A review of the randomized controlled trials of tacrine in the treatment of Alzheimer's disease: methodologic considerations

Abstract

This review examines the features of the 16 randomized controlled trials that have been published on the use of oral tacrine for treating probable Alzheimer's disease and explores the methodologic problems associated with these studies. Patient selection using the standard National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria is now a feature of all studies; however, the specificity of the diagnosis, the severity of the dementia, the heterogeneity of the dementia with respect to disease and patient genotype, and the health status of the patients all are factors that may affect responsiveness to therapy. Most studies use crossover designs; however, because of the progressive nature of the disease and the variability in the rate of decline, parallel group studies over a length of time sufficient to produce worsening in disease severity in a placebo group appear to be most suited to detecting clinically relevant therapeutic effects. The close relation between dose, efficacy, and serious adverse events has been a problem in the tacrine trials, since many studies, titrating to maximum tolerated doses, have used clinically ineffective doses. This problem can be circumvented by the use of fixed-dose regimens. Three broad classes of outcome measures have been used to assess treatment efficacy: 1) performance-based tests of cognitive function, 2) global impressions of change on the part of the clinician or care giver, and 3) functional measures of daily living. Including a limited number of each type of measure provides strong evidence of clinically relevant therapeutic benefit; however, more widely accepted and better validated instruments need to be developed for all three areas.