Published ahead of print on April 26, 2007, doi:10.1164/rccm.200610-1563OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200610-1563OC
Effect of 1-Year Treatment with Roflumilast in Severe Chronic Obstructive Pulmonary Disease1 Division of Infection and Immunity, Department of Medicine, Clinical Sciences, University Hospital Aintree, Liverpool, United Kingdom; 2 Hospital Arnau de Vilanova, Valencia, Spain; 3 Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; 4 Altana Pharma AG, The Nycomed Group, Konstanz, Germany; and 5 Department of Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy 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{at}liverpool.ac.uk
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, double-blind, parallel-group trial for 1 year. We recruited 1,513 patients (mean post-bronchodilator FEV1 41% predicted), 760 receiving oral 500 µg roflumilast and 753 receiving placebo once daily. Measurements and Main Results: We recorded post-bronchodilator FEV1, exacerbation rate, St. George's 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. George's 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.
Key Words: antiinflammatory • chronic obstructive pulmonary disease • exacerbations • lung function • phosphodiesterase-4 inhibitor
Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality worldwide (1–3). It is characterized by persistent pulmonary inflammation, which leads to airflow obstruction that intermittently exacerbates and contributes to the patient's impaired quality of life (4). Unlike the situation in bronchial asthma, antiinflammatory 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 (5–7), their overall effect on patients with COPD is modest, and they do not modify the progression of the disease, as reflected by the rate of decline in FEV1 (8). This has led to the search for alternative antiinflammatory 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 antiinflammatory properties in animal models and can reduce airway inflammation 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, roflumilast, improved FEV1 by 97 ml and reduced exacerbations defined 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 care–defined 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 µg roflumilast 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 scientific meetings (13–16).
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 post-bronchodilator 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 µg 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 deficiency, or any clinically significant 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.
Study Design Inhaled corticosteroids of 2000 µg 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 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 15–30 minutes after inhaling 200 µg 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 defined as symptomatic deteriorations treated with systemic corticosteroids and/or antibiotics. Severe events were those requiring hospitalization. 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-specific self-administered SGRQ (20). Adverse events were specifically monitored at each study visit and were identified as being treatment related by the investigator and/or by frequency in the study population. Serious adverse events were defined as those that resulted in death, were life threatening, required inpatient hospitalizations or prolongation of hospitalizations, or resulted in persistent or significant 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
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 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 predefined 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. Prespecified 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 stratified by GOLD status (stage III/stage IV) (12). Adverse events were analyzed using descriptive statistics.
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 roflumilast (odds ratio by Fisher's exact test, 1.5; confidence interval, 1.1–1.9; p = 0.002) (Figures 1 and 2). Withdrawal due to COPD exacerbation was reported in 3.5 and 3.2% of patients in the roflumilast and placebo groups, respectively.
Lung Function Treatment with roflumilast 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 roflumilast in post-bronchodilator FEV1 from baseline compared with placebo was 39 ml (SE, 12 ml; p = 0.001; Table 2). Roflumilast 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 significantly different in roflumilast- (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 roflumilast treatment (roflumilast, 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 significantly lower with roflumilast compared with placebo (p = 0.029). For this type of exacerbations, 18% fewer episodes were reported with roflumilast, 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 roflumilast group and 0.08 in the placebo group, without a difference between groups (p = 0.697).
Health-related Quality of Life Baseline SGRQ total score was high in both groups, indicating poor health status (mean, 50.1 units [SD, 17.4 units] in the roflumilast 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 (first 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 roflumilast 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 benefit in SGRQ (a reduction in total score of 4 units) was 295 (42.7%) of the roflumilast-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 roflumilast 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 significant change in SGRQ total score between treatments (roflumilast, +1.1 units greater compared with placebo; p = 0.140).
Subgroup Analyses
Safety
Nonetheless, treatment-related adverse events explained the greater number of patients withdrawing from roflumilast treatment (diarrhea, 2.8% for roflumilast and 0.0% for placebo; nausea, 1.6% for roflumilast and 0.3% for placebo; headache, 0.7% for roflumilast and 0.1% for placebo; Figure 1). Cardiac adverse events leading to discontinuation occurred more often during placebo treatment than during roflumilast treatment. Serious adverse events occurred in 18.0% of roflumilast- 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 roflumilast (20 vs. 12 patients, respectively). The most frequent 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 significant changes due to roflumilast administration.
This study is the first 1-year study of a PDE4 inhibitor in COPD, and is the first to investigate this drug class in more advanced disease as well as on exacerbations defined 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 roflumilast (11) and an approximately 40-ml increase with cilomilast (21). Our data confirm and extend these results by demonstrating that roflumilast 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 roflumilast treatment, but exacerbations were less common in GOLD stage IV patients during roflumilast treatment. Roflumilast treatment improved pre- and post-bronchodilator FEV1 to a similar degree—an effect unlikely to be due to a change in airway smooth muscle tone. The improvement in FEV1 at the study endpoint was statistically significant, but was smaller than that reported previously (11), possibly reflecting the lower baseline mean FEV1 of our patients. This finding is similar to results with inhaled corticosteroids where the change in post-bronchodilator FEV1 was smaller in severe compared with moderate disease (6, 22). In keeping with the FEV1 findings, we saw consistent improvements with roflumilast, when compared with placebo, in the secondary lung function indices FVC, FEV6, and FEF25–75. Unlike the earlier 6-month study with roflumilast (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 significant effect of roflumilast on overall exacerbation rates (defined 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 (5, 25). Moreover, a significant percentage of patients was receiving inhaled corticosteroids during the study, which could further decrease the likelihood of exacerbations (8). Roflumilast significantly reduced the number of moderate exacerbations requiring oral corticosteroids, a potential indicator of more severe events and one of the prespecified 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 significant difference in exacerbation rate was seen with roflumilast 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 sufficient frequency for a therapy to modify them. The change in health status measured over 1 year using the total SGRQ score reflects 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 findings, but improved in both the placebo- and roflumilast-treated patients—a change maintained during the trial. This could reflect 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 intensification. 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 reflect a lack of impact on exacerbations. However, in the most severe group, in which the exacerbation rate was higher, there was a trend for roflumilast to improve the SGRQ score, providing indirect confirmation that it was having a clinical effect in this subgroup of patients. PDE4 inhibitors have a well described adverse event profile, 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 first 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 µg of roflumilast (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 roflumilast, confirming 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 roflumilast treatment, maintenance of lung function could be shown, confirming previous findings from a 6-month trial (31). One year's treatment, however, is insufficient to assess the rate of decline in FEV1 accurately, and larger, longer studies with roflumilast 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 benefit in a less-restricted population. Our definition of a health care–related exacerbation does not allow us to categorize events by their etiology, and so we do not know whether roflumilast influenced 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, roflumilast, produced modest but statistically significant 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 antiinflammatory therapy in COPD with currently tolerated treatments. Roflumilast 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 benefits with roflumilast 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 efficacy and side-effect profile. Our data suggest that further trials are needed in patients with severe COPD who exacerbate frequently, and in whom we have seen a potentially useful benefit with this class of treatment. If treatment with roflumilast 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.
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. Höller, W. Pohl, M. Sweilem, J. Würtz, 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. Kafé, D. Lejay, H. Mal, J.-P. Moreau, B. Pigearias, C. Sevette, C. Verkindre, E. Weitzenblum, P. Zuck; Hungary: Z. Györi, Z. Gönczi, T. Kecskés, 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. Naudé, 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. Rodríguez 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. Breitenbücher, U. Honegger, M. Häcki, 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.
Supported by Altana Pharma, AG. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200610-1563OC on April 26, 2007 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 Society–sponsored 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. Received in original form August 21, 2006; accepted in final form April 24, 2007
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