Dataset Information

Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD.

ABSTRACT:

Background

As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.

Methods

The datasets of two previous replicate, randomized, double-blind, placebo-controlled, parallel-group studies (oral roflumilast 500 μg or placebo once daily for 52 weeks) that were inconclusive regarding exacerbations were combined in a post-hoc, pooled analysis to determine whether roflumilast reduced exacerbations in a more precisely defined patient subset.

Results

The pooled analysis included 2686 randomized patients. Roflumilast significantly decreased exacerbations by 14.3% compared with placebo (p = 0.026). Features associated with this reduction were: presence of chronic bronchitis with or without emphysema (26.2% decrease, p = 0.001), presence of cough (20.9% decrease, p = 0.006), presence of sputum (17.8% decrease, p = 0.03), and concurrent use of inhaled corticosteroids (ICS; 18.8% decrease, p = 0.014). The incidence of adverse events was similar with roflumilast and placebo (81.5% vs 80.1%), but more patients in the roflumilast group had events assessed as likely or definitely related to the study drug (21.5% vs 8.3%).

Conclusions

This post-hoc, pooled analysis showed that roflumilast reduced exacerbation frequency in a subset of COPD patients whose characteristics included chronic bronchitis with/without concurrent ICS. These observations aided the design of subsequent phase 3 studies that prospectively confirmed the reduction in exacerbations with roflumilast treatment.

Trials registration

ClinicalTrials.gov identifiers: NCT00076089 and NCT00430729.

SUBMITTER: Rennard SI

PROVIDER: S-EPMC3040135 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Publications

Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD.

Rennard Stephen I SI Calverley Peter M A PM Goehring Udo M UM Bredenbröker Dirk D Martinez Fernando J FJ

Respiratory research 20110127

<h4>Background</h4>As chronic obstructive pulmonary disease (COPD) is a heterogeneous disease it is unlikely that all patients will benefit equally from a given therapy. Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, has been shown to improve lung function in moderate and severe COPD but its effect on exacerbations in unselected populations was inconclusive. This led to the question of whether a responsive subset existed that could be investigated further.<h4>Methods</h4>The dat ...[more]

PMID: 21272339

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Project description:The aim of the present study was to characterize the gene expression profile of the phosphodiesterase-4 inhibitor CHF6001 on top of inhaled triple therapy in sputum cells and whole blood of chronic bronchitis patients. Samples for analyses were collected from a multicenter, three-period, three-way, placebo-controlled, double-blind, complete block crossover study. Eligible patients underwent three, 32-day treatment periods during which they received CHF6001 800 or 1600 µg twice daily (total daily doses of 1600 or 3200 µg) or matching placebo, all via multi-dose dry-powder inhaler (NEXThaler). Treatment periods were separated by a 28–42 day washout. Eligible patients were male or female, ≥40 years of age, current or ex-smokers with a smoking history ≥10 pack-years, a diagnosis of COPD, post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥30% and <70% predicted, ratio of FEV1 to forced vital capacity (FVC) <0.70, COPD Assessment Test score ≥10, and a history of chronic bronchitis (defined as chronic cough and sputum production for more than three months per year for at least two years) and treated with inhaled triple ICS/LABA/LAMA therapy for at least two months prior to enrollment. CHF6001 had no effect in blood, but a strong effect in sputum with 1471 and 2598 significantly differentially-expressed probe-sets relative to placebo (p-value adjusted for False Discovery Rate<0.05) for 800 and 1600µg , respectively. Functional enrichment analysis showed significant modulation of key inflammatory pathways involved in cytokine activity, pathogen-associated-pattern-recognition activity, oxidative stress and vitamin D with associated inhibition of downstream inflammatory effectors. A large number of pro-inflammatory genes coding for cytokines and matrix-metalloproteinases were significantly differentially expressed for both doses; the majority (>87%) were downregulated, including macrophage inflammatory protein-1-alpha and 1-beta, interleukin-27-beta, interleukin-12-beta, interleukin-32, tumor necrosis factor-alpha-induced-protein-8, ligand-superfamily-member-15, and matrix-metalloproteinases-7,12 and 14. In conclusion inhaled PDE4-Inhibition by CHF6001 on top of triple therapy in patients with chronic bronchitis patients significantly modulated key inflammatory targets and pathways in the lung but not in blood. Mechanistically these findings support a targeted effect in the lung while minimizing unwanted systemic class-effects

Dataset Information

Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD.

Background

Methods

Results

Conclusions

Trials registration

Publications

Reduction of exacerbations by the PDE4 inhibitor roflumilast--the importance of defining different subsets of patients with COPD.

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