ArticlesReslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials
Introduction
Despite the benefits of standard inhaled corticosteroid-based treatment, patients with inadequately controlled asthma remain at risk of asthma exacerbations.1, 2 Eosinophils play a key part in the promotion and maintenance of airway inflammation, airway wall thickening, fibrosis, and angiogenesis (ie, remodelling).3 Increased blood and sputum eosinophil counts are recognised markers of disease severity and have emerged as independent risk factors for future asthma exacerbations.4, 5, 6, 7, 8, 9
Maintenance and activation of eosinophils is dependent on the presence of interleukin 5, the prototypical eosinophil viability-enhancing factor.10 Reduction of interleukin-5-mediated signalling could therefore disrupt the maturation and survival of eosinophils and might thereby contribute to asthma symptom control and reduced airway inflammation, and could potentially help to prevent remodelling. Two different anti-interleukin-5 treatments (one antibody against interleukin 5 and another against the interleukin-5 receptor) reduced exacerbations in patients with clinical features of severe, refractory eosinophilic asthma.11, 12, 13, 14
Reslizumab is an investigational, IgG4k humanised, monoclonal antibody against interleukin 5.15, 16, 17, 18, 19, 20 Preclinical properties of reslizumab, including high interleukin-5-binding affinity, potent inhibition of interleukin-5 activity and associated lung eosinophilia were suggestive of potential clinical activity and underpinned the subsequent clinical trial programme for an intravenous formulation.15, 16, 17, 18, 19, 20 Short-term clinical efficacy of reslizumab was subsequently shown in patients with demonstrable sputum eosinophilia (≥3%) in a phase 2 trial.13
Here, we report two identically designed, 52-week, phase 3 trials (referred to as studies 1 and 2), which were done to assess the efficacy and safety of intravenous reslizumab in patients with inadequately controlled, moderate-to-severe asthma and elevated blood eosinophil counts.
Section snippets
Study design and participants
We did two duplicate, international, double-blind, parallel-group, randomised, placebo-controlled trials. Both trials enrolled patients aged 12–75 years (128 clinical research centres in study 1 and 104 centres in study 2) from Asia, Australia, North America, South America, South Africa, and Europe, with at least one blood eosinophil count of 400 cells per μL or higher during a 2–4 week screening period and inadequately controlled asthma (Asthma Control Questionnaire-7 [ACQ-7] score ≥1·5)21 who
Results
Study 1 was done between April 12, 2011, and March 3, 2014, and study 2 between March 22, 2011, and April 9, 2014. Across both studies, we screened 2597 patients, of whom 489 were randomly assigned to receive either reslizumab (n=245) or placebo (n=244) in study 1, and 464 were randomly assigned to receive either reslizumab (n=232) or placebo (n=232) in study 2 (intention-to-treat populations; figure 1). Of the 1644 patients not included in the trial after screening, 1472 did not meet the
Discussion
The results of these identical, parallel studies show that reslizumab significantly improved outcomes in patients with inadequately controlled asthma and a blood eosinophil concentration of 400 cells per μL or more. These results were achieved despite the continued use of previous asthma treatments throughout the studies. In the primary analysis, reslizumab significantly reduced the annual rate of clinical asthma exacerbations by 50–59% compared with placebo (more than 80% of overall clinical
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