Abstract
PURPOSE: This work investigates improved utilization of ADAS-cog data (the primary outcome in Alzheimer's disease (AD) trials of mild and moderate AD) by combining pharmacometric modeling and item response theory (IRT). METHODS: A baseline IRT model characterizing the ADAS-cog was built based on data from 2,744 individuals. Pharmacometric methods were used to extend the baseline IRT model to describe longitudinal ADAS-cog scores from an 18-month clinical study with 322 patients. Sensitivity of the ADAS-cog items in different patient populations as well as the power to detect a drug effect in relation to total score based methods were assessed with the IRT based model. RESULTS: IRT analysis was able to describe both total and item level baseline ADAS-cog data. Longitudinal data were also well described. Differences in the information content of the item level components could be quantitatively characterized and ranked for mild cognitively impairment and mild AD populations. Based on clinical trial simulations with a theoretical drug effect, the IRT method demonstrated a significantly higher power to detect drug effect compared to the traditional method of analysis. CONCLUSION: A combined framework of IRT and pharmacometric modeling permits a more effective and precise analysis than total score based methods and therefore increases the value of ADAS-cog data.