title: Long-interval T2-weighted subtraction magnetic resonance imaging: a powerful new outcome measure in multiple sclerosis trials.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. b.moraal@vumc.nl
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Moraal
authors.forename: Ivo J
authors.initials: IJ
authors.lastname: van den Elskamp
authors.forename: Dirk L
authors.initials: DL
authors.lastname: Knol
authors.forename: Bernard M J
authors.initials: BM
authors.lastname: Uitdehaag
authors.forename: Jeroen J G
authors.initials: JJ
authors.lastname: Geurts
authors.forename: Hugo
authors.initials: H
authors.lastname: Vrenken
authors.forename: Petra J W
authors.initials: PJ
authors.lastname: Pouwels
authors.forename: Ronald A
authors.initials: RA
authors.lastname: van Schijndel
authors.forename: Dominik S
authors.initials: DS
authors.lastname: Meier
authors.forename: Charles R G
authors.initials: CR
authors.lastname: Guttmann
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005682:Gadolinium; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D017063:Outcome Assessment, Health Care; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018709:Statistics, Nonparametric
chemical_list: D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D005682:Gadolinium; D020123:Sirolimus