Abstract
BackgroundRecent systematic reviews of randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS) revealed a decrease in placebo annualized relapse rates (ARR) over the past two decades. Furthermore, regression to the mean effects were observed in ARR and MRI lesion counts. It is unclear whether disease progression measured by the expanded disability status scale (EDSS) exhibits similar features.MethodsA systematic review of RCTs in RMS was conducted extracting data on EDSS and baseline characteristics. The logarithmic odds of disease progression were modelled to investigate time trends. Random-effects models were used to account for between-study variability; all investigated models included trial duration as a predictor to correct for unequal study durations. Meta-regressions were conducted to assess the prognostic value of a number of study-level baseline variables.ResultsThe systematic literature search identified 39 studies, including a total of 19,714 patients. The proportion of patients in placebo controls experiencing a disease progression decreased over the years (p<0.001). Meta-regression identified associated covariates including the size of the study and its duration that in part explained the time trend. Progression probabilities tended to be lower in the second year of a study compared to the first year with a reduction of 28% in progression odds from year 1 to year 2 (p = 0.017).ConclusionEDSS disease progression exhibits similar behaviour over time as the ARR and point to changes in trial characteristics over the years. This needs to be considered in comparisons between historical and recent trials.
Highlights
Recent systematic reviews of placebo groups in randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS), i.e. relapsing remitting and relapsing secondary progressive multiple sclerosis, suggest a decrease in annualized relapse rates (ARRs) over calendar time [1,2,3] as well as a decrease in relapse rates over the course of the study [4]
extended disability status scale (EDSS) disease progression exhibits similar behaviour over time as the ARR and point to changes in trial characteristics over the years. This needs to be considered in comparisons between historical and recent trials
In this paper we aim to investigate whether a decrease in placebo ARRs observed in randomized controlled trials in RMS is present in EDSS progression and, if so, whether it can be explained by changes in patient populations and study design characteristics
Summary
Recent systematic reviews of placebo groups in randomised controlled trials (RCTs) in relapsing multiple sclerosis (RMS), i.e. relapsing remitting and relapsing secondary progressive multiple sclerosis, suggest a decrease in annualized relapse rates (ARRs) over calendar time [1,2,3] as well as a decrease in relapse rates over the course of the study [4] These changes appear to relate to the changing eligibility criteria and populations entering trials and regression to the mean effects [3]. Regression to the mean effects were observed in ARR and MRI lesion counts It is unclear whether disease progression measured by the expanded disability status scale (EDSS) exhibits similar features
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