Alzheimer's Prevention Study Should Be Stopped

On September 4, 2002, Public Citizen sent a letter to Health and Human Services (HHS) Secretary Tommy Thompson asking that an Alzheimer’s Disease (AD) prevention trial be immediately stopped and that the patients be provided with information on the risks to which they may already have been exposed.

The “Alzheimer’s Disease Anti-Inflammatory Prevention Trial” (ADAPT) is sponsored by the National Institute of Aging (NIA), part of the National Institutes of Health (NIH), and led by Dr. John Breitner at the University of Washington in Seattle. The trial is testing two nonsteroidal anti-inflammatory drugs (NSAIDs) against placebos. The aim is to treat 2,625 healthy elderly people (70 or older) who have a parent or sibling with serious age related memory loss, senility, dementia, or AD, for seven years.

The ADAPT trial is being conducted in six centers across the U.S.: Johns Hopkins University (Baltimore, MD); Boston University; University of Rochester; University of Washington (Seattle, WA); Sun Health Research Institute (Sun City, AZ); and the University of South Florida (Tampa, FL). Pharmacia and Bayer pharmaceutical companies are providing the two NSAIDs: celecoxib (CELEBREX) and naproxen (NAPROSYN) and matching placebos. The study has been ongoing since January 2001, with about 1,000 enrolled to date, but new patients are still being recruited.

However, Public Citizen discovered in our search of the medical literature on AD, that there were serious problems with the scientific rationale for this trial so that, instead of helping patients, the NSAIDs being used have the potential to inflict harm on otherwise healthy individuals. This information has not been provided to patients and may not even be realized by some of the investigators involved in the trial.

There have been many hypotheses as to the cause(s) of AD. At one time, AD was thought to be due to an inflammatory reaction in the brain after finding in the brain chemicals typical of an anti-inflammatory response. There also appeared to be a lower incidence of AD in people who, for other reasons, had been on NSAIDs. However, a key paper published in the November 2001 issue of the journal Nature, established that only certain NSAIDs (ibuprofen, indomethacin, and sulindac) were effective in preventing the formation of the amyloid protein thought to be responsible for AD. Other NSAIDs tested had no such ability, including the two chosen to give to patients in the ADAPT trial (celecoxib and naproxen).

A recent reanalysis of a major observational study on NSAID use, reported in July 2002 by the International Alzheimer Congress, that the apparent protective effect was restricted to ibuprofen, indomethacin, and sulindac and, again, did not include naproxen. The ADAPT researchers have acknowledged that a reason they selected these drugs was that they were received free from the manufacturers.

The use of long term NSAIDs is putting patients at risk for many adverse events. Yet, patients are not informed fully (or at all) about many of these risks.

Gastrointestinal (GI) Effects

Even the senior investigator for the ADAPT trial, Dr. Breitner, expressed concern over “the potential to cause serious side effects when [NSAIDs were] used at high doses or over prolonged periods.” Patients are only told, “The study drugs can cause stomach irritation. This can range from mild stomach upset to ulcers” which “very rarely ... bleed”. The consent form never mentions perforation of the GI tract. The celecoxib and naproxen labels give the frequency of upper GI ulcers, gross bleeding, or perforation caused by NSAIDs as 1 percent. These FDA-approved Professional Products labels go on to say that this is true only for those treated for three to six months. However, this study will continue for seven years. The label also states that this rate increases to 2-4 percent at one year (with even higher incidences expected over longer durations of use). Furthermore, the celecoxib label states that only 20% of serious upper GI events are symptomatic. Thus, the promise in the Informed Consent sheet, “We will monitor you for any problems of this sort” does not protect patients.

Kidney Effects

The FDA-approved celecoxib label warns that the elderly are at greater risk for kidney problems and that “Long term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury” (the naproxen label also warns patients of possible serious kidney problems). However, ADAPT patients are not told that being elderly (as they all are) is an extra risk factor even if they have no problems with kidney, liver, or heart functions; they are only told that they will have lab tests and stop taking study drugs if problems develop.

Liver Effects

Although the FDA-approved labels warn of rare, severe liver reactions that can lead to death, ADAPT patients are told only that if they develop liver problems, they will be told to stop taking the drug.

Effects in the Blood

Although the FDA-approved celecoxib label warns of anemia, the ADAPT consent form says nothing about this.

Fluid Retention, Edema, and Blood Pressure

Although the FDA-approved labels warn of the need for caution in patients with high blood pressure, fluid retention, or heart failure, ADAPT patients are only told that if they develop water retention, they will be told to stop taking the drug.

Aspirin-sensitive Asthma

Although the FDA-approved labels warn of aspirin-sensitive asthma that can be fatal in susceptible individuals, ADAPT patients are told nothing about this potentially serious adverse effect.

Additional potential adverse events derived from the medical literature but not yet in either the FDA-approved label or in the Informed Consent sheet include: thrombotic (blood-clotting) tendency, delay in bone healing, and delay in ligament healing.

AD presents a frightening prospect because it involves loss of mental functioning. Because the public has come to expect pharmaceutical solutions to every disease, there is a great demand for preventive therapies for AD. Unfortunately, this trial is based on a hypothesis that is not supported by the latest research, thereby putting patients at risk of severe adverse reactions with little, if any, likelihood of a positive outcome. An especially vulnerable group is being exposed, i.e., the aged population (in this case, those 70 years old and older), who are apt to be at greater risk than younger people are. They will be exposed to a group of drugs (NSAIDs) for periods much longer than any period heretofore studied experimentally in any age group (most studies have ranged from three months to one year in duration). Thus, there may be additional adverse events about which we are currently ignorant or those we currently recognize may be more frequent or serious. More recently, the discoveries that COX-2 inhibitors like celecoxib block bone and ligament healing and may cause increased heart attack rates have added additional causes for concern, especially in the elderly. The risks to which patients are exposed are either not clearly spelled out or are missing entirely in the patient consent forms.

Even if there was a basis when the ADAPT trial was first proposed for believing that naproxen or celecoxib might have worked in preventing AD, there is no longer a scientific basis to support that hypothesis. We now know that only certain NSAIDs are candidates for a protective effect. Nevertheless, the Consent Statement for Enrollment states that, "Recent research suggests that they [celecoxib and naproxen] might [prevent AD] ... ".

We feel strongly that the ADAPT trial should be stopped and the patients enrolled should be fully informed about the extremely unlikely probability of efficacy of these two NSAIDs as well as the properties of these drugs that might put volunteers at risk of serious adverse reactions. There is no justification for continuation.