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Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials.

Abstract

BACKGROUND

The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD.

METHODS

In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125.

FINDINGS

Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg.

INTERPRETATION

Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies.

FUNDING

Nycomed.

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  • Authors+Show Affiliations

    ,

    School of Clinical Sciences, Liverpool, UK. pmacal@liverpool.ac.uk

    , , , , ,

    Source

    Lancet (London, England) 374:9691 2009 Aug 29 pg 685-94

    MeSH

    Administration, Oral
    Adrenergic beta-Agonists
    Aged
    Aminopyridines
    Analysis of Variance
    Benzamides
    Cholinergic Antagonists
    Cyclopropanes
    Double-Blind Method
    Drug Therapy, Combination
    Female
    Forced Expiratory Volume
    Humans
    Male
    Middle Aged
    Phosphodiesterase 4 Inhibitors
    Phosphodiesterase Inhibitors
    Proportional Hazards Models
    Pulmonary Disease, Chronic Obstructive
    Regression Analysis
    Severity of Illness Index
    Smoking
    Treatment Outcome
    Vital Capacity

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    19716960

    Citation

    Calverley, Peter M A., et al. "Roflumilast in Symptomatic Chronic Obstructive Pulmonary Disease: Two Randomised Clinical Trials." Lancet (London, England), vol. 374, no. 9691, 2009, pp. 685-94.
    Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-94.
    Calverley, P. M., Rabe, K. F., Goehring, U. M., Kristiansen, S., Fabbri, L. M., & Martinez, F. J. (2009). Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet (London, England), 374(9691), pp. 685-94. doi:10.1016/S0140-6736(09)61255-1.
    Calverley PM, et al. Roflumilast in Symptomatic Chronic Obstructive Pulmonary Disease: Two Randomised Clinical Trials. Lancet. 2009 Aug 29;374(9691):685-94. PubMed PMID: 19716960.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. AU - Calverley,Peter M A, AU - Rabe,Klaus F, AU - Goehring,Udo-Michael, AU - Kristiansen,Søren, AU - Fabbri,Leonardo M, AU - Martinez,Fernando J, AU - ,, PY - 2009/9/1/entrez PY - 2009/9/1/pubmed PY - 2009/9/12/medline SP - 685 EP - 94 JF - Lancet (London, England) JO - Lancet VL - 374 IS - 9691 N2 - BACKGROUND: The phosphodiesterase-4 inhibitor roflumilast can improve lung function and prevent exacerbations in certain patients with chronic obstructive pulmonary disease (COPD). We therefore investigated whether roflumilast would reduce the frequency of exacerbations requiring corticosteroids in patients with COPD. METHODS: In two placebo-controlled, double-blind, multicentre trials (M2-124 and M2-125) with identical design that were done in two different populations in an outpatient setting, patients with COPD older than 40 years, with severe airflow limitation, bronchitic symptoms, and a history of exacerbations were randomly assigned to oral roflumilast (500 microg once per day) or placebo for 52 weeks. Primary endpoints were change in prebronchodilator forced expiratory volume in 1 s (FEV(1)) and the rate of exacerbations that were moderate (glucocorticosteroid-treated) or severe. Analysis was by intention to treat. The trials are registered with ClinicalTrials.gov, number NCT00297102 for M2-124, and NCT00297115 for M2-125. FINDINGS: Patients were assigned to treatment, stratified according to smoking status and treatment with longacting beta(2) agonists, and given roflumilast (n=1537) or placebo (n=1554). In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV(1) increased by 48 mL with roflumilast compared with placebo (p<0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8-25], p<0.0003). Adverse events were more common with roflumilast (1040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was -2.17 kg. INTERPRETATION: Since different subsets of patients exist within the broad spectrum of COPD, targeted specific therapies could improve disease management. This possibility should be explored further in prospective studies. FUNDING: Nycomed. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/19716960/full_citation L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(09)61255-1 DB - PRIME DP - Unbound Medicine ER -