The National Institute on Aging (NIA) is launching a clinical trial to determine whether treatment with certain nonsteroidal anti-inflammatory drugs (NSAIDs) will slow cognitive and clinical decline in patients with Alzheimer's disease (AD). The study will evaluate two NSAIDs: rofecoxib, a new selective cyclooxygenase (COX-2) inhibitor, and naproxen, a nonselective NSAID. This is the first clinical trial to test both classes of anti-inflammatory drugs prospectively in patients with AD.
This multicenter study will be carried out by the NIA's consortium of AD clinical research centers, called the Alzheimer's Disease Cooperative Study (ADCS), which is directed by Leon Thal, M.D., of the University of California at San Diego. "We know that inflammation in the brain contributes to AD damage. We hope that treatment with NSAIDs might slow this damage and its devastating effects," says Thal.
A total of 320 patients with probable AD who are in good general health are being recruited for the trial. Patients will be randomly assigned to one of three treatment groups: rofecoxib, naproxen, or placebo for both rofecoxib and naproxen. The study is expected to be conducted at 40 centers in the U.S.
Patients will be followed for a total of 14 months. One primary outcome measure will be the 12-month change in patients' score on the Alzheimer's Disease Assessment Scale, a test evaluating memory, attention, reasoning, language, and orientation. A higher score indicates more impairment. A positive change in the score indicates cognitive worsening.
AD is an irreversible progressive brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and cognitive decline. Inflammation in the brain is one of the hallmarks of AD.
Investigators have both indirect and direct evidence that inflammation contributes to AD damage. Indirect evidence comes from epidemiologic studies and NIA's Baltimore Longitudinal Study of Aging, which found that frequent use of anti-inflammatory agents is correlated with a decreased prevalence of AD. Direct evidence comes from research showing that various compounds known to be involved in inflammatory processes can be found in and around AD plaques, as well as a number of studies that suggest ways in which inflammatory pathways could destroy neurons in an ever-repeating vicious cycle. Many scientists currently are conducting studies to understand these processes more fully.
"This is an area of intense interest among patients and families, practicing clinicians, as well as the scientific community," says Paul Aisen, M.D., of the Department of Neurology at Georgetown University Medical Center. Aisen is the project director for the rofecoxib/naproxen study. A recent report by Aisen and colleagues at the ADCS on the use of prednisone for treating AD appears in the Feb. 8, 2000, issue of the journal Neurology . (Media reports of the findings are embargoed by the journal until Feb. 7, 2000, at 4 p.m. Eastern Time.)
Enthusiasm for studying traditional NSAIDs has been tempered by two considerations: classical NSAIDs may not be the most specific class of anti-inflammatory drug to inhibit the mechanisms believed to contribute to neurodegeneration in AD, and these classical NSAIDS can be quite toxic, particularly in older patients. The newer COX-2 inhibitors—a more specific type of NSAID—may have an advantage over traditional NSAIDs as potential therapeutic agents in AD. Recent studies suggest that COX-2 may play a central role in neurodegeneration supporting their use as neuroprotective agents in AD. Also, selective COX-2 inhibitors are easier for patients to tolerate than nonselective NSAIDs.
Naproxen was included in this study because it is one of the two drugs most widely used by subjects in the epidemiologic studies suggesting NSAID neuroprotection. (The other was ibuprofen.) A major advantage of naproxen is that it can be given twice daily. It also is reasonably well tolerated in older people. Naproxen is widely prescribed by rheumatologists to treat pain and inflammation and also is used extensively in lower doses obtained over the counter. The naproxen to be used in this study is being provided by Bayer Corp.
Scientists caution that individuals should not take NSAIDs just in hopes of preserving cognitive function. "Research needs to be done in clinical trials such as this one to determine whether the treatment is safe and whether it has a beneficial effect on AD progression," says Marcelle Morrison-Bogorad, Ph.D., Associate Director of the Neuroscience and Neuropsychology of Aging Program at NIA, where the bulk of the Federal Government's Alzheimer's disease research is coordinated.
The major risk of NSAID therapy is upper gastrointestinal toxicity, ranging from mild, tolerable dyspepsia, or stomach upset, to bleeding gastric ulcers or perforation. To minimize this risk, this study will use the over-the-counter dose of naproxen. To further minimize potential risk, patients with recent peptic ulcer disease, kidney disease, liver disease, bleeding disorder, or congestive heart failure will be excluded from the study.
The only currently FDA-approved treatments for AD are tacrine and donepezil. Use of these drugs, as well as vitamin E and ginkgo biloba, is allowed in this trial.
For more information about this study and Alzheimer's disease, call NIA's Alzheimer's Disease Education and Referral (ADEAR) Center toll free at 1-800-438-4380 or visit the ADEAR Center website at www.nia.nih.gov/alzheimers .
The NIA, one of 25 Institutes and Centers at the National Institutes of Health, leads the Federal effort in studying Alzheimer's disease and supporting basic, clinical, epidemiological, and social research on aging and the special needs of older people.