Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? the REACT study protocol

Background: Many patients with chronic obstructive pulmonary disease (COPD) continue to suffer exacerbations, even when treated with maximum recommended therapy (eg, inhaled combinations of long-acting beta(2)-agonist and high dose inhaled corticosteroids, with or without a long-acting anticholinergic [long-acting muscarinic antagonist]). Roflumilast is approved to treat severe COPD in patients with chronic bronchitis - and a history of frequent exacerbations - as an add-on to bronchodilators. Purpose: The REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment) study (identification number RO-2455-404-RD, clinicaltrials.gov identifier NCT01329029) will investigate whether roflumilast further reduces exacerbations when added to inhaled combination therapy in patients still suffering from frequent exacerbations. Patients and methods: REACT is a 1-year randomized, double-blind, multicenter, phase III/IV study of roflumilast 500 mu g once daily or placebo on top of a fixed long-acting beta(2)-agonist/inhaled corticosteroid combination. A concomitant long-acting muscarinic antagonist will be allowed at stable doses. The primary outcome is the rate of moderate or severe COPD exacerbations. Using a Poisson regression model with a two-sided significance level of 5%, a sample size of 967 patients per treatment group is needed for 90% power. COPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year will be recruited. Conclusion: It is hypothesized that because roflumilast (a phosphodiesterase-4 inhibitor) has a different mode of action to bronchodilators and inhaled corticosteroids, it may provide additional benefits when added to these treatments in frequent exacerbators. REACT will be important to determine the role of roflumilast in COPD management. Here, the design and rationale for this important study is described.