Delayed-release dimethyl fumarate and disability assessed by the Multiple Sclerosis Functional Composite: Integrated analysis of DEFINE and CONFIRM

Giovannoni, Gavin; Gold, Ralf; Kappos, Ludwig; Arnold, Douglas L.; Bar‐Or, Amit; Marantz, Jing L.; Yang, Minhua; Lee, Andrew

doi:10.1177/2055217316634111

Cited by 13 publications

(10 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 6 We also observed an improvement in the overall MSFC score at 15 months, as also reported from the initial DEFINE/CONFIRM studies. 33 Although others have been able to show an improvement in QOL with DMF as measured by SF-36, 34 we were unable to replicate this finding.…”

Section: Discussionmentioning

confidence: 67%

Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS

Gafson

Kim

Cencioni

et al. 2018

Neurol Neuroimmunol Neuroinflamm

View full text Add to dashboard Cite

ObjectiveTo identify short-term changes in gene expression in peripheral blood mononuclear cells (PBMCs) associated with treatment response to dimethyl fumarate (DMF, Tecfidera) in patients with relapsing-remitting MS (RRMS).MethodsBlood samples were collected from 24 patients with RRMS (median Expanded Disability Status Scale score, 2.0; range 1–7) at baseline, 6 weeks, and 15 months after the initiation of treatment with DMF (BG-12; Tecfidera). Seven healthy controls were also recruited, and blood samples were collected over the same time intervals. PBMCs were extracted from blood samples and sequenced using next-generation RNA sequencing. Treatment responders were defined using the composite outcome measure “no evidence of disease activity” (NEDA-4). Time-course and cross-sectional differential expression analyses were performed to identify transcriptomic markers of treatment response.ResultsTreatment responders (NEDA-4 positive, 8/24) over the 15-month period had 478 differentially expressed genes (DEGs) 6 weeks after the start of treatment. These were enriched for nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inhibition of nuclear factor κB (NFκB) pathway transcripts. For patients who showed signs of disease activity, there were no DEGs at 6 weeks relative to their (untreated) baseline. Contrasting transcriptomes expressed at 6 weeks with those at 15 months of treatment, 0 and 1,264 DEGs were found in the responder and nonresponder groups, respectively. Transcripts in the nonresponder group (NEDA-4 negative, 18/24) were enriched for T-cell signaling genes.ConclusionShort-term PBMC transcriptome changes reflecting activation of the Nrf2 and inhibition of NFκB pathways distinguish patients who subsequently show a medium-term treatment response with DMF. Relative stabilization of gene expression patterns may accompany treatment-associated suppression of disease activity.

show abstract

Section: Discussionmentioning

confidence: 67%

Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS

Gafson

Kim

Cencioni

et al. 2018

Neurol Neuroimmunol Neuroinflamm

View full text Add to dashboard Cite

show abstract

“…Based on the findings from two systematic literature reviews of outcome measures in trials in multiple sclerosis, T25FW has been collected in RCTs for all approved DMTs (including the first approved DMTs interferons and glatiramer acetate), [ 21 , 22 ] and will likely continue to be collected in future RCTs of MS, owing in part to the growing interest in evaluating the efficacy of DMTs using multiple disability measures in clinical trials of MS [ 75 ]. T25FW has been reported for various DMTs, for example, dimethyl fumarate, [ 76 ] fingolimod and interferon beta-1a, [ 77 ] natalizumab, [ 78 ] and peginterferon [ 44 ]. The MSOAC Placebo Database could serve as a source of T25FW, EDSS, and relapse data for other relevant DMTs such as alemtuzumab, glatiramer acetate, and teriflunomide, [ 41 ] if data from the treatment arms of the clinical trials in the database are available to external researchers.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Health Utility in Relapsing–Remitting and Secondary-Progressive Multiple Sclerosis: Implications for Future Economic Models of Disease-Modifying Therapies

et al. 2020

View full text Add to dashboard Cite

Background Decision-analytic models used in economic evaluations of disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) have characterized disease progression and accrue quality-adjusted life-years from utility values based on the Expanded Disability Status Scale (EDSS), the occurrence of relapses, and progression to secondary-progressive multiple sclerosis (SPMS). The EDSS, used to characterize disability progression, has several limitations. If the EDSS is the only disability measure used in economic evaluations, the long-term clinical and economic implications of disease-modifying therapies may not be properly assessed. Objective The objective of this study was to explore if supplementary disability measures including the Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and Paced Auditory Serial Addition Test (PASAT) significantly contribute additional information on health utility in RRMS and SPMS otherwise not captured by the EDSS and relapses and, therefore, should be considered in future economic evaluations of disease-modifying therapies. Methods Short-Form Six-Dimension utility scores were derived from the RAND 36-Item Health Survey 1.0 individual-level data available in the Multiple Sclerosis Outcome Assessment Consortium (MSOAC) Placebo Database. Repeated-measures mixed-effects models were conducted to estimate the effects of EDSS, T25FW, 9HPT (dominant and non-dominant hand), PASAT, and relapses on changes in utility over time, controlling for demographics. Results A higher level of EDSS, longer time to complete the T25FW test, and a recent relapse were significant predictors of lower utility in people with RRMS and SPMS. 9HPT and PASAT were not significant predictors. Conclusions This study suggests that in addition to EDSS and recent relapses, T25FW significantly predicts utility in RRMS and SPMS. These findings support the use of T25FW to supplement the EDSS and the occurrence of relapses to characterize the course of disease progression and to more accurately accrue quality-adjusted life-years in future economic evaluations of disease-modifying therapies for the treatment of RRMS. Data used in the preparation of this article were obtained from the Multiple Sclerosis Outcome Assessment Consortium (MSOAC). As such, the investigators within MSOAC contributed to the design and implementation of the MSOAC Placebo Database and/ or provided placebo data but did not participate in the analysis of the data or the writing of this report.

show abstract

“…In another 1-year, propensity score-matched study comparing the effectiveness of fingolimod and natalizumab in patients with RRMS, both treatments significantly ameliorated cognitive function assessed by the BRB-N, and fingolimod was found to be more effective than natalizumab in improving cognitive function. 96 The mean change in PASAT z-scores, one part of the MSFC components, was significantly higher in patients treated with DMF compared with the placebo, showing a favorable effect of DMF on cognitive function. 95 In a post-hoc analysis of integrated data from two trials, patients treated with DMF showed continuous increases in the median MSFC z-scores throughout the entire period compared with the placebo.…”

Section: Natalizumabmentioning

confidence: 91%

“…95 In a post-hoc analysis of integrated data from two trials, patients treated with DMF showed continuous increases in the median MSFC z-scores throughout the entire period compared with the placebo. 96 The mean change in PASAT z-scores, one part of the MSFC components, was significantly higher in patients treated with DMF compared with the placebo, showing a favorable effect of DMF on cognitive function.…”

Section: Natalizumabmentioning

confidence: 91%

Clinical trials for multiple sclerosis: Outcome measures and impact on cognitive function

Ochi

2019

Clinical & Exp Neuroim

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a complex immune-mediated disease characterized by recurrent demyelinating episodes of the central nervous system, which is the most common disabling neurological disease of young people. Cognitive impairment is common and one of the disabling symptoms of MS, resulting in reduced quality of life. This often emerges early in the disease and is independent of physical disability; however, it is more prevalent in progressive disease. With the advent of a number of disease-modifying drugs, including agents with high efficacy at reducing inflammatory activity, patients with MS can receive more efficacious treatment. Although the currently available disease-modifying drugs have been shown to reduce the inflammatory disease activity, their effects on the neurodegenerative aspect or cognitive functions are still unclear. Cognitive rehabilitation and physical exercise are promising strategies to prevent cognitive decline or improve brain function. Beneficial effects of these interventions have been reported, but the evidence is still sparse. The present review article describes the clinical trial data on interventions for cognitive impairment in MS.

show abstract

Delayed-release dimethyl fumarate and disability assessed by the Multiple Sclerosis Functional Composite: Integrated analysis of DEFINE and CONFIRM

Cited by 13 publications

References 10 publications

Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS

Mononuclear cell transcriptome changes associated with dimethyl fumarate in MS

Predictors of Health Utility in Relapsing–Remitting and Secondary-Progressive Multiple Sclerosis: Implications for Future Economic Models of Disease-Modifying Therapies

Clinical trials for multiple sclerosis: Outcome measures and impact on cognitive function

Contact Info

Product

Resources

About