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Clinical Trial
. 2014 Dec;261(12):2429-37.
doi: 10.1007/s00415-014-7504-7. Epub 2014 Oct 1.

Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study

Douglas L Arnold  1 , Ralf Gold, Ludwig Kappos, Amit Bar-Or, Gavin Giovannoni, Krzysztof Selmaj, Minhua Yang, Ray Zhang, Monica Stephan, Sarah I Sheikh, Katherine T Dawson
Affiliations
Clinical Trial

Magnetization transfer ratio in the delayed-release dimethyl fumarate DEFINE study

Douglas L Arnold et al. J Neurol. 2014 Dec.

Abstract

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

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Figures

Fig. 1
Fig. 1
Mean percentage change from baseline in whole brain (a) and normal-appearing brain tissue (NABT) (b) magnetization transfer ratio (MTR). *p < 0.05, **p < 0.01, ***p < 0.001 vs placebo, based on analysis of covariance, adjusted for region and baseline whole brain or NABT MTR value
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