Reduction of exacerbations by the PDE4 inhibitor roflumilast - the importance of defining different subsets of patients with COPD

M2-111 was conducted between December 2003 and December 2005 in 188 centers in 6 countries, and M2-112 between January 2003 and October 2004 in 159 centers in 14 countries. Full details of the methodology, patient selection and efficacy assessments have been published previously for M2-112 [10]. (For details of the clinical design of both trials, and a CONSORT diagram for the unpublished study M2-111, see Additional file 1, Appendix 1, and Additional file 1, Figure S1).

The studies were approved by local ethical review committees (see Additional file 1, Appendix 2 for a list of committee names and approval numbers) and performed in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.

The statistical analysis was performed as described previously [10] with some modifications (i.e., all data were re-analyzed based on the methods used in two other 52-week studies) [15]. The primary endpoint (pre-bronchodilator FEV₁) and main secondary lung function endpoint (post-bronchodilator FEV₁) were evaluated using a repeated measures analysis of covariance (ANCOVA, mixed effects model). This model is able to handle missing data points by taking into account all available data from scheduled visits of the treatment period and the correlation in repeated measurements. The co-primary endpoint of rate of moderate or severe exacerbations per patient per year was defined by the need for oral or parenteral corticosteroid treatment, hospitalization, or death, and was evaluated using a Poisson regression model with a correction for over-dispersion. The natural logarithm of the trial duration, in terms of years, was included in this model as an offset variable to correct for the time a patient participated in the trial. Rate ratios from this model were expressed as percent reductions. Time to onset of exacerbations was analyzed using a Cox proportional hazards regression model. For the regression models (ANCOVA, Poisson, and Cox), the covariates included treatment (roflumilast/placebo), age, sex, smoking status (current/former smoker), study, concomitant treatment with inhaled corticosteroids (ICS) and country pool (only for the overall population). In the Poisson regression analysis, baseline post-bronchodilator FEV₁ (% of predicted value) was also included as a covariate. Adverse events were analyzed using descriptive statistics.

Data are presented as mean and standard deviation (SD), unless otherwise indicated. Safety endpoints were analyzed using descriptive statistics. Results are presented as mean ± SD or standard error (SE) as appropriate, with data derived from the statistical modeling being adjusted means. All p values are reported two-sided with a level of significance of 0.05.

To identify subpopulations, the two primary endpoints were analyzed additionally in subgroups stratified by sex, smoking status, concomitant use of ICS, concomitant use of anticholinergics, study completion status, COPD severity (severe, very severe), history of chronic bronchitis or emphysema (investigator-diagnosed), as well as cough and sputum score during the week before randomization.

Of 3630 patients enrolled into the run-in period, 2686 patients met the inclusion criteria and were randomized to treatment; 1905 patients completed the studies (Figure 1). The reasons for withdrawal were similar between groups except for adverse events, which occurred more frequently with roflumilast.

Demographics and baseline characteristics of the randomized patients were comparable between treatments (Table 1). Patients were predominantly male, and spirometric severity was consistent with severe-to-very-severe disease [8]. FEV₁ reversibility to short-acting β₂-agonists was similar in both treatment groups. As the inclusion criterion of FEV₁ reversibility to short-acting β₂-agonists ≤15% was defined only in study M2-112, mean reversibility was lower in M2-112 (11%) than in M2-111 (19%). All other demographic and baseline characteristics were comparable (or with only small differences not considered clinically relevant) between the two studies. On study entry and during the course of the studies, about 60% of the patients continued to receive ICS, while 60% continued to receive short-acting anticholinergics (Table 1).

The rate of moderate-to-severe exacerbations in the pooled analysis was 14.3% lower with roflumilast compared with placebo (0.52 vs 0.61 exacerbations per year; p = 0.026, Table 2 and Figure 2). However, the median time to first moderate or severe exacerbation was comparable in the roflumilast and placebo groups (120 and 126 days, respectively, p = 0.236).

There were several subgroups in which the exacerbation rate appeared lower with roflumilast compared with placebo (Table 2), including patients with chronic bronchitis with or without emphysema (26.2% reduction in exacerbation rate vs placebo; p = 0.001). Other subgroups, such as current vs former smokers or those based on spirometrically defined COPD severity, showed no or little difference in the exacerbation rate with roflumilast. Patients receiving concomitant ICS experienced an 18.8% reduction in exacerbations compared with placebo (p = 0.014). Patients not receiving ICS exhibited no clinical benefit compared with placebo (Table 2). A significant reduction in exacerbation rate in favor of roflumilast was also seen in the subgroup of patients receiving concomitant short-acting anticholinergic treatment (18.3%, p = 0.012).

Treatment with roflumilast resulted in significant improvement in pre-bronchodilator FEV₁ compared with placebo. In the combined analysis, the improvement was evident at Week 4 (first measured time point) and maintained throughout the 52 weeks of the studies. After 52 weeks, the change in pre-bronchodilator FEV₁ from baseline with roflumilast versus placebo was 51 mL (SE 7 mL, p < 0.0001), while the change in post-bronchodilator FEV₁ with roflumilast vs placebo was 53 mL (SE 8 mL, p < 0.0001) (Figure 3; and see Additional file 1, Table S1). In contrast to the effect on exacerbations, roflumilast consistently showed a significant improvement compared with placebo in pre-bronchodilator FEV₁ in all subgroups; the same was seen for post-bronchodilator FEV₁ (see Additional file 1, Table S1). In the group of patients with COPD associated with chronic bronchitis or combined emphysema and chronic bronchitis, those patients receiving concomitant ICS showed a greater improvement from baseline with roflumilast vs placebo (see Additional file 1, Table S1).

In the combined analysis, treatment with roflumilast resulted in no significant improvement in St George's Respiratory Questionnaire (SGRQ) total score compared with placebo. In contrast, in the subgroup analysis (Figure 4; and see Additional file 1, Table S2), a significant improvement in SGRQ total score was observed for individuals with chronic bronchitis (p = 0.0265). This difference was also evident in patients with chronic bronchitis who were concurrently treated with ICS (p = 0.0397).

Adverse events were similar to those reported for roflumilast in previous studies (see Additional file 1, Appendix 3). Importantly, roflumilast (compared with placebo) was not associated with an increase in adverse events in the subgroups that experienced a greater reduction in exacerbations with roflumilast compared with placebo (Table 3; and see Additional file 1, Appendix 3). Concomitant ICS did not affect the adverse event profile of roflumilast.