title: Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial.
abstract: Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL).
  
  
  
  We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St George's Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318.
  
  
  
  We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo).
  
  
  
  Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma.
  
  
  
  GlaxoSmithKline.
authors.affiliation: Yale Center for Asthma and Airway Disease, Yale School of Medicine, New Haven, CT, USA. Electronic address: geoffrey.chupp@yale.edu.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Chupp
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline (GSK), Research Triangle Park, NC, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Bradford
authors.affiliation: Respiratory Medical Franchise, GSK, Research Triangle Park, NC, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Albers
authors.affiliation: Clinical Statistics, GSK, Stockley Park, Middlesex, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Bratton
authors.affiliation: Respiratory Therapy Area, GSK, Stockley Park, Middlesex, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang-Jairaj
authors.affiliation: Value Evidence and Outcomes, GSK, Collegeville, PA, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Nelsen
authors.affiliation: Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Trevor
authors.affiliation: l'Institut du Thorax, Universite de Nantes, CHU de Nantes, Nantes, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Magnan
authors.affiliation: Department of Respiratory Medicine, Medical Centre Leeuwarden, Leeuwarden, Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Ten Brinke
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D001249:Asthma / Q000150:complications / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000627:therapeutic use; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004802:Eosinophilia / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008297:Male; D008875:Middle Aged; D009304:Nasopharyngitis / Q000139:chemically induced; D011788:Quality of Life; D012720:Severity of Illness Index; D063189:Symptom Assessment; D000067251:Symptom Flare Up
chemical_list: D000305:Adrenal Cortex Hormones; D061067:Antibodies, Monoclonal, Humanized; D001993:Bronchodilator Agents; C434107:mepolizumab