Background and Purpose: A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This paper describes a Bayesian outcome-adaptive method for determining the best dose of an experimental agent, and explains how this method was used to design a dose-finding trial for tPA in childhood acute ischemic stroke (AIS).
Methods: The method assigns doses to successive cohorts of patients based on each dose’s desirability, quantified in terms of the trade-off between efficacy and toxicity. The trade-off function is constructed from several pairs of equally desirable (efficacy, toxicity) probabilities specified by the physicians planning the trial. Each cohort’s dose is chosen adaptively, based on dose-outcome data from the patients treated previously in the trial, to optimize the efficacy-toxicity trade-off. Application of the method to design the tPA trial is described, including a computer simulation study to establish the design’s properties. A hypothetical cohort-by-cohort example is given to illustrate how the method works during trial conduct.
Results and Conclusions: Because only a dose that is both safe and efficacious may be selected, and the method combines Phase I and Phase II by integrating efficacy and toxicity to choose doses, it avoids the more time-consuming and expensive conventional approach of conducting a Phase I trial based on toxicity alone followed by a Phase II trial based on efficacy alone. This is especially useful in settings with low accrual rates, such as trials of tPA for pediatric AIS.
Whelan, Harry T.; Cook, John D.; Amlie-Lefond, Catherine M.; Hovinga, Collin A.; Chan, Anthony K.; Ichord, Rebecca N.; deVeber, Gabrielle A.; and Thall, Peter F., "Practical Model-Based Dose-Finding In Early Phase Clinical Trials: Optimizing tPA Dose For Treatment Of Ischemic Stroke In Children" (January 2008). UT MD Anderson Cancer Center Department of Biostatistics Working Paper Series. Working Paper 41.