Donepezil, rivastigmine, galantamine and memantine for ...

ADAS-cog of –1.7 (SEM 0.45) and those in the
placebo group (n = 55) a mean change in
ADAS-cog of 0.6 (SEM 0.57). The study
demonstrated a statistically significant difference,
p = 0.001. The mean mADAS-cog at baseline
was 23.8 (SEM 0.85) in the donepezil group and
24.1 (SEM 0.93) in the placebo group.
Cognitive responders on ADAS-cog
One study reported data on ‘cognitive
responders’. 51 Cognitive responders were defined
as those with at least a 4-point improvement on
the ADAS-cog; they also presented data on those
with at least a 7-point improvement. In this study
37.8% of participants given 5 mg donepezil and
53.5% of participants given 10 mg donepezil had
at least a 4-point improvement. These compare
with 26.8% of those participants given the placebo
intervention. Participants with at least a 7-point
improvement on ADAS-cog were 15.4 and 25.2%
in the two donepezil groups (5 and 10 mg/day,
respectively) compared with 7.8% in the placebo
group. The trial also reports that the percentage
of participants with poorer ADAS-cog scores from
baseline were 20.3% in the 5 mg donepezil group,
18.9% in the 10 mg donepezil group and 42.3%
in the placebo group, hence cognitive worsening
was higher in those treated with placebo. No
statistical analyses were undertaken to compare
differences in any of the groups’ responses on
these outcomes.
MMSE
Nine included trials report the MMSE and results
are given in Table 6. On the MMSE a positive
mean change indicates a clinical improvement.
Six trials were two-arm comparisons, two were
three-arm trials and one was a four-arm trial.
Change from baseline score for each trial is given
in Table 6. The summary that follows will
predominantly discuss comparisons between 5 mg
donepezil and placebo and 10 mg donepezil and
placebo, regardless of the number of arms in the
individual trial. The two studies 41,47 where the
intervention dose of donepezil was 5 mg/day for
28 days followed by 10 mg/day until study
completion will be treated as having a 10 mg/day
dose. The one trial where participants received
either 5 or 10 mg donepezil is reported separately.
The one trial that had 12 weeks of open-label
treatment prior to randomisation is also reported
separately. 49
Donepezil 5 mg/day versus placebo. Three trials
included an intervention group with a daily dose
of 5 mg donepezil. The mean change from
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Health Technology Assessment 2006; Vol. 10: No. 1
baseline MMSE was between 0.24 and 2.0 for the
donepezil group and between –0.97 and 1.2 for
the placebo groups. The mean treatment
difference in change from baseline scores between
donepezil and placebo was ~1 point. Overall, all
studies demonstrated improvement in MMSE in
the donepezil groups compared with the placebo
groups, although these differences reached
statistical significance in only two. 51,52 Some of the
variation between trials may be due to sample size
as the one trial that did not reach statistical
significance had small sample sizes. There may
also be differences attributed to the properties of
the scale (see discussion in Chapter 10).
Two of the three studies provided data (mean
change and standard deviation) that allowed them
to be combined in a meta-analysis (Figure 3).
Pooling the data using a fixed-effects model
showed an overall improvement in MMSE with
5 mg/day donepezil compared with placebo [WMD
1.08 (95% CI: 0.57 to 1.58)]. Heterogeneity was
not statistically significant, p = 0.63. No difference
was noted using a random-effects model.
Donepezil 10 mg/day versus placebo. Six trials
included an intervention group with a daily dose of
10 mg donepezil. The mean change from baseline
MMSE was between –0.46 and 1.7 for the
donepezil group and between –2.18 and 0.5 for the
placebo groups. This variation may in part be
explained by differences in the study duration, with
longer duration reducing the mean change MMSE
score from baseline. Baseline MMSE scores were
generally similar between these trials. The mean
treatment difference in change from baseline scores
between donepezil and placebo was ~1.5 points.
Overall, all studies demonstrated statistically
significant improvement in MMSE in the donepezil
groups compared with the placebo groups.
Two of the six studies provided data (mean change
and standard deviation) that allowed them to be
combined in a meta-analysis (Figure 4). Pooling the
data using a fixed-effect model showed an overall
improvement in MMSE with 10 mg/day donepezil
compared with placebo [WMD 1.30 (95% CI: 0.78
to 1.82)]. Heterogeneity was not statistically
significant, p = 0.85. No difference was noted
using a random-effects model.
In one study, the dose of donepezil was 5 or
10 mg/day, with approximately half receiving each
dose. 43 The reported MMSE change from baseline
in the donepezil-treated group at 60 weeks was
–1.5. The reported MMSE change from baseline
in the placebo group at 60 weeks was –1.75.
21