Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial,The Lancet

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Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial
The Lancet ( IF 98.4 ) Pub Date : 2022-08-11 , DOI: 10.1016/s0140-6736(22)01198-9
Daniel J Jackson ₁ , Leonard B Bacharier ₂ , Peter J Gergen ₃ , Lisa Gagalis ₃ , Agustin Calatroni ₄ , Stephanie Wellford ₄ , Michelle A Gill ₅ , Jeffrey Stokes ₅ , Andrew H Liu ₆ , Rebecca S Gruchalla ₇ , Robyn T Cohen ₈ , Melanie Makhija ₉ , Gurjit K Khurana Hershey ₁₀ , George T O'Connor ₈ , Jacqueline A Pongracic ₉ , Michael G Sherenian ₁₁ , Katherine Rivera-Spoljaric ₁₂ , Edward M Zoratti ₁₃ , Stephen J Teach ₁₄ , Meyer Kattan ₁₅ , Cullen M Dutmer ₁₆ , Haejin Kim ₁₃ , Carin Lamm ₁₇ , William J Sheehan ₁₄ , R Max Segnitz ₁₈ , Kimberly A Dill-McFarland ₁₈ , Cynthia M Visness ₄ , Patrice M Becker ₃ , James E Gern ₁ , Christine A Sorkness ₁₉ , William W Busse ₂₀ , Matthew C Altman ₂₁ ,

Affiliation

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.
National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Rho Federal Systems Division, Durham, NC, USA.
Department of Pediatrics, Washington University, St Louis, MO, USA.
Pediatric Pulmonary and Sleep Medicine, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
Division of Allergy and Immunology, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, Washington University, St Louis, MO, USA; St Louis Children's Hospital, St Louis, MO, USA.
Department of Medicine, Henry Ford Health System, Detroit, MI, USA.
Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Columbia University College of Physicians and Surgeons, New York, NY, USA.
Pediatrics-Allergy and Immunology, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
Department of Pediatrics, New York Columbia University Medical Center, New York, NY, USA.
Department of Medicine, University of Washington, Seattle, WA, USA.
School of Pharmacy, 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 Medicine, University of Washington, Seattle, WA, USA; Benaroya Research Institute, Seattle, WA, USA.

Background

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.

Methods

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.

Findings

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.

Interpretation

Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations.

Funding

US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

中文翻译：

美泊利单抗治疗美国城市患有易加重性嗜酸性粒细胞性哮喘的儿童 (MUPPITS-2)：一项随机、双盲、安慰剂对照、平行组试验

背景

生活在美国城市环境中的黑人和西班牙裔儿童因哮喘发病率和死亡率负担过重。针对嗜酸性粒细胞表型的治疗可减少成人哮喘发作，但在儿童和不同人群中的数据很少。此外，通过基于免疫的疗法预防或持续的恶化背后的分子机制尚不清楚。我们的目的是确定与单独基于指南的护理相比，在基于指南的护理中添加美泊利单抗是否可以减少 52 周期间哮喘发作的次数。

方法

这是一项在美国九个城市医疗中心进行的随机、双盲、安慰剂对照、平行组试验。居住在社会经济弱势社区、患有易加重哮喘（定义为前一年发作≥2次）且血液嗜酸性粒细胞至少为每μL 150个细胞的6-17岁儿童和青少年按1:1随机分配至美泊利单抗组（6-11 岁：40 毫克；12-17 岁：100 毫克）或安慰剂注射，每 4 周一次，加上基于指南的护理，持续 52 周。随机化是使用经过验证的自动化系统完成的。参与者、调查人员和收集结果指标的研究人员仍然不知道小组作业。主要结局是意向治疗人群在 52 周期间接受全身皮质类固醇治疗的哮喘急性发作次数。研究人员使用鼻转录组模块分析评估治疗反应机制。在意向治疗人群中评估了安全性。该试验已在 ClinicalTrials.gov 注册，NCT03292588。

发现

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。我们筛选了 390 人，其中 335 人符合纳入标准并被纳入。290 名患者符合随机化标准，被随机分配至美泊利单抗组 (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。52 周研究期间，美泊利单抗组哮喘发作平均次数为 0·96 次（95% CI 0·78–1·17），安慰剂组为 1·30 次（1·08–1·57）（比率为 0 ·73；0·56–0·96；p=0·027)。美泊利单抗组 146 名参与者中有 42 名 (29%) 发生了治疗引起的不良事件，而安慰剂组 144 名参与者中有 16 名 (11%) 发生了治疗引起的不良事件。没有死亡归因于美泊利单抗。