Proof-of-principle phase II MRI studies in stroke: sample size estimates from dichotomous and continuous data.
OBJECTIVE
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 (< or = 1), 80% power, and alpha = 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.
Phan
Thanh G
TG
Donnan
Geoffrey A
GA
Davis
Stephen M
SM
Byrnes
Graham
G
D001315:Australia; D015415:Biomarkers; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods / Q000706:statistics & numerical data*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000706:statistics & numerical data; D038524:Diffusion Magnetic Resonance Imaging; D005060:Europe; D006801:Humans; D007391:International Cooperation; D008279:Magnetic Resonance Imaging; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009656:North America; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D017211:Treatment Failure; D016896:Treatment Outcome
D015415:Biomarkers; D018696:Neuroprotective Agents