Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial
Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T et al.;
Commented by , 16 Apr 2008
Aim of the study
Evaluate the efficacy and tolerability of donepezil in severe Alzheimer's disease (AD).
Method
24-week, randomized, parallel-group, double-blind, placebo-controlled study with patients diagnosed with AD, at severe stage defined as Mini Mental state (MMSE) scores of 1 to 12 and Functional Assessment Staging (FAST) ≥ 6. A total of 325 patients were randomized to donepezil 5mg/day (N=110), 10mg/day (N=103) or placebo (N= 112).
A 4-week placebo observation period was done prior to the start of the randomized treatment. Primary efficacy outcomes were the least-square means change from baseline to endpoint in the Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change-plus caregiver's input (CIBIC-plus).
Secondary measures included the Alzheimer's Disease cooperative Study-Activities of Daily Living for severe AD (ADCS-ADL-sev) and the Behavioral Pathology in AD Rating Scale (Behave AD).
Results
Completion rates at 24 weeks were 80.0% on placebo, 87.1% on donepezil 5mg/day, 79.2% on 10mg/day. Donepezil 5mg/day and 10mg/day were significantly superior to placebo on the SIB (p<0.001), whereas only donepezil 10mg/day was significant over placebo for the CIBIC+ (p<0.003). A statistically significant dose-response relationship was demonstrated with the SIB and the CIBIC+ (p<0.001). There was no significant difference between treatment arms for ADCS-ADL-sev and Behave AD.
Professor Gauthier's comments
This is possibly the last 24-week placebo-controlled study using a cholinesterase inhibitor within the range of mild to severe dementia stage of AD. This is the first time that a clear advantage of 10mg over 5mg/day is demonstrated within one study (meta-analysis have been required up to know).
This is the third study showing benefit of donepezil in severe AD for cognition and global scales, in Swedish (ref. 1), multinational (ref. 2) and now Japanese populations. It is more difficult to demonstrate benefit on behavior, for reasons that may be related to how the behaviors are observed and scored, either with the Behave AD or the Neuro-Psychiatric Inventory.
We are now at a turning point in AD clinical trials as we are waiting for results from Phase III studies using potentially disease-modifying drugs (ref. 3) and authors are starting to look at the big picture of using symptomatic and disease-modifying drugs (ref. 4). The July 2008 ICAD Congress in Chicago will be an opportunity to review new data and look to the future, possibly moving to the pre-dementia stage of AD.
References
1. Winblad B, Kilander L, Eriksson S, Minthon L, Båtsman S, Wetterholm AL, et al. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367 (9516); 1057-1065
2. Black SE, Doody R, Li H, McRae T, Jambor KM, Xu Y, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology 2007; 69 (5); 459-469
3. Sallowaya S, Mintzer J, Weiner MF, Cummings JL. Disease-modifying therapies in Alzheimer's disease. Alzheimer's & Dementia 2008; 4 (2); 65-79
4. Farlow MR, Miller ML, Pejovic V. Treatment Options in Alzheimer's Disease: Maximizing Benefit, Managing Expectations.Dementia and Geriatric Cognitive Disorders 2008; 25; 408-422. [DOI: 10.1159/000122962]