Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2015 Sep 1;10(9):e0137052.
doi: 10.1371/journal.pone.0137052. eCollection 2015.

Changing EDSS Progression in Placebo Cohorts in Relapsing MS: A Systematic Review and Meta-Regression

Christian Röver  1 , Richard Nicholas  2 , Sebastian Straube  3 , Tim Friede  1
Affiliations
Meta-Analysis

Changing EDSS Progression in Placebo Cohorts in Relapsing MS: A Systematic Review and Meta-Regression

Christian Röver et al. PLoS One. .

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 study-level 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 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).

Conclusion: 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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: CR has declared that no competing interests exist. RN has received honoraria for speaking fees for advisory boards or search funds from Bayer, Biogen, Genzyme, Merck Serono, Novartis, Roche, TEVA and NICE. SS declares honoraria from Oxford Medical Knowledge and advisory board fees from Daiichi Sankyo, Inc. TF is a consultant to Novartis, Biogen, Grünenthal, Bayer, Vertex, Janssen, and AstraZeneca. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. The fractions of patients with progressing EDSS status over the years.
The chances of progression also depend on the study duration (you can see that shorter studies have smaller fractions) but even after accounting for the duration, the decreasing trend remains statistically significant (p<0.0001). The red line shows the estimated regression line for a trial duration of 1 year.
Fig 2
Fig 2. The fractions of patients with progressing EDSS in the first and second year of study, for the 13 studies of at least 2 years duration, and where the data was provided.
Connecting lines indicate the rates for the two subsequent years, line widths are proportional to study sizes (numbers of patients N). The weighted average (weighted by the inverse variances on the log odds scale) decreases from 16.9% to 13.1% from first to second year. [16.0% to 11.2% for the 8 most recent post-2000 studies].
See this image and copyright information in PMC

References

    1. Inusah S, Sormani MP, Cofield SS, Aban IB, Musani SK, Srinivasasainagendra V, et al. Assessing changes in relapse rates in multiple sclerosis. Multiple Sclerosis. 2010;16(12):1414–1421. 10.1177/1352458510379246 - DOI - PubMed
    1. Nicholas R, Straube S, Schmidli H, Schneider S, Friede T. Trends in annualized relapse rates in relapsing-remitting multiple sclerosis and consequences for clinical trial design. Multiple Sclerosis Journal. 2011;17(10):1211–1217. 10.1177/1352458511406309 - DOI - PubMed
    1. Steinvorth SM, Röver C, Schneider S, Nicholas R, Straube S, Friede T. Explaining temporal trends in annualized relapse rates in placebo groups of randomized controlled trials in relapsing multiple sclerosis: systematic review and meta-regression. Multiple Sclerosis Journal. 2013;19(12):1580–1586. 10.1177/1352458513481009 - DOI - PubMed
    1. Nicholas R, Straube S, Schmidli H, Pfeiffer S, Friede T. Time-patterns of annualized relapse rates in randomized placebo-controlled clinical trials in relapsing multiple sclerosis: A systematic review and meta-analysis. Multiple Sclerosis Journal. 2012;18(9):1290–1296. 10.1177/1352458511435715 - DOI - PubMed
    1. Stellmann JP, Neuhaus A, Herich L, Schippling S, Roeckel M, Daumer M, et al. 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. PLoS ONE. 2012;7(11):e50347 10.1371/journal.pone.0050347 - DOI - PMC - PubMed

Publication types

MeSH terms