Randomizing responders. Cardiac Arrhythmia Suppression Trial (CAST) investigators

Three clinical trial designs for use in testing the effect of long-term drug therapy on an outcome are considered: empiric (randomization to one of several specified and fixed therapies); randomization followed by dose-adjustment of the drug; and dose adjustment followed by randomization of responders. It is shown that the latter, though some information may be lost and bias may be introduced, can be more efficient because of the reduction of noise. These results are illustrated using information gathered by the Cardiac Arrhythmia Pilot Study (CAPS) and Cardiac Arrhythmia Suppression Trial (CAST), the former being a pilot study using the second design, and the latter a large clinical trial adopting the third design. For CAST, the efficiency (represented by ratio of sample sizes) is 0.78 relative to the empiric design, and 0.6 relative to the design incorporating randomization followed by dose adjustment.