Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children.
OBJECTIVE
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
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.
Whelan
Harry T
HT
Division of Pediatric Neurology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. hwhelan@mcw.edu
Cook
John D
JD
Amlie-Lefond
Catherine M
CM
Hovinga
Collin A
CA
Chan
Anthony K
AK
Ichord
Rebecca N
RN
Deveber
Gabrielle A
GA
Thall
Peter F
PF
D000293:Adolescent; D000367:Age Factors; D001499:Bayes Theorem; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002985:Clinical Protocols; D002986:Clinical Trials as Topic / Q000379:methods* / Q000592:standards*; D015331:Cohort Studies; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007223:Infant; D015233:Models, Statistical; D012107:Research Design; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator