Elsevier

The Lancet

Volume 380, Issue 9842, 18–24 August 2012, Pages 651-659
The Lancet

Articles
Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(12)60988-XGet rights and content

Summary

Background

Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab—a monoclonal antibody against interleukin 5—is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab.

Methods

We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12–74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506.

Findings

621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31–61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19–54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36–64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment.

Interpretation

Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma.

Funding

GlaxoSmithKline.

Introduction

Severe asthma is associated with substantial morbidity, mortality, and health-care costs.1 Recurrent asthma exacerbations are a major problem in some patients and can predominate in a subgroup with eosinophilic airway inflammation.2 Mepolizumab—a humanised monoclonal antibody against interleukin 5—selectively and effectively inhibits eosinophilic airway inflammation.3, 4, 5, 6 Two small proof-of-concept studies7, 8 showed that treatment with this drug reduced the risk of asthma exacerbations. A larger study with a diverse population is thus needed to establish the best possible dose, efficacy, safety, and patient characteristics associated with the response to mepolizumab treatment.

In the Dose Ranging Efficacy And safety with Mepolizumab in severe asthma (DREAM) trial, we tested the hypothesis that mepolizumab reduces the frequency of asthma exacerbations. Our secondary aims were to assess the effects of treatment on blood and sputum eosinophil counts, asthma control, asthma-related quality of life, and forced expiratory volume in 1 s (FEV1).

Section snippets

Study design and participants

We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries (Argentina, Australia, Canada, Chile, France, Germany, South Korea, Poland, Romania, Russia, Ukraine, the UK, and the USA) between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12–74 years and had a clinical diagnosis of asthma supported by one or more other characteristics: variability in diurnal peak expiratory flow (PEF) of more than 20% for at least 3 days during the 2-week run-in

Results

Figure 1 shows the trial profile. Of the 616 patients who received treatment and constituted the intention-to-treat population, 520 (84%) completed treatment. Table 1 shows baseline characteristics.

806 exacerbations requiring use of oral corticosteroids, admission, or a visit to an emergency department were reported. Of those, 776 (96%) were supported by objective assessments that asthma had worsened and were deemed clinically significant. 30 (4%; eight in the placebo group, 12 in the 75 mg

Discussion

We have shown that mepolizumab significantly reduces the number of asthma exacerbations in patients with severe eosinophilic asthma compared with placebo. Additionally, treatment lowers blood and sputum eosinophil counts and was well tolerated for 12 months. The DREAM study is the largest trial undertaken in severe asthma as yet (panel). The reported effects are clinically important and suggest that neutralising interleukin 5 addresses a major unmet medical need in a population with substantial

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