Changing EDSS progression in placebo cohorts in relapsing MS: A systematic review and meta-regression

Abstract: Background: Recent 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. Methods: A 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 baseline variables. Results: The 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 compared to the first year with a reduction of 24% in progression probability from year 1 to year 2 (p=0.014). Conclusion: EDSS disease progression exhibits similar behaviour over time as the ARR and point to changes in trial characteristics over the years, questioning comparisons between historical and recent trials.