Dataset Information

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

ABSTRACT:

Background

There is limited data analyzing the safety and effectiveness of dimethyl fumarate (DMF) in the progressive multiple sclerosis (PMS) population.

Objective

To analyze the safety and effectiveness of DMF in patients with PMS.

Methods

We used Cox proportional hazards models to compare the time to confirmed worsening and improvement on the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) between patients treated with DMF and glatiramer acetate (GA) for at least one year.

Results

We included 46 patients treated with DMF and 42 patients treated with GA. The safety and tolerability of GA and DMF were consistent with established profiles. There was no difference in confirmed EDSS progression. A trend towards reduced T25FW was seen in the DMF compared to GA after adjustment (HR = 0.86; 95% CI:0.37, 1.98; p = 0.72 and HR = 0.60; 95% CI:0.27, 1.34; p = 0.21, respectively).

Conclusion

Dimethyl fumarate showed a trend towards reduction in T25FW but no evidence of clinically significant impact on EDSS. The small sample precluded definitive determination.

SUBMITTER: Moreira Ferreira VF

PROVIDER: S-EPMC8108088 | biostudies-literature | 2021 Apr-Jun

REPOSITORIES: biostudies-literature

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Publications

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

Moreira Ferreira Vanessa F VF Liu Yanqing Y Healy Brian C BC Stankiewicz James M JM

Multiple sclerosis journal - experimental, translational and clinical 20210429 2

<h4>Background</h4>There is limited data analyzing the safety and effectiveness of dimethyl fumarate (DMF) in the progressive multiple sclerosis (PMS) population.<h4>Objective</h4>To analyze the safety and effectiveness of DMF in patients with PMS.<h4>Methods</h4>We used Cox proportional hazards models to compare the time to confirmed worsening and improvement on the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) between patients treated with DMF and glatiramer acetate (G ...[more]

PMID: 33996142

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Project description: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). 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. 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. 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. Clinicaltrials.gov identifier NCT02959658. 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.

Project description:IntroductionMultiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS.MethodsESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally.ResultsOverall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12 months before study entry (all p < 0.0001).ConclusionThe safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients.Trial registrationClinicalTrials.gov identifier NCT02047097.

Project description:IntroductionDimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS) in clinical and real-world studies. The ESTEEM study (NCT02047097) was conducted to assess the long-term safety and effectiveness of delayed-release DMF in patients with relapsing forms of MS in routine clinical practice. We report final outcomes from ESTEEM with up to 6.5 years of follow-up.MethodsPatients newly prescribed DMF were recruited from 393 sites globally. The primary objective was to assess the incidence and type of serious adverse events (SAEs) and adverse events (AEs) leading to discontinuation of DMF. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs).ResultsOverall, 5124 patients received ≥ 1 dose of DMF. The mean (standard deviation [SD]) age at enrollment was 40.0 (11.2) years; 74% of patients were female. Patients received DMF for a mean (SD) duration of 31.0 (22.7) months. Primary reasons for discontinuation were AEs (n = 1237; 24%); the most common were gastrointestinal AEs (n = 469; 9%), blood and lymphatic disorders (n = 218; 4%), and vascular disorders (n = 200; 4%). SAEs occurred in 391 (8%) patients, most commonly infections and infestations (n = 102; 2%). Adjusted ARR declined by 90% (95% confidence interval [CI]: 90-91%; p < 0.0001), from 0.81 (95% CI 0.79-0.84) 12 months before enrollment to 0.08 (95% CI 0.08-0.09) 6 years after enrollment. The estimated proportion of patients free from confirmed disability progression sustained over 48 weeks was 87.0% at month 60. Mean scores for physical and psychological impact, fatigue, health, and productivity remained stable over 5 years.ConclusionDMF demonstrated a safety profile in real-world clinical practice consistent with the known profile of DMF. Relapse rates were low and both ARR and PROs remained stable over time.Trial registrationClinicalTrials.gov Identifier NCT02047097.

Dataset Information

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

Background

Objective

Methods

Results

Conclusion

Publications

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

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