Drug Improves Some Symptoms in Severe Alzheimer's Disease

TORONTO, July 30 -- Donepezil (Aricept) helped stave off fading cognition in patients with severe Alzheimer's, but failed to otherwise stem the advance of the disease, researchers found.

Approved by the FDA in October 2006 to treat severe as well as moderate forms of the disease, the cholinesterase inhibitor proved mildly effective and safe in helping preserve memory and cognition for patients with advanced disease, Sandra E. Black, M.D., of the University of Toronto, and colleagues, reported in the July 31 issue of Neurology.

The study, supported by Esai and Pfizer, makers of the drug, included 343 patients with severe disease in the U.S., Canada, France, the United Kingdom, and Australia.

Community-dwelling patients with severe Alzheimer's, mean age 78, were enrolled in this six-month multinational, double-blind, placebo-controlled trial at 98 sites. Enrollment ran from May 2001 to mid-January 2005.

Patients were randomized to donepezil, 10 mg daily, or placebo for 24 weeks. Drug costs for patients run to or more a day.

Primary endpoints were results on the Severe Impairment Battery (SIB) and the Clinician's Interview-Based Impression of Change-Plus caregiver input (CIBIC-Plus).

Secondary endpoints included the mini-mental state score (MMSE), an activities-of-daily-living score, a neuropsychiatric inventory, a caregiver burden questionnaire, and a use of resources score.

Of the patients, 176 were randomized to donepezil and 167 received a placebo. Safety assessments were done regularly for both groups.

Donepezil was superior to placebo from baseline to endpoint on the Severe Impairment Battery (SIB) score (least squares mean difference 5.32; P=0.0001).

According to this score, cognitive function, similar in the two groups at baseline, stabilized or improved in 63% of people taking donepezil compared with 39.4% of those given a placebo.

Those taking donepezil showed improvement in memory, language, attention, and recognizing one's name, but orientation was essentially unchanged.

The "clinician's interview-based impression of change" score (CIBIC-Plus) and the mental state (MMSE) score favored donepezil (P=0.0473 and P=0.0267).

The mean mental state score (MMSE) at baseline was 7.5 for the donepezil group and 7.4 for the placebo patients. Small improvements were seen in the donepezil group (+ 0.65), whereas the value for the placebo group was virtually unchanged from the original screening score of -0.03.

Care should be taken, however, in using the MMSE score to point to improvement in these patients, Dr. Black said, because of the lack of further decline in the placebo patients.

The donepezil patients also showed a smaller decline in social interaction, and visuospatial function and construction (skills needed to complete a jigsaw puzzle, for example).

Behavioral disturbances are another concern in Alzheimber's patients, the authors noted, often tipping the balance toward nursing home placement. As in previous studies of such patients, the researchers said, both groups improved so that no significant benefit for donepezil was seen.

The drug was also not significantly different from placebo on other scores. These included activities of daily living (dressing, bathing, toileting), the neuropsychiatric inventory, and the scores for the caregiver burden and the use of resources.

Donepezil was relatively well tolerated in this population, the researchers said. Adverse events -- diarrhea, insomnia, nausea, infection, and bladder problems -- were mild to moderate, reported by 5% of patients in the donepezil group and at twice the rate of the placebo group, and were consistent with the known cholinergic effects of donepezil and with the drug's safety profile in patients with mild to moderate disease.

Donepezil patients were more likely than placebo patients to reduce the study drug dose because of an adverse event (2.3% versus 1.2%). The most common adverse events leading to discontinuation included anorexia, agitation, pneumonia, and somnolence.

"These findings, taken together with those of prior studies, provide evidence to support what more recent basic research has already suggested -- that cholinergic therapy can benefit patients with severe disease," the researchers concluded.