Page 25 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

trials 55, 57, 66 and 5 unpublished phase II and phase III clinical trials involving 3,450 patients. All trials but
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one were sponsored by rivastigmine’s manufacturer. The fair-rated systematic review included data
from two published trials 55, 57 and one unpublished phase III clinical trial.

Although both systematic reviews included data from two of the same trials, we include them both

because each study drew unique conclusions. However, because the Cochrane review received a better
quality rating and was more comprehensive, we believe the good-rated Cochrane review gives the best

overall summary.

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The good-rated systematic review included data from eight trials; studies ranged in duration from 9 to
26 weeks. In most trials, the mean baseline MMSE score was between 18 and 20. Analyses were
stratified by dose, characterizing rivastigmine 1-4mg/day as low dose and rivastigmine 6-12mg/day as

high dose. Common outcome measures included the ADAS-cog, CIBIC-plus, GDS, MMSE, and PDS.
Caregiver activities also were assessed using the CAS. Pooled results suggest significantly greater
improvement on the CIBIC-plus for all doses of rivastigmine compared to placebo. Significantly greater

improvement also was found for high-dose rivastigmine (6-12mg/day) compared to placebo on the
ADAS-cog, MMSE, GDS, and the PDS; pooled results were not significant for low-dose rivastigmine (1-
4mg/day) for these outcome measures. The high-dose regimen currently is the recommended dosing

range for rivastigmine.

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The fair-rated systematic review included data from two published trials 55, 57 and one unpublished trial
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(B351). In contrast to the good-rated Cochrane review, this review reported statistically significant
differences favoring all doses of rivastigmine compared to placebo. Statistically significant differences

were reported for the ADAS-cog, CIBIC-plus, GDS, MMSE, and PDS. Although this pooled population
includes data from the three largest placebo-controlled trials conducted by Novartis, it does not include a
similarly designed phase III trial (i.e., B304). Furthermore, this review presents observed cases analyses

for the ADAS-cog and CIBIC-plus but uses LOCF analyses for the PDS. The less conservative LOCF
data may allow the natural course of the disease to overestimate treatment effect. This review was funded

by Novartis, the makers of rivastigmine.

To contrast differences in the pooled evidence from these reviews, we review data from three published
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placebo-controlled trials that met the criteria for our review. 55-57 In contrast to the Cochrane review, one
trial found statistically significant differences in the ADAS-cog and GDS for all doses of rivastigmine
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compared to placebo; a second reported statistically significant differences in these measures only for

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