El. Conway, A REVIEW OF THE RANDOMIZED CONTROLLED TRIALS OF TACRINE IN THE TREATMENT OF ALZHEIMERS-DISEASE - METHODOLOGIC CONSIDERATIONS, Clinical neuropharmacology, 21(1), 1998, pp. 8-17
This review examines the features of the 16 randomized controlled tria
ls that have been published on the use of oral tacrine for treating pr
obable Alzheimer's disease and explores the methodologic problems asso
ciated with these studies. Patient selection using the standard Nation
al Institute of Neurological and Communicative Disorders and Stroke/Al
zheimer's Disease and Related Disorders Association (NINCDS/ADRDA) cri
teria is now a feature of all studies; however, the specificity of the
diagnosis, the severity of the dementia, the heterogeneity of the dem
entia with respect to disease and patient genotype, and the health sta
tus of the patients all are factors that may affect responsiveness to
therapy. Most studies use crossover designs; however, because of the p
rogressive nature of the disease and the variability in the rate of de
cline, parallel group studies over a length of time sufficient to prod
uce worsening in disease severity in a placebo group appear to be most
suited to detecting clinically relevant therapeutic effects. The clos
e relation between doses efficacy, and serious adverse events has been
a problem in the tacrine trials, since many studies, titrating to max
imum tolerated doses, have used clinically ineffective doses. This pro
blem can be circumvented by the use of fixed-dose regimens. Three broa
d classes of outcome measures have been used to assess treatment effic
acy. 1) performance-based tests of cognitive function, 2) global impre
ssions of change on the part of the clinician or care giver, and 3) fu
nctional measures of daily living. Including a limited number of each
type of measure provides strong evidence of clinically relevant therap
eutic benefit; however, more widely accepted and better validated inst
ruments need to be developed for all three areas.