Elsevier

The Lancet

Volume 366, Issue 9485, 13–19 August 2005, Pages 563-571
The Lancet

Articles
Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(05)67100-0Get rights and content

Summary

Background

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD.

Methods

This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned roflumilast 250 μg (n=576), roflumilast 500 μg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat.

Findings

1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 μg group, and 124 (22%) from the roflumilast 500 μg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 μg (by 74 mL [SD 18]) and roflumilast 500 μg (by 97 mL [18]) compared with placebo (p<0·0001). Improvement in health-related quality of life was greater with roflumilast 250 μg (−3·4 units [0·6]) and roflumilast 500 μg (−3·5 units [0·6]) than with placebo (−1·8 units [0·8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1·13 (2·37), 1·03 (2·33), and 0·75 (1·89) with placebo, roflumilast 250 μg, and roflumilast 500 μg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study.

Interpretation

Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in adults worldwide. A meta-analysis showed that the overall prevalence is between 4% and 10%.1 COPD is the fifth leading cause of death worldwide, and its increasing prevalence and limited treatment options suggest that it will become the third leading cause of death by the year 2020.2, 3 As defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) scientific committee, COPD is a disease characterised by airflow restriction that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.4 The disease is usually related to cigarette smoking, but other causative factors, such as exposure to air pollution, exist.5, 6

Airflow obstruction in COPD arises as a result of chronic inflammation and structural changes in small airways and lung parenchyma.7 The inflammation is characterised by increased numbers of neutrophils, macrophages, and cytotoxic T cells, as well as by the presence of multiple inflammatory mediators such as cytokines, chemokines, and growth factors. The recognition that chronic inflammation is a key pathophysiological mechanism in COPD provided the rationale for the use of inhaled corticosteroids as a treatment option. However, corticosteroids have little effect on inflammatory processes associated with COPD, and even high doses of these drugs do not reduce the progression of the disease.8 Bronchodilators, such as β2-agonists or anticholinergics, provide some symptomatic relief, but there is a definite unmet medical need to develop agents that specifically target chronic inflammation associated with COPD.4

The search for an anti-inflammatory treatment for COPD is now focusing on inhibitors of phosphodiesterase 4, the major hydrolase of cyclic adenosine monophosphate (cAMP) in inflammatory cells.9 Inhibition of phosphodiesterase 4 increases intracellular cAMP concentrations. The rise in concentrations of cAMP can lead to activation of protein kinase A, resulting in phosphorylation and inactivation of target transcription factors, which ultimately result in reduction of cellular inflammatory activity. Targeted inhibition of phosphodiesterase 4 is thought to elicit anti-inflammatory effects in patients with asthma or COPD.9, 10 Phosphodiesterase-4 inhibitors could potentially provide better anti-inflammatory activity than corticosteroids because corticosteroids do not suppress neutrophil activation or production of cytokines and chemokines.8

Roflumilast is a targeted inhibitor of phosphodiesterase 4 and is given once daily via the oral route. The anti-inflammatory potential of roflumilast has been proven in vitro and in animal models and includes inhibition of the synthesis of leukotriene B4 and reactive oxygen species in neutrophils as well as inhibition of TNF-α release by mononuclear cells.11, 12 Roflumilast also inhibits T-cell proliferation, cytokine production, and cell infiltration of the lungs.11, 12 Preliminary clinical data suggest that roflumilast could improve lung function in patients with COPD while being well tolerated.13 We undertook a large clinical phase III, randomised, multicentre, multinational, double-blind, placebo-controlled study to assess whether once-daily roflumilast (250 μg or 500 μg) given orally for 24 weeks has a clinically meaningful effect on lung function and health-related quality of life when compared with placebo in patients with moderate to severe COPD.

Section snippets

Patients

All patients were recruited from an outpatient setting. Inclusion criteria for patients were: history of COPD >12 months, as defined by GOLD guidelines;14 age 40 years or older; current smoker or ex-smoker (>1 year of smoking cessation) with a smoking history of >10 pack-years; postbronchodilator FEV1 (forced expiratory volume in 1 s) of 30–80% of predicted value; postbronchodilator FEV1/FVC (forced vital capacity) ratio <70%; reversibility of FEV1 of <12% and/or <200 mL after 400 μg inhaled

Results

Figure 1 shows the trial profile. Two patients randomly assigned roflumilast 250 μg did not take any study medication and were therefore excluded from the intention-to-treat population. 1157 patients completed the trial. Table 1 shows the baseline characteristics for the three treatment groups.

Treatment with roflumilast 250 μg and roflumilast 500 μg increased postbronchodilator FEV1 from baseline, whereas a decline was recorded with placebo (figure 2A). Patients treated with placebo had a

Discussion

Chronic inflammation is generally regarded as a central mechanism in the pathogenesis of COPD.5 The significant morbidity and mortality associated with the disease, combined with the lack of effective treatments, warrant the development of drugs that target the underlying chronic inflammation rather than solely the clinical symptoms of COPD. Inhibition of phosphodiesterase 4 has been shown to inhibit the inflammatory processes associated with COPD, and thus represents a promising new treatment

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