Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial.

There have been very limited investigations of cholinesterase inhibitor therapy in more advanced stages of Alzheimer's disease (AD). The efficacy and safety of donepezil were evaluated in post hoc analyses of a subgroup of patients with more severe AD (standardized Mini-Mental State Examination [sMMSE] score 5-12) within a randomized, placebo-controlled trial in moderate to severe AD (MSAD study). Additional analyses examined whether donepezil's treatment effects were consistent across the full range of baseline AD severity studied (sMMSE score 5-17). Patients with moderate to severe AD (n = 290) who were living in the community or in assisted living facilities received donepezil or placebo for 24 weeks; n = 145 in the more severe AD subgroup. The primary outcome measure was the Clinician's Interview-Based Impression of Change (CIBIC-plus) with secondary outcomes including the sMMSE, Severe Impairment Battery, Neuropsychiatric Inventory, and Disability Assessment for Dementia. Analysis of Variance and Analysis of Covariance models tested for treatment x disease severity interaction in the full MSAD study sample. CIBIC-plus scores for donepezil patients were significantly improved compared with placebo for each time-point, with a 0.70 mean treatment difference at Week 24 last observation carried forward (LOCF; p = 0.0002). Significant differences favoring donepezil were noted at Week 24 LOCF for all secondary measures. There were no treatment x severity interactions for any of the efficacy measures. In this analysis, donepezil had significant benefits over placebo on global, cognitive, functional, and behavioral measures in a subgroup of patients with more severe AD. Furthermore, the treatment effects of donepezil were not driven by a particular stratum within the moderate to severe dementia range.

Feldman H ，Gauthier S ，Hecker J ，Vellas B ，Xu Y ，Ieni JR ，Schwam EM ，Donepezil MSAD Study Investigators Group ... -  《INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY》

A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.

Tariot PN ，Cummings JL ，Katz IR ，Mintzer J ，Perdomo CA ，Schwam EM ，Whalen E ... -  《JOURNAL OF THE AMERICAN GERIATRICS SOCIETY》

Donepezil preserves cognition and global function in patients with severe Alzheimer disease.

Black SE ，Doody R ，Li H ，McRae T ，Jambor KM ，Xu Y ，Sun Y ，Perdomo CA ，Richardson S ... -  《-》

Long-term safety and efficacy of donepezil in patients with severe Alzheimer's disease: results from a 52-week, open-label, multicenter, extension study in Japan.

A 6-month, randomized, double-blind, placebo-controlled study was extended to evaluate long-term safety and efficacy of donepezil in community-dwelling Japanese patients with severe Alzheimer's disease (AD). 189 patients were enrolled from the double-blind study into a 52-week, open-label extension study. After a 2- to 8-week washout, donepezil was escalated within 6 weeks to 10 mg/day. Main outcomes were Severe Impairment Battery (SIB), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale for severe AD (ADCS-ADL-sev) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). Safety parameters were monitored throughout. Overall, mean change from extension study baseline in SIB scores improved until week 24; however, scores were influenced by prior treatment during the double-blind study and by length of washout. Patients treated with donepezil retained some treatment benefits after a washout of 2-4 weeks but lost all treatment benefits after a washout of 4-8 weeks. There was no change in ADCS-ADL-sev or BEHAVE-AD scores. Adverse events were consistent with the known donepezil safety profile. Donepezil is effective and safe for symptomatic treatment of severe AD for at least 1 year. Patients who receive donepezil 10 mg daily with little or no interruption achieve the best long-term outcome.

Homma A ，Imai Y ，Tago H ，Asada T ，Shigeta M ，Iwamoto T ，Takita M ，Arimoto I ，Koma H ，Takase T ，Ohbayashi T ... -  《-》

Donepezil treatment of patients with severe Alzheimer's disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial.

A 24-week, randomized, parallel-group, double-blind placebo-controlled study was conducted to evaluate the efficacy and tolerability of donepezil in severe Alzheimer's disease (AD). Patients with severe AD (Mini-Mental State Examination score 1-12; modified Hachinski Ischemic Score < or =6; Functional Assessment Staging > or =6) were enrolled in this study in Japan. A total of 325 patients were randomized to donepezil 5 mg/day (n = 110), donepezil 10 mg/day (n = 103) or placebo (n = 112). Primary outcome measures were change from baseline to endpoint in the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIC-plus) at the endpoint visit. Donepezil 5 mg/day and 10 mg/day were significantly superior to placebo on the SIB, with a least-squares mean treatment difference of 6.7 and 9.0, respectively (p < 0.001 compared with placebo). CIBIC-plus analyses showed significant differences in favor of donepezil 10 mg/day over placebo at endpoint (p = 0.003). A statistically significant dose-response relationship was demonstrated with the SIB and CIBIC-plus. Donepezil was well tolerated. This study confirmed the effectiveness of donepezil 10 mg/day in patients with severe AD and demonstrated a significant dose-response relationship. Donepezil at dosages of both 5 mg/day and 10 mg/day is safe and well tolerated in Japanese patients with severe AD.

Homma A ，Imai Y ，Tago H ，Asada T ，Shigeta M ，Iwamoto T ，Takita M ，Arimoto I ，Koma H ，Ohbayashi T ... -  《-》