Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.
BACKGROUND
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.


METHODS
Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications.


METHODS
Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium.


METHODS
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 were enrolled.


METHODS
Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo.


METHODS
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.


CONCLUSIONS
The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.
Aisen
Paul S
PS
Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. psa@georgetown.edu
Schafer
Kimberly A
KA
Grundman
Michael
M
Pfeiffer
Eric
E
Sano
Mary
M
Davis
Kenneth L
KL
Farlow
Martin R
MR
Jin
Shelia
S
Thomas
Ronald G
RG
Thal
Leon J
LJ
D000203:Activities of Daily Living; D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins; D009288:Naproxen / Q000009:adverse effects / Q000627:therapeutic use*; D009483:Neuropsychological Tests; D016016:Proportional Hazards Models; D011451:Prostaglandin-Endoperoxide Synthases; D012044:Regression Analysis; D013450:Sulfones; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; C116926:rofecoxib; D009288:Naproxen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases