Effects of donepezil 23 mg on Severe Impairment Battery domains in patients with moderate to severe Alzheimer's disease: evaluating the impact of baseline severity.

Steven Ferris,Marwan Sabbagh,Jeffrey Cummings,Daniel Christensen,Martin Farlow,Joan Mackell,Liang Liu,Randi Fain,Rachelle Doody

doi:10.1186/alzrt166

Abstract

IntroductionThe US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer's disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Results from this study indicated that after 24 weeks, donepezil 23 mg/day provided significant cognitive benefits over donepezil 10 mg/day, measured using the Severe Impairment Battery (SIB). In the analyses reported herein, we further characterize the range of cognitive domains impacted by treatment with donepezil 23 mg/day.MethodsA post hoc analysis was conducted using data from a 24-week, randomized, double-blind trial comparing donepezil 23 mg/day versus 10 mg/day in 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20). Changes from baseline to week 24 in the nine SIB domain scores were analyzed in the intent-to-treat (ITT) population (baseline MMSE 0 to 20), in patients with more severe baseline AD (MMSE 0 to 16), and in severity strata based on baseline MMSE scores (0 to 5, 6 to 10, 11 to 15, 16 to 20).ResultsIn the ITT population, changes in six of the nine SIB domains favored donepezil 23 mg/day over donepezil 10 mg/day. LS mean treatment differences were significant for the language, visuospatial ability, and construction domains. In the more advanced cohort of patients (MMSE 0 to 16 at baseline), LS mean treatment differences were statistically significant favoring donepezil 23 mg/day in five of the nine domains: language, memory, visuospatial ability, attention, and construction. Descriptive analysis of LS mean changes in SIB domain scores in the four baseline severity strata showed variable patterns of response; overall, cognitive benefits of donepezil 23 mg/day were greatest in patients with MMSE scores of 0 to 15.ConclusionsThese results suggest that donepezil 23 mg/day provides benefits over 10 mg/day across a range of cognitive domains. The magnitude of benefit and domains impacted varied depending on the stage of AD; significant benefits with higher dose donepezil were most apparent at more advanced stages of AD and were most prominent in the language domain.

Highlights

The US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer’s disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose
Cognitive dysfunction in the early stages of AD has been well studied using clinical trial assessment scales http://alzres.com/content/5/1/12 such as the Alzheimer’s Disease Assessment Scale (ADAS) [5,6], a valid and reliable tool for evaluating cognition in patients at less advanced stages of the disease; when patients progress to moderate to severe stages of AD, this scale is no longer effective or reliable
There were no notable differences in individual Severe Impairment Battery (SIB) domain baseline scores (MMSE 0 to 20) (Table 1)

Summary

Introduction

The US Food and Drug Administration approved a 23 mg daily dose of donepezil for treatment of moderate to severe Alzheimer’s disease (AD) based on outcomes from a large trial comparing the 23 mg/day dose with the standard 10 mg/day dose. Based on the latest estimates, more than half of these individuals would be classified as having moderate or severe AD [2] These more advanced stages of the disease can last for up to a decade [3,4], placing a great burden on families and caregivers and resulting in substantial health care costs [1]. It has been widely used and validated as a measure of cognitive function in several clinical trials [3,7,12,13,14,15]. The SIB was designed to assess cognitive function across nine domains: language, memory, praxis, visuospatial ability, attention, orientation, social interaction, construction, and orienting to name [8]

Methods

Results

Conclusion