Statistical methods for a three-period crossover design in which high dose cannot be used first

Design and analysis methods for the three-period crossover trial defined by the sequences: (D0, D1, D2), (D1, D0, D2), and (D1, D2, D0), where D0 is a placebo, and D1 and D2 are a low dose and a high dose of a drug, respectively, are developed. This design may be used when investigators are unwilling to administer a higher dose of a new drug to a patient before administering a lower dose. In using this design, patients should be randomized to sequences in blocks that are integer multiples of 3. Both parametric and non-parametric analysis methods are based on contrasts that capture intrapatient variability only and provide unbiased estimates and hypothesis tests of pairwise differences between carryover, direct dose, and period effects. The design and methods are illustrated with data reflecting the cognitive component of the Alzheimer's disease assessment scale collected in a large clinical trial of Tacrine at doses of 0, 40, and 80 mg/day.