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From the Alzheimer's Disease and Memory Disorders Center (R.S.D.), Baylor College of Medicine, Houston, TX; Alzheimer's Disease Center (S.H.F.), Silberstein Institute, New York University School of Medicine, New York, and Nathan Kline Institute, Orangeburg, NY; Memory and Aging Program (S.S.), Butler Hospital, Warren Alpert Medical School, Brown University, Providence, RI; Eisai Inc. (Y.S., A.K.M.), Woodcliff Lake, NJ; Pfizer Inc. (R.G., Y.X.), New York, NY; and PAREXEL (W.E.W.), Stamford, CT.
Address correspondence and reprint requests to Dr. Rachelle S. Doody, Alzheimer's Disease Center, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030
Background: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms.
Methods: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale–cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale–sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function.
Results: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p 
0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change–MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%).
Conclusions: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.
Abbreviations: AD = Alzheimer disease; ADAS-Cog = Alzheimer Disease Assessment Scale–cognitive subscale; ADCS = Alzheimer's Disease Cooperative Study; CDR-SB = Clinical Dementia Rating Scale–sum of boxes; CGIC-MCI = Clinical Global Impression of Change–Mild Cognitive Impairment; ChEI = acetylcholinesterase inhibitor; DSB = Digit Span Backwards test; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ITT = intent-to-treat; LOCF = last observation carried forward; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; N/A = not available; NPI = Neuropsychiatric Inventory; NS = not significant; PDQ = Perceived Deficits Questionnaire; PDQ-R = PDQ for Relatives; PGA = Patient Global Assessment; SDMT = Symbol Digit Modalities Test.
e-Pub ahead of print on January 28, 2009, at www.neurology.org.
Sponsored by Eisai Inc. and Pfizer Inc. Study design, data collection, and manuscript content were conceived by the authors. Editorial support was funded by Eisai Inc. and Pfizer Inc.
Disclosure: This study was supported by Eisai Inc. and Pfizer Inc. Drs. Doody, Ferris, and Salloway or their institutions received funding in excess of $10,000 for other research activities and received honoraria in excess of $10,000/year from Eisai and Pfizer. Drs. Sun and Murthy are employees of Eisai Inc. Drs. Goldman and Xu are employees of Pfizer Inc. and have equity ownership in excess of $10,000. Mr. William Watkins reports no disclosures.
Received July 22, 2008. Accepted in final form November 21, 2008.
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