Prediction of Disease Progression, Treatment Response and Dropout in Chronic Obstructive Pulmonary Disease (COPD)

Purpose Drug development in chronic obstructive pulmo-nary disease (COPD) has been characterised by unacceptably high failure rates. In addition to the poor sensitivity in forced expiratory volume in one second (FEV1), numerous causes are known to contribute to this phenomenon, which can be clustered into drug-, disease- and design-related factors. Here we present a model-based approach to describe dis-ease progression, treatment response and dropout in clinical trials with COPD patients. Methods Data from six phase II trials lasting up to 6 months were used. Disease progression (trough FEV1 measurements) was modelled by a time–varying function, whilst the treatment effect was described by an indirect response model. A time-to-event model was used for dropout Results All relevant parameters were characterised with accept-able precision. Two parameters were necessary to model the dropout patterns, which was found to be partly linked to the treatment failure. Disease severity at baseline, previous use of corticosteroids, gender and height were significant covariates on disease baseline whereas disease severity and reversibility to salbutamol/salmeterol were significant covariates on Emax for salmeterol active arm. Conclusion Incorporation of the various interacting factors into a single model will offer the basis for patient enrichment and improved dose rationale in COPD. KEY WORDS chronic obstructive pulmonary disease. diseas