Authors: Peter Lockwood Wayne Ewy David Hermann Nick Holford
Publish Date: 2006/08/12
Volume: 23, Issue: 9, Pages: 2050-
Abstract
Clinical trial simulation CTS was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimers disease AD Typically a parallel group placebo controlled 12week trial in 200–400 AD patients would be used to establish drug effect relative to placebo ie Ho Drug Effect = 0 We evaluated if a crossover design would allow smaller and shorter duration trialsA family of plausible drug and disease models describing the time course of the AD assessment scale ADASCog was developed based on Phase I data and literature reports of other treatments for AD The models included pharmacokinetic pharmacodynamic disease progression and placebo components Eight alternative trial designs were explored via simulation One hundred replicates of each combination of drug and disease model and trial design were simulated A ‘positive trial’ reflecting drug activity was declared considering both a dose Trend test p 005 and pairwise comparisons to placebo p 0025A 4 × 4 Latin Square design was predicted to have at least 80 power to detect activity across a range of drug and disease models The trial design was subsequently implemented and the trial was completed Based on the results of the actual trial a conclusive decision about further development was taken The crossover design provided enhanced power over a parallel group design due to the lower residual variability
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