Effect of dupilumab on exhaled nitric oxide, mucus plugs, and functional respiratory imaging in patients with type 2 asthma (VESTIGE): a randomised, double-blind, placebo-controlled, phase 4 trial

Abstract

Background: Asthma is a respiratory disease characterised by chronic airway inflammation and mucus hypersecretion. VESTIGE used functional respiratory imaging to assess changes in airway structure and function, including mucus plugging, in response to dupilumab.

Methods: VESTIGE was a randomised, double-blind, placebo-controlled, phase 4 trial done at 72 research sites or academic centres in 14 countries. We recruited adult patients (aged 18-70 years) with physician-diagnosed, uncontrolled, moderate-to-severe type 2 asthma (blood eosinophil count ≥300 cells/μL and fractional exhaled nitric oxide [FeNO] ≥25 parts per billion [ppb]) being treated with medium-dose to high-dose inhaled corticosteroids combined with other controller medications. Patients were randomly assigned (2:1; block size of 6) via interactive voice-web response technology to receive add-on dupilumab 300 mg subcutaneously once every 2 weeks or volume-matched placebo up to week 24. Randomisation was stratified by inhaled corticosteroids dose level and region (eastern Europe vs the rest of the world). Participants and investigators, including those assessing outcomes, were masked to group assignment. The primary endpoints were the proportion of patients with a FeNO concentration below 25 ppb at week 24, and percentage change from baseline to week 24 in airway volumes (specific regional airway volumes corrected for lung volume, [s]iV_aw) at total lung capacity (TLC), both assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug or placebo. The trial is registered with ClinicalTrials.gov, NCT04400318, and is completed.

Findings: Patient recruitment occurred from July 18, 2020, to Jan 6, 2023. Patients (mean age 50·4 years [SD 12·6]; 68 [62%] female and 41 [38%] male) were randomly assigned to receive dupilumab 300 mg (n=72) or placebo (n=37). At week 24, patients in the dupilumab group were significantly more likely than those in the placebo group to have a FeNO concentration below 25 ppb (41 [57%] of 72 patients vs four [11%] of 37; odds ratio: 9·8 [95% CI 3·1 to 30·8]; p<0·001). Treatment with dupilumab versus placebo led to a numerical increase in (s)iV_aw at TLC from baseline to week 24, although the difference was not significant (least squares [LS] mean percentage change from baseline to week 24: 19·7% [SE 8·1] for dupilumab and -2·0% [11·5] for placebo; LS mean difference vs placebo: 21·8% [95% CI -7·7 to 51·3]; p=0·14). Safety was consistent with the reported safety profile for dupilumab. Treatment-emergent adverse events related to study intervention were reported in 11 (15%) of 72 patients who received dupilumab and four (11%) of 37 who received placebo; no deaths occurred during the intervention period.

Interpretation: The full results of this study indicate that dupilumab reduced airway inflammation and mucus plugging, and improved airway volume and flow, corresponding to improved lung function and asthma control. This study highlights the potential of imaging technology to assess disease burden, monitor progression, and evaluate therapeutic responses, which can provide valuable insights to guide clinical decision making for patients with uncontrolled, moderate-to-severe type 2 asthma.

Funding: Sanofi and Regeneron Pharmaceuticals.