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Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study.

Abstract

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD.

METHODS

We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278.

FINDINGS

We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related.

INTERPRETATION

Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia.

FUNDING

MedImmune.

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  • Authors+Show Affiliations

    ,

    Institute for Lung Health, National Institute for Health Research Respiratory Biomedical Research Unit, Department of Infection, Immunity, and Inflammation, University of Leicester, Leicester, UK. Electronic address: ceb17@leicester.ac.uk.

    ,

    Wake Forest University Health Sciences, Winston-Salem, NC, USA.

    ,

    University of Pennsylvania Medical Center, Philadelphia, PA, USA.

    ,

    Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.

    ,

    MedImmmune, Gaithersburg, MD, USA.

    ,

    MedImmmune, Gaithersburg, MD, USA.

    ,

    AstraZeneca, Gaithersburg, MD, USA.

    ,

    MedImmune, Cambridge, UK.

    MedImmune, Cambridge, UK.

    Source

    The Lancet. Respiratory medicine 2:11 2014 Nov pg 891-901

    MeSH

    Aged
    Antibodies, Monoclonal, Humanized
    Disease Progression
    Double-Blind Method
    Eosinophilia
    Eosinophils
    Female
    Forced Expiratory Volume
    Humans
    Interleukin-5 Receptor alpha Subunit
    Leukocyte Count
    Male
    Middle Aged
    Pulmonary Disease, Chronic Obstructive
    Severity of Illness Index
    Sputum
    Surveys and Questionnaires

    Pub Type(s)

    Clinical Trial, Phase II
    Journal Article
    Multicenter Study
    Randomized Controlled Trial
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    25208464

    Citation

    Brightling, Christopher E., et al. "Benralizumab for Chronic Obstructive Pulmonary Disease and Sputum Eosinophilia: a Randomised, Double-blind, Placebo-controlled, Phase 2a Study." The Lancet. Respiratory Medicine, vol. 2, no. 11, 2014, pp. 891-901.
    Brightling CE, Bleecker ER, Panettieri RA, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891-901.
    Brightling, C. E., Bleecker, E. R., Panettieri, R. A., Bafadhel, M., She, D., Ward, C. K., ... van der Merwe, R. (2014). Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. The Lancet. Respiratory Medicine, 2(11), pp. 891-901. doi:10.1016/S2213-2600(14)70187-0.
    Brightling CE, et al. Benralizumab for Chronic Obstructive Pulmonary Disease and Sputum Eosinophilia: a Randomised, Double-blind, Placebo-controlled, Phase 2a Study. Lancet Respir Med. 2014;2(11):891-901. PubMed PMID: 25208464.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. AU - Brightling,Christopher E, AU - Bleecker,Eugene R, AU - Panettieri,Reynold A,Jr AU - Bafadhel,Mona, AU - She,Dewei, AU - Ward,Christine K, AU - Xu,Xiao, AU - Birrell,Claire, AU - van der Merwe,René, Y1 - 2014/09/07/ PY - 2014/9/12/entrez PY - 2014/9/12/pubmed PY - 2015/11/18/medline SP - 891 EP - 901 JF - The Lancet. Respiratory medicine JO - Lancet Respir Med VL - 2 IS - 11 N2 - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with eosinophilic airway inflammation in 10-20% of patients. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, depletes blood and sputum eosinophils. We aimed to establish whether benralizumab reduces acute exacerbations of COPD in patients with eosinophilia and COPD. METHODS: We did this randomised, double-blind, placebo-controlled, phase 2a study between Nov 18, 2010, and July 13, 2013, at 26 sites in the UK, Poland, Germany, Canada, the USA, Denmark, and Spain. Adults aged 40-85 years, with moderate-to-severe COPD, at least one acute exacerbation of COPD, and a sputum eosinophil count of 3·0% or more within the previous year, were randomly assigned (1:1) via computer-generated permuted block randomisation (block size of four), with an interactive voice or web-response system, to receive placebo or 100 mg benralizumab subcutaneously, every 4 weeks (three doses), then every 8 weeks (five doses) over 48 weeks. Study site personnel included in study assessments, participants, and data analysts, were masked to treatment allocation. The primary endpoint was the annualised rate of acute exacerbations of COPD at week 56, defined as the number of acute exacerbations divided by total duration of person-year follow-up. Secondary and exploratory endpoints included COPD-specific Saint George's Respiratory Questionnaire (SGRQ-C), Chronic Respiratory Questionnaire self-administered standardised format (CRQ-SAS), pre-bronchodilator forced expiratory volume in 1 second (FEV1), and safety. We did a prespecified subgroup analysis by baseline blood eosinophil count. Analyses were by intention to treat and per-protocol. This trial is registered with ClinicalTrials.gov, number NCT01227278. FINDINGS: We randomly assigned 101 patients to receive placebo (n=50) or benralizumab (n=51), of whom 88 (87%) patients completed the study. Six patients who completed the study were excluded from the per-protocol population because of major protocol violations; the per-protocol population thus included 82 patients. Benralizumab did not reduce the annualised rate of acute exacerbations of COPD compared with placebo in the per-protocol population, with rates of 0·95 (0·68-1·29; n=40) versus 0·92 (0·67-1·25; n=42). Mean pre-bronchodilator FEV1 change from baseline to week 56 was -0·06 L (SD 0·24) with placebo, and 0·13 L (0·41) with benralizumab (p=0·014). Numerical, albeit non-significant, improvement in acute exacerbations of COPD, SGRQ-C, CRQ-SAS, and FEV1 were greater in benralizumab-treated patients with baseline blood eosinophil concentrations of 200 cells per μL or more or 300 cells per μL or more. Incidence of treatment-emergent adverse events was similar between the two groups, with the most common events being respiratory disorders (31 [62%] of 50 patients given placebo vs 32 [63%] of 51 given benralizumab) and infections (28 [56%] vs 27 [53%]). A higher incidence of serious treatment-emergent adverse events were recorded in patients in the benralizumab group than in those in the placebo group (14 vs nine patients), although none of these events were considered by the investigator to be benralizumab related. INTERPRETATION: Compared with placebo, benralizumab did not reduce the rate of acute exacerbations of COPD. However, the results of prespecified subgroup analysis support further investigation of benralizumab in patients with COPD and eosinophilia. FUNDING: MedImmune. SN - 2213-2619 UR - https://www.unboundmedicine.com/medline/citation/25208464/Benralizumab_for_chronic_obstructive_pulmonary_disease_and_sputum_eosinophilia:_a_randomised_double_blind_placebo_controlled_phase_2a_study_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2213-2600(14)70187-0 DB - PRIME DP - Unbound Medicine ER -