Page 34 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

specialists, the investigators established a change in MMSE score of 3.72 points as a clinically significant
difference.

Most of the included studies in this report have used arbitrary cut-off points on cognitive measures such
as the ADAS-cog (≥ 4 points improvement from baseline) to define a clinical response. Others have

considered any improvement on global assessment scales such as the CGI-C or the CIBIC-plus to define a
clinical response. These definitions are arbitrary and have not been validated; consequently, comparisons

across trials are impossible.

One generic indicator that influences time to effect is the time to titration of therapeutic dose. Statistically

significant differences between donepezil and placebo were reported in most trials for 5mg and 10mg
daily doses; because the recommended starting dose of donepezil is 5mg/day (titrating to 10mg/day at 4 to

6 weeks), this finding suggests that donepezil-treated patients are given a therapeutic dose from day 1 of
treatment (although steady state of therapeutic concentrations is not achieved for approximately 2 weeks).
Titration of rivastigmine-treated patients to a therapeutic dose (i.e., 6mg to 12mg/day) is recommended at

week 2, again inferring a relatively short time to therapeutic dose. Conversely, patients treated with
galantamine, tacrine, or memantine typically are not titrated to therapeutic doses until 3 weeks or later.
Although titration schedules are designed to minimize potential adverse events, some patients may be

titrated sooner than recommended. Furthermore, titration schedules do not reflect the time it takes to
maintain steady state concentrations. Given the typically long natural course of disease and the modest
treatment effects, the clinical significance of these differences is questionable, however.

Alzheimer's Drugs Page 34 of 205