Page 23 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

A fair US-based study (n = 431) examined the functional decline of donepezil compared to placebo-

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treated patients over 1 year. The primary endpoint was time to clinically evident decline in function
(defined in study protocol). A higher proportion of placebo than of donepezil- treated patients reached the
primary endpoint (56% vs. 41%; P < 0.005). The median time to clinically evident functional decline was

significantly shorter for placebo than for donepezil-treated patients on donepezil (208 vs. 380 days; P =
0.0051).

The placebo-controlled study not included in any meta-analysis assessed the efficacy of donepezil on
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cognitive outcomes . Findings are consistent with results from meta-analyses. Results reported
significantly better outcomes for the donepezil than for placebo groups after 24 weeks of treatment.

Galantamine vs. placebo
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One good-rated systematic review (updated in 2005 ), two good-rated RCTs, 49, 53 and four fair-rated
RCTs 50-52, 54 compared galantamine to placebo. We focus the majority of our discussion on the updated
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systematic review because it provides a comprehensive summary of four of the five RCTs identified in
our search. However, for measures of behavior and functional capacity we focus our discussion on
individual trials because data in these domains were not pooled in the systematic review.

Trials ranged from 12 to 52 weeks in duration. The most frequent galantamine dose tested was
24mg/day; in most trials patients began at 8 mg/day and increased over time to the daily maximum.

Patients reached their maximum daily dose 2 to 8 weeks into the respective trials. All trials used the
ADAS-cog to assess cognitive change; other measures of symptomatic change included the European
adaptation of the ADAS scale, the expanded ADAS-cog, and the Digit Symbol Substitution Test. Most

trials used global rating scales such as the CIBIC-plus or the ADCS-CGIC. Changes in behavior were
assessed by the NPI and functional status was assessed using the PDS, DAD, and ADCS-ADL.

Overall, galantamine was significantly better than placebo for improving intermediate outcome measures
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of cognitive symptoms and global rating scales. Pooled analyses of ADAS-cog scores from trials
lasting 5 to 6 months revealed statistically significant differences for all doses of galantamine compared
to placebo (8mg: WMD -1.3; 95% CI -2.6-0.3; 16mg: WMD -3.1; 95% CI -4.1- -2.1; 24mg/day: WMD -
3.3; 95% CI -3.9- -2.7; 32mg/day: WMD -3.3; 95% CI -4.1- -2.4). Results from trials of 3 months’

duration were similar. Pooled ITT analyses for global rating scales also favored galantamine over
placebo. Trials lasting 5 to 6 months demonstrated similar differences (16mg/day: OR 2.04; 95% CI 1.4-

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