Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial

Helene Højsgaard Chow, Jacob Talbot, Henrik Lundell, Camilla Gøbel Madsen, Lisbet Marstrand, Theis Lange, Mie Reith Mahler, Sophie Buhelt, Rikke Holm Hansen, Morten Blinkenberg, Jeppe Romme Christensen, Per Soelberg Sørensen, Marina Rode von Essen, Hartwig Roman Siebner, Finn Sellebjerg, Helene Højsgaard Chow, Jacob Talbot, Henrik Lundell, Camilla Gøbel Madsen, Lisbet Marstrand, Theis Lange, Mie Reith Mahler, Sophie Buhelt, Rikke Holm Hansen, Morten Blinkenberg, Jeppe Romme Christensen, Per Soelberg Sørensen, Marina Rode von Essen, Hartwig Roman Siebner, Finn Sellebjerg

Abstract

Background and objective: To study whether dimethyl fumarate is superior to placebo in decreasing CSF concentrations of neurofilament light chain (NFL) in patients with primary progressive MS (PPMS).

Methods: In the double-blind, placebo-controlled phase 2 study dimethyl FUMArate treatment in Progressive Multiple Sclerosis (FUMAPMS), patients with PPMS were randomly assigned to treatment with 240 mg dimethyl fumarate or placebo in a 1:1 ratio for 48 weeks. The primary endpoint was change in concentration of NFL in the CSF. Secondary endpoints included other CSF biomarkers and clinical and MRI measures. Efficacy was evaluated for the full data set by multiple imputations to account for missing data. Safety was assessed for the full data set.

Results: Fifty-four patients (mean age 54.9 years [SD 6.1], median Expanded Disability Status Scale 4.0 [nterquartile range 4.0-6.0], disease duration 14.1 [SD 9.4], and 21 [39%] female) were randomized to either placebo (n = 27) or dimethyl fumarate (n = 27) therapy. At screening CSF concentrations, adjusted for age and sex, of NFL, myelin basic protein (MBP), soluble CD27, chitinase 3-like 1, and B-cell maturation antigen were higher than in a group of symptomatic controls. Twenty-six patients (96%) in the dimethyl fumarate group and 24 patients (89%) in the placebo group completed the randomized phase. Mean change in CSF concentrations of NFL did not differ between groups (mean difference 99 ng/L; 95% CI -292 to 491 ng/L). MBP in CSF decreased in the treatment group (-182 ng/L, 95% CI -323 to -41 ng/L compared with placebo). The difference observed in the multiple imputation data set was not significant in a per protocol analysis. This was nominally significant in the multiple imputation data set but not in the per protocol analysis This was not found in the per protocol analysis Other secondary and tertiary outcomes were not affected. Various infections, lymphopenia, flushing, and gastrointestinal side effects were more frequent in the dimethyl fumarate group. Serious adverse events were similar between groups.

Discussion: Dimethyl fumarate treatment for 48 weeks had no effect on any of the investigated efficacy measures in patients with PPMS. We did not observe adverse events not anticipated for dimethyl fumarate treatment.

Trial registration information: Clinicaltrials.gov identifier NCT02959658.

Classification of evidence: This study provides Class I evidence that for patients with PPMS, dimethyl fumarate treatment has no effect on CSF NFL levels compared with placebo treatment.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Trial Profile
Figure 1. Trial Profile
Figure 2. Comparison of Biomarkers Between Patients…
Figure 2. Comparison of Biomarkers Between Patients With PPMS and Symptomatic Controls
This figure shows concentrations of NFL, MBP, CHI3L1, sCD14, sCD27, and BCMA in CSF at screening in patients with PPMS (n = 59) and symptomatic controls (NFL, CHI3L1, and BCMA n = 35; MBP n = 31). The symptomatic controls were all included in the validation study of the immunoassays used for measuring CHI3L1, sCD14, sCD27, and BCMA. The patients with PPMS were older (p < 0.001) and more commonly male than the symptomatic controls (p = 0.001). p-values are based on ANCOVA with correction for age and sex. ANCOVA = analysis of covariance; sBCMA = soluble B-cell maturation antigen; MBP = myelin basic protein; NFL = neurofilament light chain; PPMS = primary progressive MS; sCD14 = soluble CD14; sCD27 = soluble CD27.

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