RANDOMIZED DISCONTINUATION TRIALS - UTILITY AND EFFICIENCY

The randomized discontinuation trial (RDT) is a two-phase trial. In ph ase I all patients are openly treated with the medication being evalua ted. In phase II, those who have responded are randomly assigned to co ntinue the same treatment or switch to placebo. Usually, non-compliers and ''adverse reactors'' identified in phase I are excluded from phas e II. To investigate the value of this design, we reviewed the advanta ges and limitations of discontinuation studies, and compared the RDT d esign to the classic randomized clinical trial design in terms of clin ical utility and efficiency (sample size). A computer model was used t o study the efficiency of the two designs under a broad range of assum ptions. The RDT design is particularly useful in studying the effect o f long-term, non-curative therapies, especially when the clinically im portant effect is relatively small, and the use of placebo should be m inimized for ethical or feasibility reasons. However, its use is limit ed if the objective of an investigation is to estimate the magnitude o f absolute treatment effects and toxic effects in the source populatio n, or to evaluate a potentially curative treatment. Our results indica te that selecting responders prior to randomization has a very strong effect on the relative efficiency of the trial. Further improvement ma y be achieved by excluding non-compliers and adverse reactors. Under t he assumptions tested in our model, the sample size required in phase II of an RDT was only 20-50% of that in a classic trial.