Chronic disease long-term drug prevention trials: lessons from the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT).

A randomized trial is a randomized trial. The basic ingredients do not change with different purposes whether for treatment or prevention of disease. Likewise, the problems and difficulties are mostly the same. But there are differences in approach and philosophy. Here we discuss problems in trials focused on healthy people to determine whether drugs can delay or prevent adverse health events, with the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) as an example. An important difference separating treatment trials from prevention trials is the length of time needed to demonstrate a difference with treatment. Related to this is the risk-benefit calculus of the trial. Treatment trials are aimed at "curing" or ameliorating disease, for example, as with trials involving people with Alzheimer's disease (AD) dementia to determine whether treatment is useful in dealing with the AD-induced dementia. Like other treatment trials, those targeting AD dementia balance these benefits against the risks of treatment. But by contrast, benefit in prevention trials, if any, will be found only in the absence or delay in disease onset, often after years of continuous treatment. As in ADAPT, the separation in timing of risk versus benefit often brings difficult decisions about how long to continue the trial in the absence of any apparent benefit to treatment. Other difficulties similarly relate to the length of prevention trials. In hopes that some lessons learned from ADAPT will assist future prevention trials, especially in the elderly, we describe several conundrums and problems experienced in this trial and attempt when possible to extend our observations to the larger class of long-term drug prevention trials.