Donepezil preserves cognition and global function in patients with severe Alzheimer disease.
OBJECTIVE
To evaluate the efficacy and safety of donepezil for severe Alzheimer disease (AD).


METHODS
Patients with severe AD (Mini-Mental State Examination [MMSE] scores 1 to 12 and Functional Assessment Staging [FAST] scores > or =6) were enrolled in this multinational, double-blind, placebo-controlled trial at 98 sites. Patients were randomized to donepezil 10 mg daily or placebo for 24 weeks. Primary endpoints were the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus). Secondary endpoints included the MMSE, the Alzheimer Disease Cooperative Study-Activities of Daily Living-severe version (ADCS-ADL-sev), the Neuropsychiatric Inventory (NPI), the Caregiver Burden Questionnaire (CBQ), and the Resource Utilization for Severe Alzheimer Disease Patients (RUSP). Efficacy analyses were performed in the intent-to-treat (ITT) population using last post-baseline observation carried forward (LOCF). Safety assessments were performed for patients receiving > or =1 dose of donepezil or placebo.


RESULTS
Patients were randomized to donepezil (n = 176) or placebo (n = 167). Donepezil was superior to placebo on SIB score change from baseline to endpoint (least squares mean difference 5.32; p = 0.0001). CIBIC-Plus and MMSE scores favored donepezil at endpoint (p = 0.0473 and p = 0.0267). Donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP. Adverse events reported were consistent with the known cholinergic effects of donepezil and with the safety profile in patients with mild to moderate AD.


CONCLUSIONS
Patients with severe AD demonstrated greater efficacy compared to placebo on measures of cognition and global function.
Black
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Division of Neurology, Department of Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada. sandra.black@sunnybrook.ca
Doody
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Richardson
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D000203:Activities of Daily Living; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D017028:Caregivers / Q000706:statistics & numerical data; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018450:Disease Progression; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D010919:Placebos; D000077265:Donepezil