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Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial
Helene Højsgaard Chow1, Jacob Talbot1, Henrik Lundell1
1From the Danish Multiple Sclerosis Center (H.H.C., J.T., L.M., M.M., S.B., R.H.H., M.B., J.R.C., P.S.S., M.E., F.S.), Copenhagen University Hospital, Rigshospitalet Glostrup, Glostrup; Danish Research Centre for Magnetic Resonance (H.L., C.G.M., H.R.S.), Copenhagen University Hospital Hvidovre, Hvidovre; Section of Biostatistics (T.L.), Department of Public Health, University of Copenhagen, Copenhagen K; Department of Neurology (H.R.S.), Copenhagen University Hospital Bispebjerg, Copenhagen; and Institute for Clinical Medicine (H.R.S.), University of Copenhagen, Copenhagen N, Denmark.
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.
Insights
Dimethyl fumarate did not reduce cerebrospinal fluid neurofilament light chain levels in primary progressive multiple sclerosis (PPMS) patients over 48 weeks. The treatment showed no significant efficacy benefits compared to placebo.
Area of Science:
- Neuroscience
- Immunology
- Clinical Trials
Background:
- Primary progressive multiple sclerosis (PPMS) is a debilitating neurological condition.
- Cerebrospinal fluid (CSF) neurofilament light chain (NFL) is a biomarker for neuroaxonal damage in MS.
- Identifying effective treatments for PPMS remains a critical unmet need.
Purpose of the Study:
- To evaluate the efficacy of dimethyl fumarate in reducing CSF NFL concentrations in PPMS patients.
- To assess the impact of dimethyl fumarate on other CSF biomarkers and clinical outcomes in PPMS.
Main Methods:
- A 48-week, double-blind, placebo-controlled phase 2 study (FUMAPMS) involving 54 PPMS patients.
- Randomized assignment to dimethyl fumarate (240 mg) or placebo in a 1:1 ratio.
- Primary endpoint: change in CSF NFL concentration; secondary endpoints: other biomarkers, clinical, and MRI measures.
Main Results:
- No significant difference in mean change of CSF NFL concentrations between dimethyl fumarate and placebo groups.
- A significant decrease in CSF myelin basic protein (MBP) was observed in the dimethyl fumarate group compared to placebo.
- Increased incidence of infections, lymphopenia, flushing, and gastrointestinal side effects in the dimethyl fumarate group.
Conclusions:
- Dimethyl fumarate treatment for 48 weeks did not demonstrate efficacy in reducing CSF NFL levels or other investigated measures in PPMS patients.
- The safety profile of dimethyl fumarate in this PPMS cohort was consistent with known side effects.
- This study provides Class I evidence that dimethyl fumarate is not superior to placebo for this indication.
