A Multicenter Trial of Rofecoxib and Naproxen in Alzheimer's Disease (NSAID Study)

Evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer's disease along with a number of epidemiological studies suggests that non-steroidal anti-inflammatory drugs (NSAIDs) may slow the rate of cognitive deterioration. We have selected two such drugs for a therapeutic trial: rofecoxib and naproxen. The trial employs a double-blind parallel design with three primary treatment groups: rofecoxib, naproxen and placebo. A total of 320 patients will be enrolled in the trial and randomized to the three groups. Stable use of cholinesterase inhibitors, estrogen, low dose aspirin, and vitamin E will be allowed. Patients with inflammatory diseases that might respond to the study medications will be excluded.

The primary outcome measure will be the one year change in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAScog). The attainment of significant endpoints will be examined as a secondary outcome measure. Other secondary measures include the CDR sum-of-boxes, Neuropsychiatric Inventory, the Quality of Life-AD and the ADCS pharmacoeconomic scale. The influence of HLA-DR (Human Leukocyte Antigen) genotype on clinical progression and response to treatment will also be examined.

Inclusion criteria

• NINCDS/ADRDA criteria for probable AD
• MMSE between 13 and 26, inclusive
• Stable medical condition for 3 months
• Screening visit
• Physically acceptable for this study as confirmed by medical history, physical exam, neurologic exam, and clinical laboratory tests
• Supervision available for administration of study medications; caregiver/informant to accompany patient to all scheduled visits
• Fluent in English or Spanish
• Age greater than or equal to 55 years old
• Modified Hachinski of less than or equal to 4
• CT or MRI since onset of memory impairment demonstrating absence of clinically significant focal lesion
• Able to complete baseline assessments
• 6 years of education or work history sufficient to exclude mental retardation
• Able to ingest oral medication

Exclusion criteria

• Hypersensitivity to aspirin or NSAID
• Active peptic ulcer disease within 5 years
• Renal insufficiency with creatinine greater than 1.5
• Clinically significant liver disease
• Poorly controlled hypertension
• Congestive heart failure
• Bleeding ulcer
• Active neoplastic disease (skin tumors other than melanoma are not exclusionary; patients with stable prostate cancer may be included at the discretion of the project director)
• Inflammatory diseases (including crystal arthropathy, rheumatoid arthritis, systemic lupus, erythematosus, Sjogren's syndrome, inflammatory bowel disease)