Published Online
on August 24, 2006

A more recent version of this article appeared on October 1, 2006

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Submitted on May 25, 2006
Revised on June 6, 2006
Accepted on June 13, 2006

Proof-of-Principle Phase II MRI Studies in Stroke. Sample Size Estimates From Dichotomous and Continuous Data

Thanh G. Phan MD, PhD; Geoffrey A. Donnan MD^*; Stephen M. Davis MD; Graham Byrnes PhD; on behalf of the MR Stroke Collaborative Group

From the Department of Neurology, Royal Melbourne Hospital and University of Melbourne, Parkville, Australia.

^* To whom correspondence should be addressed. E-mail: gdonnan{at}unimelb.edu.au.

Background and Purpose--Since the failure of a number of phase III trials of neuroprotection in ischemic stroke, the need for smaller phase II studies with MRI surrogates has emerged. There is, however, little information available about sample size requirements for such phase II trials and rarely enough patients in single studies to make robust estimates. We have formed an international collaborative group to assemble larger datasets and from these have generated sample size tables for MRI-based infarct expansion as the outcome measure.

Methods--Twelve centers from Australia, Europe, and North America contributed data from patients with hemispheric ischemic stroke. Infarct expansion was defined from initial diffusion-weighted images and later fluid-attenuated inversion recover or T₂ images. Sample size estimates were calculated from data on infarct expansion ratios treated as dichotomous or continuous variables. A nonparametric approach was used because the distribution of infarct expansion was resistant to all forms of transformation.

Results--As an example, a 20% absolute reduction in infarct expansion ratio (1), 80% power, and =0.05 requires 99 patients in each arm. To achieve an equivalent effect size with a continuous approach requires 61 patients.

Conclusions--These tables will be useful in planning phase II trials of therapy with the use of MRI outcome measures. For positive studies, biologically plausible surrogates such as these may provide a rationale for proceeding to phase III trials.

Key words: magnetic resonance imaging • neuroprotection • sample size • stroke

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