Faculty Collaboration Database

Practical model-based dose finding in early-phase clinical trials: optimizing tissue plasminogen activator dose for treatment of ischemic stroke in children. Stroke 2008 Sep;39(9):2627-36

Date

07/12/2008

Pubmed ID

18617665

DOI

10.1161/STROKEAHA.107.510164

Scopus ID

2-s2.0-52449120660 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

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: 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.

Author List

Whelan HT, Cook JD, Amlie-Lefond CM, Hovinga CA, Chan AK, Ichord RN, Deveber GA, Thall PF

MESH terms used to index this publication - Major topics in bold

Adolescent
Age Factors
Bayes Theorem
Brain Ischemia
Child
Child, Preschool
Clinical Protocols
Clinical Trials as Topic
Cohort Studies
Computer Simulation
Dose-Response Relationship, Drug
Drug-Related Side Effects and Adverse Reactions
Fibrinolytic Agents
Humans
Infant
Models, Statistical
Research Design
Stroke
Tissue Plasminogen Activator
Treatment Outcome