title: Regression to the mean and predictors of MRI disease activity in RRMS placebo cohorts--is there a place for baseline-to-treatment studies in MS?
abstract: BACKGROUND
  Gadolinium-enhancing (GD+) lesions and T2 lesions are MRI outcomes for phase-2 treatment trials in relapsing-remitting Multiple Sclerosis (RRMS). Little is known about predictors of lesion development and regression-to-the-mean, which is an important aspect in early baseline-to-treatment trials.
  
  
  OBJECTIVE
  To quantify regression-to-the-mean and identify predictors of MRI lesion development in placebo cohorts.
  
  
  METHODS
  21 Phase-2 and Phase-3 trials were identified by a systematic literature research. Random-effects meta-analyses were performed to estimate development of T2 and GD+ after 6 months (phase-2) or 2 years (phase-3). Predictors of lesion development were evaluated with mixed-effect meta-regression.
  
  
  RESULTS
  The mean number of GD+-lesions per scan was similar after 6 months (1.19, 95%CI: 0.87-1.51) and 2 years (1.19, 95%CI: 1.00-1.39). 39% of the patients were without new T2-lesion after 6 month and 19% after 2 years (95%CI: 12-25%). Mean number of baseline GD+-lesions was the best predictor for new lesions after 6 months.
  
  
  CONCLUSIONS
  Baseline GD-enhancing lesions predict evolution of Gd- and T2 lesions after 6 months and might be used to control for regression to the mean effects. Overall, proof-of-concept studies with a baseline to treatment design have to face a regression to 1.2 GD+lesions per scan within 6 months.
authors: Institute for Neuroimmunology and MS (inims) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Jan-Patrick
authors: JP
authors: Stellmann
authors: Institute for Neuroimmunology and MS (inims) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Klarissa Hanja
authors: KH
authors: Stürner
authors: Institute for Neuroimmunology and MS (inims) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Kim Lea
authors: KL
authors: Young
authors: Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Susanne
authors: S
authors: Siemonsen
authors: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
authors: Tim
authors: T
authors: Friede
authors: Institute for Neuroimmunology and MS (inims) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Christoph
authors: C
authors: Heesen
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003287:Contrast Media / Q000627:therapeutic use*; D005260:Female; D005682:Gadolinium / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000628:therapy*; D011859:Radiography; D016032:Randomized Controlled Trials as Topic
chemical_list: D003287:Contrast Media; D005682:Gadolinium