Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohorts

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.

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Recurrence of disease activity during pregnancy after cessation of fingolimod in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517731913 ◽

2017 ◽

Vol 24 (7) ◽

pp. 991-994 ◽

Cited By ~ 21

Author(s):

Ingrid Meinl ◽

Joachim Havla ◽

Reinhard Hohlfeld ◽

Tania Kümpfel

Keyword(s):

Multiple Sclerosis ◽

At Risk ◽

Disease Activity ◽

Effective Treatment ◽

Disease Course ◽

Risk Of Recurrence ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis ◽

Risk Of Relapse

Background: Fingolimod is an effective treatment for active relapsing–remitting multiple sclerosis (MS). Discontinuation of therapy may be followed by recurrence of disease activity. Thus, female MS patients may be at risk of relapse during pregnancy after stopping fingolimod. Objectives and methods: To report the disease course during pregnancy of five women who interrupted therapy with fingolimod for pregnancy. Results: All patients experienced relapses during pregnancy and/or postpartum after stopping fingolimod. Conclusion: The risk of recurrence of disease activity during pregnancy after stopping fingolimod may be substantial. This should be considered and discussed with MS patients who are planning to become pregnant.

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The Case for Early Diagnosis and Treatment In Relapsing Remitting Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073-1.1.50 ◽

1999 ◽

Vol 1 (1) ◽

pp. 50-63 ◽

Cited By ~ 1

Author(s):

Richard A. Rudick

Keyword(s):

Multiple Sclerosis ◽

Tissue Injury ◽

Disease Course ◽

Disease Modifying Drugs ◽

Relapsing Remitting ◽

Neurologic Disability ◽

Research Findings ◽

Disease Modifying ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Abstract The emergence of partially effective disease-modifying drugs for patients with relapsing remitting multiple sclerosis (RR-MS) has raised important questions. Which patients with RR-MS should be started on disease-modifying drugs? Can some patients be observed without treatment? Treatment decisions are difficult in part because currently available drugs must be administered by injections, and the drugs are expensive. Emerging research findings support the view that most people diagnosed with RR-MS are at risk for irreversible brain tissue injury and resultant neurologic disability. Importantly, the pathologic process is active during the early stages in many RR-MS patients who appear clinically stable. These findings provide a rationale for proactively treating patients with RR-MS early in their disease course with disease-modifying drugs in order to suppress disease activity, minimize tissue injury, and prevent disability at a later stage. Evidence in support of this approach is reviewed in this report, as are practical issues related to the use of disease-modifying drugs in RR-MS patients.

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

Journal of Central Nervous System Disease ◽

10.4137/jcnsd.s10150 ◽

2012 ◽

Vol 4 ◽

pp. JCNSD.S10150 ◽

Cited By ~ 1

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.

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Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials

Multiple Sclerosis International ◽

10.1155/2014/262350 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 17

Author(s):

Amy M. Lavery ◽

Leonard H. Verhey ◽

Amy T. Waldman

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Neurodegenerative Disease ◽

Disease Progression ◽

Outcome Measures ◽

Primary Endpoint ◽

Surrogate Endpoints ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials.

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