title: Explaining temporal trends in annualised relapse rates in placebo groups of randomised controlled trials in relapsing multiple sclerosis: systematic review and meta-regression.
abstract: BACKGROUND
  Recent studies have shown a decrease in annualised relapse rates (ARRs) in placebo groups of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS).
  
  
  METHODS
  We conducted a systematic literature search of RCTs in RMS. Data on eligibility criteria and baseline characteristics were extracted and tested for significant trends over time. A meta-regression was conducted to estimate their contribution to the decrease of trial ARRs over time.
  
  
  RESULTS
  We identified 56 studies. Patient age at baseline (p < 0.001), mean duration of multiple sclerosis (MS) at baseline (p = 0.048), size of treatment groups (p = 0.003), Oxford Quality Scale scores (p = 0.021), and the number of eligibility criteria (p<0.001) increased significantly, whereas pre-trial ARR (p = 0.001), the time span over which pre-trial ARR was calculated (p < 0.001), and the duration of placebo-controlled follow-up (p = 0.006) decreased significantly over time. In meta-regression of trial placebo ARR, the temporal trend was found to be insignificant, with major factors explaining the variation: pre-trial ARR, the number of years used to calculate pre-trial ARR and study duration.
  
  
  CONCLUSIONS
  The observed decline in trial ARRs may result from decreasing pre-trial ARRs and a shorter time period over which pre-trial ARRs were calculated. Increasing patient age and duration of illness may also contribute.
authors.affiliation: Department of Medical Statistics, University Medical Center Göttingen, Germany.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Steinvorth
authors.forename: Christian
authors.initials: C
authors.lastname: Röver
authors.forename: Simon
authors.initials: S
authors.lastname: Schneider
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.forename: Sebastian
authors.initials: S
authors.lastname: Straube
authors.forename: Tim
authors.initials: T
authors.lastname: Friede
mesh_terms: D000328:Adult; D018450:Disease Progression; D004608:Eligibility Determination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000453:epidemiology*; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012008:Recurrence; D012107:Research Design
keywords: Multiple sclerosis; annualised relapse rate; baseline characteristics; clinical study design; eligibility criteria; meta-analysis; meta-regression; placebo group; relapse; systematic review