Challenges to clinical trials in multiple sclerosis: outcome measures in the era of disease-modifying drugs

Hyland, Megan; Rudick, Richard A.

doi:10.1097/wco.0b013e3283460542

Cited by 30 publications

(19 citation statements)

References 59 publications

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“…Issues with reliability (Amato et al, 1988, Koziol et al, 1996), responsiveness (Hobart et al, 2000), and other limitations (Avasarala, 2015, Meyer-Moock et al, 2015) of the EDSS have also been well-documented. Although valid, its use in clinical trials for tracking disease progression is based primarily on international acceptability (Meyer-Moock et al, 2015) and has been criticized for both high variability and because the non-linearity of the scale makes determination of change challenging (Amato and Ponziani, 1999, Hyland and Rudick, 2011). Quantitative measures of walking and strength impairment address the weaknesses of the EDSS (Zackowski et al, 2015) and may improve disease monitoring.…”

Section: Introductionmentioning

confidence: 99%

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis

Fritz

Keller

Calabresi³

et al. 2017

NeuroImage: Clinical

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At least 85% of individuals with multiple sclerosis report walking dysfunction as their primary complaint. Walking and strength measures are common clinical measures to mark increasing disability or improvement with rehabilitation. Previous studies have shown an association between strength or walking ability and spinal cord MRI measures, and strength measures with brainstem corticospinal tract magnetization transfer ratio. However, the relationship between walking performance and brain corticospinal tract magnetization transfer imaging measures and the contribution of clinical measurements of walking and strength to the underlying integrity of the corticospinal tract has not been explored in multiple sclerosis. The objectives of this study were explore the relationship of quantitative measures of walking and strength to whole-brain corticospinal tract-specific MRI measures and to determine the contribution of quantitative measures of function in addition to basic clinical measures (age, gender, symptom duration and Expanded Disability Status Scale) to structural imaging measures of the corticospinal tract. We hypothesized that quantitative walking and strength measures would be related to brain corticospinal tract-specific measures, and would provide insight into the heterogeneity of brain pathology.Twenty-nine individuals with relapsing-remitting multiple sclerosis (mean(SD) age 48.7 (11.5) years; symptom duration 11.9(8.7); 17 females; median[range] Expanded Disability Status Scale 4.0 [1.0–6.5]) and 29 age and gender-matched healthy controls (age 50.8(11.6) years; 20 females) participated in clinical tests of strength and walking (Timed Up and Go, Timed 25 Foot Walk, Two Minute Walk Test ) as well as 3 T imaging including diffusion tensor imaging and magnetization transfer imaging.Individuals with multiple sclerosis were weaker (p = 0.0024) and walked slower (p = 0.0013) compared to controls. Quantitative measures of walking and strength were significantly related to corticospinal tract fractional anisotropy (r > 0.26; p < 0.04) and magnetization transfer ratio (r > 0.29; p < 0.03) measures. Although the Expanded Disability Status Scale was highly correlated with walking measures, it was not significantly related to either corticospinal tract fractional anisotropy or magnetization transfer ratio (p > 0.05). Walk velocity was a significant contributor to magnetization transfer ratio (p = 0.006) and fractional anisotropy (p = 0.011) in regression modeling that included both quantitative measures of function and basic clinical information.Quantitative measures of strength and walking are associated with brain corticospinal tract pathology. The addition of these quantitative measures to basic clinical information explains more of the variance in corticospinal tract fractional anisotropy and magnetization transfer ratio than the basic clinical information alone. Outcome measurement for multiple sclerosis clinical trials has been notoriously challenging; the use of quantitative measures of strength and walking alon...

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Section: Introductionmentioning

confidence: 99%

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis

Fritz

Keller

Calabresi³

et al. 2017

NeuroImage: Clinical

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“…[2][3][4][5] Although EDSS 6 has wide scientific and regulatory precedent for disability progression assessment in multiple sclerosis (MS), 7,8 it has proven insensitive in detecting all clinically relevant contributors to disability progression in SPMS patients, especially upperextremity and cognitive dysfunction. [9][10][11][12][13] In addition, the mid-range of the EDSS overvalues long-distance ambulation. [9][10][11][12] The Multiple Sclerosis Functional Composite (MSFC) 14,15 components that quantitate short-distance ambulation (timed 25-foot walk (T25FW)) and upper-extremity function (9-Hole Peg Test (9HPT)) have identified disability progression in SPMS patients more frequently than EDSS, although the third MSFC component (Paced Auditory Serial Addition Test (PASAT)) has not been shown to sensitively detect cognitive progression in SPMS.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13] In addition, the mid-range of the EDSS overvalues long-distance ambulation. [9][10][11][12] The Multiple Sclerosis Functional Composite (MSFC) 14,15 components that quantitate short-distance ambulation (timed 25-foot walk (T25FW)) and upper-extremity function (9-Hole Peg Test (9HPT)) have identified disability progression in SPMS patients more frequently than EDSS, although the third MSFC component (Paced Auditory Serial Addition Test (PASAT)) has not been shown to sensitively detect cognitive progression in SPMS. 16 Based on such results, 17 a composite measure of disability progression incorporating the EDSS, T25FW, and 9HPT endpoints has been considered.…”

Section: Introductionmentioning

confidence: 99%

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis

et al. 2016

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“…MRI is often used as primary endpoint in phase II and as secondary endpoint in phase III MS trials because it is more sensitive than clinical outcomes, although the relationship between MRI and clinical activity has still not been perfectly established (Hyland and Rudick 2011). Clinical outcomes in MS mainly include relapse rates and disease progression measurements by a scoring system called EDSS (standing for expanded disability status scale), which spans from zero (ie, no complaints and normal neurological examination) to 10 (death due to MS) (Kurtzke 1983).…”

Section: Clinical Relevance Of Nabmentioning

confidence: 99%

Interferon-Beta: Neutralizing Antibodies, Binding Antibodies, Pharmacokinetics and Pharmacodynamics, and Clinical Outcomes

Deisenhammer

2014

Journal of Interferon & Cytokine Research

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Antibodies to interferon-beta (IFNb) may occur during treatment with this drug and can be measured at several levels, the totality of antibodies referred to as antidrug antibodies (ADA) or binding antibodies, and in case of interference with the drug activity referred to as neutralizing antibodies (NAB). Antibodies can also interfere with the biological activity of IFNb as measured by pharmacodynamic markers. To get a complete picture of the interference between IFNb as a drug and the ADA, all the 3 above levels need to be considered. Furthermore, the interaction of these biomarkers changes over time with a shift of antibody properties with respect to immunoglobulin subtypes, affinity, and titers of antibodies. In case of persistent NAB, the clinical benefit of IFNb in the treatment of multiple sclerosis is abolished. In this report, the current knowledge on these issues will be reviewed. The data have been presented at a meeting in Coral Gables, Florida on April 18-21, 2012.

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Challenges to clinical trials in multiple sclerosis: outcome measures in the era of disease-modifying drugs

Abstract: Progress in MS clinical trials requires critical evaluation of existing and future outcome measures and their relationships to one another.

Cited by 30 publications

References 59 publications

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis

Interferon-Beta: Neutralizing Antibodies, Binding Antibodies, Pharmacokinetics and Pharmacodynamics, and Clinical Outcomes

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