Effects of BG-12 on Magnetization Transfer Ratio in Whole Brain and Normal-Appearing Brain Tissue: Findings from the DEFINE Study (S11.004)

Arnold, D.; Gold, Ralf; Kappos, Ludwig; Bar‐Or, Amit; Giovannoni, Gavin; Selmaj, Krzysztof; Yang, Minhua; Stephan, Monica; Kp, Dawson

doi:10.1212/wnl.78.1_meetingabstracts.s11.004

Cited by 3 publications

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“…Statistically significant treatment effects of DMF on MTR outcomes (both doses) and brain atrophy (BID only) were observed in DEFINE. 27 , 28 However, MTR outcomes and brain atrophy results with DMF did not reach statistical significance in CONFIRM. The rate of atrophy in the placebo arm during the CONFIRM study was lower in comparison with the placebo arms of other phase 3 studies of oral MS therapies.…”

Section: Discussionmentioning

confidence: 88%

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Miller¹,

Fox²,

Phillips³

et al. 2015

Neurology

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Objective:To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study.Methods:CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort).Results:DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance.Conclusions:The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS.Classification of evidence:This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

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Section: Discussionmentioning

confidence: 88%

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Miller¹,

Fox²,

Phillips³

et al. 2015

Neurology

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“…Changes in magnetization transfer have relative specificity for changes in myelin density, which is of particular interest in MS. However, the changes that occur in whole brain magnetization transfer are extremely small 3 and, as in the case of whole brain atrophy, the interpretation of such small changes may involve subtleties related not only to remyelination but also to other physiological changes that affect myelin density, such as changes in brain water or the relative partial volume of other cell types. DTI seems to be less pathologically specific for axons or myelin than one would like.…”

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confidence: 99%

Preventing brain atrophy should be the gold standard of effective therapy in multiple sclerosis (after the first year of treatment): Commentary

Arnold

Stefano

2013

Mult Scler

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MULTIPLE SCLEROSIS MSJ JOURNALCerebral atrophy has been used for centuries by pathologists as a marker of the loss of cerebral tissue due to injury or degeneration, and the tissue damage and loss associated with atrophy has been well documented. Thus, atrophy as a marker of neurodegeneration has incontrovertible face validity, at least over the long term. So, why is the use of whole brain atrophy as an outcome measure in multiple sclerosis (MS) the subject of debate?Magnetic resonance imaging (MRI)-based computational methods provide sensitive and reproducible measures of brain volumes that are capable of detecting changes on the order of 0.2%: changes that are much smaller than those described at the time of postmortem examination. The interpretation of such small changes, particularly over the short term, involves subtleties that are not relevant over the long term. For example, small physiological fluctuations, due to shifts in water, 1 can produce brain volume fluctuations of this order. Furthermore, the accelerated atrophy seen after initiation of some anti-inflammatory therapies, often referred to as pseudoatrophy, also complicates the interpretation of changes in brain volume. Although the pathophysiological mechanisms responsible for pseudoatrophy are still unclear, pseudoatrophy appears to be related to the nature of the anti-inflammatory therapy and the amount of inflammation present at the start of therapy.Despite these limitations, as argued by Rudick and Fisher, a substantial body of evidence supports the use of whole brain atrophy, at least after the first year following initiation of anti-inflammatory therapy, as a marker of the end-stage of tissue injury of whatever sort and, as such, as a candidate for the best MRI marker of effective therapy in MS.Filippi and Rocca also value atrophy as an outcome measure but, because it is an end-stage process, argue for outcome measures that provide a more pathologically specific indication of the processes that contribute to tissue loss, including gray matter (GM) atrophy, magnetization transfer imaging (MTI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS). Each of these measures has advantages and disadvantages.Since GM is less inflamed than white matter (WM) in MS, it should be less susceptible to pseudoatrophy. However, the correct segmentation of GM on MRI is challenging 2 and less precise than the segmentation of whole brain. Changes in magnetization transfer have relative specificity for changes in myelin density, which is of particular interest in MS. However, the changes that occur in whole brain magnetization transfer are extremely small 3 and, as in the case of whole brain atrophy, the interpretation of such small changes may involve subtleties related not only to remyelination but also to other physiological changes that affect myelin density, such as changes in brain water or the relative partial volume of other cell types. DTI seems to be less pathologically specific for axons or myelin than one would like. MRS is patho...

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Dimethyl fumarate for multiple sclerosis

Zhu¹,

Zhang²,

Sun³

et al. 2015

Cochrane Database of Systematic Reviews

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There is moderate-quality evidence to support that dimethyl fumarate at a dose of 240 mg orally three times daily or twice daily reduces both the number of patients with a relapse and the annualised relapse rate over two years of treatment in comparison with placebo. However, the quality of the evidence to support the benefit in reducing the number of patients with disability worsening is low. There is no high-quality data available to evaluate the benefit on MRI outcomes. The common adverse effects such as flushing and gastrointestinal events are mild-to-moderate for most patients. Lymphopenia and leukopenia are uncommon adverse events but significantly associated with dimethyl fumarate. Both dosages of dimethyl fumarate have similar benefit and safety profile, which supports the option of low-dose administration. New studies of high quality and long-term follow-up are needed to evaluate the benefit of dimethyl fumarate on prevention of disability worsening and to observe the long-term adverse effects including progressive multifocal leukoencephalopathy.

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Effects of BG-12 on Magnetization Transfer Ratio in Whole Brain and Normal-Appearing Brain Tissue: Findings from the DEFINE Study (S11.004)

Cited by 3 publications

References 0 publications

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Preventing brain atrophy should be the gold standard of effective therapy in multiple sclerosis (after the first year of treatment): Commentary

Dimethyl fumarate for multiple sclerosis

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