The Effect of Different National Treatment Strategies on Disability Outcome in Relapsing-Remitting Multiple Sclerosis: A Propensity Score Adjusted Comparison between Denmark and Sweden

2021 ◽  
Author(s):  
Tim Spelman ◽  
Melinda Magyari ◽  
Fredrik Piehl ◽  
Anders Svenningsson ◽  
Peter Vestergaard Rasmussen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Propensity Score ◽  
Treatment Strategies ◽  
National Treatment ◽  
Relapsing Remitting ◽  
Disability Outcome ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Comparison of the EDSS, Timed 25-Foot Walk, and the 9-Hole Peg Test as Clinical Trial Outcomes in Relapsing-Remitting Multiple Sclerosis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012690
Author(s):  
Marcus W. Koch ◽  
Jop P. Mostert ◽  
Jerry S. Wolinsky ◽  
Fred D. Lublin ◽  
Bernard Uitdehaag ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Controlled Trial ◽  
Cross Sectional ◽  
Link Type ◽  
Kaplan Meier ◽  
Relapsing Remitting ◽  
Disability Outcome ◽  
Remitting Multiple Sclerosis ◽  
Presentation Methods ◽  
Relapsing Remitting Multiple Sclerosis

Background:Clinical trials in relapsing-remitting multiple sclerosis (RRMS) usually use the Expanded Disability Status Scale (EDSS) as their primary disability outcome measure, while the more recently developed outcomes timed 25 foot walk (T25FW) and nine hole peg test (NHPT) may be more useful and patient-relevant.Objective:To compare the EDSS to the T25FW and NHPT in a large RRMS randomized controlled trial (RCT) dataset.Methods:We used the dataset from CombiRx (clinicaltrials.gov identifier NCT00211887), a large phase 3 RCT, to compare the EDSS to the alternative outcomes T25FW and NHPT. We investigated disability worsening versus similarly defined improvement, unconfirmed versus confirmed and sustained disability change, and the presentation methods cumulative Kaplan-Meier survival curves versus cross-sectional disability worsening.Results:CombiRx included 1,008 participants. A comparison of confirmed versus sustained worsening events showed that throughout the trial, there were substantially fewer sustained than confirmed events, with a positive predictive value of confirmed for sustained worsening at 24 months of 0.73 for the EDSS, 0.73 for the T25FW, and 0.8 for the NHPT. More concerning was the finding that worsening on the EDSS occurred as frequently as similarly defined improvement throughout the three years of follow up, and that improvement rates increased in parallel with worsening rates. The T25FW showed low improvement rates of below 10% throughout the trial. We also found that Kaplan-Meier survival analysis, the standard presentation and analysis method in modern RRMS trials, yields exaggerated estimates of disability worsening. Using the Kaplan-Meier method, the proportion of patients with worsening events steadily increases, until it reaches several fold the number of events seen with more conservative analysis methods. For 3 month CDW at 36 months the ‘Kaplan-Meier’ method yields 2.6 fold higher estimates for the EDSS, 2.9 fold higher estimates for the T25FW and 5.1 fold higher estimates for the NHPT compared to a more conservative presentation of the same data.Discussion:Our analyses raise concerns about using the EDSS as the standard disability outcome in RRMS trials, and suggest that the T25FW may be a more useful measure. These findings are relevant for the design and critical appraisal of RCTs.

scholarly journals Approved Beta Interferons in Relapsing-Remitting Multiple Sclerosis: Is there an odd one Out?

2012 ◽  
Vol 4 ◽  
pp. JCNSD.S10150 ◽  
Author(s):  
Alexis Clapin
Keyword(s):  
Multiple Sclerosis ◽  
Pivotal Trial ◽  
Attrition Bias ◽  
Raw Data ◽  
Relapsing Remitting ◽  
Early Progression ◽  
Disability Outcome ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Three interferons are marketed for the treatment of relapsing-remitting multiple sclerosis. In its pivotal trial, one of them demonstrated impressive efficacy as a once-weekly regimen, but later head-to-head studies and reviews questioned its superiority. Analysis of this pivotal trial in publications and health authority reviews has shown that its early termination might have caused attrition bias. Censored patients were different from those completing the study on magnetic resonance imaging parameters and benefited from placebo in terms of relapse rate. Early progression of disability and differences in follow-up duration could have favored the benefit observed for the progression of disability outcome. Only the raw data could be of help to confirm or refute doubts about this trial. Raw data should be made available to the scientific community.

scholarly journals No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP)

2021 ◽  
Vol 14 ◽  
pp. 175628642110424
Author(s):  
Helmut Butzkueven ◽  
Ludwig Kappos ◽  
Tim Spelman ◽  
Maria Trojano ◽  
Heinz Wiendl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Propensity Score ◽  
Confidence Interval ◽  
Hazard Ratio ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Matched Comparison ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Observational Program ◽  
Relapse Rates

Background: Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts. Methods: Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts. Results: This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented. Conclusion: These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing. ClinicalTrials.gov identifier: NCT00493298

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