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Observational Study
. 2018 Jun;24(7):963-973.
doi: 10.1177/1352458517709619. Epub 2017 May 30.

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Ludwig Kappos  1 , Helmut Butzkueven  2 , Heinz Wiendl  3 , Timothy Spelman  4 , Fabio Pellegrini  5 , Yi Chen  6 , Qunming Dong  6 , Harold Koendgen  5 , Shibeshih Belachew  6 , Maria Trojano  7 ; Tysabri® Observational Program (TOP) Investigators
Affiliations
Observational Study

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Ludwig Kappos et al. Mult Scler. 2018 Jun.

Abstract

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses.

Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP).

Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a "roving" system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score.

Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively).

Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

Keywords: Expanded Disability Status Scale; Multiple sclerosis; disease progression; natalizumab; relapsing-remitting; secondary progressive multiple sclerosis.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.K.’s Institution (University Hospital Basel) received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; license fees for Neurostatus products; and grants from Bayer HealthCare, Biogen, F. Hoffmann-La Roche Ltd, Merck, Novartis, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation, the European Union, and the Roche Research Foundation. M.T. received compensation for consulting from Biogen, Merck Serono, and Novartis; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi, and Teva; and research grants from Biogen, Merck Serono, and Novartis. H.B. received compensation for consulting from Biogen, Merck Serono, and Novartis and research support from Biogen and Merck Serono. H.W. received honoraria from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, and Teva; was a consultant for Bayer Vital/Schering, Biogen, Medac, Merck Serono, Novartis, Novo Nordisk, Sanofi, and Teva; and received research support from Bayer, Biogen, Medac, Merck Serono, Novo Nordisk, Sanofi, Schering, and Teva. T.S. received honoraria for consultancy and funding for travel from Biogen and Novartis. F.P., and Q.D. are employees of and own stock and/or stock options in Biogen. S.B. and H.K. were employees of Biogen at the time this analysis was performed and are now employees of F. Hoffmann–La Roche Ltd. Y.C. was an employee of Biogen at the time this analysis was performed and is now an employee of Shire. (F. Hoffmann–La Roche Ltd and Shire were not in any way associated with this study).

Figures

Figure 1.
Figure 1.
Schematic of the roving Expanded Disability Status Scale (EDSS) reference system. Confirmed EDSS worsening (a) ⩾24 or (b) ⩾48 weeks apart using a roving reference is illustrated. Also shown are hypothetical examples of confirmed EDSS worsening (c) ⩾24 or (d) ⩾48 weeks apart that would be captured using a roving EDSS reference and not accounted for using the conventional study baseline as EDSS. *Increase in EDSS score of ⩾1.5 points from a score of 0.0, ⩾1.0 point from a score of 1.0–5.5, or ⩾0.5 points from a score ⩾6.0.
Figure 2.
Figure 2.
Schematic of methodological assessment of Expanded Disability Status Scale (EDSS) progression unrelated to relapses confirmed (a) ⩾24 or (b) ⩾48 weeks apart using a roving EDSS reference. t: time following EDSS increase with no concurrent relapse. *Increase in EDSS score of ⩾1.5 points from a score of 0.0, ⩾1.0 point from a score of 1.0–5.5, or ⩾0.5 points from a score ⩾6.0.
Figure 3.
Figure 3.
Cumulative probabilities (Kaplan–Meier analysis) of 24-week-confirmed Expanded Disability Status Scale (EDSS) overall worsening or progression and of 24-week-confirmed EDSS progression unrelated to relapses identified using a conventional study baseline reference for events occurring (a) ⩾24 weeks apart or (b) ⩾48 weeks apart or using a roving reference for events occurring between two EDSS assessments (c) ⩾24 weeks apart or (d) ⩾48 weeks apart. *Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽30 days post progression assessment. †Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽12 weeks post progression assessment.
Figure 4.
Figure 4.
Cumulative probabilities (Kaplan–Meier analysis) of 24-week-confirmed Expanded Disability Status Scale (EDSS) overall worsening or progression and of 24-week-confirmed EDSS progression unrelated to relapses using sensitivity analysis criteria (roving baseline confirmed at 12 weeks). Kaplan–Meier plots show the cumulative probability of events occurring between two EDSS assessments: (a) ⩾24 weeks apart or (b) ⩾48 weeks apart. *Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽30 days post progression assessment. †Defined as a relapse that was recorded from ⩽30 days prior to the reference EDSS assessment to ⩽12 weeks post progression assessment.
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References

    1. Meyer-Moock S, Feng YS, Maeurer M, et al. Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis. BMC Neurol 2014; 14: 58. - PMC - PubMed
    1. Rudick RA, Lee JC, Cutter GR, et al. Disability progression in a clinical trial of relapsing-remitting multiple sclerosis: Eight-year follow-up. Arch Neurol 2010; 67: 1329–1335. - PubMed
    1. Kalincik T, Cutter GR, Spelman T, et al. Defining reliable disability outcomes in multiple sclerosis. Brain 2015; 138: 3287–3298. - PubMed
    1. European Medicines Agency. Guideline on clinical investigation of medicinal products for the treatment of multiple sclerosis, 2015, http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin... (accessed 11 June 2015).
    1. Phillips JT, Giovannoni G, Lublin FD, et al. Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: Treatment effects with natalizumab in patients with relapsing multiple sclerosis. Mult Scler 2011; 17: 970–979. - PubMed

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