Get access

Long-interval T2-weighted subtraction magnetic resonance imaging: A powerful new outcome measure in multiple sclerosis trials

Authors

  • Bastiaan Moraal MD,

    Corresponding author
    1. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    • VU University Medical Center, Department of Radiology, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
    Search for more papers by this author
  • Ivo J. van den Elskamp MD,

    1. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Dirk L. Knol PhD,

    1. Department of Epidemiology and Biostatistics, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Bernard M. J. Uitdehaag MD, PhD,

    1. Department of Epidemiology and Biostatistics, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    2. Department of Neurology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Jeroen J. G. Geurts PhD,

    1. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    2. Department of Pathology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Hugo Vrenken PhD,

    1. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    2. Department of Physics and Medical Technology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Petra J. W. Pouwels PhD,

    1. Department of Physics and Medical Technology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Ronald A. van Schijndel MSc,

    1. Department of Informatics, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author
  • Dominik S. Meier PhD,

    1. Center for Neurological Imaging, Departments of Radiology and Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Charles R. G. Guttmann MD,

    1. Center for Neurological Imaging, Departments of Radiology and Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Frederik Barkhof MD, PhD

    1. Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
    Search for more papers by this author

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. ANN NEUROL 2010;67:667–675

Ancillary