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Published on: February 28, 2021
Effects of Dimethyl Fumarate on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: Pooled Analysis Phase 3
Kunio Nakamura1, Oksana Mokliatchouk2, Douglas L Arnold3
1Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
Objective:
In the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center.
Methods:
MRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48-96.
Results:
Across studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0-48, mean ± SE percentage change in BPF was -0.44 ± 0.04 vs. -0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48-96, mean ± SE percentage change in BPF was -0.27 ± 0.03 vs. -0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48-96, estimated change (95% confidence interval) in BPF was -0.0021 (-0.0027, -0.0016) for DMF vs. -0.0033 (-0.0039, -0.0028) for PBO (35.9% reduction; p = 0.0025).
Conclusions:
The lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials.
Insights
Dimethyl fumarate (DMF) demonstrated a reduced rate of brain volume loss in multiple sclerosis (MS) patients during the second year of treatment compared to placebo. This finding supports DMF
Area of Science:
- Neurology
- Radiology
- Pharmacology
Background:
- Previous analyses of dimethyl fumarate (DMF) in multiple sclerosis (MS) trials showed differing brain volume change patterns, potentially due to analysis at multiple centers.
- Reanalysis of pooled data from the DEFINE and CONFIRM trials aims to clarify DMF's effect on brain volume changes in MS patients.
Purpose of the Study:
- To reanalyze pooled MRI data from the DEFINE and CONFIRM trials at a single reading center to accurately assess the effects of dimethyl fumarate (DMF) on brain volume changes in multiple sclerosis (MS) patients.
- To evaluate brain parenchymal fraction (BPF) changes over 96 weeks, accounting for pseudoatrophy, to better understand DMF's impact on brain volume loss in MS.
Main Methods:
- Utilized MRI data from 615 patients (301 DMF, 314 placebo) across the DEFINE and CONFIRM trials, analyzed at the Cleveland Clinic.
- Measured brain parenchymal fraction (BPF) at weeks 0, 24, 48, and 96, re-baselining at week 48 to mitigate pseudoatrophy effects for the 48-96 week interval.
- Employed a mixed-effects model for repeated measures to analyze BPF changes and assess statistical significance.
Main Results:
- In weeks 0-48, mean BPF change was -0.44% for DMF vs. -0.34% for placebo.
- In weeks 48-96, mean BPF change was -0.27% for DMF vs. -0.41% for placebo, indicating a slower rate of brain volume loss with DMF.
- The mixed-effects model confirmed a statistically significant reduction in BPF change with DMF versus placebo between weeks 48-96 (35.9% reduction, p=0.0025).
Conclusions:
- Dimethyl fumarate (DMF) significantly reduced the rate of whole brain volume loss in MS patients during the second year of treatment compared to placebo.
- The observed brain volume changes in the first year may be attributed to pseudoatrophy, a phenomenon noted in other MS trials.
- These findings align with DMF's established efficacy in reducing relapses, disability progression, and MRI lesions in multiple sclerosis.
