Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease

Peter M. A. Calverley1, Fernando Sanchez-Toril2, Andrew McIvor3, Peter Teichmann4, Dirk Bredenbroeker4, and Leonardo M. Fabbri5
Division of Infection and Immunity, Department of Medicine, Clinical Sciences, University Hospital Aintree, Liverpool, United Kingdom; Hospital Arnau de Vilanova, Valencia, Spain; 3Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; 4Altana Pharma AG, The Nycomed Group, Konstanz, Germany; and 5Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy
2 1

Rationale: The oral phosphodiesterase-4 (PDE4) inhibitor, roflumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown. Objectives: To determine whether roflumilast improves lung function and decreases exacerbation frequency over 1 year in patients with stable COPD. Methods: We conducted a randomized, placebo-controlled, doubleblind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 g roflumilast and 753 receiving placebo once daily. Measurements and Main Results: We recorded post-bronchodilator FEV1, exacerbation rate, St. Georges Respiratory Questionnaire total score at the study end point, and number and type of reported adverse events during treatment. Post-bronchodilator FEV1 increased by 39 ml with roflumilast compared with placebo by 52 weeks (p 0.001). The mean exacerbation rate was low and comparable in both treatment groups (0.86 vs. 0.92 exacerbations/patient/yr for roflumilast and placebo, respectively). In a retrospective analysis, the exacerbation rate in patients in GOLD stage IV disease was 36% lower in patients treated with roflumilast than in those treated with placebo (1.01 vs. 1.59 exacerbations/patient/year, respectively; p 0.024). The St. Georges Respiratory Questionnaire total score did not differ between treatments. The commonest adverse events related to roflumilast treatment were diarrhea, nausea, and headache, which usually subsided during continued treatment. However, roflumilast resulted in more withdrawals within the first 3 to 4 weeks of administration. Conclusions: In severe, stable COPD, PDE4 inhibition with roflumilast produced a modest but significant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roflumilast. Keywords: antiinflammatory; chronic obstructive pulmonary disease; exacerbations; lung function; phosphodiesterase-4 inhibitor

AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject

The oral phosphodiesterase-4 (PDE4) inhibitor, roumilast, can improve lung function in moderate chronic obstructive pulmonary disease (COPD). Whether treatment is effective in more severe COPD (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) over a longer period is unknown.
What This Study Adds to the Field

In severe, stable COPD, PDE4 inhibition with roumilast produced a modest but signicant improvement in lung function without changing the exacerbation rate or health status. However, patients with very severe disease experienced fewer exacerbations with roumilast.

Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality worldwide (13). It is characterized by persistent pulmonary inammation, which leads to air-

(Received in original form August 21, 2006; accepted in final form April 24, 2007 ) Supported by Altana Pharma, AG. Correspondence and requests for reprints should be addressed to Peter M.A. Calverley, M.D., Aintree Chest Centre, Fazakerley Hospital, Longmoor Lane, Liverpool L97AL, UK. E-mail: pmacal@liverpool.ac.uk This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 176. pp 154161, 2007 Originally Published in Press as DOI: 10.1164/rccm.200610-1563OC on April 26, 2007 Internet address: www.atsjournals.org

ow obstruction that intermittently exacerbates and contributes to the patients impaired quality of life (4). Unlike the situation in bronchial asthma, antiinammatory therapy with inhaled corticosteroids has been relatively disappointing in COPD. Although they improve lung function and reduce exacerbation frequency, particularly in severe and very severe COPD (57), their overall effect on patients with COPD is modest, and they do not modify the progression of the disease, as reected by the rate of decline in FEV1 (8). This has led to the search for alternative antiinammatory agents suitable for use in stable COPD. Phosphodiesterase-4 (PDE4) inhibitors potentially offer an orally active alternative to inhaled corticosteroids in COPD. They have been shown to have antiinammatory properties in animal models and can reduce airway inammation in airway wall biopsies and induced sputum in stable COPD (9, 10). A 6-month study of 1,413 patients with moderate to severe COPD (mean post-bronchodilator FEV1 54% predicted) found that the PDE4 inhibitor, roumilast, improved FEV1 by 97 ml and reduced exacerbations dened by increased use of rescue therapy (11). However, it is not known whether these improvements in lung function are maintained, or if they translate into clinically important outcomes, such as fewer health caredened exacerbations or better patient well being. We hypothesized that the improvement in lung function and reduction in exacerbations would persist over 1 year of treatment, and that this would be seen in patients with more severe disease (GOLD [Global Initiative for Chronic Obstructive Lung Disease] stages III and IV) (12) than had been studied previously. To test this hypothesis, we have conducted a prospective, double-blind, randomized, controlled trial comparing 500 g

Calverley, Sanchez-Toril, McIvor, et al.: Oral PDE4 Inhibition with Roflumilast in Severe COPD

155

roumilast once daily with placebo therapy during usual care in patients with more severe COPD than has been reported previously. Preliminary findings from this study have been presented at scientic meetings (1316).

METHODS
Patients
We recruited patients meeting the GOLD diagnostic criteria for COPD (12). All were at least 40 years old, current or ex-smokers (no tobacco 1 yr) with a smoking history of at least 10 pack-years, had a postbronchodilator FEV1 of 50% predicted or less, a post-bronchodilator FEV1:FVC ratio of 0.70 or less, FEV1 reversibility of 15% or less and/ or 200 ml or less after 200 g inhaled salbutamol, and were clinically stable with unchanged COPD treatment (e.g., no exacerbation or lower respiratory tract infection) for 4 weeks before the run-in period. Exclusion criteria included a history of asthma or other relevant lung diseases (e.g., lung cancer, bronchiectasis), the need for long-term oxygen therapy, known 1-antitrypsin deciency, or any clinically signicant cardiopulmonary comorbidity. For complete entry and exclusion criteria, see the online supplement. Study approval was obtained from ethics committees for each of the study centers, and all patients provided written, informed consent.

Health-related quality of life was assessed at Week 2 of run-in, baseline, and Weeks 12, 28, 36, 44, and 52 postrandomization using the disease-specic self-administered SGRQ (20). Adverse events were specically monitored at each study visit and were identied as being treatment related by the investigator and/or by frequency in the study population. Serious adverse events were dened as those that resulted in death, were life threatening, required inpatient hospitalizations or prolongation of hospitalizations, or resulted in persistent or signicant disability. At entry and trial completion, 12-lead electrocardiography, blood pressure measurement, and physical examination were performed. Routine biochemistry and hematology testing were done at study entry, and at Weeks 28 and 52 of the treatment period.

Statistical Analysis
Efcacy data were analyzed by intention to treat in randomized patients receiving at least one dose of study medication. The study was powered so that 550 patients per group gave a 91% chance of detecting a difference of 50 ml in FEV1 between treatments (assuming a common SD of 250 ml). At the same time, we estimated that the study was also powered with a 91% chance of detecting a 20% reduction in exacerbation rate, assuming from previous studies a mean of one exacerbation per patient per year in the placebo group. Both the difference in FEV1 as well as the difference in exacerbation rate between roumilast and placebo treatment were designated as primary endpoints. Assuming independence of the two variables, the study had a power of at least 82% to identify a treatment difference in both variables. Differences in lung function variables and SGRQ were tested using analysis of covariance with the factors and covariates of treatment, sex, country, value at baseline, smoking status, pretreatment with inhaled corticosteroids, and age included in the model. For missing values, the last observation carried forward imputation technique was applied. For within- and between-group comparisons, the two-sided tests are reported at an level of 0.05. Results are presented as mean ( SD or SE) as appropriate, with data derived from the statistical modeling providing the adjusted means. The coprimary variable of frequency of moderate or severe exacerbations per patient per year was analyzed nonparametrically using the Wilcoxon rank sum test. To account for the effects of premature study withdrawal for any reason, the number of exacerbations for those patients was annualized considering their study duration. In addition, a predened analysis of exacerbation frequency was performed using a Poisson regression model, with the covariates of treatment, age, sex, smoking status, country, and pretreatment with inhaled corticosteroids to estimate the rate ratio. The natural logarithm of the duration, expressed as years in the study, was used as an offset variable to correct for differences in the time individuals spent under observation. Rate ratios from this model are expressed as percent reductions. Prespecied subgroup analyses based on smoking status (current/ ex-smoker) and concomitant inhaled corticosteroid use (yes/no) were performed, as was a retrospective analysis in subgroups stratied by GOLD status (stage III/stage IV) (12). Adverse events were analyzed using descriptive statistics.

Study Design
The study was conducted between January 2003 and October 2004 in 159 centers in 14 countries. It was a 1-year, randomized, multicenter, multinational, double-blind, placebo-controlled, parallel-group study, with a 4-week, single-blind run-in period during which patients received placebo and salbutamol (as rescue medication). If they complied with study medication and were clinically stable, they were randomized (1:1) to receive either oral 500 g roumilast or an identical placebo tablet taken once daily in the morning for 52 weeks. The randomization list was generated using a multiplicative congruential pseudorandom number generator (program RANDOM, based on Fishman and Moore [17]). There was a stratication of patients according to smoking status (current smokers/ex-smokers) and treatment with inhaled corticosteroids (yes/no). Each study participant who qualied was assigned a number in sequential order. Code labeling prevented the investigator and the patient from knowing which drug was administered. Inhaled corticosteroids of 2000 g or less beclomethasone dipropionate or equivalent and short-acting anticholinergics were allowed at a constant daily dose if they were used before study entry. All patients could take salbutamol as rescue medication, but other COPD medications were stopped before the run-in. The protocol is registered on ClinicalTrials.gov (http://www.clinicaltrials.gov/; NCT00430729).

Assessments
Patients attended the clinics at recruitment, at Week 2 of run-in, at randomization ( baseline), and at Weeks 4, 8, 12, 20, 28, 36, 44, and 52. The primary efcacy variables were the change from baseline to endpoint in post-bronchodilator FEV1 and the number of moderate or severe exacerbations per patient per year. The change from baseline in St. Georges Respiratory Questionnaire (SGRQ) total score was the main secondary variable. Other efcacy variables included change from baseline in prebronchodilator FEV1, post-bronchodilator forced expiratory volume in 6 seconds (FEV6), FVC, forced expiratory ow between 25 and 75% of the vital capacity (FEF2575), and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year. Pulmonary function was measured at each visit according to American Thoracic Society standards (18) using the same model spirometer (Masterscope CT, Viasys Healthcare GmbH, Hoechberg, Germany) in each center. Measurements were made at the same time of day before and 1530 minutes after inhaling 200 g salbutamol, and were expressed relative to the European Respiratory Society predicted values (19). Throughout the study, there was independent quality control of the blinded spirometry data, with feedback to the investigators. Moderate exacerbations were dened as symptomatic deteriorations treated with systemic corticosteroids and/or antibiotics. Severe events were those requiring hospitalization.

RESULTS
Patients

The progress of patients through the study is shown in Figure 1. The demographics and baseline characteristics of the 1,513 patients in the intention to treat (ITT) population were comparable between the two treatment groups and typical of severe to very severe COPD (Table 1). Over 70% of the randomized patients completed the study (Figure 1). The reasons for withdrawal were similar between groups except for adverse events, which occurred more frequently with roumilast (odds ratio by Fishers exact test, 1.5; condence interval, 1.11.9; p 0.002) (Figures 1 and 2). Withdrawal due to COPD exacerbation was reported in 3.5 and 3.2% of patients in the roumilast and placebo groups, respectively.

156

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007

Figure 1. Trial profile. Percentages are based on the number of randomized patients in a treatment group. Note that one patient randomized to roflumilast did not take any study medication and was therefore excluded from the intention-to-treat analysis. COPD chronic obstructive pulmonary disease.

Lung Function

Health-related Quality of Life

Treatment with roumilast improved post-bronchodilator FEV1 from baseline, whereas deterioration was observed with placebo. The difference was present from 4 weeks and was maintained thereafter throughout the treatment period (Figures 3A and 3B). At the endpoint, the improvement with roumilast in postbronchodilator FEV1 from baseline compared with placebo was 39 ml (SE, 12 ml; p 0.001; Table 2). Roumilast produced similar improvements versus placebo in other lung function measurements (Figure 3C, Table 2). As expected, patients in GOLD stage IV showed a smaller improvement in post-bronchodilator FEV1 (16 ml [SE, 25 ml]) compared with GOLD stage III (42 ml [SE, 13 ml]) patients.
Exacerbations

The rate of moderate or severe exacerbations was not signicantly different in roumilast- (0.86/patient/yr) or placebo-treated patients (0.92/patient/yr) (Table 3). Exacerbations were more frequent in GOLD stage IV, with 36% fewer during roumilast treatment (roumilast, 1.01/patient/yr; placebo, 1.59/patient/yr; p 0.024; Table 3). In the whole population, the rate of exacerbations requiring treatment with systemic corticosteroids as outpatients (but not hospitalization) was signicantly lower with roumilast compared with placebo (p 0.029). For this type of exacerbations, 18% fewer episodes were reported with roumilast, as derived from the Poisson model (Table 3). The hospitalization rate due to COPD exacerbations in the study was low, the estimated rate per year being 0.08 in the roumilast group and 0.08 in the placebo group, without a difference between groups (p 0.697).

Baseline SGRQ total score was high in both groups, indicating poor health status (mean, 50.1 units [SD, 17.4 units] in the roumilast group and 49.7 units [SD, 18.2 units] in the placebo group). A decrease in total scores occurred in both groups by Week 12 (rst measured time point), and was maintained throughout the treatment period. At the end of treatment, the change in total SGRQ score was 1.7 units with roumilast and 2.0 units with placebo (both p values 0.05), with no difference between treatments (p 0.651). Overall, the number of patients with a clinically relevant benet in SGRQ (a reduction in total score of 4 units) was 295 (42.7%) of the roumilast-treated patients and 308 (43.3%) of the placebo-treated patients. In the retrospective analysis by GOLD stage, the health status at baseline was worse in patients with GOLD stage IV COPD (baseline mean total SGRQ score, 56.8 units) compared with patients with GOLD stage III (baseline mean total SGRQ score, 48.5 units). The SGRQ at Week 52 improved with roumilast by 2.97 units compared with placebo in patients in GOLD stage IV (p 0.086). In patients in GOLD stage III, there was no signicant change in SGRQ total score between treatments (roumilast, 1.1 units greater compared with placebo; p 0.140).
Subgroup Analyses

Smoking status or concomitant use of inhaled corticosteroids did not inuence the effect of roumilast on lung function, exacerbation rate, or quality of life in the population as a whole. However, in patients in GOLD stage IV, moderate or severe exacerbations were 58% fewer in patients taking roumilast

Calverley, Sanchez-Toril, McIvor, et al.: Oral PDE4 Inhibition with Roflumilast in Severe COPD TABLE 1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Characteristics No. of patients Age, yr Male sex, n (%) Body mass index, kg/m2 Smoking status Current smokers, n (%) Ex-smokers n (%) Pack-years Prebronchodilator FEV1, ml Post-bronchodilator FEV1, ml Post-bronchodilator FEV1% predicted Reversibility: change in FEV1 ml % FEV1/FVC, % Prestudy medication for COPD, n (%)* Inhaled short-acting 2-agonists Inhaled short-acting anticholinergics Inhaled corticosteroids Inhaled long-acting 2-agonists Xanthines Inhaled combination of corticosteroids and long-acting Inhaled long-acting anticholinergics Concomitant short-acting anticholinergics, n (%) Concomitant inhaled corticosteroids, n (%) Roflumilast 760 65 (9.6) 571 (75) 25 (5.0) 289 471 42 1,029 1,126 41 (38) (62) (22.9) (35) (36) (11) Placebo 753 64 (9.1) 574 (76) 26 (5.1) 265 488 45 1,047 1,145 41 (35) (65) (26.2) (34) (36) (11) Total 1,513 65 (9.3) 1,145 (76) 26 (5.1) 554 959 44 1,038 1,135 41 (37) (63) (24.6) (34) (36) (11)

157

98 (124) 11 (14) 40.3 (11.2) 415 360 363 211 213 131 39 432 472 (55) (47) (48) (28) (28) (17) (5) (57) (62)

100 (137) 11 (14) 40.7 (11.1) 405 379 364 237 201 124 30 459 471 (54) (50) (48) (32) (27) (17) (4) (61) (63)

99 (131) 11 (14) 40.5 (11.2) 820 739 727 448 414 255 69 891 943 (54) (49) (48) (30) (27) (17) (5) (59) (62)

-agonists

Definition of abbreviation: COPD chronic obstructive pulmonary disease. Data are expressed as mean (SD), unless otherwise stated. * Patients could have received more than one of these medications.

without concomitant inhaled corticosteroids (p 0.014; rate, 0.813 in roumilast [n 45] vs. 1.946 in placebo [n 30]) and 22% fewer in those taking concomitant inhaled corticosteroids (p 0.377; rate, 1.184 in roumilast [n 69] vs. 1.508 in placebo [n 82]).
Safety

During treatment, 77.9% of patients in the roumilast group and 77.6% of patients in the placebo group reported 1,997 and 1,900 adverse events, respectively. The most frequently reported adverse event was exacerbation of COPD (Table 4). The incidence of adverse events judged by the investigator to be treatment-related was 17.8% with roumilast and 5.6% with placebo. Most of the roumilast events affected the gastrointestinal tract and the nervous system. Diarrhea, nausea, and headache were the commonest treatment-related adverse events. The median duration

of adverse events was 11 and 12 days in the roumilast and placebo groups, respectively. Most events resolved with continued treatment. Nonetheless, treatment-related adverse events explained the greater number of patients withdrawing from roumilast treatment (diarrhea, 2.8% for roumilast and 0.0% for placebo; nausea, 1.6% for roumilast and 0.3% for placebo; headache, 0.7% for roumilast and 0.1% for placebo; Figure 1). Cardiac adverse events leading to discontinuation occurred more often during placebo treatment than during roumilast treatment. Serious adverse events occurred in 18.0% of roumilast- and 17.5% of placebo-treated patients. COPD exacerbation was the most frequent serious adverse event, followed by pneumonia, both having a similar incidence rate in each treatment group. More patients died during the study while receiving placebo than roumilast (20 vs. 12 patients, respectively). The most frequent

Figure 2. Time to premature withdrawal from study due to adverse event (Kaplan-Meier plot). solid line, roflumilast; dashed line, placebo.

158

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007

causes of death were respiratory disorders (1.1 vs. 0.5%, respectively), infections (0.9 vs. 0.5%, respectively), and cardiac disorders (1.1 vs. 0.1%, respectively). Physical examinations, routine laboratory tests, and electrocardiograms did not show any clinically signicant changes due to roumilast administration.

DISCUSSION
This study is the rst 1-year study of a PDE4 inhibitor in COPD, and is the rst to investigate this drug class in more advanced disease as well as on exacerbations dened by their need for treatment. Previous clinical trials in less severe COPD, over 6 months, reported a 97-ml increase in post-bronchodilator FEV1 with roumilast (11) and an approximately 40-ml increase with cilomilast (21). Our data conrm and extend these results by demonstrating that roumilast treatment provides a modest improvement in lung function in more advanced COPD over 1 year. We saw no change in the overall exacerbation frequency with roumilast treatment, but exacerbations were less common in GOLD stage IV patients during roumilast treatment. Roumilast treatment improved pre- and post-bronchodilator FEV1 to a similar degreean effect unlikely to be due to a change in airway smooth muscle tone. The improvement in FEV1 at the study endpoint was statistically signicant, but was smaller than that reported previously (11), possibly reecting the lower baseline mean FEV1 of our patients. This nding is similar to results with inhaled corticosteroids where the change in postbronchodilator FEV1 was smaller in severe compared with moderate disease (6, 22). In keeping with the FEV1 ndings, we saw consistent improvements with roumilast, when compared with placebo, in the secondary lung function indices FVC, FEV6, and FEF2575. Unlike the earlier 6-month study with roumilast (11), our patients continued previously prescribed inhaled corticosteroids, and the changes we report occurred independently of concomitant inhaled corticosteroid use, suggesting that further improvement in lung function may be possible in these patients despite their limited bronchodilator response. Similarly, the lung function improvement was independent of smoking status, which can diminish the response to corticosteroids in COPD, at least during acute treatment trials (23). We saw no signicant effect of roumilast on overall exacerbation rates (dened as episodes requiring systemic corticosteroids and/or antibiotics or the need for hospitalization). Unlike those in other trials, our patients did not need a history of previous exacerbations or of chronic bronchitis, both of which increase the likelihood of subsequent exacerbations (24), to enter the study. This may explain why the exacerbation rate in our placebo-treated patients was approximately half that seen in patients of similar spirometric severity recruited in other studies

Figure 3. Change from baseline in (A ) post-bronchodilator FEV1 over time, as (B ) placebo-adjusted change, and (C ) prebronchodilator FEV1 over time. Data are shown as least squares means. Improvements were statistically significant for roflumilast compared with placebo at all time points (*p 0.001).

TABLE 2. CHANGES IN LUNG FUNCTION

Baseline Mean (SD) Parameter Post-bronchodilator FEV1, ml Prebronchodilator FEV1, ml Post-bronchodilator FVC, ml Post-bronchodilator FEV6, ml Post-bronchodilator FEF2575%, ml/s Placebo 1,145 1,046 2,898 2,435 412 (364) (343) (853) (624) (193) Roflumilast 1,131 1,032 2,902 2,426 405 (361) (346) (878) (638) (192) Change from Baseline* Placebo 26 27 80 88 23 (11) (11) (26) (19) (7) Roflumilast 12 9 33 35 2 (11) (11) (26) (19) (7) Difference versus Placebo* 39 36 48 53 21 (12) (12) (28) (20) (7)

p Value 0.001 0.002 0.091 0.010 0.004

Definition of abbreviations: FEF2575% forced expiratory flow, midexpiratory phase; FEV6 * Data are expressed as difference in least squares means (SE). Two-sided p value for between-treatment difference; significance level, 5%.

FEV in 6 seconds.

Calverley, Sanchez-Toril, McIvor, et al.: Oral PDE4 Inhibition with Roflumilast in Severe COPD TABLE 3. ANALYSIS OF EXACERBATIONS
Rate/Patient/yr* Exacerbations Overall moderate or severe exacerbations Moderate exacerbations requiring systemic corticosteroids Moderate or severe exacerbations requiring systemic corticosteroids Moderate or severe exacerbations in patients in GOLD stage IV Roflumilast (n 760) 0.857 0.395 0.474 1.014 Placebo (n 753) 0.918 0.483 0.549 1.588 Effect Size* Rate Ratio (SE) 0.934 0.816 0.864 0.639 (0.075) (0.090) (0.090) (0.131) Difference versus Placebo (% ) 6.6 18.4 13.6 36.1

159

p Value 0.451 0.029 0.183 0.024

Definition of abbreviation: GOLD Global Initiative for Chronic Obstructive Lung Disease. * Poisson regression estimates. Two-sided p value for between-treatment difference; significance level 5% (Wilcoxon rank sum test).

(5, 25). Moreover, a signicant percentage of patients was receiving inhaled corticosteroids during the study, which could further decrease the likelihood of exacerbations (8). Roumilast signicantly reduced the number of moderate exacerbations requiring oral corticosteroids, a potential indicator of more severe events and one of the prespecied outcomes in our trial. In further exploratory analyses in patients in GOLD stage IV, where the exacerbation rate in placebo-treated patients was higher, a signicant difference in exacerbation rate was seen with roumilast treatment. This difference was primarily due to events in patients not previously treated with inhaled corticosteroids. These data emphasize the importance of apparently minor differences in trial design on the subsequent outcome, and also the need to ensure that the events of interest, in any clinical trial, occur with sufcient frequency for a therapy to modify them. The change in health status measured over 1 year using the total SGRQ score reects both the impact of the clinical trial itself and of the relatively low exacerbation rate. Baseline health status was impaired, in keeping with the initial spirometric ndings, but improved in both the placebo- and roumilast-treated patientsa change maintained during the trial. This could reect the relatively close supervision we provided during the study (11 visits over a 12-mo period), as patient healthcare contact can modify exacerbation rate and patient well being (26). Similar improvements in total SGRQ have been reported in other 1-year studies (5, 6, 25) in which the run-in phase has not involved treatment intensication. Exacerbation frequency is an important determinant of the change in health status over time (27), and the lack of difference between our groups may well reect a lack of impact on exacerbations. However, in the most severe group, in which the exacerbation rate was higher, there was a trend for roumilast to improve the SGRQ score, providing indirect conrmation that it was having a clinical effect in this subgroup of patients.

TABLE 4. PATIENTS WITH FREQUENTLY REPORTED ADVERSE EVENTS (AT LEAST 5% OF PATIENTS IN ANY TREATMENT GROUP)
No. of Patients (% of group) Characteristic Patients experiencing COPD exacerbation Diarrhea Nasopharyngitis Headache Influenza Nausea 1 adverse event Roflumilast (n 760) 592 339 71 53 47 40 38 (77.9) (44.6) (9.3) (7.0) (6.2) (5.3) (5.0) Placebo (n 753) 584 362 20 56 18 34 10 (77.6) (48.1) (2.7) (7.4) (2.4) (4.5) (1.3)

Definition of abbreviations: COPD

chronic obstructive pulmonary disease.

PDE4 inhibitors have a well described adverse event prole, and are typically associated with nausea, diarrhea, and headache (28), which have been reported for cilomilast in 11%, 9%, and 7% of patients, respectively (29). In our trial, drug-related side effects were observed mainly in the rst 4 weeks, the commonest being diarrhea (9%), nausea (5%), and headache (6%). The incidence of these side effects was similar to that in the 6-month study of 500 g of roumilast (11). Although most side effects lasted less than 4 weeks and resolved with continued treatment, they are the likeliest explanation for the excess of adverse event related dropouts in the early phase of the study. Whether changes in the treatment regime with a stepwise increase to optimum dosing would modify this pattern of side effects remains to be determined. We saw no cardiovascular toxicity with roumilast, conrming its selectivity for PDE4, unlike other drugs with PDE3-inhibiting properties that are associated with cardiovascular arrhythmias (30). Despite its size, our study still has a number of limitations. Over 1 year of roumilast treatment, maintenance of lung function could be shown, conrming previous ndings from a 6-month trial (31). One years treatment, however, is insufcient to assess the rate of decline in FEV1 accurately, and larger, longer studies with roumilast will be required to determine if this is the case. Our patients were selected, in keeping with European practice, to be poorly reversible to bronchodilator drugs, and so the magnitude of the lung function change we report is likely to be a conservative estimate of the benet in a less-restricted population. Our denition of a health carerelated exacerbation does not allow us to categorize events by their etiology, and so we do not know whether roumilast inuenced bacterial and viral exacerbation (32) to a similar degree. Finally, we do not know whether a dose titration from lower to higher doses might reduce the number of patients reporting gastrointestinal or central nervous system side effects. In summary, the PDE4 inhibitor, roumilast, produced modest but statistically signicant and sustained improvements in post-bronchodilator lung function in patients with stages III and IV COPD. These are similar in magnitude to that seen after inhaled corticosteroids alone, and may represent what can be achieved with antiinammatory therapy in COPD with currently tolerated treatments. Roumilast treatment may also reduce the frequency of exacerbations requiring systemic corticosteroids, as well as that of exacerbation rates in a subset of very severely impaired patients in whom exacerbations occur more frequently. Treatment was safe, with the majority of treatment intolerance occurring within a few weeks of instituting therapy. How treatment benets with roumilast can be integrated into current therapeutic regimens remains to be established, although a role as a stand-alone therapy in all grades of COPD severity appears unlikely, given the limited efcacy and side-effect prole. Our data suggest that further trials are needed in patients with severe

160

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007
7. van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C. Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study. Am J Respir Crit Care Med 2002;166:13581363. 8. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med 2002;113:5965. 9. Gamble E, Grootendorst DC, Brightling CE, Troy S, Qiu Y, Zhu J, Parker D, Matin D, Majumdar S, Vignola AM, et al. Antiinammatory effects of the phosphodiesterase-4 inhibitor cilomilast (Ario) in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;168:976982. 10. Grootendorst DC, Gauw SA, Sterk PJ, Bethke TD, Hospers JJ, Hiemstra PS, Rabe KF. Treatment with PDE4 inhibitor roumilast reduces sputum neutrophil and eosinophil numbers in patients with COPD [abstract]. Am J Respir Crit Care Med 2005;2:A543. 11. Rabe KF, Bateman ED, ODonnell D, Witte S, Bredenbroker D, Bethke TD. Roumilastan oral anti-inammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366:563571. 12. National Heart, Lung, and Blood Institute/World Health Organization. Global strategy for the diagnosis, management and prevention of chronic pulmonary disease (GOLD): NHLBI/WHO workshop report; Bethesda, MD: National Institutes of Health; 2005. NIH Publication No. 2701. 13. Calverley PM, Fabbri LM, Teichmann P, Bredenbroeker D. Effect of roumilast on lung function and exacerbations in patients with COPD: results of a one-year study [abstract]. Thorax 2005;60(Suppl 2):ii42. 14. Fabbri LM, Sanchez-Toril F, McIvor RA, Teichmann P, Bredenbroeker D, Calverley PM. Effect of roumilast on exacerbations: a 1-year study in patients with severe to very severe COPD. Proc Am Thorac Soc 2006;3:A841. 15. McIvor RA, Calverley PM, Sanchez-Toril F, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of roumilast on quality of life: a 1-year study in patients with severe to very severe COPD. Proc Am Thorac Soc 2006;3:A850. 16. McIvor RA, Fabbri LM, Sanchez-Toril F, Silberborth S, Rempel A, Garner C, Bredenbroeker D, Calverley PMA. Long-term effect of roumilast on exacerbations in patients with severe to very severe COPD. Eur Respir J 2006;28:526s. 17. Fishman G, Moore L. A statistical evaluation of multiplicative congruential random number generators with modulus 2E31-1. J Am Stat Assoc 1982;77:129136. 18. American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med 1995;152:11071136. 19. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory ows: Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Ofcial Statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:540. 20. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airow limitation: the St. Georges Respiratory Questionnaire. Am Rev Respir Dis 1992;145:13211327. 21. Rennard SI, Schachter N, Strek M, Rickard K, Amit O. Cilomilast for COPD: results of a 6-month, placebo-controlled study of a potent, selective inhibitor of phosphodiesterase 4. Chest 2006;129:5666. 22. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912919. 23. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001;15:11101112. 24. Burge S, Wedzicha JA. COPD exacerbations: denitions and classications. Eur Respir J Suppl 2003;41:46s53s. 25. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efcacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J 2003;21:7481. 26. Bourbeau J, Julien M, Maltais F, Rouleau M, Beaupre A, Begin R, Renzi P, Nault D, Borycki E, Schwartzman K, et al. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specic self-management intervention. Arch Intern Med 2003; 163:585591. 27. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004;23:698702.

COPD who exacerbate frequently, and in whom we have seen a potentially useful benet with this class of treatment. If treatment with roumilast is effective in this group of patients, combining it with long-acting bronchodilators may provide an acceptable alternative to systemic or inhaled therapy with corticosteroids in patients with more severe COPD.
Conflict of Interest Statement : P.M.A.C received $1,500 from Altana Pharma in advisory board fees in October 2005, $2,000 as a European Respiratory Society (ERS) symposium chair in 2006, and $1,500 as an ERS symposium speaker in 2004. He also received an honorarium of $500 in lecture fees for an American Thoracic Societysponsored evening symposium in 2004 that was supported by a grant from Altana, and has spoken at and chaired scientific meetings sponsored by Altana Pharma, which supported this study. F.S.-T received financial support from Altana as a clinical investigator in clinical trials. A.M. has participated as a speaker in scientific meetings or courses organized and financed by GlaxoSmithKline, AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer, and also participated in Canadian advisory boards for Altana, AstraZeneca, Bayer, GlaxoSmithKline, and Boehringer Ingelheim. P.T. has been an employee of Altana Pharma since March 1, 1999. D.B. has been an employee of Altana Pharma since January 7, 2000. L.M.F. received 30,000 per year from Altana in consultancy fees, 5,000 per year in advisory board fees, 3,000 per year in lecture fees, and 20,000 per year in industry-sponsored grants from 2004 to 2006. He has served on an advisory board and received fees from Altana Pharma for lectures, consulting, and advisory board meetings, and his institution received research grants from Altana Pharma. The study described has been conducted as part of the clinical drug development program of roflumilast, for which Altana Pharma AG aims for regulatory approval. Acknowledgment : The authors thank all of the investigators who recruited and treated patients at the 159 centers involved in this study: Austria: J. Grillenberger, G. Holub, W. Holler, W. Pohl, M. Sweilem, J. Wurtz, H. Zwick; Australia: H. Crawford, P. Frith, M. Holmes, M. Hurwitz, C. Jenkins, P. Middleton, C. Mitchell, M. Peters, A. Rubinfeld, A.M. Southcott, P. Thompson; Canada: M. Alexander, E. Amer, D. Dattani, T. Fera, G. Ford, J. Hebert, R. Hodder, L. Homik, F. Jardine, R. Luton, R. Maleki-Yazdi, F. Maltais, D. Marciniuk, S. Mintz, J. Muscedere, W. Ramesh, B. Ramjattan, P. Renzi, D. Small, R. Somani; France: L. Bernabeu, J.-M. Chavaillon, J.-M. Degreef, J. Dupouy, L. Fouquert, E. Fournier, J. Gonzalez, H. Jullian, H. Kafe, D. Lejay, H. Mal, J.-P. Moreau, B. Pigearias, C. Sevette, C. Verkindre, E. Weitzenblum, P. Zuck; Hungary: Z. Gyori, Z. Gonczi, T. Kecskes, K. Major, Z. Mark, K. Puha, I. Vinkler; Italy: V. Bellia, A. Ciaccia, M. Confalonieri, F. Falcone, G. Idotta, A. Potena, M. Rossi, M. Scarpitta; The Netherlands: R. Aalbers, T. Bantje, D. Cheung, J.P. Creemers, D. De Munck, S. Gans, W. Pieters, J. Prins, P. Sips, R. Stallaert, H. Timmer, C. de Graaff, J.A. van Noord; Poland: A. Bochenek, M. Czajkowska-Malinowska, E. Gross-Tyrkin, I. Grzelewska-Rzymowska, B. Kaczmarek-Czeczotka, P. Miekus, D. Nowak, M. Piepiorka, E. Trebas-Pietras, Portugal: J. Cardoso, J. de Sousa Almeida, J. Munha Fernandes, M. Rodrigues; Russia: B. Bart, Y. Belousov, A. Bezlepko, A. Chuchalin, S. Malanichev, Y. Popova, E. Shmelev, A. Sinopalnikov, A. Solomatin; South Africa: M. Abdool-Gaffar, I. Abdullah, I. Abdullah, E. Bateman, E. Irusen, J. Joubert, M. Middle, G. Naude, A.M. Nel, M. Plit, M. Prins, G. Ras, S. Visser; Spain: N. Abad Santamaria, A. Arnedillo, P. Cabrera, J. Echave-Sustaeta, F. Fuentes, J. Galdiz, E. Llorca Martinez, J. Marin-Trigo, J. Rodrguez Suarez, C. Shum Funk, B. Steen, A. Torres Marti, L. Valdes, H. Verea, P. de Lucas; Switzerland: J. Barandun, W. Bauer, J. Leuppi, H.-U. Bettschen, A. Breitenbucher, U. Honegger, M. Hacki, E. Imhof, J.-P. Ketterer, M. Tamm; United Kingdom: G. Ambepitiya, P. Anderson, G. Mc Bride, D. Dutchman, A. George, G. Gibson, J. Hamling, S. Lane, J. Langan, S. Langley, C. McKinnon, A. Millar, N. Savani, S. Stenton.

References
1. Halbert RJ, Isonaka S, George D, Iqbal A. Interpreting COPD prevalence estimates: what is the true burden of disease? Chest 2003;123: 16841692. 2. Pauwels RA, Rabe KF. Burden and clinical features of chronic obstructive pulmonary disease (COPD). Lancet 2004;364:613620. 3. Chapman KR, Mannino DM, Soriano JB, Vermeire PA, Buist AS, Thun MJ, Connell C, Jemal A, Lee TA, Miravitlles M, et al. Epidemiology and costs of chronic obstructive pulmonary disease. Eur Respir J 2006; 27:188207. 4. Calverley PM, Walker P. Chronic obstructive pulmonary disease. Lancet 2003;362:10531061. 5. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of uticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:12971303. 6. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. Combined salmeterol and uticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2003;361:449456.

Calverley, Sanchez-Toril, McIvor, et al.: Oral PDE4 Inhibition with Roflumilast in Severe COPD
28. Hebenstreit GF, Fellerer K, Fichte K, Fischer G, Geyer N, Meya U, Sastre-y-Hernandez M, Schony W, Schratzer M, Soukop W, et al. Rolipram in major depressive disorder: results of a double-blind comparative study with imipramine. Pharmacopsychiatry 1989;22: 156160. 29. Compton CH, Gubb J, Nieman R, Edelson J, Amit O, Bakst A, Ayres JG, Creemers JP, Schultze-Werninghaus G, Brambilla C, et al. Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with

161

chronic obstructive pulmonary disease: a randomised, dose-ranging study. Lancet 2001;358:265270. 30. Soto FJ, Hanania NA. Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease. Curr Opin Pulm Med 2005;11:129134. 31. Rabe KF. Roumilast for chronic obstructive pulmonary disease: authors reply. Lancet 2005;366:18451847. 32. Sapey E, Stockley RA. COPD exacerbations. 2: aetiology. Thorax 2006; 61:250258.