Longitudinal FEV(1) and Exacerbation Risk in COPD: Quantifying the Association Using Joint Modelling

BACKGROUND: Lung function, measured as forced expiratory volume in one second (FEV(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(1) and exacerbation risk reduction. METHODS: A joint model of longitudinal FEV(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<0.0001) association between FEV(1) and exacerbation risk was estimated, with an approximate 10% reduction in exacerbation risk per 100 mL improvement in FEV(1), consistent across trials and treatment arms. The risk reduction associated with improvements in FEV(1) was relatively small compared to the overall exacerbation risk reduction for treatment arms including budesonide (10–15% per 160 µg budesonide). High baseline breathlessness score and previous history of exacerbations also influenced the risk of exacerbation. CONCLUSION: Joint modelling can be used to co-analyze longitudinal FEV(1) and exacerbation data in COPD clinical trials. The association between the endpoints was consistent and appeared unrelated to treatment mechanism, suggesting that improved lung function is indicative of an exacerbation risk reduction. The risk reduction associated with improved FEV(1) was, however, generally small and no major impact on exacerbation trial design can be expected based on FEV(1) alone. Further exploration with other longitudinal endpoints should be considered to further evaluate the use of joint modelling in analyzing COPD clinical trials.