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

Röver C, Nicholas R, Straube S, Friede T - PLoS ONE (2015)

Bottom Line: A systematic review of RCTs in RMS was conducted extracting data on EDSS and baseline characteristics.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

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].
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pone.0137052.g002: 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].

Mentions: Fig 2 illustrates the probabilities of progression during the first and second years of follow-up for the 13 studies where relevant data could be extracted. Overall progression probabilities tend to be lower in the second year, with the exception of two small studies from the 1990’s. The combined odds ratio comparing the progression probabilities from year 2 to year 1 is 0.72 (95% CI [0.56; 0.93], p = 0.017; between-trial heterogeneity τ2 = 0.096 (95% CI [0.017; 0.40], I2 = 57.7% (95% CI [19.2; 85.1]), p = 0.0028) which translates to a reduction of 28% in progression odds from year 1 to year 2. In the S2 Fig, a forest plot of the progression odds ratios is given providing a more conventional summary of the effects. Looking at combined progression probabilities from random-effects meta-analyses, chances are 16.9% during the first year, and 13.1% during the second year. These studies used confirmed disease progression as the endpoint. When considering only the eight most recent studies published during the last decade, the numbers change slightly to 16.0% and 11.2% during first and second year, respectively.


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

Röver C, Nicholas R, Straube S, Friede T - PLoS ONE (2015)

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].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556534&req=5

pone.0137052.g002: 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].
Mentions: Fig 2 illustrates the probabilities of progression during the first and second years of follow-up for the 13 studies where relevant data could be extracted. Overall progression probabilities tend to be lower in the second year, with the exception of two small studies from the 1990’s. The combined odds ratio comparing the progression probabilities from year 2 to year 1 is 0.72 (95% CI [0.56; 0.93], p = 0.017; between-trial heterogeneity τ2 = 0.096 (95% CI [0.017; 0.40], I2 = 57.7% (95% CI [19.2; 85.1]), p = 0.0028) which translates to a reduction of 28% in progression odds from year 1 to year 2. In the S2 Fig, a forest plot of the progression odds ratios is given providing a more conventional summary of the effects. Looking at combined progression probabilities from random-effects meta-analyses, chances are 16.9% during the first year, and 13.1% during the second year. These studies used confirmed disease progression as the endpoint. When considering only the eight most recent studies published during the last decade, the numbers change slightly to 16.0% and 11.2% during first and second year, respectively.

Bottom Line: A systematic review of RCTs in RMS was conducted extracting data on EDSS and baseline characteristics.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus