嗜酸性粒细胞至少为 150 个细胞/μL）的儿童和青少年被随机分配 1:1 接受美泊利珠单抗（6-11 岁：40mg；12-17 岁：100mg）或安慰剂，每四周一次，共 52 周。使用经过验证的自动化系统进行随机分组。参与者、研究人员和收集结果的研究人员对分组情况保持盲态。主要结局是在治疗意向人群中 52 周内使用全身皮质类固醇治疗的哮喘恶化次数。研究人员使用鼻腔转录组模块分析评估治疗反应的机制。在治疗意向人群中评估安全性。该试验在 ClinicalTrials.gov 注册，NCT03292588。
2017 年 11 月 1 日至 2020 年 3 月 12 日期间，我们招募了 585 名儿童和青少年。我们筛查了 390 人，其中 335 人符合纳入标准并被纳入。335 人符合入组标准，并被随机分配至美泊利珠单抗组（n=146）或安慰剂组（n=144），并纳入意向治疗分析。290 人符合随机分组标准，随机分配至美泊利珠单抗组（n=146）或安慰剂组（n=144），并纳入意向治疗分析。248 人完成了研究。在 52 周的研究期间，美泊利珠单抗组哮喘恶化的平均次数为 0.96（95%CI 0.78-1.17），安慰剂组为 1.30（1.08-1.57）（率比 0.73；0.56-0.96；p=0.027）。美泊利珠单抗组 146 名参与者中有 42 名（29%）出现治疗相关不良事件，安慰剂组 144 名参与者中有 16 名（11%）出现治疗相关不良事件。没有死亡归因于美泊利珠单抗。
在具有嗜酸性粒细胞表型的易恶化哮喘的城市儿童中，表型定向治疗美泊利珠单抗可减少哮喘恶化的次数。
美国国家过敏和传染病研究所和葛兰素史克。
