Long-Interval T2-Weighted Subtraction Magnetic Resonance Imaging A Powerful New Outcome Measure in Multiple Sclerosis Trials

B. Moraal, I.J. van den Elskamp, D.L. Knol, B.M.J. Uitdehaag, J.J.G. Geurts, H. Vrenken, P.J.W. Pouwels, R.A. van Schijndel, D.S. Meier, C.R.G. Guttmann, F. Barkhof

    Research output: Contribution to JournalArticleAcademicpeer-review

    Abstract

    Objective: To compare long-interval T2-weighted subtraction (T2w-Sub) imaging with monthly gadolinium-enhanced. T1-weighted (Gd-T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting. Methods: Magnetic resonance imaging (MRI) data over 9 months from 120 patients (61 treatment, 59 placebo) from the oral temsirolimus trial were used. T2w-Sub images were scored for active lesions, independent of the original reading of the monthly Gd-T1w images. Treatment efficacy was evaluated using the nonparametric Mann-Whitney U test, and parametric negative binomial (NB)-regression and power calculations were conducted. Results: Datasets from 116 patients (58 treatment, 58 placebo) were evaluated. The mean number of T2w-Sub lesions in the treatment group was 3.0 (±4.6) versus 5.9 (±8.8) for placebo; the mean cumulative number of new Gd-T1w lesions in the treatment group was 5.5(±9.1) versus 9.1(±17.2) for placebo. T2w-Sub imaging showed increased power to assess treatment efficacy compared with Gd-T1w imaging, when evaluated by Mann-Whitney U test (p = 0.017 vs p = 0.177), or NB-regression without (p = 0.011 vs p = 0.092) or with baseline adjustment (p < 0.001 vs p = 0.002). Depending on the magnitude of the simulated treatment effect, sample size calculations showed reductions of 22 to 34% in the number of patients (translating into reductions of 81-83% in the number of MRI scans) needed to detect a significant treatment effect in favor of T2w-Sub imaging. Interpretation: Compared with monthly Gd-T1w imaging, long-interval T2w-Sub MRI exhibited increased power to assess treatment efficacy, and could greatly increase the cost-effectiveness of phase 2 MS trials by limiting the number of patients, contrast injections, and MRI scans needed. © 2010 American Neurological Association.
    Original languageEnglish
    Pages (from-to)667-675
    JournalAnnals of Neurology
    Volume67
    Issue number5
    DOIs
    Publication statusPublished - 2010

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