Page 33 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

KEY QUESTION 2

How do donepezil, galantamine, rivastigmine, tacrine, and memantine compare in
their time to effect and in the time required to assess the clinical response?

We did not identify any study that directly compared the time to effect or time required to assess the
clinical response of one AD drug compared to another. One open-label head-to-head trial provides

28
evidence on the time to effect between donepezil and galantamine. The study reports a trend favoring
28
donepezil in cognition at weeks 4 and 8 that reached statistical significance at week 12 (P < 0.05). DAD
scores were significantly greater in donepezil-treated patients at weeks 4 and 12. Other head-to-head

trials reported only long-term outcomes.

Placebo-controlled trials are too heterogeneous with respect to study design, outcomes assessment, and
populations to allow any inferences about the comparative time to effect. Given that the overall placebo-
controlled evidence indicates that long-term treatment with ChEIs and memantine will produce only

modest beneficial effects on cognition and global assessment, the clinical significance of time to effect is
likely to be of minimal importance to physicians and patients.

In general determining time to effect and time required to assess clinical response is difficult, given the
design of most trials and the nature of measurement scales. First, trials commonly were not designed to

measure the time required to produce a statistically different response. In most trials, the first follow-up
visit was not conducted until 4 to 12 weeks after randomization. Given this relatively large and
inconsistent gap in follow-up between randomization and first clinical assessment, comparison across

placebo-controlled trials cannot provide accurate information. Second, different studies used different
outcome scales that are not necessarily comparable to assess effect sizes. Third, the ability of a trial to
detect statistically significant difference depends on the sample size of each respective trial; trials with

large sample sizes have greater power to present statistically significant findings at earlier time points.

Interpretation of clinical response (and time to assess it) is also of concern. Three published studies have
78
sought to shed light on the clinical significance of treatment effects in AD trials. 51, 78, 79 In one the
authors calculated standardized effect sizes from ChEI trials to assess clinically detectable responses.

Effect sizes greater than 0.20 were considered to be clinically detectable, but one cannot determine from
the article if this assumption was derived from validated evidence. In another study using a survey of

Alzheimer's Drugs Page 33 of 205