The nature and symptoms of Alzheimer's disease present unique issues and problems related to the design and analysis of clinical trials for assessing the efficacy of potential therapies. Based on the author's involvement with two multicenter studies in Alzheimer's patients, issues related to the design and analysis of such trials are discussed. Due to the progressive nature of the disease and the potential for carryover and withdrawal effects, crossover and enriched population designs are not recommended. Instead, parallel group comparisons are preferable. Since Alzheimer's disease has both cognitive and behavioral symptoms, both an objective cognitive test and a global assessment are recommended primary outcome variables. Other important design issues are specification of efficacy criteria, length of the double-blind treatment period, dose escalation, and follow-up of dropouts. With respect to statistical analysis, it is important to include all randomized patients in the analysis and to make every possible attempt to analyze the protocol-specified endpoint for all patients. The Mantel-Haenszel mean score statistic is useful in analyzing continuous and ordered categorical outcome variables used in Alzheimer's disease research.
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