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Abstract:
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No disease modifying treatment has been approved for Alzheimer's disease and Parkinson's disease. In the absence of acceptable biomarkers that could be combined with a clinical benefit to demonstrate disease modification (DM) in these 2 neurodegenerative disorders, a delayed-start design can be applied to demonstrate a lasting effect on the disease course. The delayed-start design includes two treatment periods, where in Period 1 patients are randomized to receive an active treatment or placebo, and in Period 2 placebo patients are switched to active treatment. The hypothesis is that patients who start the active treatment later (in Period 2) fail to catch up treatment benefit with patients who receive the active treatment in both periods. A common analytical approach has been used to demonstrate the divergence of slope during Period 1 and the parallelism of slopes during Period 2 as necessary conditions for the DM effect. However due to heterogeneity in timing and the magnitude of maximal effect among patients, non-linear response over time could be seen in both periods. In this research, we propose an approach to establish the DM effect without the linearity assumption.
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