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(Stroke. 2008;39:2627.)
© 2008 American Heart Association, Inc.

Progress Review

Practical Model-Based Dose Finding in Early-Phase Clinical Trials

Optimizing Tissue Plasminogen Activator Dose for Treatment of Ischemic Stroke in Children

Harry T. Whelan, MD; John D. Cook, PhD; Catherine M. Amlie-Lefond, MD; Collin A. Hovinga, PharmD; Anthony K. Chan, MD; Rebecca N. Ichord, MD; Gabrielle A. deVeber, MD Peter F. Thall, PhD

From the Division of Pediatric Neurology (H.T.W., C.M.A.-L.), Medical College of Wisconsin, Milwaukee; the Department of Biostatistics (J.D.C., P.F.T.), University of Texas, M.D. Anderson Cancer Center, Houston; the Departments of Pharmacy and Pediatrics (C.A.H.), University of Tennessee Health Science Center, Memphis; Health Sciences Centre (A.K.C.), McMaster University, Hamilton, Canada; the Department of Neurology and Pediatrics (R.N.I.), Children’s Hospital, Philadelphia, Pa; and the Division of Neurology (G.A.d.V.), Hospital for Sick Children, Toronto, Canada.

Correspondence to Harry T. Whelan, MD, Division of Pediatric Neurology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail hwhelan{at}mcw.edu

Background and Purpose— A safe and effective tissue plasminogen activator (tPA) dose for childhood stroke has not been established. This article 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.

Methods— The method assigns doses to successive cohorts of patients on the basis of each dose’s desirability, quantified in terms of the tradeoff between efficacy and toxicity. The tradeoff 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 tradeoff. Application of the method to design the tPA trial is described, including a computer simulation study to establish design 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 acute ischemic stroke.

Key Words: stroke • tPA • dose finding • Bayesian statistics • phase I/II trial

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