Effects of Dimethyl Fumarate on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: Pooled Analysis Phase 3 DEFINE and CONFIRM Studies

Kunio Nakamura; Oksana Mokliatchouk; Douglas L Arnold; Tarek A Yousry; Ludwig Kappos; Nancy Richert; Katherine Ayling-Rouse; Catherine Miller; Elizabeth Fisher

doi:10.3389/fneur.2022.809273

Effects of Dimethyl Fumarate on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: Pooled Analysis Phase 3 DEFINE and CONFIRM Studies

Front Neurol. 2022 Mar 18:13:809273. doi: 10.3389/fneur.2022.809273. eCollection 2022.

Authors

Kunio Nakamura¹, Oksana Mokliatchouk², Douglas L Arnold³, Tarek A Yousry⁴, Ludwig Kappos⁵, Nancy Richert², Katherine Ayling-Rouse⁶, Catherine Miller², Elizabeth Fisher²

Affiliations

¹ Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States.
² Biogen, Cambridge, MA, United States.
³ McConnell Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁴ Lysholm Department of Neuroradiology, National Hospital for Neurology and Neurosurgery, University College London Institute of Neurology, London, United Kingdom.
⁵ Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland.
⁶ Envision Pharma Group, Horsham, United Kingdom.

Abstract

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.

Keywords: brain parenchymal fraction; brain volume loss; dimethyl fumarate; multiple sclerosis; pseudoatrophy.