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Donepezil Improves Cognition in Severe Alzheimer's Disease Patients: Presented at EFNS

By Chris Berrie

GLASGOW, UK -- September 7, 2006 -- The selective acetylcholine esterase inhibitor donepezil provides greater improvements in cognition and global function than placebo in patients who have severe Alzheimer's disease (AD) and reside in the community or in assisted-living facilities. Donepezil is also well tolerated and provides benefits throughout the course of AD.

This multinational, randomised, double-blind, placebo-controlled trial was presented here on September 3^rd at the 10^th Congress of the European Federation of Neurological Societies (EFNS) on behalf of the authors by Elias Schwam, PhD, senior clinical director, Worldwide Alzheimer's Team, Pfizer Inc., New York, New York, United States.

Donepezil is approved for treatment of mild to moderately severe AD. Dr. Schwam and colleagues conducted their study as a result of findings from a recent post hoc analysis, which showed that donepezil provided benefits in cognitive, functional, and behavioural measures in patients with advanced AD.

The main entry criteria were age 50 years or greater and a diagnosis of probable AD consistent with the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) Revision 4 and the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and AD and Related Disorders Association (NINCDS-ADRDA).

"These patients resided either at home, with their spousal caregiver usually, or else they were in assisted-living facilities," Dr. Schwam stressed. They also had Functional Assessment and Staging scores greater than or equal to 6, and modified Hachinski Ischaemic scores less than or equal to 6.

A total of 167 patients were randomised to placebo (mean age, 78.0 years; male, 32.3%) and 176 to donepezil 5 mg/day for 6 weeks and 10 mg/day thereafter (mean age, 78.0 years; male, 27.3%).

Discontinuation rates over the 24 weeks of the study were similar in the 2 groups (placebo, 24.0%; donepezil, 33.5%).

Baseline screening neurological and cognitive characteristics of the 2 patient groups were not significantly different, showing (placebo vs donepezil): mean modified Hachinski Ischaemic score, 0.9 versus 0.7; FAST total scores of mainly 6.A to 6.E (85.8% vs 87.0%); mean Mini-Mental State Examination (MMSE) score, 7.4 versus 7.5; and MMSE score distributions of mainly 1 to 5 (30.5% vs 30.7%) and 6 to 12 (68.3% vs 68.8%).

Primary efficacy measures included Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change plus caregiver interview (CIBIC-plus). The primary analysis was based on the least squares (LS) mean change from baseline to end point (week 24) in the intention-to-treat (ITT) population, as last observation carried forward (LOCF). Change from baseline to weeks 8, 16, and 24 was also measured for continuous variables in the observed case (OC) population.

For the SIB score at endpoint (week 24-LOCF), the donepezil-treated patients showed significant improvement over the placebo group (P = .0001), as was seen for the ITT-OC population at weeks 8, 16, and 24 (P less than or equal to .0001) in favour of donepezil.

For the CIBIC-plus, the categories were collapsed from 7 to 3, with the analysis showing significant differences in favour of donepezil treatment for both week 24-LOCF (P = .0473) and week 24 OC (P = .0409). The details of the collapsed categories for the former saw (placebo vs donepezil): improved, 22.7% versus 27.8%; no change, 29.2% versus 38.3%; worsened, 48.1% versus 34.0%.

Most adverse events were mild or moderate (73.6%), and 10.8% of the placebo group and 19.3% of the donepezil-treated group withdrew from the study. There were more serious and severe adverse events reported in the placebo group (15.0% and 15.6%, respectively) over the donepezil-treated group (11.4% and 10.8%).

There were no significant differences seen in other measures examined, including laboratory test results, physical examination, vital signs, electrocardiograms, and Unified Parkinson's Disease Rating Scale scores.

"So the main message is that in this study there was benefit both on cognition as well as on the clinician's global impression of change," as Dr. Schwam detailed, "with the distribution of adverse events primarily the ones that are seen with mild to moderate [AD] studies as well, such as the cholinergic side effects, like diarrhoea and nausea, with insomnia also having been associated with donepezil in the past."

This study was sponsored by Pfizer Inc., New York, United States, and Eisai Inc., New Jersey, United States.


[Study title: Donepezil Treatment of Severe Alzheimer's Disease: Results From a 24-Week, Multinational, Randomised, Double-Blind, Placebo-Controlled Trial. Abstract P1110]

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