Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study
Winblad B, Kilander L, Eriksson S, Minthon L, Batsman S, Wetterholm AL, et al.;
Commented by , 28 Apr 2006
Aim of the study
To ascertain the effectiveness of donepezil in patients with severe Alzheimer’s disease (AD).
Method
6-month, double-blind, parallel-group, placebo-controlled randomized study with 248 patients with severe AD defined as Mini Mental State Examination MMSE scores of 1 to 10, Functional Assessment Staging (FAST) of 5 to 7c, living in 50 Swedish assisted care facilities. Donepezil or placebo were increased from 5 to 10 mg at one month and the dose was adjusted based on tolerability.
Primary efficacy outcomes were the Severe Impairment Battery (SIB) and the Alzheimer’s Disease Cooperative Study Activities for Daily Living inventory modified for severe AD (ADCS-ADL-severe). Secondary outcomes included the MMSE, the NeuroPsychiatric Inventory (NPI) and a Clinical Global Impression of Improvement (CGI-I). Statistical analysis was done on modified intention-to-treat population (primary analysis), intention-to-treat population and completer population.
Results
334 patients were screened, 248 were randomized and 194 completed the 6-month study. Mean MMSE at baseline was 6. Mean dose of donepezil was 8.2 mg. In the primary analysis at 6 months, patients on donepezil had a 5.7 points difference with those on placebo for the SIB (p=0.008), 1.7 for the ADCS-ADL-severe (p=0.03), 1.4 for the MMSE (p=0.009).
The differences were not significant for the NPI and the CGI-I. The tolerability was good except for diarrhea and hallucinations which were reported at more than twice the rate in donepezil-treated patients compared to placebo.
Professor Gauthier's comments
The authors interpretation of these results is that donepezil can improve cognition and preserve function in patients with severe AD living in assisted-care facilities. Most of the patients in this study had not been treated previously with a cholinesterase inhibitor.
In a population of patients with AD where severity was defined as MMSE 5 to 12 but still living in the community, similar doses of donepezil showed larger effects on the SIB after 6 months compared to placebo (7.42, p=0.0017) and the MMSE (1.99 p= 0.0022); equivalent measures of ADL, global change and the NPI were significantly different (ref. 1).
It is thus clear that there are measurable benefits in treating patients with severe AD with donepezil if they never had a therapeutic trial with a cholinesterase inhibitor. The question is whether at that stage of disease these benefits are clinically relevant, as discussed in the accompanying editorial (ref. 2).
Further work is required on this point, perhaps using a goal attainment strategy that was pioneered by Ken Rockwood and tested in a randomized study comparing galantamine to placebo in mild to moderate AD (ref. 3). Such an approach where treatment goals are individualized and limited in time could possibly be adapted to more severe stages of AD.
References
1. Feldman H, Gauthier S, Hecker J, Vellas B, Xu Y, Ieni JR, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry 2005; 20; 559-569
2. Hogan DB. Donepezil for severe Alzheimer's disease. Lancet 2006; 367 (9516); 1031-2.
3. Rockwood K, Fay S, Song X, MacKnight C, Gorman M. Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial Canadian Medical Association Journal; published online April 11, 2006; 174 (8). Free full text article