Context Laboratory evidence that inflammatory mechanisms contribute to neuronal
injury in Alzheimer disease (AD), along with epidemiological evidence, suggests
that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence
the course of the disease.
Objective To determine whether treatment with a selective cyclooxygenase (COX)
-2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows
cognitive decline in patients with mild-to-moderate AD.
Design Multicenter, randomized, double-blind, placebo-controlled, parallel
group trial, with 1-year exposure to study medications.
Setting Forty ambulatory treatment centers affiliated with the Alzheimer's Disease
Cooperative Study consortium.
Participants Participants with mild-to-moderate AD (Mini-Mental State Examination
score of 13-26) were recruited from December 1999 to November 2000 using clinic
populations, referrals from community physicians, and local advertising. Stable
use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin
E was allowed. Participants with inflammatory diseases that might respond
to the study medications were excluded. Of 474 participants screened, 351
Interventions Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg,
Main Outcome Measures The primary outcome measure was the 1-year change in the Alzheimer Disease
Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures
included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric
Inventory, the Quality of Life-AD, and the time to attainment of significant
end points (4-point decline from baseline ADAS-Cog score, 1-step worsening
on the global Clinical Dementia Rating scale, 15-point decline on the ADCS
activities of daily living inventory, institutionalization, or death).
Results The 1-year mean (SD) change in ADAS-Cog scores in participants treated
with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different
from the change in participants treated with placebo (5.7 [8.2]). Results
of secondary analyses showed no consistent benefit of either treatment. Fatigue,
dizziness, and hypertension were more commonly reported in the active drug
groups, and more serious adverse events were found in the active treatment
group than in the placebo group.
Conclusion The results of this study indicate that rofecoxib or low-dose naproxen
does not slow cognitive decline in patients with mild-to-moderate AD.