An integrated design for dose comparison trials.

Abstract

An integrated design, which incorporates the dose titration scheme into the parallel comparative design, is proposed for dose comparison trials of drugs that may cause a first-dose phenomenon. This design includes a concurrent placebo control group, thereby providing valid estimate of drug effect. The other groups are defined by the maximum allowable dose. Except for the maximum allowable dose, both the titration schedule and the titration interval are standardized. The effect of the pace of titration is thus controlled. In extreme cases, all patients need only the lowest dose tested, and all patients need the highest dose tested to achieve the required efficacy response. In nonextreme cases, this design answers questions that are usually asked of dose comparative trials: overall drug effects, adequacy of starting dose, effects of dose increment, maximum effective dose, dose-response relationship, and time effect. Because both efficacy and safety analyses can be performed similarly, risk-benefit analysis thus can be evaluated in the same group of patients, and an optimum titration regimen may be determined rationally.