title: Sample-size calculations for short-term proof-of-concept studies of tissue protection and repair in multiple sclerosis lesions via conventional clinical imaging.
abstract: BACKGROUND
  New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking.
  
  
  OBJECTIVE
  The objective of this paper is to report sample-size calculations for assessment of new lesion recovery.
  
  
  METHODS
  In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations.
  
  
  RESULTS
  In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions ⩾15 mm(3), as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%.
  
  
  CONCLUSIONS
  Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset.
authors: Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA reichds@ninds.nih.gov.
authors: Daniel S
authors: DS
authors: Reich
authors: Department of Statistics, University of British Columbia, Canada.
authors: Richard
authors: R
authors: White
authors: Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA.
authors: Irene Cm
authors: IC
authors: Cortese
authors: Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA.
authors: Luisa
authors: L
authors: Vuolo
authors: Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA.
authors: Colin D
authors: CD
authors: Shea
authors: Myelin Repair Foundation, USA.
authors: Tassie L
authors: TL
authors: Collins
authors: Department of Statistics, University of British Columbia, Canada.
authors: John
authors: J
authors: Petkau
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D056747:Immunomodulation; D008279:Magnetic Resonance Imaging; D008297:Male; D009103:Multiple Sclerosis / Q000175:diagnosis* / Q000628:therapy*; D018401:Sample Size; D016896:Treatment Outcome; D066127:White Matter / Q000473:pathology*
keywords: MRI; T2 lesions; clinical trial design; repair