Tuesday, December 5, 2023
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August 3, 2007 -- Research shows donepezil improves memory and global functioning in patients with severe Alzheimer's disease (AD).
Led by Sandra E. Black, MD, from Sunnybrook Health Sciences Center in Toronto, Canada, the randomized, double-blind, placebo-controlled trial found donepezil improved or stabilized cognitive function in 63% of treated patients vs 39% of control subjects receiving placebo.
Patients taking the drug had improvement in memory, language, attention, and name recognition compared with individuals taking placebo. In addition, the treated group showed less decline in social interactions compared with the placebo group.
"This study is good news. It shows you can still do something to preserve function even in patients who are in the very late stages of this disease. This provides clinicians with solid evidence that treatment does make a difference," Dr. Black told Medscape.
The study is published in the July 31, 2007, issue of Neurology.
Community-Based Study
The 6-month community-based study involved 343 people with severe AD attending 98 outpatient clinics in the United States, Canada, France, Australia, and the United Kingdom.
Patients were recruited for the study from May 1, 2001, through January 17, 2005. A total of 343 patients were randomized to receive 10 mg of donepezil daily (n = 176) or placebo (n = 167).
All individuals recruited for the study were ambulatory and were aged 50 years or older with probable AD. To be included in the study, patients had to have a Mini-Mental State Examination (MMSE) score of between 1 and 12, a modified Hachinski Ischemic score of 6 or less, and a Functional Assessment Staging score of 6 or greater.
In addition, only patients who had either not received previous AD treatment with cholinesterase inhibitors, memantine, or propentofylline or who had discontinued such treatment a minimum of 3 months prior to assessment were eligible for the study. Experimental AD treatment had to be discontinued 1 month, or 5 drug half-lives, before screening, whichever was longer.
Most (76.7%) patients lived in their own homes with their caregiver. The remainder resided in assisted-living facilities or retirement homes but not full skilled nursing homes. In addition, all individuals had a caregiver for a minimum of 3 days per week and 4 hours per day during waking hours.
The study's primary endpoints were changes in the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change–Plus caregiver input (CIBIC-Plus) scores.
Positive Effect
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 Resources Utilization for Severe Alzheimer Disease Patients (RUSP).
Safety was assessed by monitoring adverse events. Adverse events were considered severe if patients died, life was threatened, or hospitalization or prolonged hospitalization was required.
At baseline, mean total SIB scores were similar for both groups: 64.6 for donepezil vs 65.2 for placebo. However, at study completion, donepezil-treated patients improved in 5 of the 9 SIB domains, including language, attention, memory, praxis, and orienting to name. Orientation remained unchanged, and in the 3 remaining domains of social interaction, visuospatial function, and construction donepezil-treated patients showed significantly less decline than those in the placebo group.
"More patients [in the donepezil group] were stabilized or improved than in the placebo group. This demonstrates that even at a late stage in the disease it is possible through manipulation of the cholinergic system -- that is, by helping to restore and replace cholinergic function -- to have a positive effect," Dr. Black said.
In practical terms, said Dr. Black, this could mean patients could remain in a more independent living situation for a longer period, thereby reducing the substantial healthcare costs associated with institutionalization for AD.
In addition, CIBIC-Plus and MMSE scores also favored donepezil at study endpoint. However, the authors report donepezil was not significantly different from placebo on the ADCS-ADL-sev, NPI, CBQ, or RUSP outcomes.
Severe AD Subgroup?
Although the reasons for this are not clear and require further study, Dr. Black speculated this finding might result from the study group representing a subgroup of patients with severe AD.
That these individuals are able to be cared for at home or in an assisted-living situation suggests they may have fewer behavioral disturbances than their counterparts who are institutionalized. Therefore, said Dr. Black, treatment is less likely to demonstrate a dramatic benefit on behavioral outcomes.
Donepezil was well tolerated with few adverse effects, which included gastrointestinal upset, insomnia, infection, and bladder problems. However, said Dr. Black, subjects in the placebo group had more adverse events than those receiving active treatment.
In the United States, memantine, an N-methyl- D-aspartate receptor antagonist, was the first approved treatment for severe AD. Results from this trial, along with those of 2 other recent studies of cholinesterase inhibitors, now give clinicians another treatment option for this patient group," said Dr. Black.
"It has always been a bit of a dilemma for clinicians as to whether or not to continue treatment when patients reach the severe stage of disease. I think a lot of physicians already continue to use these drugs in the severe-stage patients, but I hope the benefit demonstrated in this study provides them with the evidence they need to confidently use the drug throughout the disease course," she said.
The study was sponsored by Eisai Inc, a maker of donepezil, and Pfizer Inc.
Neurology. 2007;69:459-469.
