CHICAGO — Patients with severe Alzheimer's disease showed improved cognition and function when treated with donepezil in a 24-week, placebo-controlled trial, Dr. Sandra Black and her associates reported in a poster at the annual meeting of the American Geriatrics Society.
The results are consistent with a Swedish nursing home study in a similarly severe, institutionalized population (Lancet 2006;367:1262–70), suggesting that even patients with severe disease can benefit from treatment with donepezil.
“The two studies taken together suggest that this stage of disease can show measurable benefits of treatment with donepezil,” Dr. Black, professor of medicine and head of neurology at Sunnybrook Health Sciences Centre, University of Toronto, said in an interview. “They give a new evidence-based option for treatment, which gives hope for a better quality of life in the final phase of this devastating disease.”
Currently, donepezil (Aricept) is approved for mild to moderate Alzheimer's disease. In February 2006, the U.S. Food and Drug Administration accepted a supplemental new drug application for donepezil in severe Alzheimer's disease.
Doses of 5 mg and 10 mg of donepezil are typically administered once daily, although the higher 10-mg dose did not provide significantly greater clinical benefit in previous clinical trials.
Dr. Black and her colleagues' study randomized 343 patients with severe Alzheimer's disease to an initial dose of donepezil 5 mg/day for 6 weeks and then 10 mg/day donepezil (176 patients) or placebo (167 patients) for 24 weeks. Patients resided in the community or in assisted-living facilities. Baseline characteristics were similar in both groups. Their mean age was 78 years, their mean Mini-Mental State Exam score was 7.5, and the majority (86.3%) had Functional Assessment Staging scores of 6.a–6.e.
Overall, 117 of the 176 donepezil-treated patients and 127 of the 167 placebo patients completed the study, which was supported by Eisai Inc. and Pfizer Inc. Dr. Black holds no financial interest in either firm, but has been a study investigator for both. She is an ad hoc consultant and speaker, and has received honoraria from Pfizer.
Primary end points were change from baseline in Severe Impairment Battery (SIB) total score and Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus) at 24 weeks.
The primary analysis was based on the intent-to-treat population using a last observation carried forward analysis at 24 weeks. The intent-to-treat population consisted of all patients who were randomized, received at least one dose of either donepezil or placebo, and had a baseline and at least one postbaseline efficacy value.
Categories in the CIBIC-plus analysis were collapsed (1–3 equals improved, 4 equals no change, and 5–7 equals worsened) because the distribution of values was sparse in categories 1, 2, and 7.
Donepezil was significantly superior to placebo on the SIB score at week 24 in the intent-to-treat population (mean difference 5.3), and at weeks 8, 16, and 24 in patients who completed the study, she said.
The collapsed category CIBIC-plus analysis significantly favored donepezil at week 24 in the intent-to-treat population and in patients who completed the study. Among donepezil-treated patients, 28% improved, 38% had no change, and 34% worsened, compared with 23%, 29%, and 48% of placebo patients, respectively.
Most reported adverse events were mild to moderate (74%), the most common of which were diarrhea, nausea, and insomnia. Placebo patients reported more serious and severe adverse events than donepezil-treated patients. However, more patients discontinued treatment because of adverse events in the donepezil group than in the placebo group (18.3% vs. 10.8%, respectively), Dr. Black reported.