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(Chest. 2006;129:56-66.)
© 2006 American College of Chest Physicians

Cilomilast for COPD*

Results of a 6-Month, Placebo-Controlled Study of a Potent, Selective Inhibitor of Phosphodiesterase 4

Stephen I. Rennard, MD, FCCP; Neil Schachter, MD; Mary Strek, MD; Kathy Rickard, MD and Ohad Amit, PhD{dagger}

* From the University of Nebraska Medical Center (Dr. Rennard), Omaha, NE; Mount Sinai Medical Center (Dr. Schachter), New York, NY; the University of Chicago (Dr. Strek), Chicago, IL; and GlaxoSmithKline (Drs. Rickard and Amit), Research Triangle Park, NC. {dagger} A list of participating investigators is located in the Appendix.

Correspondence to: Stephen I. Rennard, MD, FCCP; Larson Professor of Medicine, University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885; e-mail: srennard{at}unmc.edu

Abstract

Background: COPD is a relentless, progressive disease. This study evaluated the efficacy of cilomilast, a selective phosphodiesterase (PDE) 4 inhibitor, in the treatment of COPD.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study in subjects with COPD. After a 4-week, single-blind, placebo run-in period, eligible subjects were randomized in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks. Subjects between 40 and 80 years of age who had received a diagnosis of COPD were eligible for the study. The primary efficacy variables were changes from baseline in trough (ie, predose) FEV1 and in total score of the St. George’s Respiratory Questionnaire (SGRQ). A key secondary end point was the incidence rate of COPD exacerbations.

Results: The average change from baseline in FEV1 over 24 weeks in the cilomilast group was an increase of 10 mL compared with a decrease of 30 mL in the placebo group (difference, 40 mL; p = 0.002). When averaged over 24 weeks, there was a clinically significant reduction in the mean total SGRQ score in subjects receiving cilomilast therapy, with a difference of 4.1 U compared with subjects who received placebo (p = 0.001). A greater percentage of subjects in the cilomilast group were exacerbation-free at 24 weeks (74%; p = 0.008) compared with placebo (62%). Adverse events were generally mild or moderate and were not unexpected for this class of medications. GI adverse events that interfered with daily activities (cilomilast, 17%; placebo, 8%) predominantly occurred within the first 3 weeks of initiating cilomilast therapy.

Conclusion: Cilomilast is an orally active, potent, and selective inhibitor of PDE-4. Cilomilast maintained pulmonary function and improved health status, and reduced the rate of COPD exacerbations during 24 weeks of treatment. This study supports the use of cilomilast, a novel, selective PDE-4 inhibitor, in subjects with COPD.

Key Words: cilomilast • COPD • phosphodiesterase-4 • phosphodiesterase-4 enzyme

COPD is a relentless, progressive disease that is characterized by the limitation of expiratory airflow that is poorly reversible and by accelerated lung function loss. Patients with COPD who are active smokers can expect to experience an annual decline in FEV1 of 50 to 100 mL.1 Currently the fourth most common cause of death in North America, COPD accounted for > 124,000 deaths in 2002.2

Though recent guidelines3 have acknowledged that COPD is a preventable and treatable disease, the therapeutic options for COPD are limited, and the current management options are focused on symptomatic improvement.4 Treatment with bronchodilators (eg, ß-agonists and anticholinergic agents) has been shown to improve lung function567891011; however, these medications do not address the underlying inflammation of COPD. Long-term clinical trials12131415 with inhaled corticosteroids in patients with COPD have demonstrated that they reduce the rate of acute exacerbations. While these individual clinical trials have not shown that inhaled corticosteroids alter the rate of decline in lung function, one meta-analysis16 has suggested that the use of these medications for ≥ 2 years slows the rate of lung function loss. Further research is needed to confirm this finding. However, the development of novel treatment options for individuals with COPD is an urgent health concern.

Phosphodiesterase (PDE)-4 is a major regulator of cyclic adenosine monophosphate metabolism in many cell types, including smooth muscle, proinflammatory, and immune cells.17 Since cyclic adenosine monophosphate generally down-regulates the activity of these cells, the inhibition of PDE-4 is an attractive target for COPD drug development. In previous preclinical and clinical studies with cilomilast, the inhibition of PDE-4 resulted in bronchodilation, neuromodulation, and reduction in the number and activation of inflammatory cells relevant to COPD.1819202122232425

Cilomilast is an orally active, potent, and selective inhibitor of PDE-4. In a 6-week, randomized, placebo-controlled, dose-ranging study,26 subjects with COPD who had been treated with cilomilast demonstrated significant improvements in both expiratory airflow and disease-specific health status. The objectives of this double-blind, placebo-controlled clinical study were to assess the efficacy, safety, and tolerability of oral cilomilast, 15 mg bid over 24 weeks, in subjects with COPD.

Materials and Methods

Study Design
This was a randomized double-blind, placebo-controlled, parallel-group study conducted from November 1998 to March 2000 at 102 centers located in Canada, Mexico, and the United States (protocol 039). The local ethics committee or institutional review board at each center approved the study protocol, and all subjects gave their informed written consent to participate.

Subjects were evaluated for eligibility at the screening visit. During the 4-week, single-blind, placebo run-in period, subjects were assessed for suitability for randomization. Eligible subjects were randomly assigned in a 2:1 ratio to receive twice-daily oral treatment with either cilomilast, 15 mg (GlaxoSmithKline; Research Triangle Park, NC), or placebo during a 24-week double-blind phase. Study medication was administered after a meal in the morning and in the evening.

The short-acting ß2-agonist albuterol, which was administered via a metered-dose inhaler, was supplied for the relief of acute respiratory symptoms. The only other permitted medications for the treatment of airways disease were stable doses of ipratropium, via a metered-dose inhaler, and mucolytic agents. No combination products (eg, anticholinergic/ß2-agonist combination inhalers) were allowed to be used during the study, and therapy with all other respiratory medicines was stopped either before the first study visit or at the first study visit.

Subjects attended the clinic every 2 weeks from the screening visit (week 4) up to week 4, and then at 4-week intervals. A final follow-up visit occurred at week 25. The primary variables of interest were changes from baseline in respiratory function (FEV1) and total score for the St. George’s Respiratory Questionnaire (SGRQ) averaged > 24 weeks. The SGRQ provides a disease-specific measure of health status. Secondary efficacy parameters consisted of FVC at the trough, the incidence rate of COPD exacerbations, 6-min walk distance, postexercise dyspnea, and summary symptom scores.

Subjects
Male and female subjects aged 40 to 80 years with a clinical diagnosis of COPD, as defined by the American Thoracic Society, were eligible to participate in the study.27 Subjects had to be current or ex-smokers with a cigarette smoking history of ≥ 10 pack-years and to be in stable condition with COPD. Lung function criteria for hospital admission were defined as a postbronchodilator FEV1 of ≥ 30% and ≤ 70% of the predicted normal value, and a ratio of the prebronchodilator FEV1 to the FVC of 70%. Subjects also had to have fixed airways disease (ie, an increase in FEV1 of ≤ 15% or ≤ 200 mL 15 to 30 min after the administration of 180 µg of albuterol). Subjects with active tuberculosis, lung cancer, or clinically overt bronchiectasis were excluded. Additionally, subjects with clinically significant cardiovascular, neurologic, renal, endocrine, GI, hepatic, or hematologic abnormalities that were uncontrolled with permitted therapy were not eligible for inclusion in the study.

Subjects with poorly controlled COPD, or those requiring corticosteroids, antibiotics, or other interventions for the treatment of an exacerbation during the 4-week run-in period were withdrawn from the study prior to randomization. Randomization criteria included stability of pulmonary function, which was defined as a variability in FEV1 between the first and last run-in visit of not more than 20% of the absolute trough pre-albuterol administration measurement. Other randomization criteria included medication compliance of 80 to 120% between visits and diary compliance of at least 20 days during the run-in period. Additionally, the required minimum combined symptom score for cough, sputum production, and breathlessness was ≥ 3 (of 10) on at least 5 of the 10 days immediately before the baseline visit (week 0).

The following agents were not permitted throughout the study: corticosteroids (inhaled or oral); xanthines; inhaled cromolyn sodium or nedocromil; inhaled long-acting ß2-agonists; inhaled short-acting ß2-agonists (other than albuterol); oral or nebulized ß2-agonists; nebulized anticholinergic agents; long-term oxygen therapy; or nocturnal positive-pressure therapy for sleep apnea. However, for the short-term management of COPD exacerbations, antibiotics and/or the above medications, with the exception of xanthines, were permitted.

Study Procedures
At the screening visit, subjects gave a full medical, surgical, and pulmonary history. Subjects were assessed for history of COPD exacerbations, and any prohibited respiratory medications were discontinued. Vital signs were recorded, and blood and urine specimens were taken for routine hematology and biochemistry testing, and urinalysis. Chest radiographs were taken if they had not been obtained within the previous 12 weeks. At all visits during the double-blind study period, subjects were assessed for compliance with the medication as well as for use of concomitant medications. Investigators specifically questioned study participants at each study visit regarding the occurrence of adverse events. Adverse experiences were recorded, and subjects were examined for exacerbations of COPD. Exacerbations were evaluated as subjective or objective reports based on health-care utilization. Subjective reports of exacerbation were those that were managed by increasing the usual COPD medication (level 1). Objective reports of exacerbations were those that required additional treatment prescribed by a physician or as a result of a hospital outpatient visit, including a visit to the emergency department (level 2) or hospitalization (level 3).28

Respiratory Assessments
Subjects were asked to refrain from taking any respiratory medication or smoking for at least 2 h before each clinic visit. The following pulmonary function tests were performed at all visits, with the exception of week 1 during the run-in period: trough (predose) FEV1; FVC; and the peak expiratory flow rate. Centralized spirometry was used to ensure consistent and standardized data.29 All pulmonary function tests were performed using the same type of spirometer, and the data were transmitted electronically to the data management facility. At the screening visit, at baseline, and at week 24, pulmonary function was assessed before and after a standard dose of albuterol, whereas at subsequent visits only prebronchodilator assessments were made. Overall and postexercise (6-min walk) dyspnea were assessed using the modified Borg scale.30 The diffusing capacity of the lung for carbon monoxide was determined at the screening visit if it had not been assessed within the 24 weeks preceding the week 4 visit.31 Symptoms of COPD were recorded in a home diary card by subjects on a daily basis, at the end of the day.

Health Status Assessments
The SGRQ, a disease-specific health status tool, was administered at weeks 0, 12, and 24.32 The version of the SGRQ used in this study was validated for use in the United States.33 This questionnaire contains 50 items and is divided into three domains, including symptoms (distress due to respiratory symptoms), activity (physical activities that either cause or are limited by breathlessness), and impacts (social or psychological effects of the disease). The weighted SGRQ score ranges from 0 to 100, where 0 indicates least impairment in health status and 100 indicates greatest impairment in health status. A decrease in score is reflective of an improvement in health status. A 4-point change in the total score is deemed clinically meaningful.

Safety and Tolerability Assessments
Adverse experiences, vital signs, and clinical laboratory test results were recorded during the study. At each visit, investigators questioned subjects about GI adverse experiences causing the subject concern or interfering with daily activities (including eating and sleeping). These GI adverse experiences of concern were monitored until resolution.

Statistical Analysis
The co-primary efficacy assessments were the change from baseline in FEV1 and the change from baseline in total score of the SGRQ averaged over the 24 weeks of the study. Secondary efficacy parameters included clinic FVC at trough, the rate of COPD exacerbations, postexercise dyspnea, 6-min walk distance, and summary symptom scores. All continuous measures were analyzed using a repeated-measures model with fixed effects for time, treatment, and center.34 To account for co-primary end points, the Hochberg35 method was used to adjust the significance level in the test for treatment effect.

In addition to the repeated-measures analysis described above, an analysis of variance model was performed at each protocol-defined double-blind visit as well as at the end point for all efficacy end points. The end point of treatment was defined as the last observation for a subject in the double-blind period.

Differences between groups in the time to first COPD exacerbation were assessed using the log-rank test. The exacerbation-free survival rate at 24 weeks and the associated 95% confidence intervals (CIs) were estimated for each treatment group using the Kaplan-Meier product limit method.

To assess the impact of age, sex, baseline smoking status, and percentage of predicted FEV1 on the time to first COPD exacerbation, a Cox proportional hazards model was used. The relative risk (for cilomilast vs placebo) of a COPD exacerbation and the associated 95% CI was estimated after adjusting for the effects of these covariates. Descriptive statistics were prepared for demographic and baseline characteristics, and for safety variables.

Results

Baseline Characteristics
Baseline characteristics of the placebo and treatment groups are shown in Table 1 . The two groups were generally well matched for baseline disease characteristics and demography with the exception that significantly more women were randomized to the cilomilast group. Consequently, baseline FEV1 was higher in the placebo group compared to the cilomilast group; however, when FEV1 was expressed as percentage of predicted, no differences were observed. Percentages of predicted FEV1 values were similar between treatment groups when adjusted for age and gender.


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  		Table 1.. Baseline Characteristics and Demographics*

 
There were no major differences between treatment groups in the profile of respiratory medications being used by subjects before study entry (Table 2 ). Nearly all subjects received albuterol prior to the start of the study. Approximately 55% of subjects were using ipratropium at screening and continued using it for the duration of the study. Prior to screening, 27% of subjects used inhaled corticosteroids. Approximately 10% of subjects used theophylline and approximately 10% used salmeterol prior to the start of the study.


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  		Table 2.. Respiratory Medications at Baseline*

 
Subject Disposition
A total of 937 subjects met the eligibility criteria and entered the single-blind (run-in) phase. A total of 647 subjects (69%) enrolled in the study were randomized to receive double-blind treatment. The primary reasons for the withdrawal of subjects from the study prior to randomization were the failure to meet inclusion/exclusion criteria (15.4%) and the presence of adverse events, including COPD exacerbations (8.5%). More subjects receiving cilomilast than placebo withdrew from the double-blind phase of the study (31.8% [n = 137] vs 24.1% [n = 52]). The four top reasons for study withdrawal included adverse events (cilomilast group, 22%; placebo group, 16%), protocol deviation (cilomilast group, 2%; placebo group, 1%), lost to follow-up (cilomilast group, 2%; placebo group, 3%), and insufficient therapeutic effect (cilomilast group, 2%; placebo group, 2%).

Efficacy
Primary Efficacy End Points: In subjects who had been treated with cilomilast, the trough FEV1 was maintained close to the baseline level throughout the study, whereas subjects who had been treated with placebo demonstrated a progressive decrease. The average change from baseline over 24 weeks in the cilomilast group was an increase of 10 mL, compared with a decrease of 30 mL in the placebo group. This difference in the cilomilast group over the placebo group in trough FEV1 (40 mL) was statistically significant (p = 0.002). The difference in the mean change in trough FEV1 values between the cilomilast group and the placebo group was statistically significant starting from week 8 (Fig 1 ). The mean difference between the cilomilast group and the placebo group in FEV1 increased from 50 mL at week 8 to 80 mL at week 24. End point analysis, defined as the last observation carried forward, revealed an 80-mL treatment difference favoring cilomilast-treated subjects (placebo group, –70 mL; cilomilast group, + 10 mL; p < 0.001). Similar changes were observed in FVC, which was a secondary end point in the study. When averaged over 24 weeks, there were significant differences between the two treatment groups in trough FVC (50 mL; p = 0.049). The end point analysis also revealed significant treatment differences in favor of cilomilast in trough FVC (110 mL; p = 0.001).


Figure 1
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  		Figure 1.. The mean (SEM) change from baseline in trough FEV1; p values for cilomilast vs placebo are as follows: week 2, p = 0.034; week 4, p = 0.160; week 8, p = 0.006; week 12, p < 0.001; week 16, p = 0.002; week 20, p = 0.001; week 24, p = 0.001; end point, p < 0.001.

 
A post hoc analysis to evaluate the effect of smoking status on improvements in trough FEV1 was performed. Mean improvements in trough FEV1 for current smokers who had been treated with cilomilast were not statistically significantly greater than those seen in patients treated with placebo throughout the study. In contrast, beginning at week 8 and continuing through the duration of the study, there was a statistically significant improvement in trough FEV1 for treatment with cilomilast vs that with placebo in former smokers (Fig 2 ).


Figure 2
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  		Figure 2.. The mean change from baseline in trough FEV1 by smoking status. For current smokers: cilomilast group vs placebo group, p = 0.084; for nonsmokers: cilomilast group vs placebo group, p = 0.036.

 
Serial measurements of disease-specific health status (ie, SGRQ, total score) showed a significant improvement in subjects who had been treated with cilomilast. When averaged over 24 weeks, there was a reduction in the mean total SGRQ score (a reduction in the score indicates an improvement in health status) in subjects receiving cilomilast, with a clinically meaningful difference of 4.1 U compared with subjects who received placebo (p < 0.001) [Fig 3 ].


Figure 3
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  		Figure 3.. Mean change from baseline in total score of SGRQ over 24 weeks of treatment (cilomilast group vs placebo group, p < 0.001).

 
COPD Exacerbations: At the end of 24 weeks, significantly more cilomilast-treated subjects (74%) were exacerbation-free compared with placebo-treated subjects (62%; p = 0.008) [Fig 4 ]. This analysis included all COPD exacerbations. Cilomilast administration was accompanied by a significant reduction (39%) in the risk of experiencing an exacerbation of COPD compared with placebo administration (95% CI, 17 to 55%; p = 0.002), adjusting for percentage of predicted FEV1, sex, and smoking status, and all risk factors for first exacerbation. In subjects experiencing more severe exacerbations (level 2/3), the risk was significantly reduced by 45% in subjects receiving cilomilast relative to those receiving placebo (95% CI, 22 to 61%; p = 0.001). More placebo-treated subjects withdrew from the study due to COPD exacerbations compared with cilomilast-treated subjects.


Figure 4
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  		Figure 4.. Kaplan-Meier estimates of exacerbation-free survival over 24 weeks of treatment at all levels (cilomilast group vs placebo group, p = 0.008).

 
Dyspnea: Cilomilast-treated subjects experienced statistically significant improvements in dyspnea after standardized exercise testing (6-min walk distance). When averaged over 24 weeks, the postexercise dyspnea score in the cilomilast treatment group decreased by 0.17 U, and in the placebo group it increased by 0.07, which was a statistically significant difference of 0.24 (p = 0.029). There were no significant differences in the 6-min walk distance and the summary of symptom scores between treatment groups.

Rescue Albuterol Use: More than 98% of subjects in both treatment groups used albuterol before the study, and this remained unchanged through the course of the study. At baseline, the mean use of rescue albuterol was similar between groups, with 3.56 puffs and 3.63 puffs of albuterol per day, respectively, for the placebo and cilomilast groups. During the 24-week study, rescue albuterol use increased by 0.24 puffs and 0.09 puffs per day, respectively, for placebo and cilomilast.

Safety and Tolerability
Overall, the percentage of adverse events leading to study withdrawal were similar between treatment groups (placebo group, 16%; cilomilast group, 22%). Similar proportions of subjects in each treatment group experienced at least one adverse event during the 24-week study (cilomilast group, 87%; placebo group, 82%). More subjects receiving placebo than those receiving cilomilast reported adverse events associated with the respiratory system (52% vs 38%, respectively).

A higher proportion of subjects receiving cilomilast (49%) experienced GI adverse events (eg, diarrhea, nausea, and abdominal pain) compared with those receiving placebo (25%), but there was a higher proportion of serious GI adverse events in patients treated with placebo (1.9%) than in those treated with cilomilast (0.2%). The majority of the events were mild to moderate in intensity. GI events interfering with daily activities, including eating and sleeping, were reported more frequently with cilomilast administration than with placebo administration (17% vs 8%, respectively; Table 3 ). The time of initial onset for the majority of GI events that interfered with daily activities in subjects who received cilomilast was in the first 3 weeks of therapy. In contrast, there was a gradual increase in incidence over the course of the treatment period in subjects who received placebo.


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  		Table 3.. GI Adverse Events Interfering With Daily Activities*

 
Two subjects, one from each group, died during the study period. Both deaths were related to cardiovascular disease and were considered unrelated to study treatment.

Laboratory Safety and Vital Signs: There were no clinically relevant differences observed between treatment groups during cardiovascular monitoring of ECG assessments, sitting, or orthostatic vital signs. The mean changes from baseline in clinical laboratory parameters were small and were comparable between the treatment groups. The laboratory parameters assessed included blood samples for hematology and clinical chemistry testing, and urinalysis, and pregnancy testing for women.

Discussion

This was the first large, well-controlled study evaluating cilomilast, a novel PDE-4 inhibitor, in subjects with COPD. This 24-week study corroborated the improvements in lung function and health status that had been observed in a 6-week dose-ranging study.26

In cilomilast-treated subjects, the trough FEV1 was maintained throughout the 24-week treatment period, whereas subjects who had been treated with placebo demonstrated a progressive decrease. In a population of COPD subjects whose conditions were poorly reversible with albuterol therapy (ie, an increase in FEV1 of 15% of predicted or 200 mL), a difference from the placebo group of 40 mL (p = 0.002) was observed for the average change from baseline over 24 weeks. A difference between treatment groups of 80 mL (p < 0.001) was observed at the end point. Similar changes from placebo were observed in FVC (average over 24 weeks, 50 mL [p = 0.049]; at the end point, 110 mL [p = 0.001]).

Exacerbations are major determinants of morbidity in COPD patients.36 In addition to characteristic increases in dyspnea, sputum production, and cough, exacerbations lead to temporary or permanent decreases in health-related quality of life and result in increased health-care utilization, totaling $18 billion annually in costs for physician’s office visits and hospitalizations.37 In this study, treatment with cilomilast produced clinically important and statistically significant differences from treatment with placebo in disease-specific health status (ie, SGRQ, total score) and significantly reduced the risk of experiencing a COPD exacerbation. When averaged over 24 weeks, a mean difference from the placebo group of 4.1 U (p = 0.001) in the SGRQ total score was observed. Cilomilast administration resulted in a 39% reduction in the risk of experiencing any COPD exacerbation (95% CI, 17 to 55%; p = 0.002) and in a 45% reduction in more severe COPD exacerbations (ie, level 2/3) [95% CI, 22 to 61%; p = 0.001] compared with placebo administration.

The clinical development of nonspecific PDE inhibitors (eg, theophylline) and first-generation selective PDE-4 inhibitors (eg, rolipram) has been limited by the occurrence of adverse effects, especially in the GI system. Cilomilast is a second-generation PDE-4 inhibitor that has been designed to retain the therapeutic activity of the first-generation compounds but with a reduced propensity to elicit GI effects. In the current study, cilomilast was generally well-tolerated, with approximately 9% of subjects withdrawing from therapy due to GI adverse events. The majority of these GI events occurred early after the initiation of treatment (ie, within the first 3 weeks).

The goals of COPD management include the prevention of disease progression, relief of symptoms, improvement in exercise tolerance, improvement in health status, prevention and treatment of complications and exacerbations, reduction in mortality, and reduction in side effects from treatment.34 The first-line therapy to achieve these goals is bronchodilator therapy.34 Inhaled glucocorticoids can reduce exacerbation frequency12383940 and should be considered in patients who have frequent exacerbations. Exacerbations have an adverse effect on health status, and inhaled glucocorticoids improve health status over time, likely by reducing the number of exacerbations. Tiotropium, a long-acting anticholinergic agent, also reduces exacerbation frequency.941 Currently available medications have not been shown to alter the natural history of the disease.

The current study demonstrated that cilomilast also achieved many of the goals for the management of COPD patients including improvement in health status and reduction in the risk of exacerbation. The mechanisms by which cilomilast achieved these effects are unclear. However, cilomilast is unlikely to be acting directly as a bronchodilator since PDE-4 is not prominent in airway smooth muscle. An antiinflammatory effect of cilomilast is a possible mechanism. Cilomilast reduced inflammatory cells within the airway wall in patients who had been evaluated by endobronchial biopsy.25 Consistent with this, PDE-4 is present in many inflammatory cells, and a series of in vitro studies have demonstrated the antiinflammatory actions of cilomilast.18192021222324 In vitro studies4243 have also demonstrated that cilomilast can inhibit fibroblast recruitment and the contraction of the extracellular matrix. Thus, while further studies are needed, cilomilast may also reduce fibrotic scarring that contributes to the progressive loss of function in patients with COPD.44

No therapeutic intervention other than smoking cessation has been demonstrated to slow the rate of decline of lung function in COPD patients.45 Inhaled glucocorticoids have been assessed in four large trials,12131415 and none achieved a statistically significant reduction in the decline of lung function. A meta-analysis16 has been performed on these data sets, and the results suggested that an effect may have been present. The suggestion has been made that the inclusion of current smokers in the trials of inhaled glucocorticoids may have masked a beneficial effect of treatment. In COPD, smoking is thought to initiate the inflammatory response. Once the disease becomes established, however, inflammation may persist despite smoking cessation.46 The current study was not designed to selectively evaluate smokers vs nonsmokers. Nevertheless, a post hoc analysis demonstrated a greater effect of cilomilast among former smokers. This observation suggests that therapeutic intervention may be able to modify the inflammatory response in COPD patients, particularly if the stimulus of smoke exposure has been removed.

In summary, the present study demonstrated the clinical effectiveness of cilomilast in a group of subjects with poorly reversible COPD. Cilomilast therapy maintained pulmonary function, improved health status, and reduced the rate of exacerbations of COPD during the study period. Although a minority of subjects discontinued therapy due to GI side effects, GI effects that interfered with daily activities occurred within the first 3 weeks of initiating therapy and were considered self-limiting in approximately half of these subjects. No unanticipated drug-related toxicities were observed. To the extent that these findings are confirmed in future studies, they suggest that cilomilast may provide clinical benefits for the management of individuals with COPD. Future studies should (1) confirm the cellular mechanisms of actions of cilomilast in patients with COPD, (2) further explore the physiologic effects of the drug on small airway function and pulmonary hyperinflation, (3) evaluate the possibility that the administration of cilomilast reduces the rate of decline of pulmonary function in patients with COPD, and (4) investigate the use of cilomilast in combination with other medications.

Appendix

Participating Investigators
R. Abboud, MD, Vancouver, BC; J. Allison, MD, Columbia, SC; S. Amill-Acosta, MD, San Juan, PR; N. Anthonisen, MD, Winnipeg, MB; W. Bailey, MD, Birmingham, AL; M. Baltzan, MD, Cote St. Luc, PQ; V. Bandi, MD, Houston, TX; E. Bleecker, MD, Winston-Salem, NC; H. Blumberg, MD, St. Petersburg, FL; B. Bowlind, MD, Endwell, NY; T. Bruya, MD, Spokane, WA; W. Calhoun, MD, Pittsburgh, PA; F. Candal, MD, Slidell, LA; M. Castro, MD, St. Louis, MO; K. Chapman, MD, Toronto, ON; S. Chodosh, MD, Boston, MA; M. Clark, MD, Austin, TX; P. Costantini, MD, Linwood, NJ; P. Creticos, MD, Baltimore, MD; P. Dandona, MD, Buffalo, NY; D. Daniel, MD, Wenatchee, WA; A. DeGraff, Jr., MD, Hartford, CT; J. Donohue, MD, Chapel Hill, NC; A. D’Urzo, MD, Toronto, ON; D. Dvorin, MD, Forked River, NJ; P. Economou, MD, Albequerque, NM; P. Emrie, MD, Wheat Ridge, CO; S. Field, MD, Calgary, AB; J. Fish, MD, Philadelphia, PA; J. Fitzgerald, MD, Dallas, TX; J. Flescher, MD, Raleigh, NC; C. Fogarty, MD, Spartanburg, SC; E. Frost, MD, Greer, SC; G. Giessel, MD, Richmond, VA; R. Gilman, MD, East Providence, RI; R. Gower, MD, Spokane, WA; J. Green, MD, Martinez, CA; J. Grossman, MD, Tucson, AZ; D. Henninger, MD, Murrieta, CA; V. Hoffstein, MD, Toronto, ON; J. Hyman, MD, Northfield, NJ. E. Israel, MD, Boston, MA; A. Jain, MD, Slidell, LA; W. Jannetti, MD, Buena Park, CA; J. Jayne, MD, Absecon, NJ; L. Johnson, MD, West Chester, PA; H. Kaiser, MD, Minneapolis, MN; St. Kauffman, DO, Feasterville, PA; M. Kaye, MD, Minneapolis, MN; S. Kelsen, MD, Philadelphia, PA; G. Kinasewitz, MD, OK, OK; B. Levine, MD, Phoenix, AZ; R. Lipetz, MD, Spring Valley, CA; F. Liu, MD, Richmond Hill, ON; F. Maggiacomo, DO, Cranston, RI; F. Maltais, MD, Ste-Foy, PQ; S. Manaker, MD, Philadelphia, PA; C. Marchini, MD, Grants Pass, OR; A. Martin, MD, New Brunswick, NJ; R. Martinez, MD, Calzada De Tlalpan, Mexico; W. McBride, MD, Wenatchee, WA; J. McFeely, MD, Berkeley, CA; A. McIvor, MD, Halifax, NS; D. Meyer, MD, Carmichael, CA; B. Michlin, MD, San Diego, CA; D. Mishkin, MD, Pikesville, MD; B. Miskin, MD, West Palm Beach, FL; P. Montner, MD, Albuquerque, NM; J. Morelli, MD, Stoneboro, PA; M. Mullarkey, MD, Seattle, WA; A. Nayak, MD, Bloomington, IN; J. Neutel, MD, Orange, CA; T. O’Barr, MD, Marietta, GA; R. Ovetsky, MD, Atlanta, GA; A. Patel, MD, Corona, CA; P. Patel, MD, Mississauga, ON; H. Patrick, MD, Philadelphia, PA; D. Paulson, MD, Richmond, VA; J. Pinto, MD, Las Vegas, NV; J. Quigley, DO, Encinitas, CA; J. Ramsdell, MD, San Diego, CA; L. Rossoff, MD, New Hyde Park, NY; S. Ruoss, MD, Stanford, CA; G. San Pedro, MD, Shreveport, LA; E. Schenkel, MD, Easton, PA; E. Schroeder, MD, Olathe, KS; J. Schul, MD, Richmond, VA; G. Scott, MD, Charleston, SC; N. Segall, MD, Atlanta, GA; P. Shapero, MD, Bangor, ME; S. Simon, MD, Austell, GA; H. Smith, MD, Boulder, CO; L. Smith, MD, Chicago, IL; T. Smith, MD, KS City, MO; J. Sokolowski, Jr., MD, Cherry Hill, NJ; S. Spector, MD, Los Angeles, CA; W. Spisak, MD, Portland, OR; I Tam, MD, West Chester, PA; J. Taylor, MD, Tacoma, WA; P. Thomas, MD, Toronto, ON; R. Tidman, MD, Blue Ridge, GA; R. Valay, MD, Madero, Mexico; T. Verdegem, MD, Covina, CA; B. Winston, MD, Houston, TX; J. Wolfe, MD, San Jose, CA; B. Yang, MD, Ottawa, ON; B. Yergin, MD, Jacksonville, FL.

Acknowledgements

We thank Kate Knobil, Colin Reisner, and Jin Zhu for assistance with analyzing and interpreting the data in this study. We would also like to thank Kim Poinsett-Holmes and Christy Brown for their assistance with manuscript preparation.

Footnotes

Abbreviations: CI = confidence interval; PDE = phosphodiesterase; SGRQ = St. George’s Respiratory Questionnaire

Dr. Rennard is a member of the speaker’s bureau and a consultant for GlaxoSmithKline, and has received research grants from GlaxoSmithKline. He is a member of the speaker’s bureau, serves as a consultant or has received research grants from Centocor, Novartis, Pfizer, Sanofi, Schering-Plough, Altana, and AstraZeneca. Dr. Schachter is a member of the speaker’s bureau for GlaxoSmithKline, Boehringer Ingleheim, and Novartis, and has received research grants from GlaxoSmithKline. Dr. Strek has received research grants from GlaxoSmithKline. Dr. Rickard and Dr. Amit are employees of GlaxoSmithKline.

This study was funded by a grant from GlaxoSmithKline.

Received for publication February 17, 2004. Accepted for publication June 1, 2005.

References

  1. Fletcher, CM, Peto, R, Tinker, CM, et al (1976) The natural history of chronic bronchitis and emphysema. Oxford University Press. Oxford, UK:
  2. Anderson, RN, Smith, BL Deaths: leading causes for 2002. Natl Vital Stat Rep 2005;53,17
  3. Celli, B, MacNee, W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23,932-946[Free Full Text]
  4. Pauwels, RA, Buist, AS, Calverley, PMA, et al Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163,1256-1276[Free Full Text]
  5. Mahler, DA, Donahue, JF, Barbee, RA, et al Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999;115,957-965[CrossRef][ISI][Medline]
  6. Rennard, SI, Anderson, W, ZuWallack, R, et al Use of a long-acting inhaled ß2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163,1087-1092[Abstract/Free Full Text]
  7. Rennard, SI, Serby, CW, Ghafouri, M, et al Extended therapy with ipratropium is associated with improved lung function in patients with COPD: a retrospective analysis of data from seven clinical trials. Chest 1996;110,62-70[CrossRef][Medline]
  8. COMBIVENT Inhalation Aerosol Study Group.. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. Chest 1994;105,1411-1419[CrossRef][ISI][Medline]
  9. Casaburi, R, Mahler, DA, Jones, PW, et al A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J 2002;19,217-224[Abstract/Free Full Text]
  10. Van Noord, JA, Bantje, ThA, Elland, ME, et al A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax 2000;55,289-294[Abstract/Free Full Text]
  11. Casaburi, R, Briggs, D, Donohue, JF, et al The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. Chest 2000;118,1294-1302[Medline]
  12. Burge, PS, Calverley, PMA, Jones, PW, et al Randomised, double-blind, placebo-controlled study of fluticasone propionate in subjects with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320,1297-1303[Abstract/Free Full Text]
  13. Lung Health Study Research Group.. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000;343,1902-1909[Abstract/Free Full Text]
  14. Pauwels, RA, Lofdahl, C-G, Laitinen, LA, et al Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999;340,1948-1953[Abstract/Free Full Text]
  15. Vestbo, J, Sorensen, T, Lange, P, et al Long-term effect of inhaled budesonide in mild to moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999;353,1819-1823[CrossRef][ISI][Medline]
  16. Sutherland, ER, Allmers, H, Ayas, NT, et al Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax 2003;58,937-941[Abstract/Free Full Text]
  17. Torphy, TJ Phosphodiesterase isoenzymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998;157,351-370[ISI][Medline]
  18. Au, B-T, Teixeira, MM, Collins, PD, et al Effect of PDE4 inhibitors on zymosan-induced AL-8 release from human neutrophils: synergism with prostaglandins and salbutamol. Br J Pharmacol 1998;123,1260-1267[CrossRef][ISI]
  19. Wooley, ST, Weyman-Jones, C, Young, A A comparison of the effect of PDE4 inhibitors on neutrophilia and cytokine expression in a murine model of LPS-induced lung inflammation [abstract]. Eur Respir J 2000;16(suppl),539S
  20. Barnette, MS, Christensen, SB, Essayan, DM, et al SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. J Pharmacol Exp Ther 1998;284,420-426[Abstract/Free Full Text]
  21. Liu, Q, Fujimura, M, Tachibana, H, et al Effect of a selective PDE4 inhibitor, SB207499, on airway cough hypersensitivity induced by allergic eosinophilic bronchitis [abstract]. Eur Respir J 2000;16(suppl),539S
  22. Griswold, DE, Martin, LD, Torphy, TJ Ariflo (SB207499) is a potent inhibitor of leukotriene B4-induced mobilization of neutrophils in rabbits [abstract]. Am J Respir Crit Care Med 1999;160,A90
  23. Ammitt, AJ, Hoffman, RK, Amrani, Y, et al Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by cyclic adenosine monophosphate. Am J Respir Cell Mol Biol 2000;6,794-802
  24. Torphy, TJ, Barnette, MS, Underwood, DC, et al Ariflo (SB207499), a second generation phosphodiesterase inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulm Pharmacol Ther 1999;12,131-135[CrossRef][ISI][Medline]
  25. Gamble, E, Grootendorst, DC, Brightling, CE, et al Antiinflammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ariflo) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168,976-982[Abstract/Free Full Text]
  26. Compton, CH, Gubb, J, Nieman, R, et al Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomized, dose-ranging study. Lancet 2001;358,265-270[CrossRef][ISI][Medline]
  27. American Thoracic Society.. Standards for the diagnosis and care of subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152,S77-S121
  28. Rodriguez-Roisin, R Toward a consensus definition for COPD exacerbations. Chest 2000;117(suppl),398S-401S[CrossRef][ISI][Medline]
  29. American Thoracic Society.. Standardization of spirometry. Am J Crit Care Med 1995;152,1107-1136[ISI][Medline]
  30. Borg, G Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982;14,377-381
  31. American Thoracic Society.. Single-breath carbon monoxide diffusing capacity (transfer factor): recommendations for a standard technique; 1995 update. Am J Respir Crit Care Med 1995;152,2185-2198[ISI][Medline]
  32. Jones, PW, Quirk, FH, Baveystock, CM The St George’s Respiratory Questionnaire. Respir Med 1991;85(suppl),25-31[CrossRef][ISI][Medline]
  33. Barr, JT, Schumacher, GE, Freeman, S, et al American translation, modification, and validation of the St. George’s Respiratory Questionnaire. Clin Ther 2000;22,1121-1145[CrossRef][ISI][Medline]
  34. Jennrich, RI, Schlucter, MD Unbalanced repeated-measures models with structured covariance matrices. Biometrics 1986;42,805-820[CrossRef][ISI][Medline]
  35. Hochberg, Y A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75,800-802[Abstract/Free Full Text]
  36. Miravitlles, M, Murio, C, Guerrero, T, et al Pharmacoeconomic evaluation of acute exacerbations of chronic bronchitis and COPD. Chest 2002;121,1449-1455[CrossRef][ISI][Medline]
  37. Snow, V, Lascher, S, Mottur-Pilson, C Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2001;134,595-599[Free Full Text]
  38. Calverley, P, Pauwels, R, Vestbo, J, et al Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361,449-456[CrossRef][ISI][Medline]
  39. Calverley, PM, Boonsawat, W, Cseke, Z, et al Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22,912-919[Abstract/Free Full Text]
  40. Szafranski, W, Cukier, A, Ramirez, A, et al Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Repir J 2003;21,74-81
  41. Vincken, W, van Noord, JA, Greefhorst, AP, et al Dutch/Belgian Tiotropium Stugy Group: improved health outcomes in patients with COPD during 1 yr’s treatment with tiotropium. Eur Respir J 2002;19,209-216[Abstract/Free Full Text]
  42. Kohyama, T, Liu, X, Wen, F-Q, et al Cytokines modulate cilomilast response in lung fibroblasts. Clin Immunol 2004;111,297-302[CrossRef][ISI][Medline]
  43. Kohyama, T, Liu, X, Wen, F-Q, et al PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of naïve collagen gels. Am J Respir Cell Mol Biol 2002;26,694-701[Abstract/Free Full Text]
  44. Hogg, JC, Chu, F, Utokaparch, S, et al The nature of small airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350,2645-2653[Abstract/Free Full Text]
  45. Anthonisen, NR, Connett, JE, Murray, RP Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002;166,675-679[Abstract/Free Full Text]
  46. Rutgers, SR, Postma, DS, ten Hacken, NH, et al Ongoing airway inflammation in patients with COPD who do not currently smoke. Thorax 2000;55,12-18[Abstract/Free Full Text]



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