Page 22 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

6%), followed by rivastigmine (9%; 95% CI 5%-12%), and galantamine (14%; 95% CI 8%-21%). Drop
out rates due to adverse events demonstrated a similar trend.

Donepezil vs. placebo

We included two meta-analyses 32, 33 and 11 trials 38-48, 61 comparing donepezil to placebo. A good meta-
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analysis pooled data from 13 trials lasting 12 or more weeks and involving 4,365 participants. Pooled
results demonstrated statistically significantly better ratings for 5mg/day and 10mg/day donepezil on all
outcomes measures at 24 weeks. For 10mg/day doses, the global assessment with CIBIC-plus,

dichotomized into those showing no change or decline and those showing improvement yielded an odds
ratio (OR) of 2.18 ( 95% CI 1.53 – 3.11; P < 0.001) and assessment of cognition with MMSE a weighted
mean difference (WMD) of 1.50, (95% CI 0.97 – 2.04; P < 0.0001) and with ADAS-Cog a WMD of -

2.92 (95% CI -3.74 - -2.10; P < 0.001). The size of the effect was dose-related and did not differ by
severity of the disease. Furthermore, pooled data from two trials assessing activities of daily living (DAD,

IADL, PSMS, CMCS) presented a statistically significant benefit for 5mg/day and 10mg/day donepezil
treatment at week 12 and week 24. No difference was reported on a patient-rated Quality of Life Scale
between donepezil and placebo. These findings were consistent with those of a fair-rated meta-analysis
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using individual patient data of placebo-controlled trials.

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Of 11 placebo-controlled trials that we examined, all but one had been included in the meta-analysis by
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Birks et al. Because some 42, 43, 45 of these included trials provide specific results on quality of life and
activities of daily living we summarize results in Table 4. 38, 40, 44

The only effectiveness study we identified was the only trial on donepezil that was not funded by the
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pharmaceutical industry. This UK study enrolled 565 patients and assessed the effectiveness of long-
term (3 years and 36 weeks) donepezil treatment in community-residents with mild to moderate AD with
or without concomitant vascular dementia. Primary outcome measures were rate of institutionalism and
functional capacity (Bristol ADL). No significant differences could be observed in the rates of

institutionalism between donepezil and placebo at 1 year (9% vs. 14%; P = 0.15) and at 3 years (42% vs.
44%; P = 0.4). After 12 weeks until the end of the trial, the Bristol ADL scores of donepezil-treated

patients were statistically significantly better, though the difference was modest (average +1.0 point, 95%
CI 0.5 – 1.6; P = 0.0004). Similarly, MMSE scores were modestly but statistically significantly higher in
donepezil- than in placebo-treated patients (average 0.8 points, 95% CI 0.5 – 1.2; P = 0.001); the clinical

significance of these findings is questionable. No significant differences were detected in progression of
disability (Bristol ADL) or behavioral and psychological symptoms (NPI).

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