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

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.

Figure 1.. Impact of Mepolizumab on Asthma Exacerbations.

A. Asthma exacerbations were significantly reduced in the mepolizumab vs. placebo groups added to guideline-based care. B. The time to first asthma exacerbation was not significantly altered by mepolizumab. C. In a post hoc analysis, a seasonal pattern of asthma exacerbation was observed with a blunting of fall exacerbations in the mepolizumab treated participants.

Figure 1.. Impact of Mepolizumab on Asthma Exacerbations.

A. Asthma exacerbations were significantly reduced in the mepolizumab vs. placebo groups added to guideline-based care. B. The time to first asthma exacerbation was not significantly altered by mepolizumab. C. In a post hoc analysis, a seasonal pattern of asthma exacerbation was observed with a blunting of fall exacerbations in the mepolizumab treated participants.

Figure 1.. Impact of Mepolizumab on Asthma Exacerbations.

A. Asthma exacerbations were significantly reduced in the mepolizumab vs. placebo groups added to guideline-based care. B. The time to first asthma exacerbation was not significantly altered by mepolizumab. C. In a post hoc analysis, a seasonal pattern of asthma exacerbation was observed with a blunting of fall exacerbations in the mepolizumab treated participants.

Figure 2.. Nasal gene module expression levels are related to exacerbation rate and treatment.

Twelve gene expression modules measured from nasal lavage at the randomization visit, week 0, showed a significant relationship to the primary clinical outcome, the number of exacerbations during the course of the study, in either the placebo and/or mepolizumab treatment groups by multivariate partial least squares regression. Shown are the weights for each of the 12 modules and for each treatment group. Orange indicates a weight value for the placebo group and green for the mepolizumab group. A positive weight (indicated with a bar on the right of center) indicates a positive association with the number of exacerbations, a negative weight (left of center) indicates an inverse association. Weight values can range from 0-1 and in part reflect the relative importance of each module in modeling exacerbation number. Module annotations and cell associations are listed. Eight of these 12 modules showed differential expression from week 0 to week 52 in the mepolizumab group, whereas no modules were differentially expressed from week 0 to week 52 in the placebo group. Significance of differential expression is indicated. No significant change in expression is indicated by “ns”. Downward arrows indicate a decrease in expression, upward arrows an increase. The number of arrows indicates the significance level: one arrow, p<0.05; two arrows, p<0.01; 3 arrows, p<0.001. Further details about each module are in table S4.