Magnetization Transfer Ratio in the Delayed-Release Dimethyl Fumarate DEFINE Study

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


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.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Brain / drug effects*
  • Brain / pathology
  • Delayed-Action Preparations / pharmacology
  • Dimethyl Fumarate
  • Double-Blind Method
  • Female
  • Fumarates / pharmacology*
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Magnetic Resonance Imaging*
  • Male
  • Middle Aged
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / pathology
  • Multiple Sclerosis, Relapsing-Remitting / drug therapy
  • Placebos
  • Treatment Outcome
  • Young Adult


  • Delayed-Action Preparations
  • Fumarates
  • Immunosuppressive Agents
  • Placebos
  • Dimethyl Fumarate