Elsevier

The Lancet

Volume 358, Issue 9278, 28 July 2001, Pages 265-270
The Lancet

Articles
Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study

https://doi.org/10.1016/S0140-6736(01)05481-2Get rights and content

Summary

Background

Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease.

Method

We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV1] 46·8% of predicted, FEV1/forced vital capacity [FVC] 54·6%, and postsalbutamol reversibility 5·4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV1 before and after use of a bronchodilator. Analyses were by intention to treat.

Findings

Cilomilast 15 mg twice daily significantly improved FEV1 compared with placebo (mean 130 mL vs −30 mL [95% Cl 90–240] at week 6, p<0·0001). FVC and peak expiratory flow were also improved (p=0·001 and p<0·0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups.

Interpretation

Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disorder characterised pathologically by airway inflammation, and physiologically by obstruction to expiratory airflow. Spirometric measurements in COPD show a reduction in the ratio of forced expiratory volume in 1 s (FEV1) to the forced vital capacity (FVC), and absolute reductions in measures of expiratory airflow.

COPD represents a major and growing worldwide health-care problem. In 1997, the death rate due to COPD was 40.7 per 100 000 persons in USA.1 In the UK in 1992, 6·4% of deaths in men and 3·9% of those in women were attributable to COPD.2 The WHO predicts that by the year 2020, COPD will become the fifth greatest disease burden and the third most common cause of death.3

With the exception of smoking cessation and the provision of supplemental oxygen for selected patients, the effect of therapy on disease progression is slight.4 Most pharmacological therapies available for COPD, including bronchodilator and anti-inflammatory agents, were first developed for the treatment of asthma. Shortacting inhaled bronchodilators, such as β2-agonist and anticholinergic drugs, are widely used for the symptomatic treatment of COPD.5, 6, 7, 8 These treatments improve lung function but do not alter disease progression or the underlying inflammatory process in the airway. Such is also the case with non-selective phosphodiesterase inhibitors—eg, theophylline. These drugs are bronchodilators but their effects can be altered by interaction with other drugs and they have a narrow therapeutic index, particularly in elderly patients. Monitoring of the drug's concentration in blood is therefore necessary to avoid side-effects.5, 6, 7, 8

Appreciation of the importance of lung inflammation in the pathogenesis of COPD has emerged over the past few years, resulting in the frequent prescription of inhaled corticosteroids. Despite their common use, the effectiveness of these agents in COPD has not been established,5, 6, 7, 8 and results of several major studies9 have failed to show a benefit with the long-term use of these agents. Although patients, particularly those with some features of asthma, can derive short-term benefit from these interventions, few treatments have a major effect on either expiratory flow or quality of life—consequently, new therapies need to be developed.10

Phosphodiesterase type 4 is the main enzyme involved in the metabolism of cyclic AMP in immune, inflammatory, and airway smooth muscle cells.11 It also plays an important part in the modulation of nonadrenergic, non-cholinergic respiratory neurotransmission.12 In view of the importance of intracellular cyclic AMP in the modulation of bronchial smooth muscle tone and pulmonary inflammatory responses, selective inhibition of phosphodiesterase 4 has emerged as a target for rational drug development in respiratory disease.

Cilomilast is a new, orally active, potent, and selective inhibitor of phosphodiesterase 4. The potential therapeutic actions of cilomilast include bronchodilatation, and effects on inflammation and neuromodulation, and suggest that this drug will be a useful treatment for airway disorders.13 We did a randomised, double-blind, placebo-controlled, parallel-group study to assess the safety, efficacy, and dose-response of cilomilast in the treatment of patients with COPD.

Section snippets

Patients

We enrolled patients aged 40–80 years, who had a clinical diagnosis of COPD consistent with European Respiratory Society definitions6 and a smoking history of at least 10 pack-years. Patients had a ratio of prebronchodilator FEV1 to FVC of less than 70%, and an FEV1 after use of an inhaled β2-agonist of 30–70% of the predicted value for age, sex, and height.14 Patients also had fixed airflow obstruction, defined as less than a 15% or less than a 200 mL improvement in FEV1 measured 30 min after

Results

We randomly assigned and included in the intention-totreat population 424 patients (figure 1). Table 1 shows the baseline demographic characteristics of these patients. Mean spirometric measurements for the whole study population included a FEV1 of 46·8% [SD 11·3] of predicted, FEV1/FVC of 54·6% [12·0], and postsalbutamol reversibility of 5·4% [8·4]. Patients had a mean smoking history of 36–43 [SD 22·4] pack-years. Most patients had had breathlessness, 254 (60%) produced sputum, and 191 (45%)

Discussion

An epidemic of smoking-related lung disease combined with the relentless decline in lung function in affected individuals19 and the ineffectiveness10 of available therapies, underlines the need to develop new treatments for COPD. In our study, cilomilast 15 mg twice daily consistently and significantly improved expiratory airflow and quality of life in patients with moderate-to-severe COPD.

The measurement of improvements in health status is important in the assessment of benefit in a population

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