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

Daniel J. Jackson, 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. Electronic address: djj@medicine.wisc.edu.
Leonard B. Bacharier, Department of Pediatrics, Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA.
Peter J. Gergen, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Lisa Gagalis, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
Agustin Calatroni, Rho Federal Systems Division, Durham, NC, USA.
Stephanie Wellford, Rho Federal Systems Division, Durham, NC, USA.
Michelle A. Gill, Department of Pediatrics, Washington University, St Louis, MO, USA.
Jeffrey Stokes, Department of Pediatrics, Washington University, St Louis, MO, USA.
Andrew H. Liu, Pediatric Pulmonary and Sleep Medicine, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
Rebecca S. Gruchalla, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Robyn T. Cohen, Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
Melanie Makhija, Division of Allergy and Immunology, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Gurjit K. Khurana Hershey, Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
George T. O'Connor, Department of Pediatrics, Boston University School of Medicine, Boston, MA, USA.
Jacqueline A. Pongracic, Division of Allergy and Immunology, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
Michael G. Sherenian, 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.
Katherine Rivera-Spoljaric, Department of Pediatrics, Washington University, St Louis, MO, USA; St Louis Children's Hospital, St Louis, MO, USA.
Edward M. Zoratti, Department of Medicine, Henry Ford Health System, Detroit, MI, USA.
Stephen J. Teach, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Meyer Kattan, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Cullen M. Dutmer, Pediatrics-Allergy and Immunology, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
Haejin Kim, Department of Medicine, Henry Ford Health System, Detroit, MI, USA.
Carin Lamm, Department of Pediatrics, New York Columbia University Medical Center, New York, NY, USA.
William J. Sheehan, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
R Max Segnitz, Department of Medicine, University of Washington, Seattle, WA, USA.
Kimberly A. Dill-McFarland, Department of Medicine, University of Washington, Seattle, WA, USA.
Cynthia M. Visness, Rho Federal Systems Division, Durham, NC, USA.
Patrice M. Becker, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA.
James E. Gern, 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.
Christine A. Sorkness, School of Pharmacy, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
William W. Busse, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Matthew C. Altman, Department of Medicine, University of Washington, Seattle, WA, USA; Benaroya Research Institute, Seattle, WA, USA.

Document Type

Journal Article

Publication Date

8-13-2022

Journal

Lancet (London, England)

Volume

400

Issue

10351

DOI

10.1016/S0140-6736(22)01198-9

Abstract

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.

Department

Pediatrics

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