Longitudinal [FEV.sub.1] and Exacerbation Risk in COPD: Quantifying the Association Using Joint Modelling

Background: Lung function, measured as forced expiratory volume in one second ([FEV.sub.1]), and exacerbations are two endpoints evaluated in chronic obstructive pulmonary disease (COPD) clinical trials. Joint analysis of these endpoints could potentially increase statistical power and enable assessment of efficacy in shorter and smaller clinical trials. Objective: To evaluate joint modelling as a tool for analyzing treatment effects in COPD clinical trials by quantifying the association between longitudinal improvements in [FEV.sub.1] and exacerbation risk reduction. Methods: A joint model of longitudinal [FEV.sub.1] and exacerbation risk was developed based on patient-level data from a Phase III clinical study in moderate-to-severe COPD (1740 patients), evaluating efficacy of fixed-dose combinations of a long-acting bronchodilator, formoterol, and an inhaled corticosteroid, budesonide. Two additional studies (1604 and 1042 patients) were used for external model validation and parameter re-estimation. Results: A significant (p