%0 Journal Article %A Gezim Lahu %A Axel Facius %A Laurent Claret %A Rene Bruno %A Dirk Bredenbröker %T Modelling and simulation in successful drug development programmes: Characterisation of exacerbation reduction with roflumilast to corroborate the importance of defining patient subsets in COPD %D 2011 %J European Respiratory Journal %P p3356 %V 38 %N Suppl 55 %X Background/Rationale: Roflumilast (ROF), an oral, selective PDE4 inhibitor, reduces the rate of exacerbations and improves lung function in severe COPD. During clinical development, modelling and simulation techniques were used to identify and confirm a paradigm to explore patient, disease and treatment covariates. This approach identified patient populations that will benefit most from ROF, and was used to help design confirmatory clinical trials.Methods: Data from two 1-year, randomised, double-blind, placebo-controlled, parallel-group trials [Rennard S, et al. Respir Res 2011;12(1):18] in 2686 patients were used to build exacerbation and lung function models to identify patient characteristics that significantly impacted the clinical endpoints.Results: Patients with chronic bronchitis, higher cough/sputum scores, concomitant ICS use and low predicted FEV1 at baseline were identified as having a higher rate of exacerbations and treatment effect. Patient characteristics as defined by the models were used, in addition to a history of exacerbations, to simulate the design of two other 1-year clinical trials [Calverley PMA, et al. Lancet 2009;374:685–94], with the inclusion criteria described in the trial protocols. The models predicted that the two trials would show a 17% reduction in exacerbation rate and a 47mL gain in FEV1 with ROF; observed results were 17% reduction and a 48mL gain.Conclusions: This modelling and simulation approach showed the importance of defining COPD subsets for drug development, and helped support phase III studies confirming exacerbation reduction with ROF. %U