title: Placebo cohorts in phase-3 MS treatment trials - predictors for on-trial disease activity 1990-2010 based on a meta-analysis and individual case data.
abstract: BACKGROUND
  Annualized relapse rates (ARR) in the placebo cohorts of phase-3 randomized controlled trials (RCT) of new treatments for relapsing remitting multiple sclerosis (RRMS) have decreased substantially during the last two decades. The causes of these changes are not clear. We consider a better understanding of this phenomenon essential for valuing the effects of new drugs and by designing new trials.
  
  
  OBJECTIVE
  To identify predictive factors of on-study ARR in early and recent MS trials.
  
  
  METHODS
  ARR, rate of relapse-free patients, trial start dates, baseline demographics, relapse definitions and the use of McDonald criteria were retrieved by literature research of the placebo cohorts from RRMS phase-3 trials. Predictors were estimated by univariate and multivariate regression analyses and random-effects meta-regression. In addition, regression models were calculated by the Sylvia Lawry Centre's (SLC), including individual case data from clinical trials performed until 2000. The most reliable meta-analytic results can be gained from pooled individual case data. In lack of this, random-effects meta-analyses are recommended.
  
  
  RESULTS
  Data from 12 published and one unpublished trial show a decrease of ARR from 1988 to 2012 (adjR(2) = 0.807, p<0.0001). Regression models identified McDonald criteria followed by baseline mean age and the pre-study relapse rate as predictors of the ARR. The pooled individual case data (n = 505) confirmed a decrease of ARR over time. The pre-study relapse rate was the best predictor for on-study relapses. Lacking individual case data after implementation of the McDonald criteria excludes a direct comparison concerning McDonald criteria.
  
  
  CONCLUSIONS
  Pre-study relapse rate was the best predictor for on-study relapse rate but failed to explain the decrease of the ARR over time alone. Higher age at baseline and the implementation of McDonald criteria were associated as well with a lowered relapse rate in the random-effects meta-regression. These findings need further clarification based on individual case data.
authors.affiliation: Institute for Neuroimmunology and Clinical MS Research (inims) and Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. j.stellmann@uke.uni-hamburg.de
authors.forename: Jan-Patrick
authors.initials: JP
authors.lastname: Stellmann
authors.forename: Anneke
authors.initials: A
authors.lastname: Neuhaus
authors.forename: Lena
authors.initials: L
authors.lastname: Herich
authors.forename: Sven
authors.initials: S
authors.lastname: Schippling
authors.forename: Matthias
authors.initials: M
authors.lastname: Roeckel
authors.forename: Martin
authors.initials: M
authors.lastname: Daumer
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.forename: Christoph
authors.initials: C
authors.lastname: Heesen
mesh_terms: D017326:Clinical Trials, Phase III as Topic; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D015233:Models, Statistical; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000628:therapy*; D017063:Outcome Assessment, Health Care; D010919:Placebos; D016012:Poisson Distribution; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012044:Regression Analysis; D012107:Research Design; D013997:Time Factors
chemical_list: D010919:Placebos