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Donepezil Provides Potential Benefits for Severe Alzheimer's Disease: Presented at AAT

By Chris Berrie

GENEVA, SWITZERLAND -- April 24, 2006 -- The acetylcholinesterase inhibitor donepezil, which has shown benefits in cognitive and global functions for patients with severe Alzheimer's disease (AD), appears to be efficacious throughout the AD treatment spectrum, according to a multinational, placebo-controlled, double-blind, randomised trial.

The 24-week study, presented here on April 22^nd at the 9^th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy (AAT), on behalf of the 315 Study Group.

This prospective study was designed to follow from a recent post-hoc analysis that indicated potential benefits of donepezil for patients in advanced stages of AD, according to the study's clinical leader, Sharon Richardson, PhD, senior director and CNS group leader, Medical Affairs, Eisei Inc., New York, New York, United States.

The 343 patients in the study had Mini-Mental State Examination (MMSE) scores of 1 to 12, indicating severe AD, were randomised to receive either placebo or donepezil, dosed at 5 mg/day for the first 6 weeks, and 10 mg/day thereafter. The clinicians could use their discretion to determine the need to reduce the final dose from 10 mg/day back to 5 mg/day.

Patients were living in the community or in assisted living facilities and were ambulatory. Inclusion criteria included a Functional Assessment and Staging (FAST) score greater than 6 and a Modified Hachinski Ischaemic (MHI) score of 6 or less.

The placebo and donepezil groups had similar mean ages at baseline and gender distribution, as well as mean MMSE scores (7.4 vs 7.5), MMSE score distribution, mean MHI scores, and FAST total scores.

The objective of the study was to evaluate the safety and efficacy of donepezil. Primary efficacy measures included the Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change -- Plus Caregiver Interview (CIBIC-Plus).

Analysis was based on the intention-to-treat (ITT) population, which included all the randomised patients who received at least 1 dosing of placebo or donepezil and who had baseline and at least 1 postbaseline evaluation.

As the analysis of CIBIC-Plus assumed sufficient distribution across the 7 categories of change -- which was not met -- its scoring was collapsed to provide categories of 1-3 (worsened), 4 (no change), 5-7 (worsened) (cCIBIC-Plus).

In the placebo arm, 76.0% of patients completed the study, as compared with 66.5% in the donepezil arm; 85% of patients randomised to donepezil were maintained on the 10-mg/day dose.

The SIB scores showed improvements over baseline for donepezil treatment that was significantly better than the clinical decline seen in the placebo arm. In the ITT observed case (ITT-OC) population, this was seen for the full range of assessments, at weeks 8, 16 and 24 (P </=.0011). The ITT last observation carried forward (ITT-LOCF) analysis at week 24 also showed a significant benefit for donepezil over placebo (P =.0001).

For the cCIBIC-Plus scores, significant differences were seen in favour of donepezil at week 24 for both the ITT-OC (P =.0409) and ITT-LOCF (P =.0473) populations. Dr. Richardson also noted that at week 24 the full 7-category CIBIC-Plus scores also significantly favoured donepezil for ITT-OC (P =.0323) and ITT-LOCF (P =.0168).

For the adverse events (AEs), overall, 73.6% were mild to moderate, and the analysis of the AEs occurring in >/= 5% of the donepezil-treated patients and at least twice the rate of placebo (for all causalities) showed 79.5% for the donepezil arm and 70.1% for placebo.

The most common of these were diarrhoea (donepezil, 14.2% vs placebo, 5.4%), insomnia (6.8% vs 2.4%), nausea (7.4% vs 1.8%), infection (6.3% vs 3.0%), urinary incontinence (5.7% vs 2.4%), and pain (5.1% vs 2.4%).

"This is telling us then that [donepezil] does provide potential benefits in the severe Alzheimer's disease population," Dr. Richardson said. Thus, donepezil can provide greater improvements in cognition and global function throughout the AD continuum, she added.

Eisai Inc. and Pfizer Inc. provided financial support for this study.


[Presentation title: Donepezil Treatment of Severe Alzheimer's Disease: Results From a 24-week, Multinational, Randomised, Double-blind, Placebo-controlled Trial. Abstract 7A]

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